Biomarin Pharmaceutical Aktie

Good afternoon, and welcome, everyone, to the BioMarin Pharmaceutical First Quarter 2026 Conference Call. Today's conference is being recorded. [Operator Instructions] At this time, I would like to turn the conference over to Traci McCarty, Head of Investor Relations. Please go ahead.

Thank you, operator. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors, and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, such as 10-Q, 10-K and 8-K reports.

In addition, we will use non-GAAP financial measures as defined in Regulation G during the call today. These non-GAAP measures should not be considered in isolation from, as substitutes for or superior to financial measures prepared in accordance with U.S. GAAP, and you can find the related reconciliations to U.S. GAAP in the earnings release and earnings presentation, both of which are now available in the Investor Relations section of our website. Please note that our commentary on today's call will focus on non-GAAP financial measures unless otherwise indicated.

Beginning on Slide 3 and introducing BioMarin's management team joining today's call are Alexander Hardy, Chief Executive Officer; Brian Mueller, Chief Financial Officer; Cristin Hubbard, Chief Commercial Officer; and Greg Friberg, Chief R&D Officer. I will now turn the call over to BioMarin's President and CEO, Alexander Hardy.

Thank you, Traci, and thank you all for joining us today. I am so pleased that we completed the Amicus acquisition last week, starting a new and exciting chapter for BioMarin with the addition of two innovative therapies, Galafold for Fabry disease and Pombiliti and Opfolda for Pompe disease. The acquisition accelerates our anticipated year-over-year 2026 revenue growth to 20% at the midpoint of today's updated guidance. The strengthening trajectory is just the beginning of BioMarin's enhanced longer-term financial outlook supported by our larger, more diversified commercial portfolio.

Since announcing our plans to acquire Amicus late last year, we have been preparing for rapid integration beginning on day 1 with the goal of increasing the peak potential of these newly added products. Following the recent close of the transaction, we initiated our targeted integration plan, focused on leveraging BioMarin's operating scale and capabilities to drive diagnosis and treatment rates for patients with Fabry disease and late onset Pompe disease. Next quarter, we plan to share this roadmap as well as more detail on BioMarin's growth acceleration with the addition of Galafold and Pombiliti and Opfolda to our commercial portfolio, and DMX200 for FSGS in Phase III to our late-stage pipeline.

Turning briefly to first quarter results and outlook for the remainder of this year and starting with enzyme therapies. I am pleased with the strong interest we are seeing from the PKU community following the recent PALYNZIQ adolescent label expansion in the United States. With Cristin will discuss in more detail. We expect enzyme therapies will deliver robust growth in 2026, further supported by the addition of Galafold and Pombiliti and Opfolda to the portfolio.

Moving to our skeletal conditions business unit. We saw strong patient demand for VOXZOGO with new patient starts increasing across all regions in the first quarter. In the U.S., the majority of new patient starts were from the under age 2 cohort. These results reflects our focused investments and increasing adoption of VOXZOGO, particularly among younger patients. Building on our leadership in achondroplasia, we are pleased to have submitted the sNDA and full approval of VOXZOGO. We expect to hear the timing of our review in the coming months. I want to congratulate our regulatory team for the outstanding work that went into this comprehensive submission package. We also look forward to pivotal results for VOXZOGO in hypochondroplasia and BMN 401 for ENPP1 deficiency both later in Q2.

In summary, we expect 2026 to be a momentous year for BioMarin. Our immediate focus remains on the seamless and rapid integration of Amicus to accelerate our growth trajectory this year and beyond, pursuing regulatory next steps following the 2 upcoming pivotal data readouts. The addition of Galafold and Pombiliti and Opfolda to BioMarin's portfolio of innovative medicines provides an opportunity to reach more patients around the world, creating significant value for all of our stakeholders in the near and longer term.

As we enter this next chapter, I would like to express my appreciation to the employees of both BioMarin and Amicus, whose dedication forms the foundation of our shared mission to serve patients. Thank you for your attention. And I will now turn the call over to Brian to provide additional financial updates. Brian?

Thank you, Alexander. Please refer to today's press release for detailed first quarter 2026 results, including reconciliations of GAAP to non-GAAP financial measures. All first quarter results will be available in our upcoming Form 10-Q, which we expect to file in the coming days.

Now moving to Slide 7. Total revenues in the first quarter were $766 million and increased year-over-year, supported by increased patient demand across both enzyme therapies and VOXZOGO. And as expected, those organic growth drivers were partly offset by order timing dynamics as well as lower revenue from Roctavian, KUVAN and royalties. Enzyme therapies revenue increased 6% year-over-year, led by growth in VIMIZIM, NAGLAZYME and BRINEURA. PALYNZIQ first quarter revenues were impacted by U.S. order timing which resulted in elevated stocking levels in the fourth quarter of 2025, as discussed last quarter. We expect the stocking dynamic to normalize and anticipate year-over-year revenue growth for PALYNZIQ in full year 2026 as growth in new patient starts in the under 18-year-old population gains momentum and patients continue to titrate to their maintenance dose.

VOXZOGO revenue was supported by new patient starts across all regions and in line with the expectations that we shared on our prior quarter earnings call. Looking ahead, due to anticipated order timing and consistent with 2025, we expect VOXZOGO revenue to be higher in the second half of 2026 compared to the first half. Cristin will provide more color on commercial dynamics in a moment.

Turning now to Slide 8. Cost of sales increased year-over-year in the first quarter primarily due to a $31 million charge associated with an unsuccessful process qualification campaign to extend NAGLAZYME manufacturing capability. Importantly, this did not impact commercial supply. While this event decreased margins and earnings per share in the first quarter, we expect this charge to be offset in full year 2026 non-GAAP diluted earnings per share guidance.

Q1 non-GAAP R&D expense increased year-over-year, primarily due to spend to support BMN 401, our Phase III clinical program acquired in the Inozyme transaction in the second half of 2025. Development activities for VOXZOGO for hypochondroplasia, BMN 333 for achondroplasia and BMN 351 for Duchenne muscular dystrophy also contributed to higher year-over-year R&D expense. Non-GAAP SG&A expense also increased, partially driven by investments to support commercial expansion across enzyme therapies and VOXZOGO and partially driven by pre-close costs associated with the Amicus acquisition.

First quarter non-GAAP diluted earnings per share was $0.76 and was significantly impacted by the drivers of increased operating expense that I just mentioned as well as the impact of Q1 revenue which we believe will be our lowest quarter of the year. The impact of the cost of sales charge and pre-close costs associated with the Amicus acquisition resulted in a $0.20 earnings per share impact to our non-GAAP earnings per share result.

Looking past those elements helped to measure BioMarin's underlying business performance as well as how this Q1 result fits into our full year earnings per share guidance, which remains unchanged for the historical BioMarin business before layering on the Amicus business.

Now moving to Slide 9 and our updated full year 2026 guidance, which now includes the Amicus financial outlook starting last week. We are raising enzyme therapies revenue guidance to a range of $2.725 billion to $2.775 billion for the full year 2026 inclusive of meaningful contributions from Galafold and Pombiliti and Opfolda, resulting in approximately 30% growth at the midpoint. Adding these high-growth products to our enzyme therapies portfolio increases our full year total revenue guidance to a range of $3.825 billion to $3.925 billion with the midpoint representing approximately 20% year-over-year growth in 2026. For VOXZOGO, we are maintaining our revenue guidance of $975 million to $1.025 billion, which continues to reflect high single-digit growth at the midpoint. On non-GAAP diluted earnings per share guidance, we are updating the guidance range to $4.85 to $5.05. As previously communicated, the acquisition of Amicus will be slightly dilutive for the full year 2026. We continue to expect the acquisition to be accretive to non-GAAP diluted earnings per share in the first 12 months after close and substantially accretive beginning in 2027. The Amicus P&L will be incorporated into BioMarin's financial results as of last week's closing of the transaction. In 2026, we expect to include the base Amicus operating expenses less initial cost synergies anticipated in 2026.

As Alexander touched on, now that the transaction is closed, we have engaged more deeply with the Amicus business, and plan to share our outlook on both commercial revenues and cost synergies on our next quarterly earnings call. To give some perspective on timing of the updated guidance, we expect order timing for the historical BioMarin products and 2 full quarters of Galafold and Pombiliti and Opfolda revenues in the second half of the year to drive significantly higher revenues as compared to the first half of 2026.

To provide context, we expect more than 55% of total 2026 revenues to be recognized in the second half of the year. And likewise, on the expected timing of our profitability, we expect Q2 non-GAAP diluted earnings per share to be just modestly higher than Q1, partially due to pre-close Amicus costs incurred in April, plus a higher amount of the 2026 Amicus dilution being weighted to the second quarter. Further, the revenue timing weighted to the second half of the year results in most of our expected profitability occurring in Q3 and Q4. These earnings timing dynamics drive approximately 2/3 of our 2026 earnings per share expected in the second half of the year.

Briefly on evolving geopolitical uncertainties. We are watching the situation in the Middle East very closely and note that today's guidance reflects an allowance for a modest amount of disruption in that region in 2026. Looking ahead, we look forward to sharing with you our expanded financial outlook, enhanced by the addition of Galafold and Pombiliti and Opfolda setting the stage for accelerated near and midterm growth. Thank you for your attention. I will now turn it over to Cristin for a commercial update. Cristin?

Thank you, Brian. We were encouraged by the commercial execution across our portfolio so far this year, with strong patient demand across enzyme therapies and VOXZOGO. We look forward to providing a more detailed commercial update on our plans to maximize the potential of both Galafold and Pombiliti and Opfolda next quarter. Our initial priorities therein are focused on driving diagnosis in Fabry and switch in Pompe. This will support increased penetration in countries where Galafold and Pombiliti and Opfolda are marketed, while we can currently work on geographic expansion plans for both products. We look forward to updating you on our Q2 call.

Now moving to Slide 11. I'll begin with an update on first quarter 2026 performance, starting with enzyme therapies. As Brian outlined, enzyme therapies delivered 6% year-over-year growth in Q1, led by VIMIZIM, NAGLAZYME and BRINEURA. Across the enzyme therapies portfolio, we continue to see strong patient demand and adherence.

Turning to PALYNZIQ. In the first quarter, we continued to expand the underlying patient base and physician engagement remains strong. Importantly, following the FDA approval of PALYNZIQ label expansion to those 12 years and older in February, we have successfully launched in this age group and are seeing encouraging early momentum. We have observed broad interest and engagement from caregivers and health care providers treating adolescents during this critical stage of their development. Since approval, we have observed meaningful enrollments and new patient starts and people under the age of 18. From a prescribing standpoint, adolescent uptake is being driven by both physicians with significant experience prescribing PALYNZIQ as well as by clinicians who are newer to the therapy. Recall that it can take a patient many months to titrate up to their maintenance dose of PALYNZIQ, so we would expect to see the results of positive early prescribing over the coming quarters. PALYNZIQ continues to standalone in its ability to enable people with PKU to reach physiologic Phe levels while reducing dietary restrictions regardless of severity. With the U.S. adolescent launch underway and European approval expected later this year, we are excited about the impact PALYNZIQ can have for additional families over time.

Turning now to VOXZOGO on Slide 12. As discussed, first quarter results reflected expected order timing dynamics following a strong Q4, particularly in international markets. Importantly, we have reserved strong growth in patient additions globally with the number of children being treated with VOXZOGO increasing by more than 20% year-over-year. With the competitor having recently entered the U.S. market, our focus has remained on executing our strategy, and we continue to see strong momentum. During the first quarter, VOXZOGO progress continued, supported by ongoing patient additions across all regions in ages, strong adherence and persistence globally and continued expansion of the prescriber base. Our teams are focused on driving new patient starts across all ages with an emphasis on children under 2 years of age, where international consensus guidelines for achondroplasia recommend early diagnosis and treatment with VOXZOGO as soon as possible.

In the United States, we are encouraged to see that our efforts educating and engaging with caregivers and HCPs, are having an impact in the under 2-year old age segment. In Q1, over half of new patient starts were from children under age 2, a greater proportion compared to last quarter. Additionally, we have seen an approximate 10% decrease in the average age of children initiating VOXZOGO treatment in the under-2 segment, narrowing the window between diagnosis and treatment states.

Internationally, building on our global expansion into 55 countries to date, our strategy remains focused on reaching more patients and regions that have further opportunity and treating infants in countries that already have high penetration rates. With our sNDA for full approval now submitted, we believe the depth and durability of VOXZOGO's clinical evidence can be further reinforced, strengthening its role in treatment decisions for infants and children with achondroplasia. At the same time, we're making progress in preparations for potential expansion of VOXZOGO into hypochondroplasia. As we get closer to the Phase III data and potential launch, our pre-commercialization activities continue to accelerate. Our initiatives in the U.S. are making a difference. More people are being diagnosed at a younger age, diagnosis rates are rising and more doctors are requesting diagnostic tests. We look forward to the Phase III top line results in the second quarter of 2026 and submitting to global health authorities in the second half of this year with potential approval in 2027. In summary, we are pleased with the strong patient demand observed across the portfolio with continued momentum in our core business units and a compelling set of near-term opportunities to accelerate growth. With that, I'll turn it over to Greg for an R&D update. Greg?

Thank you, Cristin. As expected, 2026 is shaping up to be an active year for R&D, and we're looking forward to delivering multiple meaningful milestones. Moving to Slide 14. We've built a comprehensive VOXZOGO evidence package that goes well beyond describing annualized growth velocity, highlighting long-term durability and clinically meaningful health outcomes for children with achondroplasia. Recently, at the Pediatric Endocrine Society Annual Meeting, we shared data from 3 ongoing long-term extension studies that illustrate the sustained benefits of VOXZOGO over time. Consistent and cumulative improvements in Z scores were observed across all age groups over the 6 to 8 years of follow-up as depicted on the left of Slide 14. On the right side, you again see consistent and cumulative gains in height and height Z scores with durable results out to 8 years of follow-up. In addition to anatomic measures of benefit, we also presented data demonstrating VOXZOGO's favorable impacts on quality of life measures. Importantly, these sustained efficacy findings are supported by a robust safety database now comprising more than 10,000 patient years of exposure, reinforcing VOXZOGO's well-established long-term safety profile. Taken together, this extensive body of evidence reinforces VOXZOGO's differentiated profile with no other achondroplasia therapy supported by this level of long-term data with regard to safety, efficacy and functional outcomes. Importantly, this data spans the full pediatric age population, and VOXZOGO remains the only therapy approved for use immediately from infancy. This allows for early treatment initiation and enables a long window to positively influence endochondral bone formation and all the potential downstream benefits to health outcomes. Together, these data formed a strong foundation for our full approval submission intended to fulfill our post-marketing requirement, which was submitted to the FDA in April and will afford us the opportunity to share direct evidence of VOXZOGO's long-term value with the community via peer-reviewed publications and presentations later this year.

Now moving to Slide 15. The remainder of 2026 includes several anticipated pipeline updates, including two particularly important pivotal data readouts expected in the second quarter. Starting with hypochondroplasia, we believe the health care provider community is looking forward to a targeted therapy that addresses this skeletal condition, and we are confident in the scientific rationale for VOXZOGO in this indication. That confidence is grounded in the strong proof of concept and durability demonstrated in Dr. Dauber's investigator-sponsored study and in the rapid enrollment we observed in our own Phase III pivotal trial. We look forward to sharing these Phase III top line results in the second quarter.

In parallel, enrollment is progressing very well in our Phase II study in children under the age of 3 highlighting early interest in VOXZOGO as a potential option from infancy in hypochondroplasia. We also expect Phase III top line data for BMN 401 in the second quarter of this year. As a reminder, ENPP1 deficiency is a rare, serious and progressive genetic condition affecting vascular, skeletal and soft tissue systems. BMN 401 has the potential to be the first disease targeted therapy for ENPP1 deficiency. The ENERGY III study in children aged 1 to 12 includes 2 co-primary end points. The first is change from baseline and plasma measures of inorganic pyrophosphate through week 52. The second is change in the RGIC or Rickets Global Impression of Change after 52 weeks of treatment, assessing improvement in skeletal health. Clinical experience with BMN 401 in older patients has shown that normalization of pyrophosphate is accompanied by improvements in bone mineral biomarkers, functional performance and patient and physician reported outcomes. In addition to these pivotal readouts, I also like to highlight progress with BMN 333, our long-acting CNP therapy. We are pleased to share that enrollment is underway in our global registrational-enabling Phase II/III study. We are rapidly progressing this program with the goal of establishing BMM 333 as a potential next-generation standard of care for achondroplasia and potentially for other skeletal conditions.

Before closing, I'd also like to touch on BMN 351 for the muscular dystrophy at the Muscular Dystrophy Association Congress in March, we presented initial data demonstrating dose-dependent increases in dystrophin at week 25 in both the 6 and 9-milligram per kilogram dose cohorts. These findings were accompanied by notable decreases in creatine kinase, a biomarker of muscle injury and the prevention of functional decline as measured by the North Star Assessment and the 6-minute walk test when compared to historically matched controls. So far, we are encouraged by both the dystrophin expression levels and the functional improvements observed in our development program. Enrollment in the 12-milligram per kilogram cohort is ongoing and we look forward to providing an additional update by year-end as this program continues to advance.

Finally, we would like to thank the patients, families and caregivers whose commitment continues to make this progress possible. Thank you for your attention today. We will now open the call to your questions. Operator?

[Operator Instructions] We'll go first to Sean Laaman at Morgan Stanley.

This is Mike on for Sean. I just wanted to touch on two things. First, looking at the recent data at the Pediatric Endocrine Society, can you help to contextualize the benefits you saw in bone mineral content in hypochondroplasia? And how does that maybe inform or influence your expectations heading into the top line?

Yes. Thanks for the question, Mike. This is Greg Friberg. Yes, in addition to measuring growth velocity across both achondroplasia historically and hypochondroplasia, of course, we're measuring a variety of factors of health and well-being, including bone biology and bone health. The dexa scans that were presented and that cumulative data suggests, again, that that in addition to growing bone length and stimulating endochondral bone formation, that, yes, that bone is healthy and a strength that we would like to see. And again, reiterates what we've seen in the other FGFR3-related mutation condition of achondroplasia as well. Going into the card flip for the Phase III study, we're certainly excited to see that data. The event is going to occur before the midway point of this year. So we mentioned that it's in the second quarter. We're eager to see those results. And again, I think it highlights that the data at PES highlights the fact that hypochondroplasia, while a unique and individual indication as compared to achondroplasia, the related biology suggests again that the hypothesis is a strong one. We've seen in Dr. Dauber's data from National Children's, again, we've seen the kind of growth that certainly would meet the criteria for a statistically significant improvement that our study is developed to measure. And with regard to that safety profile, we're not anticipating any unexpected events there as well. So fingers crossed, and we'll be updating you all when that data is available.

That's really helpful. And then just maybe circling back on to the intro comments. Regarding the integration Amicus, you alluded maybe there's like a road map for future growth acceleration. We were just wondering if you could help to comment. I mean, specifically for Pombiliti and Opfolda, what leverage do you see for driving increased switch rates in that market?

Yes. This is Cristin Hubbard here. And just having closed last week, I can say we are really, really excited about the commercial potential of both of these products, both in high-growth products to add to our portfolio. As we've mentioned before, but I'll expand a little bit, for Galafold specifically, we really do think that the biggest growth lever is in and around diagnosis. We know that a large proportion of the amenable patient population remains undiagnosed, and driving diagnosis is exactly where Amicus has really started to build momentum, but we feel that using BioMarin's capability in this regard, we can really continue to drive that forward. On the Pombiliti and Opfolda side, that's more about a switching opportunity. And we really do think that there's going to be a sizable opportunity here to build over the next few years as patients on their existing therapies begin to progress. So we're really working on initiatives that, again, Amicus has started, and that is around kind of starting new therapy, looking at patients that have identified their own progression and understanding what progression looks like. That's an area that we're really focused on, not to mention the continued generation of evidence to show the benefits of a switch. So again, these are areas that we feel confident in our capability at BioMarin and are very excited about the future trajectory. So we'll share more on that on our Q2 call.

We'll move to our next question from Salveen Richter at Goldman Sachs.

This is Tommie on for Salveen. Just a quick one on VOXZOGO. Wondering if you've seen any early signals of different behavior from competitor entry, whether it be switching or in new patient adds.

Yes. Thank you for the question. This is Cristin again. And as you heard in our prepared comments, our demand in the first quarter really does remain strong. Our enrollments in fact, exceeded. In Q1, our enrollments exceeded that in the average of second half last year, and that trend continued into April. So as we see it now, we're really excited. As you know, we're very much focused on the 0 to 2 population based on the consensus guidelines, and we're seeing real momentum there. Not only were our new patient starts weighted and more than half of them being in that 0 to 2 population in the first quarter. But we're also seeing a reduction in the time we have from diagnosis to treatment in that population. That is -- that's reduced by 10% already. So we know that, that real focus therein working. In addition, we're focused on the patients that are already on treatment and making sure that the -- those patients for whom they're doing well on treatment, we want to make sure that they understand the totality of the evidence that exists for VOXZOGO and continue to have a positive experience in terms of the benefit. So we're very pleased. Good how Q1 went and look forward to continuing on that trajectory. .

We'll go next to Paul Matteis at Stifel.

Great. Just kind of previewing your update next quarter as it relates to Amicus integration. I was wondering if you could set the stage for us and just what you might be providing as it relates to the duration of the revenue outlook? Would you talk about peak sales at all? Or update those us or anything else? And then secondarily, anything you can do on setting the stage on our expectations related to accretion, cost synergies, and again, the duration of the profitability outlook as well?

Paul, thanks. Appreciate the question. And yes, we wanted to highlight today having just closed the transaction a week ago, brief update on the integration to date, which a weekend is going well, and you saw the update of our revenue guidance today, adding our expected range of the 8 months of Amicus revenues, resulting in a $500 million midpoint and the updated guidance, which is 20% year-over-year. We also wanted to set the stage for the Q2 update. The transaction announcement, we discussed how the strategic fit between these two businesses was very strong. And that because of the both global and commercial and medical capabilities of BioMarin built over time in our existing portfolio, that these two medicines should truly have more potential within BioMarin. That was a key rationale underlying the transaction, and we've been making plans up to this point of closing. And now that we've closed, we're just digging in and engaging more deeply with the Amicus business. And that's why we're going to wait until Q2 to give this additional update, but it will include a number of details and metrics about the long-term potential, including our views on peak revenue. Just a reminder, based on our due diligence at the time of announcement of the transaction, we reiterated what Amicus had shared with respect to peak revenue potential of roughly $1 billion each for Galafold and Pombiliti and Opfolda. But as we developed that long-term business plans and strategies to expand both of these medicines, we think that has some potential to be higher. So that's what we'll share. We'll be -- it will be important for us to share some of the key metrics and tactics in terms of how we expect to achieve that long-term potential. So stay tuned, and we'll look forward to sharing more in Q2. And by the way, that will include some of the other financial elements as well, such as synergies, long-term profitability, accretion, et cetera. I will share that for today. We are reaffirming our previous expectation that while, as you saw in the EPS guide today, the Amicus acquisition is slightly dilutive to calendar '26, but accretive for the first 12 months following closing and then substantially accretive for beginning full year '27. So we look forward to sharing more, but we're off to a strong start.

We'll move next to Ellie Merle at Barclays.

This is Jasmine on for Ellie. So just for VOXZOGO for hypochondroplasia, what's the latest on what you're thinking will be good data and what you're looking to see on AGV? And also, how are you thinking about the contribution to VOXZOGO revenues from hypochondroplasia next year? So what do you think the cadence of uptake will be in this population? And can you talk a little bit about your commercial preparations.

Thanks, Jason. This is Greg Friberg. Maybe I'll take the first part and then hand it off to my colleague. With regard to the VOX HCH, we're turning over, of course, -- we'll be looking at the data in the second quarter of this year, absolutely looking forward to that. And of course, the success is a statistically significant improvement in growth as compared to the control arm. And in this world, of course, we're measuring a variety of other measures. We're looking, of course, at other anthropometric measures as well as, of course, the safety profile. And really any statistically positive improvement in growth, we think that that's a win for these patients.

I'll just add that we've seen pretty dramatic I think, accelerations of recruitment, both for the older children as well as I mentioned in the prepared remarks, the infants on our hypochondroplasia study, really suggesting that this is a market that's hungry for a disease targeted therapy. Again, the biology is significantly similar to that of achondroplasia with regard to the mutation that drives this condition. And so from that standpoint -- and of course, built upon the data that Dr. Dauber has seen, we're quite excited to see what those end results will be. I think there was a question also about the marketplace, and I'm going to hand that one off to Cristin.

And so overall, our goal, of course, is to continue the growth of VOXZOGO into the midterm and hypochondroplasia provides an important component of that. Really where we're focused today on our prelaunch activities is in and around diagnosis. We have shared before that the total addressable patient population globally is at 14,000, and that assumes that we can continue to drive diagnosis and awareness of this condition. So our goal at this point in time prior to launch really is around increasing the number of hypochondroplasia patients that have been identified that we're getting physicians to understand the genetic testing and make sure that they're orders for that. And really, the idea being that patients get diagnosed at a much earlie. So our goal today is to improve upon that and make sure that we have identified patients at the time of a potential launch.

And Jason, if I could just add one other factor from the medical affairs standpoint. -- we're obviously actively working in the community even prior to seeing our data to really try to accelerate the number of patients that are diagnosed with this condition. There's probably 3 prongs to that. Of course, getting patients to be able to be referred sooner, to be evaluated, of course, more testing as well as we're doing work on the genetics side to reclassify so-called VUSs variance of uncertain significance. And so in that world, we're anticipating again that there will be patients available and ready for this therapy should become available. .

To throw out a few components, if I could, quickly. On the success we've had already, when looking at the diagnosis program that we're running to date and these kind of nonpromotional prelaunch activities, we're already seeing a 90% increase in the number of hypochondroplasia patients that we've identified as well as a 70% reduction in the age. So those are precisely the types of numbers that we're driving for and want to continue throughout our launch period.

We'll move to our next question from Cory Kasimov at Evercore.

This is Adi on for Cory. I had a question on the guidance increase. The $500 million from midpoint increase in guidance. Can you frame that the contribution from Galafold, Pom-Op, is that conservative relative to the $600 million revenue that generated in fiscal year 2025? And what are the key assumptions for adding these two assets into the guidance?

Ed, this is Brian. Thanks a lot for the question. I appreciate the opportunity to provide a bit more color on this important element of today's update. So yes, I'll frame it up for you. First of all, the $500 million represents a midpoint of a range that fits within the range of our existing enzyme therapies guide for '26, but I'll speak to the midpoint. From a timing standpoint, just a reminder that with the transaction closing last week, that $500 million midpoint represents mostly the 8 months remaining from May to December for this year. I will share in terms of your question around conservatism. I would say it's neither conservative nor aggressive. We think it's realistic. I'll share that we've analyzed the unreported period of Amicus product revenue from January through April. And when we looked at that versus consensus, January through April performance, while not reported was ahead of consensus. So both Galafold and Pom-Op together are off to a strong start in 2026. So with that being said, again, it's -- this is -- the transaction closed just a week ago. We'll come back next quarter with additional color, including the long-term potential I'll also share that since you commented on the $600 million reported for 2025, the range that's underlying today's update from an Amicus organic year-over-year growth rate standpoint, ranges from the high teens to the low 20s. So we think it's a really healthy growth. And we're excited that these assets are now part of our portfolio. And again, you see this 30% increase year-over-year as a result of layering this on to the BioMarin enzyme therapies and total revenue, 20% at the midpoint. So we're feeling good about it, and we'll share more going forward.

We'll go next to Jessica Fye at JPMorgan.

This is Jose on for Jess. How should we think about the adoption of hypochondroplasia relative to achondroplasia? What do you see as similarities and differences between these markets? And second, can you help us bridge the disconnect between the 20% year-over-year patient growth in 1Q versus a 3% revenue growth. Is it entirely explained by larger orders in the fourth quarter last year?

Yes. So I'll address the first part of the question in terms of how we see it in terms of uptake going in. I think we can consider it being similar to that of achondroplasia. But I think as I've mentioned kind of earlier, what is most important to us is ensuring that the amount of disease awareness, the urgency to treat and the diagnosis are really what we're focused on because we believe this is what accelerates that adoption curve. So our intention has been to drive as much of that so that we have patients identified at the time of our potential launch in the beginning of 2027. But importantly, that we continue on with that momentum because that ultimately is going to be what drives the shape of the adoption curve.

And Cristin, from a medical standpoint, if I could just comment. Hypochondroplasia, children are not born with the same growth gross deficit that the achondroplasia patients may be born with. And as a result, they often are diagnosed a bit later. They're referred and diagnosed. So that data point that we referred to earlier, which was one of our goals to try to shrink that number in terms of age of diagnosis is something that we see as a real positive sign that the work that we're doing to get these children in the hands of the right physicians who, again, can know what to do for them. That seems like a real early success, and we're looking forward to continuing to help shape that community and make these these therapies should they become available actually in the hands of the physicians who treat the patients.

Cristin, I'll take that revenue timing or fluctuation question. I appreciate you pointing that out because it is important to emphasize that the disconnect between that underlying patient demand growth in reported revenues is entirely order timing. There's a couple of different layers to that. One -- both of which we discussed last quarter, by the way. One was large international orders that were processed in Q4 that just didn't recur in Q1. Then the second was something that was somewhat unique to our business when looking back over the years, which was a modest amount of U.S. stocking impact from Q4 to Q1. This affected both PALYNZIQ and VOXZOGO. It wasn't significant, just about an extra week of inventory, but it was enough to show up as a variance in the quarter-over-quarter revenue. So this is why we wanted to emphasize the underlying patient demand growth. There's no significant price drivers in there, by the way, it is entirely order timing dynamics.

We'll move next to Phil Nadeau at TD Cowen.

Two from us. First, could you give an update on the ITC hearing and in particular, we're curious to get your thoughts on the ITC pretrial brief that was recently posted online. That's first. And then second, in the press release, there's a a note that there's going to be some data from BMN 333's Phase II/III trial in 2027. Could you provide a little bit more details around what data will be released at that time? .

Thanks very much, Phil. It's Alexander. I'll take the first part of your question and then hand it over to Greg for the second part. So with regard to the ITC, I mean, overall, we believe that assuming an exclusion order enforcing our IP is the most expeditious way to protect our IP in the United States. As you mentioned, we recently completed the ITC evidentiary hearing and post-hearing briefs are now being submitted to the presiding Chief Administrative Law Judge. So what happens next is we expect to receive a decision on whether product infringes our patent on or about August 21. At that point, if the full commission decides to review the decision and the final decision is expected on or about December 21. So this is a little bit of where we are and what can we expect going forward. I will also add that on completion of the ITC process, we would expect to also enforce a patent in the Federal District Court, where, of course, monetary damages are available. And I'll now hand it over to Greg.

For the question, Phil, about BMN 333. And as a reminder for those on the call, this is our long-acting CNP analog, again, designed to release continuous potentially higher AUC exposures of CNP when administered on a weekly basis. Again, as a reminder, in our Phase I, we saw over 10x increases in the AUC levels that we were able to achieve safely in the healthy volunteers. And we've recently initiated our Phase II/III study in children with achondroplasia. This is a multiregional clinical trial. It's currently open in a variety of countries around the world. We're enrolling as we speak. And our goal is to run the Phase II portion, where 1 of 3 doses of BMN 333 will be administered to the children, and there will be one arm that has VOXZOGO as well. There's no placebo on this study. What we will ultimately report out in 2027 is that we will be able to measure the annualized growth velocity at the 6-month time point, and we'll be using that data along with other measures, measures, other measures of safety and well-being to make a decision based on the analysis of which dose we should bring forward into a Phase III to run head-to-head against VOXZOGO. Again, looking for a superiority profile when it comes to AGV with the presumption that more AGV will drive more in the measurements of health and wellness that we're all familiar with.

We'll go next to Chris Raymond at Raymond James.

Yes. Just a question on the pivotal trial for BMN 333. I know this has come up before, but I guess I want to just ask maybe in a more pointed way and the decision to go with a superiority trial versus noninferiority. I think I've heard what you guys have said around 333 providing 2 to 3x free CNP and that, that should translate into higher efficacy. But maybe just strategically, if a non-inferiority trial could show that data, why take the risk and run a superiority study?

Yes. Thanks for the question. This is Greg Friberg, our goal with BMN 333 is to evolve this space. not just make a more convenient version of VOXZOGO. I'll just highlight that, that 3x target was at least 3x. We're actually testing a 3x to 5x and greater than 7x AUC exposure. And so from that standpoint, we believe strongly that BMN 333 is the right reagent to test this hypothesis. I'll also add that from a non-inferiority standpoint, it's a natural question to ask, wouldn't this be easier? From a pure mathematical standpoint, it's actually much harder and the study would be upwards of 10x the size in order to show non-inferiority versus even a drug like VOXZOGO. And so from that standpoint, there's a practicality of designing the study but I do want to reassure you that we will have an opportunity to look at the data after our Phase II portion. And if there need to be adjustments that the model gives us an update that tells us we should be reevaluating those would be potential opportunities. That being said, we are very clear with what we want out of this molecule. We want a superior CNP product that can be the cornerstone for future therapies for achondroplasia.

And I would just add absolutely, as Greg said, this is -- we think the opportunity in the need here is really around superiority. In terms of efficacy, AGV and all the benefits beyond linear growth, but also by this design of a study, we actually have an active control with VOXZOGO. So the size of the study is smaller than it would have been if it was in non-inferiority design, as Greg has already covered. But we also think the proposition to both caregivers and physicians means that this should be a study that's very attractive to potential patients to sign up to be included and therefore, speed of recruitment, which is extremely important. So we think that superiority profile we're aiming for from an efficacy standpoint, together with rapid trial recruitment and milestones being achieved is really a compelling proposition.

Yes. Placebo-controlled studies, when there are active safe and effective therapies are no longer really possible to run. It's not the right thing to do either.

We'll take our next question from Mohit Bansal at Wells Fargo.

This is Chen for Mohit Bansal. So we -- I just want to double-click on the BMN a little bit. I think you guys discussed that BMN targeting improvement in achondroplasia. But just wondering with a competitor that is also advancing their weekly CNP analog together with the growth hormone and potentially reporting a higher -- just how should we think about BioMarin's view of this evolving treatment landscape and the role that 333 could potentially play it over time.

Thanks for the question. This is Greg Friberg, again. And it is true. I think the data in combination with growth hormone, of which we've seen about 12 months of data, does show in the early studies that there is potentially additional growth to be had by adding in a second agent. But I want to caution you that it is early days for the combination. Growth hormone has been around for quite a while. And in achondroplasia, it's only approved in one market that I'm aware of that's Japan. And the reason for that is that growth that can be stimulated with growth hormone ultimately has not historically resulted in increases in final adult height. It's growth that gets uncorked but at the expense of potentially closing the growth plates earlier. And that remains an open question. I think we do need to see data at 2, 3 years or more, not only to see the safety, of course, growth hormone, while it has a manageable safety profile, does have its own set of challenges that need to be monitored by a physician. But we need to see whether or not those gains are long-standing. I want to reassure you that this is something that we're watching very closely. And if there are opportunities and levers that can help CNP do its job better, so to speak, we will evaluate those at the right time and place. We don't feel that, that is the correct time right now, and we're certainly interested in seeing additional data before the paradigm shifts. And this is consistent with what we've heard from many of our stakeholders as well.

We'll move to our next question from Joe Schwartz at Leerink Partners.

I was wondering if we could get some more perspective on your guidance raise for the enzyme therapies business. We see it increase by $500 million, and we estimate that Amicus generated around $450 million in revenue for Galafold and Pam-Op in the comparable 8 months last year. And that implies low double-digit growth around 11%, I think. But I heard you reference high double-digit percent growth, Brian. So I'm just wondering if you can help us reconcile that difference?

Thanks, Joe. Appreciate the question and your math there. I'd probably attribute the reconciliation difference that you're trying to get at with two elements. One, by doing a pro rata 8 months of 2025, there's certain -- there's some in variables there and a lack of precision that we couldn't do a strict apples-to-apples comparison. And then secondly, on a full year basis, again, I pointed to that strong performance for the first 4 months of the year for both Galafold and Pombiliti and Opfolda. So again, not reported. This is internal management data. We're not disclosing it because it didn't go through the usual external reporting process like a regular quarter does. But we thought it was important to add color to that full year. So I'd say it's more important and this goes to our own business as well when we think about some of these quarterly timing dynamics. I think it's most important to compare the full year annual cycle year-over-year, and that's where when we piece together the range that's implied today over that full year $634 million that Amicus reported for '25, we have a range of high teens to low 20s. I'd encourage you to anchor that rather than trying to calculate them intra-quarter map.

We'll move next to Jason Gerberry at Bank of America.

Alex, just to follow up on the ITC question. I'm trying to just get my head around, do you have any knowledge of the Ascendis' ability to do manufacturing workaround? And just help us think through scenarios if you get a positive ruling like, could a decision be stayed pending any sort of appeals? And then just a follow-up, just on Pom-OP, I believe you've inherited the asset basically launched into 15 country markets, and I think the goal is to get it into 80 country markets. So how should we think about the phasing of that now that you've got the asset either 2026 or 2027?

Thanks very much for the question. Unfortunately, I'm not going to hear any details of the of the ITC the potential scenarios around it. So I hope you can understand that we don't want to get into too many specifics, especially whilst the case is very much pending. So I'll hand it over now to Cristin for the second part.

Yes. Thank you very much for the question Pom-Op. And you're absolutely correct in that there -- currently, we are reimbursed in 15 countries. And what we've been doing before the transaction was closed, we've been doing deep dive into discovery sessions really looking at the business in each market for both Galafold and Pam-Op, really understanding what the dynamics are therein, but then importantly, looking at, as you've mentioned, our 80-country footprint and saying, where would the potential and the opportunity be. We're identifying opportunities for both Galafold as well as Pom-Op, given that Pom-Op is much earlier in its launch trajectory, you can imagine that there will be a larger number of countries to look at therein. But it's important to note that we're not necessarily going to put it into our entire 80-country footprint but importantly, look at where we believe the potential opportunities are and then have a cadence to that, that we'll share more of in the Q2 call.

And that concludes the Q&A session. I will now turn the conference back over to BioMarin's CEO, Alexander Hardy for closing remarks.

Thank you, operator, and thank you all for joining us today. This quarter, as you can tell, marks a really important inflection point for BioMarin. With the recent close of the Amicus acquisition, expanding our commercial reach, strengthening our 2026 revenue growth outlook to 20% and enhancing our ability to serve more patients globally. We're encouraged by the robust patient demand observed across our portfolio. In enzyme therapies, we anticipate that the momentum from the PALYNZIQ launch in adolescence will continue to build. With VOXZOGO, the consistent rise in new patient initiations, more than 20% year-over-year in Q1, especially among younger children, demonstrates confidence in its long-term safety and efficacy and highlights the importance of starting treatment as early as possible.

With the integration of Amicus now well underway, several near-term catalysts ahead, pipeline readouts. We are focused on translating this momentum into accelerated growth, broader patient impact, meaningful value creation. We appreciate your continued support and look forward to updating you next quarter. Thank you.

And this concludes today's conference call. Thank you for your participation. You may now disconnect.

Good afternoon, everyone. I'm Ellie Merle, one of the biotech analysts here at Barclays. Very excited to have BioMarin here with us. Certainly, a very important year for you with commercial launches and clinical readouts. Excited to have Brian, CFO; Cristin, Chief Commercial Officer. Thank you both so much for joining us.

To kick it off with an overview question before we kind of go into some of the specifics. Just can you give us a brief overview of the key highlights of BioMarin's progress over 2025 and what we can look forward to in 2026?

Yes. Thanks, Ellie. Appreciate it. Thanks for having us. Thanks to those of you joining in person. Really pleased to be talking to you today at this point in the year as we transition out of what was a very successful 2025 for the company and a very exciting 2026.

Starting with how we finished 2025, BioMarin grew total revenue at 13% for the full year, and that included 26% revenue growth for VOXZOGO and 9% growth from our Enzyme Therapies business unit. On the profitability side, we've been on a profitability improvement journey over the last couple of years. We've had several quarters in a row where we're growing earnings per share at a rate greater than revenue, and that includes full year 2025, where -- after adjusting for some of the special items that did hit earnings in 2025, we were more than 2x leveraged on the bottom line.

And the other big momentum build coming out of '25 is the announcement of the Amicus acquisition, and this kind of sets up perhaps what we're excited about in 2026. So the Amicus acquisition we announced in December. We expect to close it in the second quarter, subject to all the customary closing conditions for an acquisition like that. And that adds 2 high growth or subject to closing, will add 2 high-growth approved rare disease assets to our existing portfolio of more than $3 billion of revenue from 8 rare disease products.

Beyond that, within the existing base business, we're expecting to grow revenue within both of our business units at the high single digits, Enzyme Therapies and Skeletal Conditions, both growing at 7%, 8%. We do have a small growth rate headwind on total revenue because some of our royalty and other revenue is decreasing, and that's about a 3% headwind. But the most critical parts of our growth are the business units, and we're excited about that.

We're also advancing our pipeline and have a number of pipeline catalysts in 2026. First is the Phase III readout for hypochondroplasia for VOXZOGO. VOXZOGO is currently approved in achondroplasia. Hypochondroplasia is a similar condition and we have proof-of-concept data from an investigator-sponsored study and the Phase III study will be reading out in the first half of this year.

Another Phase III readout is BMN 401. This was the asset that we acquired with Inozyme last year, which was our first acquisition of 2025. This is an enzyme replacement therapy for ENPP1 deficiency. And again, data in the first half of the year.

We also have clinical stage assets progressing. BMN 351, we shared some data early in the year. This is a second-generation exon skipper for Duchenne muscular dystrophy. At -- we're testing 3 dose levels. And at the middle dose, we shared that we achieved 5% dystrophin expression, which at 25 weeks, which is about halfway through to what it should take to get to steady-state dystrophin expression at 52 weeks or more. That 5% shows us that we could be on track to reach our target of 10% dystrophin expression, which while there are approved products, there's still an unmet need. And while it's a competitive space, this does have the opportunity to be best in disease. So we'll be looking forward later this year to sharing the results from the highest dose, the 12-milligram dose.

And then the other clinical program that's advancing internally is BMN 333. This is BioMarin's long-acting CNP, possibly a weekly injection, but what's noteworthy about BMN 333 is that we're designing the product and its target product profile is more than just convenience. We're designing the Phase II/III study to actually be superior in efficacy to both our own drug, VOXZOGO. It's a head-to-head program with VOXZOGO, but also potentially superior efficacy-wise to the competition.

So we appreciate that VOXZOGO is facing competition, including a recently approved competitor. But frankly, we're excited to compete. We're confident in VOXZOGO's profile. We have established ourselves in the achondroplasia community and with patients and physicians. We believe that switching will be complicated. We'll continue to have the infant label for ages 0 to 2, where it's most important to start treatment of achondroplasia with VOXZOGO as early as possible, that's published in international treatment guidelines.

And then just a reminder, since I started talking about the VOXZOGO competition that we are talking about just 25% of VOXZOGO revenues being in the U.S. that's subject to the competition, which is approximately 7% of our total revenue. So we've got this base business that's growing, including VOXZOGO in 2026. The midpoint of our guidance is $1 billion. So through competition, VOXZOGO potentially reaching blockbuster status and still growing healthily in its fifth year after launch. So that's -- we're excited about all that.

Yes. There's certainly a lot of investor focus for what, as you rightly say, is 7% of your revenue. But yes, maybe let's start there talking about VOXZOGO sort of you outlined 2026 guidance for VOXZOGO revenues. Maybe if you could sort of outline some of the assumptions behind that, both from a U.S. and ex U.S. perspective in terms of what's baked in, in the guidance.

Yes, of course. So VOXZOGO guidance is $975 million to $1.025 billion for 2026. The two most noteworthy swing factors in that range beyond the fact that it's earlier in the year, and it's an estimate at this point in the year, we need to execute and there's natural variability. That's why we estimate a range. But the two largest swing factors are, first, some international market access negotiations that we're in the process of concluding this year. On the low end of the range, that could involve a price discount. But if that's the case, in some markets, including those that we're negotiating in, that's just a short-term headwind because what we could be doing is taking a short-term price discount to actually open up access to more patients over time. So a short-term headwind because of price, but long-term tailwind because you're accessing more patients over time. And on that one, on the high end of the range, it would just assume that the pricing gets negotiated more in our favor.

And then the second swing factor is the competitive impact. So on the lower end, that assumes that there will be more VOXZOGO patients switching potentially earlier and at the high end, less switching later. But you can -- again, back to the 25% of revenue and the 7% of total revenue, you can see that our assumptions even around different levels of share loss to competition, it still fits within that $50 million band. So these are not largely material swing factors on what is a $3.3 billion, $3.4 billion portfolio.

Also important to note is the anticipation of closing the Amicus acquisition. I talked about how this brings 2 commercial assets into the portfolio. We will, of course, update our guidance at some point, assuming we close after the close. But if you look at the 2025 revenues for those Amicus products, it's over $600 million. So -- and these are high-growth assets. So as we bring in the Amicus assets, VOXZOGO becomes an even smaller portion of our total revenue.

Certainly, probably quite high margins on the Amicus products as well.

Galafold has a slightly higher margin. It's a small molecule. The Pombiliti + Opfolda product is slightly lower. It's a combination product. It does include a biologic -- but we're familiar with some of the cost of goods sold initiatives, second versions of the manufacturing process that Amicus has been working on. So we'll look forward after closing to looking at those opportunities.

I have more questions on that. So first, I just want to talk about VOXZOGO. So what's interesting is there's all this focus on competition, right? But we've talked about how 75% of your sales are ex U.S., which probably will be a lot stickier than the U.S. But then you also have hypochondroplasia, which assuming that the Phase III reads out positively in the first half of this year, which I personally think is a readout that people should be talking about more. But just from a commercial perspective and modeling, like how do we think about -- like this could be launching this time next year. So how do we think about the revenue contribution from hypochondroplasia and the cadence that we could see of that?

Yes. And we will -- we are very much looking forward to the data readout in the first half of this year. And we are, of course, gearing up on our go-to-market plans, and we'll share more about that as the data comes out. But what I think is important to note is that hypochondroplasia, while we believe that it's genetically prevalent as the same as achondroplasia, so we say that there's a total addressable patient population of 24,000 with achondroplasia. The big difference with hypochondroplasia is the diagnosis rate. It's much lower. Estimates are that it's diagnosed at about 30% of patients being diagnosed. So what we've said is that we think that the total addressable patient population is in and around 14,000 for hypochondroplasia. And again, the big reason for that is the lowering of the diagnosis rate.

So where our teams are really focused now and will continue to be after launch, after assuming we get a launch is in and around the disease awareness as well as how can we shorten that diagnosis pathway. Right now, kids are getting diagnosed around 5 to 6 years old. We want to see that happen earlier and importantly, make that journey to get that confirmation of diagnosis quicker for them so that they can get on the appropriate treatment. And should we be approved, VOXZOGO would be the only treatment for hypochondroplasia.

And feel free to not answer this question. But based on your commercial work and seeing how many patients are diagnosed today and getting a sense of awareness because presumably, these patients see that achondroplasia patients get VOXZOGO, how are you thinking about whether there could be an initial maybe bolus of patients next year? And from a revenue contribution, how we should think about that?

Yes. I think that in the centers where you have KOLs or they've been involved in our clinical trials, for instance, that's where you're going to see those that already know who those patients are, and we could expect quicker adoption in those particular centers. But the truth is these patients are spread out. They're being seen by pediatricians. They might be in endocrinology offices. So that's where you get a little bit of a slowing relative to that bolus. So I think it kind of normalizes into what I would argue would be a normal launch curve, but recognizing that the total addressable patient population will be lower because of that diagnosis rate.

Makes sense. And of course, longer term, I know you're running sort of the CANOPY Phase II trials in ISS, Noonan, Turner and SHOX. How are you thinking about the opportunity set there?

Yes. So to remind you, so we are -- as you said, we have the CANOPY trials that includes hypochondroplasia, but in these other conditions, including ISS, Noonan, Turner and SHOX. This is an area where we have said that the bolus that -- that total patient population size across those four is 385,000. But what we had said is that we would only expect to get a very, very small fraction of those patients and those that are the most severe. So I want to remind you, these are Phase II trials. We're currently enrolling them and are very much looking forward to seeing how the data turn out next year.

Yes, exciting readout. Going back to the Amicus conversation, how should we think about any -- like you already have a global rare disease sales force of commercial operation. How much more spend do you need to support these revenues? And basically, I'm asking kind of how much of the top line just goes directly down to the bottom line?

Yes. Thanks. Great question, Ellie. Maybe I'll start and Cristin can talk about how we genuinely believe that these two medicines in our hands have the potential to reach more patients because of our global capabilities and reach. But to your point on OpEx, first of all, we need to get through subject -- get through the closing period and actually engage with Amicus and get to work on the integration. But based on what we know about their business, first of all, there's a significant amount of capabilities that they've been able to leverage and be successful with through the growth of these assets. I mean, speaking of switching, they're in the switch market themselves on both of these assets, and they've been very successful in switching patients to Galafold and Pombiliti and Opfolda. And so we plan to preserve and grow those capabilities and continue to use those to drive the sustained growth in these Amicus medicines.

We also think there'll be a level of investment required. We'll get some leverage from the global BioMarin commercial infrastructure, but as Cristin will touch on, if we get into improving diagnosis or expanding the global reach, some of that will take some direct investment. So there's a level of investment in OpEx, but we also believe that the complementary nature of the business model means that there's going to be operational and -- operational expense synergies as well. So -- but that's work to do after the closing, and we'll talk more about it when we -- after close.

Okay. Got it.

Do you want to touch on the expansion?

Yes. Just on the expansion or acceleration, I should say. I mean what we want to do is make sure that we, first of all, do no harm and continue the trajectory that those medicines are on today, but then we're thinking about how do we inflect that curve. And the ways in which we think we can do that is to accelerate and deepen penetration in the countries in which they already are. So Galafold is currently in 40 countries. Pom-Op is in 15. We have a country footprint of nearly 80. And so we're looking today at where can we drive deeper penetration in the countries that they already are and importantly, to expand into our country footprint. So teams are currently looking at which markets would we want to go into first and looking at the cadence following that.

Yes, that makes sense, certainly. A lot of synergies there. So we look forward to the updated guidance because I believe I think it's much more accretive than people are appreciating. So I'll leave it there.

I appreciate the support.

Maybe just turning back to sort of the commercial dynamics. I guess, following PALYNZIQ's recent label expansion, how should we think about the impact of the near term on revenue in 2026 and over the longer term?

So we're really excited about the expansion, the adolescent expansion that we just received in PALYNZIQ. It's really exciting for these patients. So this is in 12- to 17-year-olds because what we know to be true about the adult population is that this really brings down the Phe levels to within normal range and allows you to have a normal diet. You can only imagine how that must feel for an adolescent who wants to be included with their friends, wants to eat like their friends and wants to make sure that their condition is under control.

So if we look at the adult population, just to give you relative commercial sizing, we have about 7,000 patients that are eligible for PALYNZIQ and that are not yet lost to follow-up, meaning that they're being seen in clinics. More patients as adolescents are actually in clinic, and that is in large part because their parents are having to manage this and ensure that they're staying both in clinic and adherent to therapy. So we think that there are about 1,500 patients in the U.S. who would be eligible for PALYNZIQ. And so we're really excited to bring this opportunity to them and ensure that not only can we lower Phe levels once they get up to their maintenance dose, but importantly, lead a normal life and set them off in the right direction into adulthood.

And maybe just on the revenue side. So PALYNZIQ continues to grow strong even before this label expansion grew at over 20% the last 2 years. And so -- and the medicine was approved in 2017. So that's just a good indicator of its gradual and continued uptake. And for the reasons Cristin noted, while this opens up a new segment of the population, because of that parental oversight and the benefit for adolescents in their lifestyle, we actually think we'll get deeper penetration within that segment, which we are excited about as an opportunity. But since you mentioned revenue, it is important to note that PALYNZIQ has a very gradual and steady dosing induction and titration phase where patients could be at a very low dose of the medicine for several months, up to 6 to 9 months or more until they get to the steady-state efficacy dose. And those smaller doses mean less revenue. So even if we're adding adolescent patients this year, you may not see it in revenue until next year. But again, chronic therapy for life, just like most of our other products. So once they're on drug, it's a steady revenue contributor.

And yes, we've certainly heard the feedback from physicians that once patients have finished the titration that the adherence is very high. Earlier today, we had PTC here who is launching SEPHIENCE. Curious kind of what you're seeing on your end in terms of any impact to PALYNZIQ?

Yes. So in terms of direct impact to PALYNZIQ, we are not seeing an impact in terms of patients switching from PALYNZIQ over, especially those patients that you would see at their maintenance dose, they've reached their efficacy and they're really content on therapy. What I think is really interesting, though, about having another option out there for patients is what we've heard PTC saying is that they're seeing some of those lost to follow-up patients that are now coming back into the system and being treated with their drug. And what that only does is that actually starts to enhance the patient population if you're bringing in that 60% of lost to follow-up patients, if you're bringing them back in the clinic, the hope would be that whatever therapy they're on is efficacious. If that one is not, they might then choose another therapy, which could be PALYNZIQ. So we see it as a real opportunity.

Makes sense. Heading into the Phase III data for ENPP1 this year, what are your expectations for data? And then also, how should we think about the commercial opportunity?

So we're looking forward to that reading out here in the first half, so very soon. This, of course, will be looking at normalizing pyrophosphate levels as well as having a functional endpoint, which is a radiographic endpoint. So we'll be looking to see improvement in both of those in the pediatric population. This is another one of those areas that ENPP1 deficiency, there are no current treatments for it. And so again, something that is in the sweet spot of BioMarin being that it would be the first and only therapy for the treatment of ENPP1 deficiency. We estimate the total addressable patient population to be anywhere from about 2,000 to 2,500 patients globally. Now this is something where the publications, it's unclear what the actual prevalence is. But as we've seen on our MPS products that when you have a medicine, you start to see more, the diagnosis rates increase and you start to see more of these patients coming. So for now, we think it's about 2,000, 2,500, but that number could grow over time with an efficacious therapy.

Absolutely. Brian, heading into 1Q, I know that your business is particularly subject to some seasonality with ex U.S. orders. But can you remind us just for modeling purposes, how we should think about any specific setups into 1Q?

Yes. Thanks. I appreciate you bringing that up, Ellie. It's important to reemphasize for those tracking. So if you look back over the years, we've historically seen kind of a ramp over the course of the year, specifically in Q4 and then a step down in Q1. Hard to call it true seasonality. As you know, from quarter-to-quarter, it's often these -- the variable timing of some of the large international orders that can cause some volatility quarter-to-quarter. That tends to just increase at the end of the year. It could be, for example, most of our customers outside of the U.S. are these single national health care system payers. And so it could be them consuming their budgets for the year, stocking for the next year. So we've definitely observed that.

And yes, so this year coming out of Q4 '25 into Q1 '26, I'd say it was just a bit exacerbated on the international order front. We also saw something that we haven't have observed as acutely before, which was a bit of U.S. inventory stocking. It's not much. We're talking about going from an average of 2 weeks of inventory on hand to 3 weeks. We don't have big pharma stocking and buy-ins, but that small amount on our larger products is enough to make a difference.

So overall, we expect revenue to look from a trend standpoint in '26 at the quarters similar to '25. For VOXZOGO specifically, we expect -- and for total revenues, but VOXZOGO as well, we expect Q1 to be a low point and for VOXZOGO on par with last year. Again, it's just these timing dynamics. Two last things. We do point to full year guidance and performance is the best measure for this exact reason, some of this quarterly volatility. And what's also important is that every quarter for each of our marketed and growing commercial products, we're steadily adding patients, which at the end of the day is true demand. We don't have material price volatility. That means you need to tease through revenue growth in terms of whether it's price or demand through patient additions. So when we see that nice steady growth of new patient additions across the portfolio across the last several quarters, and then you look at some of the, at times, noisy order patterns, we get comfortable that it is just timing.

Okay. But that's a helpful reminder in terms of 1Q. Lastly, I mean, I think the Amicus deal is a great deal from an M&A perspective. What is your further appetite and capacity to do further business development?

Yes. Thanks. Very important because it remains a key part of our strategy. What's most important is, of course, getting through the Amicus closing, paying very close attention to the integration and making sure that we're successful in protecting and growing their business. We did share -- we are levering up for the Amicus acquisition, and we shared a deleveraging strategy. Because of the complementary nature of the two businesses, because Amicus reached operating profitability on their own, the deal is actually operationally accretive early. We're taking on a significant interest expense load with the new debt. Part of that is why we do expect the deal to be dilutive this year, but accretive in the first calendar 12 months after the acquisition and substantially accretive beginning next year.

That leads to a rapid deleveraging strategy. So we said that our target deleveraging is less than 2.5x within 2 years after the acquisition. That was really important to go on record. We were a first-time debt issuer in the leveraged debt markets. But I'll share if you do the math, which it sounds like you've done, you can see that the two companies' combined EBITDA actually has us on a path to delever even faster than that, which means we are able to replenish firepower at a greater level and earlier.

So while the priority will be integrating Amicus and commencing on this deleveraging strategy, we will continue to look for opportunities on the BD side. And different from the Amicus transaction, we'll now be focused on pipeline clinical stage transactions. So we're excited about our internal pipeline, but recognize that building long-term shareholder value is most closely correlated with building long-term expected revenue growth. And so bringing on derisked clinical stage assets that have a clear view for investors to revenue growth is where we'll be focused.

Yes, absolutely. Great. Well, Brian, Cristin, thank you so much for the time today and sharing your insights.

Thank you, Ellie.

Thanks so much, Ellie. Appreciate it. Thanks, everyone.

Welcome to this fireside chat with BioMarin. It's my pleasure to host. I'm Joe Schwartz from the biopharma equity research team at Leerink Partners, and I'm pleased to be joined by Brian Mueller, Chief Financial Officer; and Cristin Hubbard, Chief Commercial Officer.

Thanks for joining us. Thanks for having us, Joe. Good morning.

Excited to be here.

So before we get into individual products, Brian, can you frame what's driving BioMarin's next phase of growth, particularly the mix of near-term commercial execution, upcoming pipeline milestones and portfolio expansion?

Yes, of course. Thank you, Joe. We're really excited about 2026 at BioMarin. We're coming off a strong performance year in 2025. We grew total revenues 13% in 2025. Within our business units, we grew our skeletal conditions business unit, which includes Voxzogo revenue at 26% last year and enzyme therapies at 9%.

Looking ahead to this year and beyond, I think the way to frame it up, Joe, is there's three pillars to our corporate strategy: growth, innovation and value commitment. On the growth side, we're continuing to plan for strong growth from both of our business units. The midpoint of our guidance is high single digits for both skeletal conditions and enzyme therapies. We are also very excited and look forward to the assumed closing of the Amicus acquisition in Q2, which is going to bring two high-growth products into our commercial portfolio with an outstanding strategic fit in rare genetic conditions.

On the innovation side, we're very excited to have a number of programs advancing. Just recently, we announced the approval of Palynziq in adolescents. I'm sure we'll get to it, and Cristin can elaborate on the opportunity there. We're expecting two Phase III data readouts this year, one in Voxzogo being examined in hypochondroplasia. This would be the second indication after the current approved indication of achondroplasia. And then BMN401 for ENPP1 deficiency.

This asset came to us through the Inozyme acquisition last year. And then we're also advancing our additional clinical stage pipeline assets, BMN 351 for Duchenne muscular dystrophy, BMN333, which is BioMarin's long-acting CNP for achondroplasia, as well as our early-stage research programs. And then on the value commitment side, we transformed the company over the last couple of years with a significant focus on efficient cost allocations and disciplined expense management while growing the top line. This has led to leveraged growth.

If you look through some of the special items in our 2025 P&L, we're growing earnings per share at the midpoint of our guidance at approximately 3x revenue. also looking to our third year of operating margin expansion and cash flow growth. So we're making great progress across all three pillars of the strategy, and we think creating a lot of value for shareholders.

Great. We appreciate that overview. So let's talk about Voxzogo. And I'm wondering since you're having such strong new patient starts and patients under age 2 now, how do you think about stickiness and whether -- I'm wondering if whether you have any strategies to forestall switching once new options become available and we have patients in multiple age segments? And how do you think about those dynamics?

Yes. And this is something that we've been doing a lot of thinking about, obviously. And first and foremost, I'd be the first to say that more options are great for patients. It certainly gives them the ability to choose what is right for them. And what we hear a lot of, Joe, is we're going out there and really understanding what today's market and the future market can look like is that at the end of the day, the decision makers for a switch are going to be the parents, the caregivers.

Physicians tell us very often that they are there to provide any factual truths to lay out the options that are there. But at the end of the day, it's going to come down to that caregiver and that family and the decision that they choose to make for their child. So what we see in much of our market research in addition to the conversations that we're having is that for patients -- for the patients for whom there is efficacy that is being seen that that's going to be a high burden to switch. They've gotten used to their daily injections. They've gotten used to whatever the routine is.

And so that we're seeing on average, about 2/3 of KOLs, physicians and caregiver research telling us that the chances of switch if the patient is doing well on therapy are low and not as compelling. So I think that really, at the end of the day, what it comes down to is efficacy matters, safety matters has over 10,000 patient years of that data to hold behind it, and then convenience comes third.

And that's really helpful. And as you look at the achondroplasia market, do you have a sense of how many patients are attracted to a value proposition, primarily based on growth and how many decision-makers view growth as a surrogate for other health benefits and how many individuals are just not interested in treating this condition?

Yes. And while I wouldn't say we have rigid numbers in terms of the buckets of specifically that, I will say that this landscape has evolved, and you would expect it to. Voxzogo was the first treatment ever available for achondroplasia hormone. And we're seeing this landscape evolve.

As more data is being generated, as more publications are being made, we're certainly seeing there be more focus on the benefits beyond height. So AGV was, of course, what we had agreed to with the regulators, and that was the most visible sign of the product working. But at the end of the day, what is most compelling to families, to physicians, to those who treat achondroplasia is the broader health story, and that is precisely where we're building that body of evidence, and we're really moving the needle on that front.

Great. And can you talk a little bit more about that? What kind of efficacy on proportionality, if that's the right way to think about this, that there might be read-through from that? Obviously, BioMarin has the most experience of anyone in this space. So it would be great to hear some more about the strategy to communicate those benefits.

Yes. We've continued to publish, for instance, at SB in 2025. We've continued to publish our body of evidence and we are seeing areas such as for and magnum benefits. We are seeing symptomatic spinal stenosis benefits.

We're certainly seeing proportionality where we have statistically significant data to show that proportionality is improved by treatment, including things like leg deformities, so tibial bowing, like any of the kind of various things that could affect their gait and their mobility at the end of the day, in addition to overall quality of health data, quality of life data, where you see also the kind of the more just overall life improvements and how they feel on the day-to-day. We're seeing all of these things benefit in our longer-term data, and we are continuing to publish on those and really share that story with physicians and families alike.

And just to add, this is an area where BioMarin will always be in the lead. We started our Voxzogo development program more than 15 years ago and we've got patients who have been on the therapy for 10 years now. The drug was approved in 2021. One, it was a conditional approval.

One of the post-marketing commitments to file for full approval was this long-term data set where we followed a number of patients through final adult height. We now have that data, and we'll be filing it this year. And we'll see if that turns into something on a label amendment. But at a minimum, we're always -- and this is the level of publishing that Cristin mentioned, we're generating the longest and most robust data set.

Right. Okay. That makes sense. And then BMN 333 showed much more free CNP than Voxzogo. So I'd love to, as you embarked on a Phase II/III trial, discuss the strategy there to generate height as well as other health benefits. How much of a proportionality benefit or anything else do you think it would take to encourage patients to switch from Voxzogo or maybe one of the newer options to BMN 333.

Yes. Thanks, Joe. So our strategy with BMN 333, which I touched on is BioMarin's program for a long-acting CNP. However, it's really important to note that BMN 333 is not designed as just a convenience strategy. It's designed to be superior to Voxzogo and the competition based on the data we've seen.

And to your question, we think that the Phase II/III seamless design study that we're enrolling will have the ability and the power to detect both the annualized growth velocity target as well as benefits beyond height. It's 120 patients designed to statistically detect a superiority to Voxzogo at the 90% level.

Okay. And switching gears to hypochondroplasia, the next potential opportunity for Voxzogo. How do your early indicators of market demand in hypochondroplasia compared to where you were at a similar stage of launch in achondroplasia?

So I'll start here. So we're really excited about being able to turn over the card and see the hypochondroplasia data coming up here soon in the first half of 2026. And the reason for that is that we have high confidence in the science. We saw really strong signals in Dr. Dauber's sponsored trial and therefore, are very much hoping to see that continue in our Phase III trial.

Now importantly, when you asked the question about kind of what's the excitement around this, how do you see this playing out? I think the biggest and best proxy that we have to date in terms of the excitement around this indication is how quickly our Phase III trial enrolled. It went well beyond our expectations in terms of speed of enrollment, which oftentimes is a very good proxy for the excitement level.

Now the work that we're doing today and the work that we think is very, very important for hypochondroplasia is in and around education and the diagnosis of this condition. While we believe the prevalence to be very similar to that of achondroplasia, we know that we have -- that we look at much lesser in terms of the -- or the TA, the total addressable patient population. And the reason for that is because it's not diagnosed at the rate that achondroplasia is.

So we're doing a lot of our work today focused on disease awareness in addition to really figuring out how we can enhance the diagnosis journey and also shorten it because many of these patients are on average diagnosed around the age of 5 or 6. And similar to achondroplasia, we want to ensure that we're really getting patients treated as early as possible. So that diagnosis journey is very important.

And we hear that there's a wide or a fairly wide spectrum of severity in hypochondroplasia. And at the one end, the most severe end, some patients might already be on Voxzogo, but then we hear that there's some under the pope.

That they start to ask these questions in and around what might be happening, should we get a genetic test, et cetera. So that is specifically why we are so focused on ensuring that people understand some of those early signs of the condition and importantly, what that pathway to getting diagnosed can and should be.

There are a significant proportion of these patients who would be eligible for treatment with Voxzogo, should those data turn out to be positive and importantly, in the way that we design the trial, a very significant proportion. But the bigger challenge is going to be ensuring that they are diagnosed early and that they are seen as eligible.

Okay. Great. And just one more question. Given we're almost halfway through the first half of the year, when is the hypochondroplasia Phase III data expected?

We have a few months left for the...

First half. Understood.

So stay tuned, Joe.

Great. We will, for sure. Okay. Great. Well, congratulations on the recent Amicus acquisition. It seems like a perfect fit for BioMarin. I guess to start, you've highlighted that Galafold is currently available in around 40 countries and BioMarin operates in around 80. So I'm wondering beyond simple geographic expansion, how much of the projected accretion in '27 relies on just deeper country penetration versus other dynamics?

Yes. So we are really excited about being able to say more as soon as we close, and we'll give far more detail at that point in time. But I think it's important to address your question specifically, we really do believe that there's the opportunity for both country expansion, given that, as you said, Joe, they're currently in 40 countries, and we have a larger country footprint of 80. But we also know there's opportunity for a deeper penetration in the markets in which Galafold already exists.

And we say that because we know one of the biggest opportunities for Galafold and Fabry is really in and around diagnosis. And given that that's such a sweet spot for BioMarin to really be able to drive diagnosis of disease and then get those patients on therapy and have them stay adherent to said therapy, there's a big opportunity for both expansion into new countries and deeper penetration in the ones they're already in. And we're looking at those teams working diligently on and precisely what those plans will look like right now.

Gret. Yes. Thanks, Cristin. I'll just jump in, Joe, since you touched on accretion. I'll share that through these levers, again, subject to closing of the transaction, as we get deeper into the integration, we believe that there's opportunity to unlock even more value from Galafold and PomOp when we built our model to support the deal, of course, that's something that we have to have high confidence in to be able to make a share price bid and be confident in the value of the acquisition.

What I mean by that is higher confidence usually means some base level of measured conservatism as well. So through these expansion opportunities, we think that we're actually going to be able to unlock more value over time.

And Mike, in our comments at closing around accretion, which was, should we close the transaction in the second quarter of this year because we'll be incurring significant interest expense and just integrating the company, which comes with some cost, we think the transaction could be slightly dilutive in calendar '26, but accretive for its first 12 months and substantial accretion starting next year. And that's, again, based on that deal model. We'll say more upon closing, should, assuming we close.

Okay. Understood. Look forward to that. So Amicus on their own did a great job with Galafold and penetrated the amenable Fabry patients well. And it seemed like they were starting to get good traction with PomOp. And I'm just curious, at a high level, what kinds of operational does BioMarin bring to the table to take things to the next level for those kinds of products?

So I think very similar to what we just discussed with Galafold. I think that with PomOp, there's an even big opportunity. They're currently reimbursed in 15 countries and going back to the fact that we have a much larger country footprint, that's going to be an exciting opportunity out the gates.

But I think what's really important, specifically for PomOp is the continual publication of real-world evidence that demonstrates the value of PomOp relative to those patients who have come off another enzyme therapy and Amicus has done a great job at starting to generate and publish those data, and that is something that we will very much look to continue so that you can generate a faster switch for those patients who are progressing in their disease.

It seems like there's a nice opportunity for PomOp. It's just getting started. And that takes me to my next question. Manufacturing has been a skill set that we associate with BioMarin doing in a really high-quality manner, and PomOp is a challenging product to manufacture. What is your plan on that front? I think they currently manufactured in China. They had talked about doing second source manufacturing has BioMarin settled on the strategy for manufacturing that product.

Thanks, Joe. I'll take that one. Yes, that question unfortunately falls into the category of we need to closed the transaction to be able to say more. During this period of time, it's really important that the two companies continue to operate as two independent entities. And there's some integration planning that we can do ahead of closing, but that level of deep integration with respect to manufacturing strategy is something they'll -- we'll have to wait to talk about.

But the premise of your question is the right one which is that BioMarin is world-class manufacturing entity and we've got a great track record across our portfolio, both the commercial portfolio and the research and development portfolio of manufacturing globally and look forward to bringing that skill set to the Amicus asset.

Yes. Okay. That makes sense. Okay. So moving on, I guess we're looking forward to seeing the next data cut for BMN 351. And we have MDA going on now as we speak. Can you give us an update on what the next data cut will be for the first dose cohort and when we'll see data from the second dose cohort and what you hope to see there?

Yes. Thanks. So there's 3 doses, 6, 9 and 12 milligrams. So far, we've announced data from the 9-milligram dose at 26 weeks where we observed a mean dystrophin expression of 5%, so the key next data point will be watching the higher dose in the 12-milligram reach its next couple of milestones. But beyond dystrophin expression, we're also going to be looking at clinical benefits, which is really important in this community. We're doing both the North Star Ambulatory assessment, as well as forced vital capacity. So hopefully seeing a correlation between that dystrophin expression and the clinical benefits will be something else we're looking for.

And remind us of the threshold for you deciding to advance this program.

We're aiming for 10% dystrophin expression. But again, I would point to the clinical benefits that we're observing, and we'll look at the totality of the data to decide how to move forward.

Okay. Great. And let's touch on the Inozyme programs, given you have pivotal Phase III ENERGY-3 data expected also in the first half. Can you talk a little bit about what you hope to see on that front?

Yes. So we're, again, another program that we're very excited about and feeling very much that it fits right in the BioMarin sweet spot in rare disease, and that is really in being in a rare condition in ENPP1 deficiency where there is not otherwise a treatment.

So we're very excited to see the pediatric data here coming up soon. And what we've estimated, and you can imagine the data are quite a wide range. But we believe that the total addressable patient population to be in and around 2,000 to 2,500 patients worldwide. And so our job, again, will really be to ensure that we can find those patients, get them diagnosed and get them on treatment as quickly as possible.

Now as I said, this is just an estimate. As we found on the Naglazyme story back in the day was that you can estimate something. But then when there's a treatment available, it's amazing how much you learn about the condition and how many more patients and physicians are coming out to be -- are getting diagnosis because importantly, there is actually an option, which raises awareness. So we saw that quite a bit with the Naglazyme story. I don't know if you want to elucidate on that.

I will. Thanks, Cristin. It's -- this is a profound data point. I think, first of all, doing incidence, calculations in ultrarare disease as difficult as it is. But it is often the absence of a therapy that leaves these patients identified and once the therapy exists, with the improvement in diagnosis and disease awareness, you can really start to bring those patients in. You can look back at our 10-Ks on this. Naglazyme was approved approximately 20 years ago. And we used to cite global prevalence of the disease as 1,100 patients in existence. Here we are now 20 years later, we probably have almost 150% of that number actually on commercial there. So it's -- and again, this is what BioMarin does.

Still growing. Okay. Great. Well, maybe a couple of commercial -- more commercial questions to round out the discussion. I can't resist, but go back to Voxzogo. So can you discuss what underpins your assumption that Voxzogo revenues in the second half of this year are expected to be greater than the first half. Is that entirely due to OUS orders? I know there might be several moving parts because we might have the emergence of some competition. But can you just give us some insight into your crystal ball on that front?

Yes. Thanks, Joe. I'll take that one. So that timing, we shared on our Q4 '25 call that first of all, we'd see a similar lower first quarter as we did last year in 2025. And that for the full year, Voxzogo revenues would be weighted to both the back half generally and then even more specifically Q4. This is entirely order timing and largely international order timing.

75% roughly of Voxzogo's revenue is -- comes from outside the U.S. And most of those international customers are single national payer health care systems. So whether it be the way that their cash flows and budgeting works or their procurement model, we've observed this trend before where the purchasing patterns, again, across dozens of these countries just happens to be weighted to the second half of the year.

What's really important to note and we point to this across all of our portfolio when we experience some of the -- some of this quarter-to-quarter volatility on revenue is that we've continually to steadily add patients quarter after quarter -- we expect that to be the case here in 2026. And so it really is just the timing that drives that dynamic.

Okay. Great. Well, that's helpful. Thank you so much for the update today. We look forward to following more progress at BioMarin.

Thank you, Joe.

I appreciate your time. Thank you.

Good morning, and welcome once again to TD Cowen's 46th Annual Healthcare Conference. I'm Phil Nadeau, one of the biotech analysts here at Cowen, and it's my pleasure to do a fireside chat with BioMarin Pharmaceutical. We have with us today, Alexander Hardy, the President and CEO; and Brian Mueller, the Executive Vice President and CFO. Guys, maybe I'll kick it to you to begin. Could you give a brief state of the company overview, biggest strengths, biggest challenges? And what does BioMarin need to achieve to outperform over the next year or 2?

Excellent. Well, thanks very much. Thanks, everybody, for joining us. So I've been CEO of BioMarin for the last 2 years and started off with a kind of a strategic refresh, what's the strategy of the company. It was very clear to me that BD should play a significant role in the future of BioMarin, hadn't played much of a role beyond early BD up to that point because we've got some really clear competitive advantages of being a rare disease company operating at scale. So it's really cool to have done 2 M&A last year, buying Inozyme and then obviously, the acquisition of Amicus, which is on track to close in the second quarter of this year.

So we've got that together with the enzyme therapy business is going to drop right into those -- both of those acquisitions will drop right into our enzyme therapy business, which is already operating at scale in 80 countries around the world. And then our skeletal conditions business anchored by Voxzogo, but now with 333 coming. So we've got these pillars of multiple pillars of growth, multiple paths of growth, good clarity of continued top line growth, leverage to the bottom line over the next several -- over the -- yes, through the next decade.

And so that's really cool to see that all in place. It's obviously not reflected in the share price, but we're confident that the things we're doing are creating tremendous shareholder value. In terms of the challenges, obviously, entering now a period of competitive intensity. We've been preparing hard for this over the last 2 years. We've been taking advantage of every additional delay in terms of the launch time lines for our competitors, whether it's for the overall approval or for the infant population, which is a very important part of skeletal conditions, the incident population. We've used our time well, and we're now ready to compete. But this is this period. There's no doubt about that.

And I'm sure that's going to be part of what you're going to be talking to us about, Phil. I think also in '26, and maybe Brian, you can absolutely expand upon this is, obviously, we've made the strategic decision around Roctavian. So we don't have, albeit the unpredictable sales of that in 2026. And obviously, Kuvan generic continued generic erosion. So some of our nonbusiness unit nonstrategic income is -- provides a headwind, and that's obviously part of our guide for this year.

Yes. Maybe just what Alexander is referring to is our 2026 revenue guidance. It includes effectively a 3% headwind to our growth because of the decrease in some of this other revenue. There's the removal of our expectations for Roctavian revenue. There's continued decreasing Kuvan revenue. Kuvan has been generic in the U.S. for more than 5 years now. And then lower royalty revenues. We had a partnership agreement related to an out-license years ago, and it's now run through its period where BioMarin receives royalties. So that's a substantial number of more than 100,000 -- more than $100 million. When you adjust for that headwind, both of our business units are expected to grow at the midpoints of high single digits. enzyme therapies at 7% growth at the midpoint and skeletal conditions through competition, as Alexander mentioned, at 8% at the midpoint.

Maybe while we're on guidance, what are the key risks to the guidance? What could cause performance to fall short in 2026? And then similarly, what could drive outperformance? If you were to beat the guidance, why would that be?

Yes. Thanks. It's a great question, Phil. So I mentioned just in terms of framing of the guidance, there's first that other revenue kind of downward adjustment headwind. But within the guidance itself, when we guide, we try to be measured. We have a plan. We monitor all of the material swing factors within our guidance, and then that's how we develop a range. So on enzyme therapies, I think there's a couple of underlying drivers. One, by the way, is just execution. It's early March and a long way to go in this year, and it's more than a $2 billion business now. So there's just some level of estimation.

And as you know, Phil, there's an element of our business, which is order timing. A lot of our customers and payers are single national health care system payers, and they can tend to order variably over the course of the year. So depending on how those orders stack up in a particular quarter or do not, we get some order timing. So I think that's a risk especially with the events over the last couple of weeks, we continue to monitor for geopolitical risk instability, global economic risk, again, take some of that in control.

But obviously, as events unfold, we're watching that closely. So that's enzyme therapies. In skeletal conditions, there's probably beyond the comments that I made, which apply to both enzyme therapies and skeletal conditions. The 2 key variables, I think, within the guidance for skeletal conditions are the ultimate impact of this competition. The competitor was approved by the FDA on Friday. We're ready to compete. We think we will compete. We believe that any switching of our Voxzogo patients will take time and be difficult. But to the extent there are more or earlier switches, we try to account for that. It's in the lower end of our guidance. And to the extent we do better, that would be the higher end of the guidance.

To be clear, in all points in our Voxzogo revenue guide, we do assume competition. So to the last part of your question, how can we overperform? I think it's going to be continuing to grow in the under 2 population where we are the only approved therapy, continue to expand our outside of the U.S. revenues. Only 25% of Voxzogo's revenues are in the U.S. So while this competition narrative gets a lot of attention, it's actually a small part of our business. in that 75% outside of the U.S. revenue, we are both penetrating existing markets more deeply, and some of these are large markets, and we're still expanding into new markets, launching into new countries. So to the extent we do better there, that would be an outperformance.

And the guidance also assumes a 40% operating margin this year, which is an increase year-over-year, excluding the impact of Amicus. Is that achievable? How are you increasing operating margin during 2026?

Yes. Thanks. We believe it's absolutely achievable subject to the Amicus slight dilution. We've been on this mission over the last 2 years. As Alexander mentioned in his opening remarks, -- the strategic review completed in 2024, not only refreshed and refined the overall corporate strategy, but our financial growth strategy. So we identified that $0.5 billion cost transformation program. That is complete. We're still realizing part of it this year, but it's been implemented.

We've constrained overall operating expense growth at the right levels to where we can balance investing in the business, but also cost control. If you look at our performance over the last couple of years, we've got consistent leverage growth where profitability is growing at a 2, 2.5, sometimes 3x rate of revenue growth, which is pretty healthy. We've gotten the revenue growth, I think, very clear and in line. You see that over the last year and in this year's guidance. So that revenue growth, cost under control, that gives us that margin and really healthy growth in EPS as well.

There's some debate as to what Amicus is going to do to your numbers this year. You referenced on the earnings call that there's kind of a wide range of estimates out there. We have put Amicus into our model for the second half of the year, and we have 2026 total revenue of $3.7 billion and non-GAAP EPS of [ $4.80 ], so modestly dilutive in 2026. I know you're going to update your guidance later, but just generally, does that sound reasonable?

Yes. Thanks, Phil. So yes, so we will give an updated view on 2026. All the numbers that I mentioned were excluding Amicus. And we expect to close in the second quarter. And with the sizable business that Amicus would bring subject to closing, whether it's earlier in Q2 or towards the end of Q2 could be a swing factor. But I like the way you framed it, kind of simplified it and just took second half of the year for discussion purposes here today. And this isn't guidance, but that's not unreasonable, the [ $3.7 billion ].

In earnings per share, again, we'll wait until we update the guidance to quantify that. We did share that we expect the Amicus acquisition to be slightly dilutive in calendar '26, but accretive for the first 12 months and then substantial accretion beginning next year in '27. So that's a dynamic that will be clear. We did announce as part of the Q4 earnings that there is $0.25 of loss per share related to pre-closing costs on the Amicus acquisition. We raised our debt. We're starting to incur some interest expense. There's some other transaction fees that we incurred before closing. So that's some of that headwind. but we'll talk more about.

And if I could just jump in here, little bit. I mean, this is focused very much on the short term, the '26. But the benefits of the Amicus acquisition, again, we plan to really elucidate more on this post close. As I already said in my first comments, we believe very strong hypothesis that these assets are worth more in our hands, these medicines. We'll be able to reach more patients in more geographies around the world. And therefore, during the announcement, we said we feel comfortable with their estimates for the deal of $1 billion peak for each of the assets. We believe that we'll be able to do better.

And so we'll explain what we expect and how we're going to do that. I mean the very simple math, and it's a lot more than this, is that they were in 50 countries, we're in 80 countries. It's very simplistic because we're much deeper in many of those countries. These are where the prevalent population is outside the United States and outside Europe. This is what we've built over 30 years at BioMarin. And then there's obviously the earnings leverage on top. So both of these 2 are going to be -- you're not going to see much of it in the short term. But over the next 5 to 10 years, this is going to be very, very significant and very exciting is what we believe, and we're going to share more about that.

I'm sure you're not going to comment on what I'm about to say, but when we put Amicus into our model in the late part of this decade, we had about $3 of EPS accretion. So EPS went from $7 to $10. So massive accretion. Like I said, I don't think you're going...

If I'm not commenting on '26 EPS with the transaction, I'm definitely not coming.

Before we dive into the programs in a bit more detail, just in terms of business development, Alexander, as you mentioned, you did Inozyme and Amicus last year. Where are you in your business development strategy today? Do you have more capacity to do additional deals? Or do you think for now, you're relatively full?

We're -- the BD team, again, we believe that business development is a very important part of our strategy going forward. So the BD team is right back at work. Our primary focus is further strengthening our pipeline. Obviously, we need to delever from the Amicus acquisition to do anything very significant. But given the economics that we've just been touching upon, we expect to be able to delever very rapidly. So in the meantime, you can expect us to continue to do sort of early pipeline deals, very traditional biotech business development. But in the course of time, we're really convicted that, again, BioMarin in its position as leading at-scale biotech company focused on rare diseases, there's a significant value creation opportunity for us. So watch for us to be -- continue to be active.

Turning to Voxzogo, perhaps the biggest investor debate. Brian, began to discuss the competition and the impact on the franchise. Could you go into a bit more detail, how do you consider Voxzogo's competitive position today? What is the approval of TransCon mean in the short term? And then longer term, how is the competitive environment going to play out?

Yes. Well, I'm excited about this moment. We've been preparing it for this for the last couple of years. We've been taking advantage of the delays to further prepare. We've been quite quiet about the specific competitive strategies, the very obvious one, which is the ex U.S. footprint, that's been very, very clear. We're obviously going to continue to grow significantly in the 75% of our revenue, which is outside the United States. We're still expanding, as Brian already said, in large underpenetrated countries, and we're also launching in new countries. So that is one aspect of why we're going to continue to grow through competition, we believe. But we also have the 0 to 2 indication, which we will be the only one that has that for several years.

Not surprisingly, the TransCon CNP label was for 2 and above. So we are the only drug approved for 0 to 2 population. That in achondroplasia, that is where the guidelines say you should diagnose and initiate is as early as possible. And the majority of our patient starts are in that 0 to 2 population. So essentially, our competition is coming in with a drug that looks short term, similar efficacy, similar safety with a convenience advantage. The dynamics of a switch market, which they face is a very complicated one. What's most important to caregivers and to physicians is long-term durability and safety.

We have lots of evidence for Voxzogo for that. It's a complicated decision to switch. which is between the physician and the caregiver. And we think that this is going to be a dynamic that will play out over time. This will not be a rapid switching market because again, 90% of patients on Voxzogo are adherent. They manage the injections. They're part of the family's daily routine. Patients do very well on Voxzogo. And this convenience aspect is well down the list of what's most important to both caregivers and physicians. And all of our market research reinforces that the switching dynamic will be a complicated one and a long conversation between caregivers and physicians and a lot of different dynamics.

There's a big burden on the physician's office and on the caregiver to go through that whole switch dynamic. to going through the payer coverage to the training. It's a burden on the physician practice. This is not going to be something our research shows that the physician is going to drive. Again, it's going to be a dialogue. Some patients will switch, and we have taken a conservative approach in our guidance with regard to that. And now we're ready to compete and looking forward to this playing out. I think part of our knowledge from this is our relationship built over 5 years. We have a 5-year head start. We have, for example, again, this is the sort of detail that I was not going to share until the point of approval. We have an outstanding clinical coordinator team.

These are nurses -- these are BioMarin employees who train the family on the injection process and then stay in continued contact with the child and the family as the child grows up. So as investors, what you should be thinking about here is that we have a relationship and eyes on every single patient in the United States with achondroplasia. We have a very strong relationship and a really good understanding of what's most important to those patients and a relationship. And again, we've been preparing for this, and we're ready to compete.

Can you remind us of the status of the case in front of the ITC?

Yes. This is about to be heard. So they went through the Markman hearings with regard to what the basis of the court case would be. That happened just recently. And now it's in April that the judge will start hearing the case expecting a preliminary decision in the August time frame.

Competition isn't the only thing going on with Voxzogo this year. You do have the hypochondroplasia trial reading out. Can you remind us of the design of that study? And what are BioMarin's expectations for the results?

Yes. So hypochondroplasia, we're very excited about that study. I mean it's -- as a rare disease company, anytime you potentially bringing a first-in-disease treatment, this is what we're really about. This will be our seventh first-in-disease treatment. So a cause for celebration and pride. And the treatment community is really looking forward to this. Again, there's no targeted treatment option right now for these patients. With regard to the study design, we designed it and powered it based on a 1.5 centimeter annualized growth velocity, which is the same as we saw in achondroplasia.

In the -- what is called the [ Dauber data ], we call it the Dauber data, Andrew Dauber from National Children's Hospital. He did the proof-of-concept study. He saw a 1.8 centimeter annualized growth velocity in hypochondroplasia. So we powered at 1.5. We think there's good reason to believe that we can actually achieve, and there's good scientific reasons with this, actually, based on the differences between achondroplasia and hypochondroplasia that actually do suggest that you're probably going to get better growth velocity.

So we're quietly confident. We want to see that card turnover. We see excitement from the treatment community. The work that we're doing right now in the prelaunch, pre-promotional phase is shortening the diagnostic journey. These unlike achondroplasia, these patients are diagnosed later in childhood. Obviously, just like achondroplasia, the later the start, the less the benefits in terms of long-term outcomes. So we want to start to really increase the diagnosis rate and shorten the pathway to a specialist, and that's the work we're doing right now whilst we wait for the Phase III results.

How large is the diagnosed patient population today? And how rapidly would a drug like Voxzogo be taken up by the community?

Yes. We talk about a total addressable global population of about 14,000 patients. So the genetic prevalence is very similar to achondroplasia, about 24,000, but we reduce it down because of that diagnosis rate isn't as high. And these patients are there. In many cases, they're sitting outside the skeletal dysplasia clinics because there's no approved treatment. So this is -- again, this is the story of rare diseases. Once there's an approved treatment option, we expect that many patients will be reaching out to a specialist, and that's the work that we need to do.

Maybe one more on this franchise. BMN 333, you released promising data last year. It's moving into a pivotal study. Can you discuss the design of the pivotal and what you think 333 could do for the franchise.

Yes. We're -- this is another reason why we're confident with regard to Voxzogo's profile, its durability of its profile, its benefits with the evidence that we've got of its benefits beyond height and the geographic footprint. These are the reasons why Voxzogo is going to continue to grow through this next several years. And then we have 333 coming. And this was the exciting thing for us to see with the data from BridgeBio that we didn't see a similar AGV result as the Phase II. The Phase III annualized growth velocity looks very similar to Voxzogo. So the lane is still open for superior efficacy.

And that is our goal with 333 is not only to offer the convenience benefit of weekly but also superior efficacy than the gold standard Voxzogo and better than anything else that's in clinical development. The PK data that you mentioned, we were very excited about this. I mean it's PK data, so it's in healthy human volunteers. But we were aiming our threshold to move ahead with 333 was to achieve 2 to 3x the level of free CNP that our other -- the other long-acting CNP had shown, 2 to 3x in that PK study, the highest dose cohort, we had 3 dose cohorts that exceeded that 2 to 3x. And the highest dose actually had a 13x the level of free CNP. We believe, and we have reasons to do this, reasons to believe this, that there's a strong predictive that high free CNP sustained over a period of time will translate to higher efficacy.

We now need to show that in patients with achondroplasia, and that is the work that we're going to do in this Phase II, Phase III operationally seamless design study. So we're taking the 3 cohorts that exceeded that 2 to 3x into that Phase II. We'll then choose the best dose to take the single dose into that Phase III study, and it will be head-to-head versus Voxzogo. We have said that we're aiming for 2.25 centimeters of annualized growth velocity. So this is approximately 50% better than Voxzogo. That is the floor. The target product profile, as you can imagine, is not the same as that, but that's how the study is powered.

During the first half of this year, you will get pivotal data from BMN 401, which you acquired through Inozyme. Can you remind us of the design of that study and what BioMarin's expectations are for the data?

Yes. So I mean, this is -- it's exciting. Again, this will be another -- this is another first -- so this year, 2 Phase III readouts, potential first-in-disease treatment. So this is definitely worth highlighting that there are no treatment options for ENPP1 right now. So this first Phase III is in a pediatric population. The design of the study is a co-primary endpoint of phosphate levels together with Radiographic endpoint, a functional endpoint, which is a radiographic scan. And this is what we'll see reading out, and we're expecting that readout in the first half of this year.

How does BioMarin size the market and the market opportunity?

Yes. We've been -- again, this is always challenging to do when you've got a first-in-disease treatment. There's no treatment options. We end up -- in most cases, it ends up being more patients, but we want to be on the conservative side. We're saying around 2,000 to 2,500 patient potential for this. Important to note that around 70% of the patient potential is in the adult population.

So based on these results in this pediatric population, we will then design the Phase III in the adult population. So this would then be potentially an indication would be approved in the early 2030s and then part of that continued sustained revenue growth that we plan for BioMarin. So there's a lot more to come, a lot more indications to come with the NPP1. We're not just in the interest of time, we won't get into ABBC6, but there are other indications and other interesting possibilities with that.

Palynziq's label was expanded this weekend. What impact will that have on revenue growth?

Yes. We're excited. I mean, even before this adolescent indication, Palynziq last year grew by 22% -- so in our very successful high single-digit growing enzyme therapies, this is an asset that probably gets -- doesn't get the attention that it really deserves. And this will then add on top of that growth potential. Why is the adolescent population so important?

Well, whilst numerically, it represents about a 10% increase in the total addressable population, that significantly understates its potential. We, with Palynziq, have been seeking to treat the adult population. And in PKU, this is the hardest population to reach and to get on treatment. As many of these patients are lost to follow-up, not under the care of a specialist, whereas in the adolescent population, they're still under the care of a specialist. They're under the roof of their parents who may or may not have some degree of control over an adolescent.

And they're motivated by the fact that they're going through a stage in life where they're about to go off to work, independents, college, et cetera. And so everybody is really motivated to try and get their Phe levels under control and to them to have the possibility of a life which is less limited by PKU. And here, I'm alluding to a very important aspect of an unrestricted diet. So I think you've got a really worthy treatment goal. You've got a drug which clearly works and you've got conditions which I think, again, specialists, adult, I think we're going to see a higher penetration in this population, and it will be a significant contributor to Palynziq's growth.

Great. With that, I think we're out of time. Thanks for making the trip to Boston for the conference.

Thank you for standing by. My name is Kate, and I will be your conference operator today. At this time, I would like to welcome everyone to the BioMarin Pharmaceutical Fourth Quarter and Full Year 2025 Conference Call. [Operator Instructions]

I would now like to turn the call over to Traci McCarty, Head of Investor Relations. Please go ahead.

Thank you, operator. And starting on Slide 2. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, such as 10-Q, 10-K and 8-K reports.

In addition, we will use non-GAAP financial measures as defined in Regulation G during the call today. These non-GAAP measures should not be considered in isolation from, as substitutes for or superior to financial measures prepared in accordance with U.S. GAAP, and you can find the related reconciliations to U.S. GAAP in the earnings release and earnings presentation, both of which are now available in the Investor Relations section of our website. Please note that our commentary on today's call will focus on non-GAAP financial measures unless otherwise indicated.

Moving to Slide 3 and introducing BioMarin's management team joining today's call, Alexander Hardy, Chief Executive Officer; Brian Mueller, Chief Financial Officer; Cristin Hubbard, Chief Commercial Officer; and Greg Friberg, Chief R&D Officer.

I will now turn the call over to BioMarin's CEO, Alexander Hardy.

Thank you, Traci. And moving now to Slide 5. Thank you all for joining us today to discuss BioMarin's fourth quarter and full year 2025 results as well as our outlook for 2026, which will be an exciting year. We are particularly proud to have accomplished our strategic goals for 2025, while achieving outstanding growth. In 2025, total revenues grew by 13% to a record $3.22 billion for the year and operational excellence led to strong profitability and increasing cash flow. This result was fueled by a 9% increase in enzyme therapies revenue and a remarkable 26% rise in Voxzogo revenues. Importantly, enzyme therapies revenue has grown at a 9% CAGR over the last 5 years, demonstrating the durability and reach of this $2 billion-plus franchise across our 80-country footprint. With Voxzogo, now in its fifth year on the global market, we're very pleased with the consistent strong growth already achieved and have deep conviction in our ability to continue expanding should another product be approved.

BioMarin's 2025 performance and 2026 outlook highlight both our deep global capabilities and the vital importance of our targeted therapies to patients we serve. Building on the strong foundation in 2026, we will expand our therapeutic and commercial reach with the addition of assets from two significant acquisitions announced last year. The first, Inozyme, strengthened our enzyme therapies portfolio with the addition of BMN 401 for ENPP1 deficiency. This is a condition for which there is no approved targeted therapy. So we're really pleased about the possibility of launching what could be our sixth first-in-disease enzyme therapy should pivotal data be supportive. We look forward to sharing that update in the coming months and to filing submissions soon thereafter. Our second acquisition, Amicus, potentially adds both Galafold for the treatment of Fabry disease, and pombility and folder for Pompe disease to our commercial portfolio and is expected to close next quarter. This transaction presents a particularly compelling opportunity that further build on Amicus' success by leveraging our scale and global capabilities to serve even greater numbers of patients. In addition to the expansion of BioMarin's portfolio from acquisitions, we're particularly excited to build upon at Voxzogo's leadership in achondroplasia with a potential addition for treatment of hypochondroplasia. Because CNP is the master regulator of bone growth, and supported by the 1-year results from the investigator-sponsored study, we are excited to see and share the upcoming pivotal results with Voxzogo for the treatment of hypochondroplasia in the coming months. We look forward to the possibility of adding hypochondroplasia to our global skeletal conditions treatment offerings by early next year.

On top of Voxzogo indication expansion, based on the very encouraging PK data recently shared, we're preparing to begin enrollment in our Phase II/III study of BMN 333. We believe this next-generation, long-acting CNP therapy has the potential to set a new standard of care and to demonstrate superiority compared to any candidates under development for achondroplasia. Those are just a few of the anticipated pipeline highlights expected this year so you can understand our enthusiasm for what's ahead in the coming months.

Turning to innovation. During the period where we are delevering the financing associated with the announced acquisition of Amicus, we will remain actively engaged in business development activities targeting pipeline assets. This is an important component of a larger pipeline expansion plan, a plan that both accelerates our financial performance and further diversifies our portfolio to drive durable long-term growth.

In closing, we are pleased that the transformational work implemented over the last 24 months has already delivered significant results and positions us for even more revenue growth, profitability and pipeline expansion. Prior to any contributions from the Amicus assets, this year, we anticipate BioMarin's enzyme therapies will deliver high single-digit growth and Voxzogo will continue along its trajectory towards blockbuster status. Following the completion of the transaction, we anticipate that integrating Galafold and Pombiliti and Opfolda will enable both medicines to reach more people around the world living with Fabry and Pompe, significantly enhancing our 2026 outlook and enabling accelerated revenue growth through the 2030s.

With that, I will turn the call over to Brian provide additional financial updates. Brian?

Thank you, Alexander. Please refer to today's press release for detailed fourth quarter 2025 results, including reconciliations of GAAP to non-GAAP financial measures. All 2025 results will be available in our upcoming Form 10-K, which we expect to file in the coming days. Starting on Slide 7. Our fourth quarter results reflect strong global demand, with total revenues of $875 million, representing 17% year-over-year growth. This strong performance was broad-based across our portfolio with Voxzogo delivering 31% year-over-year growth and enzyme therapies achieving 13% year-over-year growth in the fourth quarter. Palynziq revenue increased 25% in Q4, marking its fourth consecutive quarter of 20% or higher year-over-year revenue growth. For the full year, Voxzogo revenue increased 26% over 2024, totaling $927 million and underscoring the strong global expansion since its launch over four years ago. For the full year 2025, approximately 73% or nearly $680 million of the $927 million of total Voxzogo revenue was generated outside of the United States, reflecting BioMarin's differentiated global reach and infrastructure, deep rare disease expertise and ability to execute at scale.

Full year 2025 enzyme therapy revenue increased 9% year-over-year, led by 22% growth for Palynziq and 7% growth for Vimizim underscoring the durability and strong demand for these established brands. As expected, Q4 revenue benefited from the timing of large orders in both Voxzogo and enzyme therapies. In Q4, we recognized revenue from an approximately $30 million contracted government order for Voxzogo, the magnitude of which we do not expect to repeat in Q1 2026. Additionally, in Q4, we saw stocking levels increase in the U.S. and select global markets for Voxzogo, Palynziq and Vimizim.

Now moving to Slide 8. As an update on our plan to divest Roctavian, we recently made the strategic decision to withdraw it from the market. As a result, during the fourth quarter, we recorded approximately $240 million in special items on a GAAP basis. Approximately half of that amount relates to an inventory write-off that does not get adjusted out of non-GAAP income. BioMarin reported $3.15 of full year 2025 non-GAAP diluted earnings per share. And looking past the 2025 IPR&D and Roctavian charges, included in non-GAAP income, our underlying business earnings per share grew by approximately 34%. This performance contributed to $828 million in full year 2025 operating cash flow, a 45% increase versus full year 2024, further demonstrating the strength of our operating model and providing meaningful capital to reinvest in innovation.

We are pleased to see the operational transformation implemented over the last 24 months drive this level of profitability. Together with our revenue growth plans, BioMarin is positioned to sustainably grow profitability and cash flow while still investing in the business. As we prepare to close the Amicus acquisition, we were pleased to secure approximately $3.7 billion of debt financing consistent with the strategy that we shared upon announcement of the transaction. Confidence in the strength of BioMarin's business and financial outlook supported a positive credit ratings outcome and helps drive demand for all components of the capital raise, which enabled favorable pricing across the capital structure.

Now moving to Slide 9. Looking ahead to 2026, we are providing initial guidance that reflects BioMarin's growth expectations, excluding any post-close contributions from the announced acquisition of Amicus. Please note that currently available BioMarin consensus estimates include a combination of revenue estimates, some that include Galafold and Pombiliti and Opfolda revenues and some that do not. We plan to provide updated guidance on the combined business following the close of the acquisition expected in the second quarter of 2026, and we request that you wait for those details prior to updating BioMarin's models with the post-close Amicus contributions.

Turning to 2026 guidance items. We expect enzyme therapies revenue of between $2.225 billion to $2.275 billion, and Voxzogo revenue of $975 million to $1.025 billion. We expect continued high patient demand across both the enzyme therapies and Voxzogo in 2026, resulting in high single-digit growth rates of both business units at the midpoint. Outside of enzyme therapies in Voxzogo, we are expecting significantly lower royalty KUVAN and Roctavian revenue in 2026, which affects year-over-year comparisons of total revenue. We estimate those revenues to be between $100 million and $125 million in 2026, representing a 3% headwind to total revenue growth when compared to 2025.

Taken together, we anticipate 2026 total revenues in the range of $3.325 billion to $3.425 billion Again, this excludes any contributions from the Amicus products. And while we will wait for the acquisition to close to provide more details on 2026 revenues for the combined business, we are expecting a meaningful uplift to our 2026 total revenue growth rate once the transaction closes. We anticipate 2026 non-GAAP diluted earnings per share in the range of $4.95 to $5.15. Please note that our guidance reflects approximately $0.25 per share of preclose integration preparation costs and interest expense related to the Amicus transaction.

On non-GAAP operating margin, our underlying organic operating margin expectation without the Amicus transaction is approximately 40% for 2026, consistent with our previously communicated target. In the announcement of the Amicus transaction, we shared that we expect the Amicus acquisition to be modestly dilutive in 2026, which we expect to be a slight headwind to operating margin that could drive it slightly below 40% for the year. Aside from the impact of the Amicus transaction, we recognize that over the last two years, BioMarin has been able to solidify its revenue growth potential and transform its cost structure to realize the potential of a strong operating margin profile well into the future.

I will also comment briefly on quarterly dynamics in 2026. Coming off our strongest revenue quarter on record, we expect similar trends in 2026 as those observed in 2025. For example, we expect the first quarter of this year to be the lowest total revenue quarter of 2026, with both total revenues and Voxzogo revenue expected to be on par with Q1 2025. Q1 non-GAAP diluted earnings per share will have the additional impact of the vast majority of the pre-close Amicus cost just described, resulting in it being our lowest anticipated EPS quarter for 2026. For both Voxzogo and enzyme therapies, we anticipate large international order timing to contribute to higher revenue in the second half of 2026 compared to the first half and weighted to Q4, similar to the 2025 dynamic.

Our underlying business has consistently produced profitability growth that has outpaced top line growth, and today's guidance reflects our commitment to continue to grow the business operational efficiency and prioritized reinvestment and innovation.

Thank you for your attention, and I will now turn it over to Cristin for a commercial update. Cristin?

Thank you, Brian. I'll open by highlighting the outstanding work of our teams around the world. Their focus and deep expertise have been instrumental in driving another year of impressive commercial performance. Now moving to Slide 11, starting with enzyme therapies. In 2025, enzyme therapies delivered year-over-year revenue growth across every product in the portfolio, leading to 9% growth, driven by new patient starts across all products and consistently strong therapy-adherence rate. With 22% year-over-year revenue growth, Palynziq, again, outperformed expectations. As the only approved enzyme replacement therapy for PKU, Palynziq stands alone in its ability to enable people with PKU to reach physiologic fee levels while reducing dietary restrictions regardless of severity.

The performance further highlights our leadership in the PKU market having established invaluable partnerships with our stakeholders during almost 20 years treating people living with PKU. In 2026, Palynziq is expected to remain the primary growth driver in today's enzyme therapies portfolio, supported by the anticipated adolescent-label expansion with the U.S. PDUFA target action date of February 28 and an anticipated European approval later this year. Excitement is building among the treating physicians and families around the value proposition that Palynziq represents to the adolescent PKU community. This label expansion will enable young people with PKU to start treatment while living at home, supported by caregivers and under the guidance of their health care providers.

Adolescence is a pivotal time where dietary therapy typically starts to become unsustainable for those living with PKU, which can result in rising blood fee levels. The opportunity for adolescents to use Palynziq may provide dramatic fee lowering, the ability to eat more like their peers for social inclusion and ultimately, a better setup for them to enjoy an independent successful life.

Now turning to Slide 12. Voxzogo continued to be a standout growth driver, delivering 26% year-over-year growth in 2025. It's particularly gratifying to know that well over 5,000 children with achondroplasia worldwide were being treated with Voxzogo at the end of 2025. Now going forward, with Voxzogo its fifth year of commercialization, our growth strategy is focused on a multipronged approach. First and foremost, we are driving new starts globally across all ages with a particular emphasis in children under a few years of age, an age group where we do not expect another approved product for the next several years.

Next, in highly penetrated countries, which have become incident markets, our priority is to continue to find and start treatment-eligible infants going forward. In addition, we see meaningful opportunity to more deeply penetrate larger countries where we already have established commercial presence and large growth potential remains. And finally, we are expanding uptake in fast-growing newly launched markets where significant pools of eligible patients exist and streamlined care pathways are enabling access.

To provide more context on the results that these strategies are producing, I'll share a couple of recent examples illustrating BioMarin's deep global capabilities, commercial scale and more than 20-year track record serving patients around the world. In a recently launched country in the Asia Pacific region, Voxzogo reached approximately 40% penetration within seven months of launch. This success stemmed from early non-promotional prelaunch activities and strong relationship building with clinicians.

We ensure that there was a focus on patient identification beforehand and strong support for each patient's experience throughout the journey. In another example, in a midsized European country, Voxzogo achieved approximately 70% penetration within 12 months of launch. This was driven by early non-promotional engagement with clinicians and patient advocacy groups to build strong relationships with local stakeholders and drive momentum and awareness of Voxzogo. We tailor our approach to meet the needs of the patients and the respective country's ecosystem. We will build on these successes to drive deeper penetration in existing markets and to prepare for new country launches in 2026. These strategies are crucial to our growth outlook with Voxzogo since roughly 75% of total revenues are generated from countries outside of the United States.

In the United States, we are driving increased penetration across all age groups, supported by investments in data, digital and field force. We're seeing particularly strong momentum in the under 2-year age group, reflecting international guidelines for achondroplasia, recommending early diagnosis and treatment with Voxzogo as soon as possible and long-term data supporting its safety and efficacy from infancy. Approximately half of the new starts in the fourth quarter were children under age 2. Since we believe Voxzogo will be the only approved therapy in this age segment for the next several years, driving new patient starts in children under 2 is a key pillar of our growth strategy. With the potential full approval of Voxzogo on the horizon, we believe families and caregivers will have even greater confidence in Voxzogo's established safety and efficacy profile when considering treatment for their infants and children with achondroplasia.

In conclusion, I'm incredibly proud of what our teams have accomplished and energized by the opportunities ahead. I will now hand it over to Greg for an R&D update.

Thank you, Cristin. We have a very busy year ahead for R&D with multiple meaningful milestones. Moving to Slide 14. As Cristin mentioned, we are preparing to submit the full approval package for Voxzogo and achondroplasia. This submission will allow us to present a comprehensive story around final adult height as well as a broader health and wellness outcome data set. We have collected over 10,000 patient years of safety data, including data for some children who have been on Voxzogo treat for more than 10 years underscoring the value of Voxzogo across all age groups, including meaningful impacts on quality of life and anatomic outcomes. In addition to linear growth, Voxzogo's broad evidence package demonstrates the treatment's impact on key complications associated with achondroplasia, including foramen magnum stenosis and symptomatic spinal stenosis as well as improvements in body proportionality, arm span and leg deformities like genua varum and tibial bowing. These extensive data also show clear functional benefits with improvements in measures of mobility, gate and quality of life. Together, these findings support our plans to submit the full approval package to the FDA and to continue sharing additional data through peer-reviewed publications and scientific forums later this year.

Now moving to Slide 15. BMN 333 is our long-acting CNP therapy for achondroplasia. We previously shared our plan to initiate a combined Phase II/III study in the first half of this year. Today, we're pleased to share more details on the Phase III study design and powering assumptions. The Phase III portion of the study will enroll 60 patients into each arm and will have 90% power to detect a 50% increase in annualized growth velocity versus Voxzogo. This translates into a growth increase of 2.25 centimeters per year over placebo, an effect size that would represent a clear best-in-disease effect. This represents a floor, not a ceiling. We also anticipate that this would translate into greater benefits and other measures of health and wellness for achondroplasia, including portionality, and health-related quality of life. Our goal is to establish BMN 333 as the new standard of care for achondroplasia and potentially for other skeletal conditions.

Now turning to Slide 16. We have several additional exciting highlights expected across the pipeline in 2026. To note a few, we anticipate Phase III data readouts for Voxzogo in hypochondroplasia and for BMN 401 in ENPP1 deficiency, both serving as key steps towards potential approvals as the first genetically targeted therapies for each of their indications. We are approaching the U.S. sBLA action date for Palynziq for the treatment of adolescents with PKU. Given the unique clinical benefits of Palynziq, we believe families with teenagers seeking treatment will be particularly interested in a therapy that can deliver potent fee reduction as well as the potential to enjoy an unrestricted diet. Our PDUFA action date is February 28, and and we look forward to sharing that outcome when it becomes available.

Finally, BMN 351 for Duchenne muscular dystrophy demonstrated 5% mean absolute dystrophin expression at week 25 and in the 9-milligram per kilogram cohort, a level that translates to a predicted 10% absolute level at steady state. We are currently enrolling in a 12-milligram per kilogram cohort and plan to share those results in the second half of the year. Full results for the 6- and the 9-milligram per kilogram cohort will be presented in an oral presentation at the Muscular Dystrophy Association meeting in March.

In summary, 2026 will be an important year of many data readouts clinical advancements and regulatory activities across our R&D portfolio. We'd like to thank all of the patients, families and caregivers whose dedication and support enabled the advancement of these programs.

Thank you for your attention today. We will now open the call to your questions. Operator?

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[Operator Instructions] Your first question comes from the line of Mohit Bansal with Wells Fargo.

Congrats on all the progress. Just -- one point just -- and the dynamic in the achondroplasia market now that we have data for the oral medicine also out there, so how do you see this market evolving with the availability of weekly as well as oral at some point? And then the last part of the question is basically, if you do deliver 2.25 centimeters or above growth velocity, above or -- and/or placebo with BMN 333. Do you think injections could be the first-line therapy there before oral dose?

Thank you, Mohit. This is Greg Friberg. I think I'll take the first half of your question, and then I'll hand it off to Cristin. With regard to the recently released data for the FGFR3 inhibitor, our take there, of course, was that this was generally comparable to other CNP class effects at 1 year. Of course, this is 1-year data. We'll need to see both durability as well as safety data over time. And the read through, of course, in terms of how we believe Voxzogo can deliver value here is that Voxzogo not just having one year of data has a tremendous amount of supporting evidence behind it. We talk about the 10,000 patient years of safety. We also, of course, have a deep a wealth of information with regard to evidence beyond height, whether it's foramen magnum, physical function, tibial bowing, quality of life, all of this data, again, creates a real confidence that, that data is something that patients can rely on. With regard to 333 and the effect size, we've dated again what the powering assumptions would be, and we do believe that the 2.25 centimeters of growth not only are differentiating on a clinical level, but we have some preliminary market research that suggests as well that, that would be important. It's important not to get too caught up in the growth being the outcome that we care most about because the growth is a surrogate for the health and wellness of these patients. Again, going back to Voxzogo, we do believe that, that that increase in growth would, in all likelihood, again, lead to a best-in-disease profile to patients, payers and physicians with value. So with regard to the market dynamics, I'm going to hand it off to Cristin.

Yes. Thank you so much, Greg, and thank you so much, Mohit. I do think -- and as we've said before, I think having more options is certainly important for patients. So we're going to see how that continues to play out. But I think Greg has done a nice job articulating what we've seen in the recent data releases. But what I do think is really important is to understand kind of where Voxzogo plays in this dynamic and in this landscape. First and foremost, it's really important and the data continue to show as do the international guidelines that treating early is the most important thing you can do for patients. And that is something that we really have been able to generate, not only does our label allow us to do that, but importantly, the evidence that we continue to generate supports this that treating early will provide the longest-term benefit, and we have that in 1,000 patient years across all these groups actually in the pediatric space. So I think that's a really important component. The other piece is going to be the switching dynamic or patients that are doing really well going to switch over to another therapy. And what we see and what we hear in our market research and what we have in our field interactions is actually a fair amount of reticence, the large majority of what we're hearing in the marketplace and in our market research is that for patients that are doing well on Voxzogo. There's not going to be a huge incentive to switch right away, especially because the long-term data for safety and efficacy hasn't yet played out for the other products, and that's really important. We've learned that HCPs and KOLs alike are not going to be the drivers of switch, they will provide the data that is out there, but they are going to be the ones that they will be the patients and the caregivers who are actually driving the switch. So this is where that long-term safety and efficacy data really comes through, and I think that, that is going to play out as we see this dynamic continue.

Your next question comes from the line of Chris Raymond with Raymond James.

I'm hearing you guys on the switcher dynamic and the comment that if patients are doing well, there will be a limited motivation to switch, but we were kind of surprised to learn one of your competitors is anticipating about half of their patients in their early achondroplasia trials will be Voxzogo experienced. And I think their commentary is that there actually is a decent amount of parents and patients out there that are interested in switching to something. Just talk about what you're seeing more broadly. Is there a demographic or some attribute other than just performance that might drive this decision or desire to switch? And then if I can maybe ask a question on I'm kind of struck by this drug is mentioned in your commentary, but just looking at the dystrophin data, it looks pretty differentiated, if not superior to what's out there, maybe just talk a little bit about your plan to communicate this. I know there's data, the full data is going to be at the MDA conference next month, but just talk about your plan to communicate the way points on that drug, please?

Thanks so much, Chris, and this is Greg Friberg, again. Let me take your second question first. I would agree with you. The data is quite encouraging from BMN 351. The 5% absolute dystrophin measure, again, which -- if you look at our PKPD model predicts roughly 10% at steady state, that is an unprecedented number the exon 51 skip amenable patients. Now what we also know from the program is that data monitoring committee has allowed us, again, to go to a higher dose level and complete the study. So we see quite a bit of value to continuing the experiment for a variety of reasons. Number one, of course, the 12-milligram per kilogram level, we'll see whether we can see something superior to that number, knowing that within all these patients, there's some degree of variability. Number two, we'll obviously get to see more chronic safety data as well. And this is something, again, that in this field, of course, where benefit burden is key is something that we absolutely want to continue to follow. And finally, we'll get our first look at some functional data as well as we treat these patients for longer and look at, for example, the Stride Velocity 95C data. We expect that this next tranche of data will have it before the end of the year. And in the meantime, we will be presenting our complete 6- and 9-milligram per kilogram data at the Duchenne Muscular Dystrophy Association meeting in March, just a couple of weeks away. So we're sitting tight. And again, encouraged by what we've seen. We want to see more data there. for this weekly IV administered antisense oligonucleotide. With regard to Voxzogo, your question is a nuanced one. It's one of whether or not, again, patients, physicians, their caretakers, whether they can have the confidence in the data package for the medicine that they're given in many cases, to very, very young infants. And of course, with Voxzogo, we have a wealth of data. We're looking forward to present that in our full evidence package that we'll be presenting for full approval to the FDA in the coming months. And I think I've gone through some of the package there, that goes through, again, some of those data points. With that, though, from the commercial perspective, I want to Cristin, a chance to share her perspective.

Yes. Thanks for the question, Chris. And I'd be happy to kind of both dig in on the switching dynamic but also important on the market dynamic in the different geographies in which we operate. Again, going back to that notion of why switch, what we hear disproportionately is that above all else, efficacy and safety are the highest priority. Convenience is the third. So the fact that we have both kind of long-term safety and efficacy data, but also importantly, durability. We are showing data now that shows that Voxzogo continues to work year-over-year data that we published going 7 years out, which really matters to these caregivers, these patients and importantly, the physicians. So I think that this is going to be in the near term, in particular, when there is more data in favorite Voxzogo, I think that, that's going to be part of the switch decisions. Now importantly, when I think about the markets, we've got very different categories or phenotypes, if you will, on markets. We've got some which are larger markets, which we have highly penetrated. And these have become ends in markets. So really where we intend to grow Voxzogo there is going to be really in newborns, where our label enables us to. Then moving over to some of the bigger growth opportunities, I think we have where Voxzogo can really play a meaningful role. That's going to be both in countries that we're already in that still have meaningful opportunity ahead of us. Now let me be clear, these are more complex markets. They take a little bit more time. But we think that the value proposition of Voxzogo is there, and we'll continue to grow there in also, as you heard me say in the prepared remarks, we have some exciting markets where they are fast growing, there's access pathways, and we're growing quickly in those. And so between all of this, when you look at kind of 75% of our revenues being weighted outside the U.S. I think there's an important value story and important story for Voxzogo and all.

Your next question comes from the line of Phil Nadeau of TD Cowen.

The question on Voxzogo brand hypochondaplasia. Can you help us frame the upcoming results? What magnitude of growth velocity increase do you think would be meaningful in hypochondroplasia patients. And can you talk about the dynamics of that market? Would you expect the as quick as in achondroplasia, or are there other factors which could make it less rapid?

Thanks, Phil. This is Greg again. I'm going to take it for stab, and again, I hand it to Cristin at that point. With regard to the study, again, we're very excited that we'll be turning the card over in the first half of this year. The study is designed to measure an effect size roughly equivalent to what Voxzogo delivers for achondroplasia. That being said, that's a fairly conservative assumption. We know that Dr. Dauber's data, for example, is showing slightly larger, more like a 1.8-centimeter growth of AGV in the hypochondroplasia patients. And it's our goal and intent also to follow through, as I mentioned previously, not just measuring AGV, but also looking at measures of health and wellness for these patients. So we believe we've designed the right study. Now it's a question of reaching the endpoint and turning it over, and we're very excited to see the data. Cristin?

Yes. So I think once we see the data, the scientific rationale will have been proven. But I do think that the enrollment rate of the trial in and of itself shows the excitement level that could be here for hypochondroplasia, assuming that all plays out well. And I think that this is yet another example, though, of our leadership in skeletal conditions where we're out there defining area where nothing exists now. And so when I think about what the biggest opportunity is, and we've said it before, it's really in and around diagnosis. This is an underdiagnosed condition, and it doesn't quite have the infrastructure that is needed to ensure that, that can happen rapidly for these patients. So we're out there now doing a prelaunch non-promotional work. We're educating on signs and symptoms requiring further evaluation and genetic testing for hypochondroplasia. We're really talking a lot about the burden of the condition to really enhance that sense of urgency to treat. And we're working actually on establishing and disseminating guidelines for when to refer and test for these patients so that we can shorten that journey to diagnosis. So all in all, we really are working at ensuring that diagnosis which I think will be the biggest problem statement for hypochondroplasia that we can get out there and tackle that early. To remind you, the total TAP side that we understand it to be today is we expect that the prevalence is in and around that of achondroplasia. But because of these diagnosis rates being so much lower, we said that the TAP is around 14,000 patients. I hope that helps you to understand. We're really excited about this and think there's a lot of work there and help to grow space.

And that targeted patient profile includes what we studied in the clinical trial, which is those patients that are more negatively effective in terms of standard deviations for growth deficit.

Your next question comes from the line of Akash Tewari with Jefferies.

This is Siyue Wang on for Akash. One on Bokova again, just following on the infigratinib data, where does this fall in your scenario analysis for your 2027 revenue outlook? And additionally, can you talk about the importance of the full approval for Voxzogo with the final adult height, and how you expect that to impact patient preference?

This is Brian. I'll take the first part of the question on '27 and any impact from infigratinib data. We don't have new updates on '27 at this time. I will say in response to your question, that the assumptions we made in competition impacted scenarios when we did update our views on that range, this is in line, we assumed two competitors and comparable data to Voxzogo.

And this is Greg Friberg. Just commenting on the full approval. This is a real chance for us to work with regulators to present our totality of the data set. We know that we have confidence in the 7, 8, 9, 10 years of SDI and efficacy data that we have in achondroplasia. We will have the opportunity to also put in front of them those measures of health and wellness. I mentioned the foramen magnum data, the physical function, tibial bowing to see again whether or not it meets criteria for label inclusion. It's an important moment, having full approval, build on that confidence, there are some other technical, I think, benefits that come along with full approval. But most importantly, again, we see this as our opportunity to put forward what we see as a leading evidence package for achondroplasia.

Your next question comes from the line of Salveen Richter with Goldman Sachs.

This is Tommie on for Salveen. We just wanted to drill a little bit more into the factors assumed in your Voxzogo guidance, especially as it relates to new starts and potential switching in the context of upcoming competition. And also for 333, kind of your confidence in establishing as the preferred option for new patients from switching given that the long-acting competitor will have a bit of a head start here.

Tommy, it's Brian. I'll start with the first part of your question. Thank you. In terms of the Voxzogo guidance for '26, first of all, just to note, we're really pleased to have grown the product 26% in '25. Its fourth year on the market. And with respect to the range, the $975 million to $1.025 billion really just reflects a handful of scenarios. On the lower end of that range, you can assume a stronger competitive impact from the first competitor potentially coming to market in '27. I'll also share that we're being guarded on a couple of routine market access renegotiations in '26. These are normal course of business. Again, the product is fifth year on the market. Those will resolve this year, but we're being measured on those. And then at the high end of the range, it would just assume a lesser impact from those couple of swing factors in the guidance. Cristin, anything I say on patient additions, and where they're coming from.

Well, I mean, we're continuing to generate patient demand. And really, our priorities remain the same. Now our execution at a country level may look different depending on what choices are available inside country. But at the end of the day, our priorities remain the same. And these profile we've seen so far are very much in line with with what we anticipated. And importantly, where we tend to continue growing patient demand is what I've said, it's in that 0 to 2 population and ensuring that we're really protecting switching.

Yes, [indiscernible], this is Greg. With regard to the 333 question, the ultimate issue here is whether or not convenience is the lever that we're focused on or whether or not patients, physicians, regulators can have confidence in the data package we put forward. We believe that we've designed the appropriate study to show that 333 can have a superior growth profile over all the available agents. And in that regard, really have an opportunity to differentiate itself as the most active agent in the field, not just for AG, but also the pull-through of health and wellness as well. The study is certainly powered to detect the size difference that we mentioned there. But the question I think behind your question was whether that those powering assumptions were aggressive or conservative. And I would argue that they're somewhat conservative. Our animal model data as well as our PK/PD model, or dose response model suggests that any one of the doses that we're putting into Phase II could potentially deliver the profile we're looking for.

Your next question comes from the line of Ellie Merle with Barclays.

Just your latest expected timing for the data readouts from the Phase II CANOPY basket study for Voxzogo, and second, just to ask a bit more on the Voxzogo guidance. Could you comment specifically on what the guidance reflects or how you're thinking about U.S. growth versus ex U.S. growth over the course of the year? And then if you could just elaborate on that last comment that you're being guarded on a few routine market access conversation and sort of the implications for that for Voxzogo.

And this is Greg. Maybe I'll knock down the CANOPY question first, if that's okay. We're anticipating that we're on track for data in the 2027 time frame, as we've stated previously. No updates in that regard. And that refers to IFS, and the Noonan's and Turner SHOX program. Our CANOPY study, of course, also includes hypochondroplasia, which we're excited to turn the card over in the first half of this year.

Thanks, Ellie, this is Brian. I'll start with the first part of your guidance follow-up. We're not delineating further individual growth dynamics in the U.S. and ex U.S., again, we've discussed before about growing in all markets. By the way, even with competition coming to market, Voxzogo's 50 on the market, we are satisfied with to be able to confidently guide to a high single-digit growth rate in '26 and at the midpoint, having the product reach blockbuster status, I'll remind you that the -- we're expecting to have the infant market in the U.S. even if competition comes to market, so that will remain 100% of Voxzogo and Cristin's already touched on the level of opportunities ex U.S. So we'll keep you updated from quarter-to-quarter on the growth dynamics, but not breaking it out further at this time.

Hi, Ellie, this is Alexander. I'm just going to come back to your question about the reimbursement processes that Brian mentioned to just give a little bit more color on those. They're in a number of markets, when you get into 5 years on the market and the product is very well established and has broad usage. You tend to go under formal reimbursement processes. And this represents actually an opportunity for us to broaden the access in those countries. Up to that point, they may well have been under a name patient single patient access type approach. So you go into a negotiation and you offset potentially a reduction in price, but with the opportunity to significantly expand the population. Obviously, in the first year that it happens, and there's two of these countries where it's going to be happening in you obviously have a price reset on your entire population. But then in front of you, you have the potential to reach many more patients. So it's a very exciting actual opportunity for Voxzogo in those markets and overall.

Your next question comes from the line of Cory Kasimov with Evercore ISI.

This is Adi on for Cory. I had a question on BMN 333. Based on the preclinical data and initial first -- should we expect the safety profile to largely mirror Voxzogo, or are there any meaningful differences emerging that could differentiate the profile one way or the other?

Thank you for the question, Adi. Our preclinical models, and in this case, the Cynomolgus Monkey models, in particular, have not demonstrated any additional safety concerns for 333 over Voxzogo as a free drug. The reality actually is that the profile for free CNP allows us to go up to much higher exposures when given in the form of 333 as compared to the daily administration of Voxzogo. And again, that's opened this therapeutic window that has allowed us to go to 3, 5, 7x and higher AUC exposures. And again, we're quite hopeful that recapitulate what we've seen in efficacy animal models that we're going to have a bet in disease profile.

Your next question comes from the line of Paul Matteis with Stifel.

I'm not sure how limited you are, and how you can speak about Amicus and things going forward, but I thought I'd give it a brief try. Just -- as it relates to the integration of the business, Alexander, you, I guess, reorg BioMarin's commercial infrastructure with different business units, and this was kind of, I think, more in reaction to [ Valarox ] a number of years ago. But how do you think about Amicus fitting into that going forward? And how much do you think you can leverage a lot of the reps you have, the units you have existing relationships versus kind of building out a whole new way of selling some of these products?

Thanks very much for the question, Paul. Yes, I mean these two products, our intention is post closure, these are going to drop right into our enzyme therapy business unit. I mean they just fit perfectly. The entire go-to-market model is exactly the same as our current portfolio. So the opportunities and the opportunities for us to drive synergies on the top line as well as synergies in terms of the way that we operate are tremendous. We're looking forward to sharing more post lows. We're on track right now for a second quarter close. And then we'll share more about our specific plans and our expectations for what these really exciting products that Amicus has done such a good job bringing to market what the pro forma looks like when you add those into BioMarin. So more to come, Paul.

Okay. And if I could just ask one quick follow-up. But Brian, I think you said earlier in the call, please don't update your models just yet for the deal. I think a number of models have been updated. Are you seeing anything in the way people are modeling this, that is missing the point that you want to make sure you guys can articulate your vision first, or I guess I'm not -- by any means asking you to give kind of guidance or context here, but from our end, it seems like as Alexander lists, it isn't all that -- it's fairly straightforward. So where are you coming from on that point?

Yes. Thanks a lot, Paul. I appreciate the opportunity to clarify that. the comment was based on entirely just the mixed bag of some analysts having post-close Amicus revenues clouded in their bone remodels and some not. Thanks for the opportunity to clarify that had nothing to do with the direction of what we see and those that are including it.

Your next question comes from the line of Joe Schwartz with Leerink Partners.

So one of the levers you highlighted for longer-term growth when you announced the Amicus acquisition was some initiatives to identify patients who might have Fabry and Pompe that wasn't diagnosed yet. I think Amicus had some pilot programs to do this. And in a few centers -- and I was just wondering if BioMarin had the opportunity to see the results of the pilot programs and if they are along the lines of what you expect to roll out. Can you just talk a little bit about your initiatives there?

For the question, Joe, it's Cristin. So you are indeed exactly what you just said that there are -- they've been running pilots. There's different models. And just to reiterate that we are in the process now of really digging between sign and close really understanding what's going on, what makes sense, given what we already have in our company versus going on over there. And at the end of the day, we are running as two independent businesses at this point in time. And so they're continuing their work on any of the pilots that they have ongoing. I think the real opportunities that we're excited about for both Galafold and Pom Op as Alexander has already spoken to is certainly how it fits to -- it fits within our business unit model here on enzyme therapies. But also importantly, the really big opportunity there is to increase the diagnosis rates both Galafold as well as Pom Op. But then when you're talking about Pom Op, really driving that switch. So important areas that we'll continue to work on, but we're in the process now of really diving in and understanding what's exactly going on.

Your next question comes from the line of Olivia Brayer with Cantor.

I have a few follow-ups on Voxzogo. First is just maybe can you talk about level of confidence in actually hitting the numbers that you laid out this year? Just in light of a weaker first quarter due to those ordering patterns that you highlighted, Brian. Anything more you can tell us on those ordering patterns, and why they might be so heavily weighted to the fourth quarter this year. I'm just trying to understand how having a new entrant on the market could impact some of those patterns and just cadence of quarterly Voxzogo revenue this year? And then a quick follow-up on hypochondroplasia. When do you think we could realistically see that launch and uptake in those patients? And any comments at this point just around how quickly you could start to see added sales from hypochondroplasia patients especially as you think about navigating some of the competitive headwinds in the achondroplasia market next year.

Thanks, Olivia, this is Brian. I'll start with a little more color on the quarter. I appreciate the question. Yes, so a few brief things there. First of all, we've always experienced these kind of bolus orders and the potential volatility of quarterly revenue. And by the way, we've typically seen step-down from Q4 to Q1. We do -- I think we -- especially after this year, we definitely observed some Q4 buying globally. It isn't always inventory levels. It could be, in some cases, of single national payers kind of just making their way through their budgets. There's a number of factors. But we've seen this in Q4, it was -- seen this before for Q4 was exacerbated here in '25. Another item I'd share is, and this is to your point about the competition, I mean two things. One, when we map our revenue to global Voxzogo patient additions. It is amazing how clear of a straight line, the study patient additions have been quarter-after-quarter over the last several years, frankly. But yes, when you look at revenue, it bounces around a bit because of these -- because of the order timing. In fact, while Q4 had a bolus effect, there's actually some markets where it was kind of a catch-up because revenue was flagging patient additions, so that's number one. And number two is I think we're going to continue to observe that this year. I'll share and this should also help you all estimate the proportions of revenue for Voxzogo, we expected the quarters will be similar to last year. So I already said that Q1 is on par with Q1, but we also expect a lot of it to be back-loaded to Q4, and any confidence, any assumptions around the competition are fully baked to?

And with regard to your second question, so as you've heard us say, we'll be presenting or sharing the top line data in the first half of this year for hypochondroplasia, and then our submissions will happen in the second half of this year. So what that means is, hopefully, approvals coming 2027, and we would expect to see immediate revenue impact at that point in time. And we'll share as we see the data, we'll share more on our go-to-market plans as we move further along in the process.

Your next question comes from the line of Jason Gerberry with Bank of America.

Just on the Phase III powering in the 2.25 centimeter per year. Is that a threshold effect when you're doing your Phase IIs ranging, if you're learning that perhaps that may be too ambitious of a target, would you just kind of adjust your statistical analysis plan. Is it -- I think in your earlier comments, not to get too hung up, I think, on that 2.25 number. So if it looks like you're on a trajectory for, say, 2 or 2.15, is it still worth moving forward in the Phase III with BMN 333. So I just wanted to clarify if that's the title of effect in a go no-go threshold in the dose-ranging work?

Yes. Thanks for the question, Jason. And that 2.25 really comes from the sample size that we've laid out, that's 60 versus 60. There's some standard deviation, some alpha numbers behind that as well. But we wanted to share with you again what our ambition was, what we thought not only statistically significant, but clinically meaningful. We will have a chance to look at our Phase II data. It's not a straightforward black-or-white situation. We're doing actually a basin approach where we'll be looking at the totality of the data. And setting a certain threshold for confidence to move forward. Rather than get into the details there, I will just answer your question directly and say we would have the opportunity to potentially modify the protocol thereafter. But those numbers and announcing them again, I think they stated appropriately our ambition of what we think a meaningful and clinically relevant improvement over what is already a well-established, safe and effective therapy in Voxzogo would look like.

This concludes the Q&A portion of the call. I will turn it back to the CEO, Alexander Hardy, for closing remarks.

Thank you, operator, and thank you all for joining us today. We're particularly proud to have accomplished our strategic goals for 2025 while achieving an outstanding growth. In 2026, we will build on this momentum and expand our therapeutic and commercial reach with the addition of high-growth assets from two significant acquisitions announced last year. We also look forward to sharing a number of key regulatory milestones, data readouts and label expansions throughout the year, setting us up to deliver even more growth, profitability and pipeline expansion. We're energized by what lies ahead this year and intend to deliver again on an ambitious set of priorities, demonstrating our dedication to innovation and sustained growth in ways that we will believe patients, we will believe we'll benefit patients, employees and shareholders. Thank you for your continued support, and we will speak to you soon.

Ladies and gentlemen, that concludes today's call. You can now disconnect. Thank you, and have a great day.

Great. Good morning, everyone. Welcome. My name is Jess Fye, and we're continuing the 44th Annual JPMorgan Healthcare Conference today with BioMarin. First, you're going to hear a presentation from the management team, and then we're going to go into some Q&A. [Operator Instructions] Before we get started, I have to read this. It says, please note that JPMorgan has a role on the potential transaction involving Amicus and is subject to restrictions. As a result, I will not be discussing the transaction during the session nor taking questions from the audience on that topic during Q&A. So with that out of the way, let me pass it over to BioMarin's CEO, Alexander Hardy for the presentation.

Thank you very much, Jess, and thank you all for joining us this morning, 2 years in the role as CEO of BioMarin. We've been busy as a team working on transforming BioMarin and setting the path for another era of significant growth and really excited to update you on our progress and our plans today. I'm going to be talking about BioMarin's future plans. And so please take note of the forward-looking statement.

Okay. So BioMarin is a leader in genetically defined conditions with an extraordinary track record of innovation. We have 6 first-in-disease treatments, many best-in-disease treatments. And this is all driven by the capabilities we've built over almost 25 years of our history, capabilities such as our geographic footprint in 80 countries, our track record for a global regulatory and approval standpoint are really impressive R&D capabilities and our in-house manufacturing that has driven not only tremendous progress for patients with these conditions, but has also delivered an extraordinary and strengthening financial outlook, of growth on the top line and increasingly growth on the bottom line.

And this is only further strengthened by the changes we've made over the last several years and most recently, the Amicus transaction. But very importantly, what is our focus at BioMarin, but all the employees every day think about is our purpose. To be the biotech leader that translates the promise of genetic advances and discovery to really make a profound difference on the patients that are depending on us. This is what motivates us every day. By doing this really well, we actually also create an enormous amount of value for our other stakeholders.

So what have we been doing over the last 24 months, we've been very, very busy. These are the pillars that we outlined at our Investor Day in September of '24. And I'll briefly summarize our progress on each. First, with regard to innovation that we prioritized our pipeline to focus on the things which -- in our pipeline, which we believe have the most transformative potential for patients. That focus is great to see in the next 12 months, we're going to see a lot of different readouts. And Gregory Friberg, our Head of R&D, will be up next to tell you a little bit about our significant progress. And we have some important updates to share today with you all.

It's great to see the fruits of that focus acceleration of key assets like 333 and 351. And that ability now that we have with regard to BD to supplement our internal innovation with external innovation. Our second pillar growth, we've really been able to significantly drive our growth rates. Today, we'll be announcing our preliminary '25 revenue and if you look at our CAGR over the last 2 years, we've achieved a 15% CAGR during that period. This has been driven by our Enzyme Therapies business unit. We've refocused into business units and our Enzyme Therapies with additional focus. We've really achieved very significant growth, growing at approximately a high single-digit growth rate.

And then our skeletal conditions and our drug VOXZOGO is now in 55 countries. We have the standard of care in achondroplasia, and we're looking forward to pivotal data in hypochondroplasia this year with a potential launch if approved in 2027 of hypochondroplasia. Just as a reminder, this is the first of 5 additional indications we're going to be seeking with VOXZOGO. So we're really only at the beginning of the impressive growth potential of this asset.

And then our third pillar, value commitment. As a team, we've been really optimizing BioMarin's ability to operate at scale, cost transformation, where we identified $0.5 billion of cost to take out of our ongoing and forward-looking business operations, this allowed us to dramatically increase profitability and also, therefore, improve our cash flow, generating a really compelling balance sheet. And we talked to you all about our capital allocation strategy. Very, very proud of the team at BioMarin for putting that to work and completing 2 M&A deals in 2025, doing what we said we were going to do, do value-creating deals for all of our important stakeholders.

When I take a step back and look at this progress over 24 months, I am incredibly proud of the team at BioMarin. Many of the leadership team is sitting here in the front row, we have delivered on an executed in terms of our financial performance, all at the same time, while transforming fundamentally BioMarin and setting us up for a really, really exciting future. That is really impressive. I really can't think of companies that have managed to do those two things at the same time, and it's a tremendous credit to the employees of BioMarin, so that is the past and the present.

Let's talk about the future. What are our priorities for 2026? And this -- I will start to bring in some of the new news today. It's very, very exciting. So our first priority is to accelerate revenue. We've already had an impressive level of revenue growth over the last several years. We're aiming to build upon that with VOXZOGO in achondroplasia. And then as I already mentioned, the growth in hypochondroplasia, which is ahead of us. Our Enzyme Therapies are performing extremely well. We have the potential addition of an important indication expansion for PALYNZIQ in adolescents. And then, of course, the Amicus integration, which you can expect, I would be talking about, it's going to come in the next few slides. It's going to be a really important addition to our growth rates out into the future years.

But secondly, this is the lifeblood of biotech is innovation. We've really got an exciting year from a catalyst standpoint ahead of us. We have 2 Phase III data readouts this year. We also have announcing today a filing for full approval for VOXZOGO in achondroplasia. So we have completed the post-marketing requirements for that drug, and we're going to be seeking full approval. Greg will share more details. There's a lot more additional that we're aiming to do with that regulatory update. We also have 2 label expansions expected in the next 12 months and we have 2 data readouts, which are really important in terms of our pipeline molecules for 333 and 351.

And Greg. Again, Greg will share more details in a moment. And then finally, our priority -- the third priority for us is strengthening our pipeline. We're very excited about our innovation engine at BioMarin, but we're supplementing that with external innovation. This BD capability that has secured us 2 important M&As in 2025. Whilst our current or short-term focus is deleveraging following the financing of the Amicus acquisition. Our focus from a BD standpoint will be earlier-stage pipeline deals to supplement our growth outlook in the longer run.

So a very, very exciting 2026 ahead of us. So let's talk a little bit about the Amicus transaction. I'm going to be quite brief here. We announced this obviously on December 19, equity value of $4.8 billion. Why is this really exciting? I mean, this is an incredibly compelling transaction for BioMarin. And we believe for patients with Fabry and Pompe disease around the world because it's first and foremost, this is an exceptional strategic fit. These 2 drugs just drop perfectly into our enzyme therapy business is a perfect match with what BioMarin does really, really well and our track record of success in enzyme therapies built over 20 years.

So exceptional strategic fit. The second compelling proposition from this acquisition is this is further accelerates and diversifies our revenue growth. We've got a compelling revenue growth picture of BioMarin alone. Adding Amicus further strengthens that growth outlook and diversify our revenue base. So following this acquisition, we'll have 4 major growth drivers within our portfolio. This is pretty compelling and quite differentiated versus the rest of the sector. And because of very much the similarities in mission and purpose between Amicus and BioMarin. We are able to realize significant financial benefits from this transaction.

And we're confident of our ability to begin to be accretive within 12 months post closure of the deal and to be substantially accretive beginning in 2027. So all in all, an exceptional fit bringing exceptional value to all of our stakeholders. But let's talk about the 2 key products that are part of the acquisition of Amicus. The first is Galafold. Galafold in Fabry disease. This is the only oral therapy in Fabry disease. The proposition that we have here is to build upon Amicus' tremendous success. Galafold has been a very successful launch. Amicus is an extraordinary company that's done a great job, but under our -- in our hands and with our capabilities, we believe we'll be able to reach more patients around the world. The simple point is that at the moment, Galafold is available in around 40 countries around the world. And we'll be aiming to bring it into our 80 country footprint over a period of time.

But this is more than just about numbers of countries. It's also about depth in countries. We have BioMarin operations in many of the 80 countries BioMarin employees, not only distributors. So we have a depth of capability, which really we will put to work to really maximize the impact of Galafold and reach those patients. There's also a tremendous opportunity to increase the diagnosis and treatment rate of Galafold. Fabry disease is a prevalent population of about 100,000 patients globally. There's only about 18,000 of those patients that are actually diagnosed right now with Fabry disease, 12,000 of those are treated.

So you can see here that we have an opportunity to increase the treatment rate and the diagnosis rate, increase the switch rate and increase the naive patient initiation rate with Galafold. Again, building upon what Amicus has done, we believe we can do even more. With regard to Pombiliti and Opfolda or Pom Op, in Pompe disease, there's also a significant opportunity here. There is also the opportunity for us to maximize the impact of our global footprint.

Pom Op is available and reimbursed in 15 countries around the world. So you can probably very quickly see that there's a growth potential there with, again, the breadth and the depth. But with Pom Op, we're also very, very exciting about the really impressive data, real-world data that Amicus has been producing. This is really very important. This is really compelling in driving the switch where that is on label, driving the switch to Pom Op. And then in addition, there are tremendous opportunities for label expansions with the potential to increase the age population, for late-onset Pompe disease, but also to expand this drug into Infantile-onset Pompe disease.

Bottom line is you can see here significant additional growth opportunities ahead for Pom Op as well as Galafold. But in terms of growth drivers, it's important not to look past VOXZOGO, a really impressive growth rate over the last several years as we also expand this out into our geographic footprint. Now today, we're announcing the 2025 preliminary revenue of $920 million for VOXZOGO translated on a quarter-to-quarter basis, fourth quarter of this year, that would effectively mean a growth rate of 27% year-over-year. So you can see VOXZOGO is growing extremely well and very strongly.

And this is even before we expand out into those additional indications. And then, of course, you've got the geographic growth opportunity as well. We're in approximately 55 countries out of our 80 country footprint. So there's also the opportunity to bring VOXZOGO to more patients around the world. In terms of our Enzyme Therapies business, we've -- as already mentioned, we've been achieving high single-digit growth rates up to this point. But we're really at an exciting point because ahead of us are really some exciting growth opportunities.

We have BMN 401, which we acquired as part of the Inozyme acquisition with pivotal data reading out this year and potentially first indication next year. And then, of course, on top of that, we've got the Amicus drugs Galafold and Pom Op contributing to our growth rates in the future. Now I'm sure this is probably going to be a question. You're not going to hear from us today what we project that future growth rate is going to be. But you can imagine that we're confident we can do a lot better than we were saying of a high single-digit growth rate.

Let us integrate, complete the transaction, close the deal, integrate Amicus and we will then provide you additional color on a really exciting growth rate and potential for our Enzyme Therapy business unit going forward. So my last slide before I hand over to Greg. This is the overall outlook for BioMarin, and it's a really compelling outlook. Today, for 2025, we're also announcing our estimated preliminary revenue number of $3.2 billion for 2025. When we look ahead to this year, of course, with the closure of Amicus projected in the second quarter, we'll be adding on top of our growth rate this year, we hope, Pom Op and Galafold. And again, we'll -- when we provide additional outlook following closure, will provide the guidance as to what that looks like.

But what I'm particularly excited about is when you layer all of this on top of each other, you layer on top the 401, the momentum we've already got with VOXZOGO in the Enzyme Therapy business. And on top of it, Pom Op and Galafold from the Amicus acquisition. And then pipeline assets like 351 and 333, we think we're well on the way of achieving our ambition of targeting sustained double-digit CAGR from now into the 2030s and this is enormously exciting.

So with that, I'm very pleased to hand over now to Greg, our Head of R&D, to provide some clinical updates.

Thank you Alexander, it is an absolute privilege to be able to represent the countless individuals who work in the R&D group at BioMarin and have prepared much of this data for us. As Alexander highlighted, we've got a busy 2026 when it comes to events from R&D, 3 major data readouts, including the newly announced filing for full approval for VOXZOGO this year, adolescent expansions, six new Phase II indications where we're doing indication evaluations in a variety of skeletal conditions.

And then, of course, 2 pipeline agents, BMN 351 and 333, which will have some data that we're going to share with you today. First of all, with BMN 351, this is our antisense oligonucleotide for Duchenne muscular dystrophy. We have turned over the cards for the first 2 cohorts and we have seen encouraging dystrophin responses. The study is continuing as planned. And with the 12-milligram per kilogram cohort initiated as we've noted, we're hoping to have that data and be able to present a more totality of information before the end of the year. So what did we exactly see? What you see on the left is actually a depiction of the actual data. These are mean absolute dystrophin numbers from patients on the study. They were treated at 9 and 6 milligrams per kilogram and you see a clear dose-dependent dystrophin response in the data that we've seen.

The findings were consistent across multiple assays. That's Western blot as well as mass spec. Mass spec is what's shown here, it's the better assay to look at quantification. And just as a reminder, we look at these numbers without the double correction for histologic adjustment for muscle content. So that 5% number certainly was a number that gave us what we thought were encouraging results that this study demands continuation.

We know that the tissue half-life for this chemistry is longer than what's seen for the so-called morpholinos, so we expect that these numbers, as you see in gray, depicted on the left, will continue to rise over the course of the next 6 months. Now what will we see by the end of this year? What we're going to see is, of course, dystrophin expression at the next dose level, the 12 milligrams per kilogram. But we're also going to see long-term safety data, both for that 12-milligram per kilogram cohort, but also the 6 and the 9. Those patients are all remaining on treatment.

And of course, for daily -- weekly administered chronic therapy that benefit burden argument is something that we want to flesh out more -- with more granularity. Finally, we'll also get a first glimpse at functional data. The intermediate endpoints, looking at dystrophin expression, I think we're all familiar with that this is a good start, but ultimately functional measures, including Stride Velocity 95C, that's the kind of data that I think will be really transformative for this community. You can expect to see these full results for the 6 and the 9-milligram per kilogram cohort in an oral presentation at the Muscular Dystrophy Association meeting in March.

Moving to BMN 333. We have mentioned that the early results supported the initiation of the Phase II/III study in achondroplasia, as a quick reminder, we had wanted to develop and engineer a long-acting product that would allow us to reach multiple fold increases in free CNP AUC as compared to another long-acting CNP agent. Our target was to see a 3x increase. And what you see today is the data that we're newly releasing that actually, not only did we beat that 3x margin in 3 consecutive cohorts, Cohort 4, 5 and 6, but the highest was -- increased that AUC by over 13-fold. So clearly, what you have there. These aren't necessarily going to be the doses we bring into Phase II, but it gives us a range to work with.

A very clear range where it's not just a small amount of increase, but a dramatically improved exposure to free CNP that we believe we will be able to offer patients with achondroplasia. So the next stop is to initiate the Phase II/III study -- that study is going to initiate shortly in the first half of this year. We're actively working currently. It will be a combined Phase II/III study. We're in the first stage, 1 of 3 doses, high, medium and low. Of BMN 333 will be benchmarked straight up against VOXZOGO.

Once we have a winner from that arm, we anticipate moving rapidly into Phase III and doing a head-to-head against VOXZOGO looking for superiority. AGV, of course, is the primary endpoint here. That's growth-related -- though that's not what patients, again, are most interested in. We've learned a lot from VOXZOGO. We're going to come back to this in a moment, but we will be measuring a variety of factors in this study, including, of course, proportionality, anatomical changes and importantly, mobility changes as well.

So more to come there, and we anticipate that this could be potentially on the market as soon as 2030. And we're, of course, trying to accelerate that with every lever that we have at our disposal. Quickly, just wrapping up. BMN 401, first-in-disease, ENPP1 deficiency, card turning over in the 1- to 12-year olds midyear. And of course, we're working on other age groups as well, looking forward to that data and building upon the legacy that Inozyme is nicely prepared.

As Alexander noted, hypochondroplasia also, we talk a lot about achondroplasia, but whether we look at Dr. Dauber's Phase II data or again, our own experience, we're quite hopeful that this is going to be an active, safe and effective therapy that is VOXZOGO for hypochondroplasia as well. We recruited the study very quickly, and we'll be turning the cards over for that Phase III study in the first half of this year. That's just the beginning of the journey. We're also working to prepare the community, make sure that they understand the disease and again, the genetics behind it and so forth. So more to come there.

I'll just wrap up in terms of the regulatory updates on Rare Disease Day February 28 is our FDA PDUFA action date for the adolescent expansion in PALYNZIQ. The results were quite effective similar to what we've seen in adults, both in terms of decreasing phenylalanine levels, but also the opportunity to increase native intact food that these adolescents could consume. This is important, of course, because before these individuals go off, into adulthood, having this window from 12 to 17 years with the support of their community and their family is really important to be able to get them to a point where this would be a therapy that they could benefit from maximally. So more to come there.

I'll just wrap up by highlighting that it will be a catalyst-rich year for R&D. We've talked about the Phase III cards turning over. We've talked about age expansion. We've talked about pipeline data being revealed, but I do want to highlight and end on this VOXZOGO submission for full approval. So this is something that in the first half of this year that we will be filing with the FDA. We've engaged with regulators about structure and format.

And it will be our opportunity not just to talk about final adult height, not just to talk about length, but really about the health and wellness of patients. We have a comprehensive and consistent wealth of data -- there's over 10,000 patient years of safety data. And of course, patients as old as having been on the therapy for as many as 10 years. We want to be able to show the data that really supports the value of this molecule across all age groups including some of those factors we noted previously, when we talked about certainly quality of life, but also anatomical changes.

In particular, we have some FRAME and MAGNUM data that we're very excited to share later this year. This data won't just be for regulators. It will also be for public presentation, and we expect a rich set of presentations that we'll be able to show this year to show the value of currently the only available and approved therapy for achondroplasia, that being VOXZOGO.

So with that, I want to hand it back to Alexander.

Thanks very much, Greg. It's really exciting to see all the catalysts that you and your team are going to be realizing this year. It's going to be a tremendously exciting seeing the difference we can make for patients across so many important genetically defined conditions. Just by way of closure, first off, we provided some preliminary financial data today. In the appendix to the presentation, you will see a summary of that. So you have that information in writing. In addition, information about EPS and Roctavian. So please refer to the appendix for that.

But in closing, I hope you can see the progress we've made the refresh strategy, the execution against that. And now we're in a period of realization of the enormous potential that BioMarin has as a leader in genetically defined conditions.

The potential to achieve sustained double-digit CAGR growth rates on the top line, a period of tremendous R&D excitement and catalysts. And we're going to aim to do supplement that with external innovation from our really impressive BD capability. And as a team, we're going to continue to execute, deliver significant profitability and cash growth.

And with that, I'd love to hand it back to Jess for questions on anything apparently except Amicus.

And as a reminder, for any questions in the room, just raise your hand or you can always submit them on the portal. Maybe just starting with VOXZOGO, what are the specific drivers that factor into how you're thinking about VOXZOGO's growth in achondroplasia kind of from here?

Yes. Thanks very much, I mean, VOXZOGO is still in a phase of growth in achondroplasia. We're in 55 countries. We're still expanding the number of countries with important launch countries happening within our global footprint of 80 countries. In addition, we have opportunities to further penetrate in currently developed markets where we already have a presence. We have an advantage of the 0 to 2 indication, the infant indication. This is extremely important. The guidelines now the international global guidelines for the treatment of achondroplasia talk about the importance of diagnosing and treating patients as early as possible. So often, the diagnosis is actually made before birth, the treatment decision in many cases is made before birth.

And increasingly, now the treatment is initiated within weeks or months of birth. And the advantage of our indication, which we will sustain for, we believe, for several years, whilst other potential competitors have to generate that data and seek approval is very, very important. So there's lots of room for additional growth and this is even before, obviously, we talk about the 5 subsequent indications we're developing VOXZOGO for.

So you mentioned at the beginning having, I think, hit whatever amount of data is you need to bring to the FDA to seek full approval for VOXZOGO? Can you just elaborate on kind of what that is that you've collected and when that filing could go in?

Yes, I'm going to ask Greg to elucidate further on that. But I would say this is very, very important. Beyond the regulatory milestone, the treatment of achondroplasia efficacy and safety are critically important. And when we talk about efficacy, it's actually sustained durable efficacy. So to be in this position where we're able to provide full final adult height is extremely important, not only from a regulatory standpoint, but we believe in terms of the treatment decision of physicians and caregivers in the treatment of achondroplasia. Greg, over to you.

Yes. From the standpoint, the drug has been on the market for nearly 5 years now. So we have a lot of data. The 10,000 patient years of safety data, of course, every year, we update the FDA. But this particular time is our opportunity to also look at different efficacy endpoints. I can refer you to the post-marketing commitments that are public in terms of some of the data that were required there. Clearly, final adult height, which is a bit of a misnomer. It's really 5 years' worth of treatment and how much height folks who reached a certain age group have achieved.

But also, it's an opportunity for us to look at data, whether it's body morphometry, looking at anatomic changes, that's both in the spine as well as tibial bowing. We've presented some of this data, though we've also uncovered some new findings, some new presentations that we're looking forward to later this year. In particular, this isn't just an update, for example, the older children. It will include all of the ages, including the infants. And in particular, we're hopeful that the data with regard to the FRAME and MAGNUM is something that will -- at least when we present it will be of interest to the community.

So these are, I would say, a comprehensive and a consistent set of data that really show what that value argument is for VOXZOGO. It's one thing to be an investigational therapy and to have that promise. It's another thing to have the data. I think that physicians and patients care about that and certainly, the payers care that. And we're looking forward to being able to present this wealth of data as the year continues.

What does patient retention look like thus far with VOXZOGO? And what do you think it will look like once there are additional players in the market?

The adherence rates on VOXZOGO currently extremely high. I mean obviously, across 55 countries, there are different data sources, but we've talked hitherto of adherence rates of approximately 90%, which really speaks to really how important a therapy this is, but also how caregivers, the family builds the daily injection into their routine. Looking ahead to when and if these currently investigational therapies if and when they're approved. It's great. There will be further treatment options available for caregivers and HCPs, but there is going to be a decision to be made. And it's going to be a shared decision in many cases between the caregiver and the HCP. I've already talked and I think it's very, very important.

We will sustain for several years, it's likely that infant indication, the 0 to 2 population. So we will be the only option for several years for the patients that most commonly now initiated in these first months and a couple of years of life. But for patients who are already on therapy, that switch decision will be a conversation between the HCP and the caregiver. And as is very similar to many of these pediatric rare diseases, the factors are safety, efficacy and convenience. You've already heard from Greg, the wealth of data, the long-term data and the benefits beyond height from an efficacy standpoint. That's going to be part of that conversation. The established safety profile, we have 10,000 patient years' worth of safety. It's very, very clear and very understood. And a very positive safety reputation.

And then they'll consider potentially convenient, but that will be a third factor in any decision. I think we fully expect and it's built into our plans. There will be some patients that will switch to more convenient formulations, but those other factors of safety and efficacy will remain paramount. And as a company, we continue to focus on generating that really compelling evidence, which is important as well as advancing BMN 333, you saw the data here that the PK data, you see now why we're so excited about this molecule and the potential for this to actually be in advance from an efficacy standpoint.

With those higher free levels of sustained CNP. So we think that, that will be a real game changer and an opportunity for us to further advance the treatment of achondroplasia in the longer run.

And can you recap the status of your various strategies to delay competition for VOXZOGO and just talk about how BioMarin plans to kind of defend its market position in the event these other products you gain approval?

Yes. Yes. We feel very strongly about the work that we did for many, many years to really identify the role of CNP in the treatment of achondroplasia, so we are going to vigorously defend our intellectual property. This is an important year in 2026 with regard to that. We have petitioned the FDA with regard to the Orphan Drug Exclusivity associated with achondroplasia requesting that the FDA delay the approval of any, I should say, of the currently -- the product currently under review until the expiry of our Orphan Drug Exclusivity, which is remaining 3 years left, but in addition, we have other intellectual property litigation ongoing. This year, you can expect the decision from the International Trade Commission in the United States as well as other litigation activities in the U.S. and in Europe potentially.

So maybe kind of stepping back, the company has undergone significant changes, right? You've implemented a lot of change over the past just 2 years. How and maybe when do you envision those changes translating into a valuation more aligned with your growth outlook?

I think that's happening as we speak. I mean I think we've -- it's been a work in progress of big, big changes that we've made. I think we very quickly made significant improvements in our profitability and in the growth rates on the top line for our Enzyme Therapies and the VOXZOGO business unit. But now I think the most important thing with regard to valuations is sustained long-term revenue growth. And I think with the strength of our business units, supplemented now by these wonderful products that developed by Amicus Pom Op and Galafold. In our hands, the possibility for them to reach even more patients. They're growing assets with very, very high significant potentials. We believe that in our hands, we believe that ramp and that peak is going to be higher. When you add that in and the combination, we think that's really compelling. And we think that investors are now starting to really -- they've seen the changes, and I think we believe you can really see the results projected now into the future.

And maybe with the last kind of minute here. You started out the presentation talking about BioMarin's unique attributes capabilities that are differentiated. So what would it take for another company to build that?

Yes. I mean it's taken BioMarin, and it's a huge credit to the organization and leadership over the years has taken BioMarin over 20 years to build those capabilities. It does take time. It takes a -- it also is about relationships and reputation in many of the markets we operate. This is not something that you can do overnight. So I think it will take time, and it will take focus from any potential competitor or anybody looking to build a presence in these genetically defined conditions.

Great. Perfectly out of time, so we'll stop there. Thank you.

Thank you very much.

Thank you.

Thank you for standing by. My name is Jayel, and I will be your conference operator today. At this time, I would like to welcome everyone to the BioMarin business update. [Operator Instructions] I would now like to turn the conference over to Traci McCarthy, Head of Investor Relations. You may begin. Perhaps, your line is on mute, Traci.

Thank you, Jayel, and good morning, everyone. Thank you for joining us to discuss BioMarin's acquisition of Amicus Therapeutics, expanding BioMarin's position as a leader in rare diseases and creating value for shareholders from day 1. Please find our press release and PowerPoint on the Investor Relations section of the website.

Moving to Slide 2, our forward-looking statements. This call is being recorded, and a press release and slide presentation are now available. I would like to direct you to our safe harbor statement, which in summary says that we will be making forward-looking statements through the course of our discussion today, and actual results may differ materially.

Moving to the agenda on Slide 3. Joining the call today from BioMarin is our CEO, Alexander Hardie; and CFO, Brian Mueller. Joining us for the Q&A portion of the call are Kristin Hubbard, BioMarin's Chief Commercial Officer; and Greg Freiberg, BioMarin's Chief R&D Officer. With that, I will turn the call over to you, Alexander.

Thank you, Traci, and thank you for joining our call on what is an important day for BioMarin and our colleagues at Amicus Therapeutics. Like BioMarin, Amicus seeks to deliver innovative therapies to people living with rare diseases, specifically Galafold for the treatment of Fabry disease and Pombiliti and Opfolda or Pompe, treatment of late-onset Pompe disease. I am tremendously excited about this deal for 3 main reasons.

First, BioMarin and Amicus are an exceptional strategic fit. BioMarin is operating at scale with a broad global commercial footprint, a proven ability to find patients living with genetically defined rare diseases and industry-leading manufacturing capabilities. Galafold and Pompe will add therapies to our commercial portfolio that have already transformed care for thousands of patients around the world. And this combination will enable us to reach more patients, consistent with the missions of both companies.

Second, this deal will accelerate BioMarin's revenue growth immediately upon close, adding 2 high-growth products with numerous global expansion opportunities. Galafold and Pompe each have the potential to reach $1 billion in peak sales. With the announcement today of the Galafold IP settlement, this growth is projected to continue through much of the 2030s. Third, the transaction will increase our already strong financial outlook.

The combined company will generate additional cash flow, enabling us to delever rapidly and continue to invest in both internally developed and externally sourced innovation. We expect this deal will be accretive to non-GAAP diluted EPS in the first 12 months after close and substantially accretive beginning in 2027. Brian will provide more financial deals in a moment. As we have shared with many of you over the last few quarters, any sizable transaction would need to have a compelling rationale for all of BioMarin stakeholders, patients, employees and shareholders.

With this exceptional strategic fit, the immediate acceleration of revenue growth and the strengthening of our long-term financial outlook, the value of this deal is clear. With that, I will now turn the call to Brian to review transaction terms and financial highlights. Brian?

Thank you, Alexander. Turning to Slide 5. We are pleased with the terms of this transaction, and I will take this opportunity to walk you through the financial highlights of this agreement. Under the terms of the definitive agreement, BioMarin will acquire all of the shares of Amicus Therapeutics in an all-cash transaction at $14.50 per share, valued at $4.8 billion.

As Alexander shared, we believe the addition of Galafold and [ Pompe ] revenues to our existing portfolio represents an attractive opportunity to strengthen our financial outlook and add value from day 1. This transaction will be financed through a combination of cash on hand and approximately $3.7 billion of nonconvertible debt financing. We expect to close the transaction in the second quarter of 2026, subject to regulatory clearances, approval by the stockholders of Amicus and other customary closing conditions.

The addition of Amicus products will immediately accelerate total BioMarin revenue upon close. As we integrate Amicus into BioMarin, our priority will be to maintain and build upon the company's capabilities and resources to support the ongoing growth of Galafold and Pompe. We also believe that there are benefits that can be realized through the synergies given the complementary nature of the 2 businesses and BioMarin's scale of operations.

We expect this combination to increase our profitability and cash flows, which provides the opportunity to delever quickly with a target of being under 2.5x gross leverage within 2 years from the transaction close.

Turning to Slide 6. One of the most compelling aspects of this deal is the ability to benefit from BioMarin's operating scale to accelerate the growth of Galafold and Pompe. On top of our growing 2025 full year total revenues seen on the left, we believe Galafold and Pompe will be significantly additive to BioMarin's top line growth through much of the 2030s.

On the right side, the addition of Galafold and Pompe will contribute substantially to revenues and further diversify BioMarin's commercial portfolio. We believe this is a clear and compelling opportunity that creates significant value, benefiting from the combined capabilities of BioMarin and Amicus. I will hand it back to Alexander for Slide 7. Alexander?

Thanks, Brian. I'm extremely excited by the strategic fit of Galafold and Pompe as part of BioMarin's Enzyme Therapies business unit and the opportunity that we have to increase market share, these differentiated products in growing markets. We believe the estimated prevalence for both Fabry and Pompe is higher than the current number of diagnosed patients, whether treated or untreated.

We will draw upon our years of experience finding patients and driving treatment rates, building on the success of Amicus to date. Moving now to Slide #8. Galafold, the only approved oral therapy for Fabry disease is currently available in more than 40 countries. We believe we have the opportunity to deepen the reach of Galafold in those existing markets as well as reach patients in new geographies across our 80-country footprint by driving diagnosis and treatment rates for both naive and switch patients.

Part of BioMarin, Galafold has the potential to reach many more patients around the world. Moving now to Slide #9. As you have seen in our press release this morning, Amicus has entered into settlement agreements with [ Aurobindo ] and Lupin, concluding the ongoing litigation related to Galafold IP. These settlements will not allow either manufacturer to enter the U.S. market before 2037, in line with the previously announced Teva settlement.

Based on our review of Amicus' intellectual property during diligence, we are highly confident in the growth of Galafold through much of the 2030s now that these IP challenges have been resolved.

Moving now to Slide #10. Similar to Fabry, we believe that Pompe disease is significantly underdiagnosed. Unlike existing single component enzyme replacement therapies, Pompe combines an ERT with an orally administered enzyme stabilizer. We are also encouraged by the real-world data that Amicus has generated, showing that more than 50% of patients switching to Pompe experienced clinically meaningful improvements in functional outcomes.

We believe this growing body of evidence differentiating Pompe from the 2 alternative enzyme replacement therapies is gaining momentum and will drive new patient starts. We have been really impressed with the work that Amicus has done with the launch of this innovative therapy, which was approved in 2023. Because Pompe is still early in its launch, we have a unique opportunity at this stage to accelerate growth by taking full advantage of BioMarin's scale and capabilities.

Moving now to Slide #11 and the conclusion of our prepared remarks. This is the second significant public company acquisition this year for BioMarin, positioning us for an exceptional 2026 and well into the future. The 2 deals together strengthen our financial outlook with potential for accelerated revenue growth now and in the future and an increasing cash flows from the combined organization immediately after close.

BioMarin has been dedicated for almost 30 years to transforming care for people living with genetically defined rare conditions. As I've gotten to know the team at Amicus, I see the same dedication to patients and shared mission-driven culture. I'd like to acknowledge the incredible work that the team at Amicus has done over the years to reach patients living with Fabry and Pompe.

I am confident in our ability to build on their success and to deliver on BioMarin's pipeline catalysts from our clinical portfolio. Today's announcement adds significant value for shareholders, employees and most importantly, patients around the world. I look forward to sharing more as we continue to make progress. Thank you for joining us today. Kristen and Greg will join us for the Q&A portion of the call. Operator?

[Operator Instructions]

Your first question comes from the line of Paul Matteis of Stifel.

This is Julian on for Paul. Very interesting acquisition, obviously. It's clearly on the larger size, I think, with respect to what people were maybe expecting. Can you just talk about the timing of this and why now is the right time to transact and just sort of assumptions and thinking about how this opportunity can bridge the revenue gap when thinking about competition from your existing product portfolio right now? Congrats on the deal.

Thanks very much, Julian, and thanks for the question. I mean I've talked about typical deal size. And I've also said that any larger deal would have to be clearly value creating. And this deal is clearly value creating. I mean it's an exceptional strategic fit. These products will fit very, very nicely into our enzyme therapy business unit. It will draw off the capabilities. We'll be able to leverage our incredible 80-country global commercial footprint.

Secondly, it's going to be additive to our revenue growth. And finally, it's very compelling from a financial outlook standpoint in terms of additional EPS growth, cash flow, et cetera. So this is really an exceptional fit, an exceptional opportunity for BioMarin. We're doing this, as we said, with regard to BD because we have a compelling set of capabilities, and we have the abilities to do deals and create value for our shareholders. This fits perfectly into that. At the same time, we're very confident of our ability to compete with Voxzogo in achondroplasia. But we can do many things at the same time, and we can create extraordinary value, we believe, for all of our stakeholders by doing deals such as this one.

Your next question comes from the line of Phil Nadeau of TD Cowen.

Let us add our congratulations strategically. This does seem like a hand-in-glove fit. We want to drill down on revenue growth for the franchises here and ask you kind of a 2-part question on that. First, just overall, what type of revenue growth do you think the franchises -- the Amicus franchises can achieve over the next 4 or 5 years?

And then second, in your prepared remarks, you suggested that the number of patients with Pompe and Fabry is greater than the number of patients on therapy. Curious to understand why that would be. Obviously, Fabrazyme and Myozyme have been on the market for nearly 20 years. So how can BioMarin help increase the penetration of therapies into these what seem to be rather mature markets?

Phil, this is Brian. I'll start with the revenue growth question. Thank you. So first, let's start with the 2 products that we're acquiring with Amicus and Galafold and Pompe. These are 2 on-market products. So despite the transaction size, this is a transaction that does not carry clinical risk and brings a base of revenue to BioMarin on day 1. We also know that both products are growing at a faster rate than the already healthily growing BioMarin-based portfolio. And therefore, we do believe that the addition of these products will be additive to our growth rate over the next few years.

Thanks, Brian. And maybe I'll build on the second part of your question, Phil, kind of talking a little bit more specifically about where we see the opportunity, both in Fabry and Pompe with these 2 assets. So our ambition overall, as you've heard from Alexander, is to really leverage our capabilities to build on the extraordinary momentum that Amicus has already built.

And when we think about Fabry with Galafold, this is an area where Amicus has done a brilliant job at really carving out a leadership position for those amenable patients or those patients with amenable mutations. And what we know about Fabry is that it is a dramatically underdiagnosed condition. So it's estimated today that there's 18,000 patients that have been diagnosed, but there are 6,000 that aren't treated. That right there is a really big opportunity for us to think about where Galafold could play.

In addition to that, we know that the prevalence is estimated to be much higher. And so we intend to build on BioMarin's capabilities of driving diagnosis and treatment rates to expand upon the Galafold growth story. Now moving over to Pompe and thinking about Pombiliti and Opfolda. This is an asset that's much earlier in its launch trajectory, and we really do believe that we have a unique opportunity again to leverage our scale to accelerate the growth of these assets.

Now this is something that given that they're only reimbursed in 15 countries today, we believe that we can deepen penetration in the countries they're in, but also importantly, expand across our large nearly 80 country footprint over time, of course, that will take some time to do. But that's a huge expansion opportunity, we think.

Not to mention, driving switch in this space -- we know that this is a progressive disease and driving switch in this space is really important, which I think is building on the real-world evidence that they've been generating and thinking about the benefit that they're seeing as people move from enzyme replacement therapy over to Pompe, they've seen some really compelling real-world evidence that I think will help to drive that switch. So we do see tremendous opportunity here, and our ambition is to grow share in growing markets.

Your next question comes from the line of Chris Raymond of Raymond James.

Congrats from us on the deal as well. So just 2 questions. I guess, Alexander, you guys have guided at length to having firepower of $4 billion to $5 billion. I guess, can you just clarify, does this sort of max out your capacity in this area, just doing this one deal? And then I have a leverage ratio question. I see that you guys, Brian, you're guiding to delever to less than 2.5 in 2 years. What are you projecting that number to be just after close?

Brian, do you want to cover the second question first?

Sure. Yes. Thanks. Appreciate the questions. And Yes. So we're taking on $3.7 billion of nondilutive debt as part of the transaction. As noted in the press release, we do have a bridge loan secured here at announcing of the transaction, and we will begin executing on the financing here in short order. Also mentioned the target gross leverage ratio of 2.5x by the end of '27 or within 2 years after close. To your question, at closing, on a pro forma basis, the gross leverage will be about between 3.0 to 3.5x.

And with regard to your first question, as you can tell, this is very compelling from a cash flow generation standpoint. We believe that with the cash flow that we'll be able to generate from our existing business together with Amicus and the value we'll create from the 2 assets, we think we're going to be able to rebuild our firepower within 12 to 24 months after the deal closes.

In the meantime, we have a level of strategic reserves. We have a revolving credit line, and we intend to do additional smaller deals to further build our R&D pipeline during the meantime. But taking a step back, we do believe, and I think these 2 deals that we've done this year show that BioMarin can do really compelling deals, leveraging our capabilities, adding value for our stakeholders. And we very much intend to use this cash flow generation to continue to do deals, which add value.

Your next question comes from the line of Sean Laaman of Morgan Stanley.

Alexander and team, congratulations on the transaction. I have 2 questions. Just the first one, using all debt essentially to do the transaction, what that might say about the enduring cash flow generating nature of your existing business sort of pre-acquisition and your view there? And the second one is just your feel for what OpEx synergies could be observed.

John, this is Brian. Thanks a lot for the question. So of note on this transaction, again, given the scale that Amicus has achieved on a stand-alone basis, approximately $600 million of revenue over the last 12 months. And they've been on their own successful profitability journey.

They reported non-GAAP income in 2024 and have said they're on track for GAAP net income in the second half of this year. So importantly, the combined business actually generates operating profits and operating cash flow on day 1. We do believe the transaction will be slightly dilutive in calendar 2026 and then starting to be accretive in full year '27, substantially accretive beginning at the end of that year.

And that's largely due to the interest cost that we're taking on with the debt associated with the transaction. But back to the cash flows, we do believe that this will be very quickly additive to BioMarin's cash flows. And while we will incur integration costs, we don't anticipate an impact on that BioMarin-based business cash flow. And then in terms of synergies, our priority is going to be to merge the 2 companies to maintain and build the great capabilities that Amicus has built over the years so that we together can continue to grow Galafold and Pompe.

We do expect that there will be synergies available. Again, as I mentioned in the prepared remarks, these are 2 very complementary synergistic orphan disease businesses. And again, while the priority will be maintaining operations and growing these products, we will commence integration and there will be synergies available to us over time that together with the scale of the combined companies will actually increase the net fully integrated profits and cash flows over time.

Your next question comes from the line of Corey Kasimov of JPMorgan.

Congrats to both teams on this deal. So I guess I'm curious, just the outlook here, commercially speaking, based -- first, based on Brian's comment that these Amicus assets are growing faster than BioMarin's base enzyme therapy portfolio. Do you expect to raise your long-term CAGR expectations for this side of the business? And how do you think about the competitive landscape in Fabry and Pompe?

Corey, it's Brian again. Thanks for the question. Yes. So just to start, the purpose of today's call is to announce the transaction. We're very excited to be adding these 2 approved high-growth products to our portfolio. Companies will continue to operate, of course, on a stand-alone basis until we close the transaction.

As I mentioned, we do believe that the combined business will grow at a higher rate through the rest of this decade and beyond. We do believe that the products will be meaningful contributors to revenues in '27, both absolute dollar and growth rate. However, we're not offering additional guidance at this time for 2027 or beyond. What is important to note is that we continue to grow revenue from BioMarin's base business, and these products both add to the growth and very importantly, diversify BioMarin's overall portfolio.

This is Craig Frabert. I'll take a stab at the competition question. Certainly, Galafold is an orthogonal mechanism to the other approaches that are out there. It's oral, it's targeted, it's highly active. And in a disease like Fabry where sadly, patients can respond, but that response can wane over time, having additional arrows in the quiver, so to speak, is really important for physicians and patients.

And we see Galafold for the amenable mutations is playing a really important part there. When you think about the landscape for Fabry beyond that, again, we see that Galafold is going to play a really important role for some time to come. There are substrate reduction therapies that are being looked at, though, again, unproven.

And from that standpoint, we see the opportunity to have a unique mechanism within our portfolio, building on the great work that Amicus has done to be a tremendous opportunity. On the Pompe side, it's another situation, another lysosomal storage disorder where first-generation enzyme replacement therapies did transform this disease. A real breakthrough in that sense, though newer therapies really have focused on this ability to drive more drug into the muscle and most importantly, of course, into the lysosome of the cells in the muscle.

So Pompe actually has been engineered to do that in a couple of different ways. One is through the so-called M6P. It's been selected to really get into the lysosome and do its job better. And then, of course, adding the stabilizing agent not only increases PK, you can actually see in the label, they show the PK very nicely and exposures when the stabilizer is added. But in preclinical studies, again, the suggestion is that, that goes even further.

This double whammy really is a next-generation approach to enzyme replacement therapies. And in that regard, while there are other options out there, again, we think the real-world evidence with Pompe and other preclinical data sets that Amicus has nicely been generating really show its value in this space, and that will only continue.

Of course, there are label expansions going on as well into the -- younger Pompe, for example, is only approved in adults right now, but there's -- certainly, I believe it's 12 to 17 is on the way shortly. So from that standpoint, hopefully, that answers your question, but we're really thrilled about the biology behind these molecules and their opportunity to help patients in fields where options are going to be important. These patients live a long time with these diseases and preventing end organ damage is absolutely the goal of therapies like this.

Your next question comes from the line of Joe Schwartz of Leerink Partners.

Congratulations to everyone on a very interesting deal. A lot of my questions have been answered. So maybe I'll ask about BioMarin's view on DMX200 in FSGS. Given you're acquiring Amicus shortly before another company has their PDUFA in FSGS. I'm wondering if you can give us your view of the clinical prospects and regulatory path forward for DMX200? And to what extent is BioMarin prepared to capitalize on that opportunity given nephrology would be a new commercial area for the company?

Yes. Thanks for the question. So for those who aren't entirely familiar, focal segmental [ glomerulosclerosis ] is the disease we're talking about. It's a rare and fatal kidney disease, probably about 40,000 patients in the U.S. are living with this at any given time. It's a therapy that while there's multiple different mechanisms of action being studied, there's really no approved therapies despite the fact that significant opportunity in terms of number of patients that are out there.

With regard to DMX200, so it's a potentially first-in-class small molecule. It's an oral agent given twice a week. CCR2 is the target. It's really a promising approach to inhibit the inflammatory cells that really drive recruitment of monocyte-driven diseases like FSGS. And in that regard, the early experience with the molecule, the Phase II data look quite promising.

I believe it was 86% of patients had reductions in proteinuria in that albeit early and smaller study. In the Phase III study, studying this new mechanism of action is ongoing right now. A recent announcement by [ Dimerics ] was that they completed enrollment, which is fantastic to see. And we're going to be closely watching this, assessing the opportunity and evaluating next steps.

What we do believe is, again, this is a condition that could benefit from, again, multiple orthogonal different mechanisms of action. We will, of course, be watching the competitor space closely. That being said, again, we're hopeful that there's a great opportunity here with DMX200 as well.

Your next question comes from the line of Olivia Brayer of Cantor Fitzgerald.

Congrats as well on the deal. Can I ask how you guys are thinking about peak sales potential for either of these new products? And I mean, how would you rank the 2 as you think about them driving long-term growth for the company? And then on the Pompe program, how are you guys thinking about competitive dynamics here in that space, just given the traction that Sanofi has been seeing in these patients?

Yes. Thanks for the question, Olivia. This is Brian. I'll start with just speaking to the revenue potential and then hand it over to Kristen for more color on the second part of your question. So we believe that each of the Amicus products has the opportunity to reach $1 billion each in peak sales. We aim to add the unique BioMarin capabilities and large global presence to potentially even build upon that outlook. This will take time. Again, we expect substantial growth through the remainder of this decade. We don't expect to achieve peak revenues until into the 2030s, but we're confident in the opportunity.

And on the competitive side on Pompe, thanks for the question, Olivia. Really, this is an area where, as I mentioned earlier, this is in the earlier phases of launch for Pompe. But importantly, what we're seeing is that there is a lot of momentum that Amicus has been building with regard to switch from enzyme replacement therapies.

And this is in large part based on the experience that they're having out there in the field that they've been demonstrating very encouraging real-world data that during the prepared remarks, had mentioned that more than 50% of patients switching from an enzyme replacement therapy to Pompe in Phase III experienced a clinically meaningful improvement in functional outcomes.

And these type of data, which we'll continue to generate are really important in understanding for a progressive disease, why it is important to have other options, as Greg had mentioned, and Pompe is a very powerful option for these patients. So we expect that we'll continue to see growth well into -- much into the 2030s, and we're really excited to build on that momentum.

Your next question comes from the line of Alex Hammond of Wolfe Research.

I guess what's the integration road map here, especially regarding commercialization, manufacturing, the global footprint expansion? And I guess as a follow-up as well, will this deal affect prioritization or funding for BioMarin 333 and 351? And then on 351, if I may, should we still expect results by year-end?

Maybe I'll take the first -- the last question first, if that's okay. For 351, we ask you to sit tight. And I will just comment that we view BMN 333 as well as BMN 351 as priorities independent of what we're discussing today.

With regard to the integration plans, I mean, obviously, as you well know, until the deal closes, BioMarin and Amicus are going to continue to operate as separate independent companies. We have, though, started integration planning. And when the deal is closed, then we'll obviously start the integration process. has already been covered in some of the prepared remarks and questions, we are operating at scale. We are in a very large global footprint.

We think there's -- there are synergies from the combination, but it's way too early to be specific around that. On the -- particularly on the commercial side, again, these are growing products at very important parts of their ramp. We aim to continue that ramp and then build upon it. So we'll be very, very focused on really building upon the really excellent success that Amicus has had commercially in many geographies. And that will be a very important part of our integration. We will absolutely not distract from the efforts from a sales and marketing perspective and growth perspective.

Your next question comes from the line of Jason Gerberry of Bank of America.

Just 2 follow-ups, just more specifically, I guess, on Pompe, your $1 billion-ish outlook in terms of peak potential here. For P&O, I'm just kind of curious, that implies maybe about 2,500 patients out of the 5,000 to 10,000 late onset prevalence. So I'm just wondering, does that assume that you drive an even greater level of switch versus the Sanofi product? I'm just kind of curious the general directional assumption there. And then just a follow-up on Alex's question. Just on the manufacturing, I believe that WuXi in China was the manufacturer, but they were in the process of moving that to Ireland. Would that just generally be the assumption? Or would you plan to move manufacturing into the U.S.?

So in terms of the first question, really our ambition, I mean, as we've said before, this is really in a very important part of the launch phase of this program, generating high-growth numbers 2024 going into 2025, as you've likely seen from Amicus -- and we intend to build on that. This is a very exciting time in a launch. And our intention here is to really build on what they've already -- on what Amicus has already done, but importantly, continue to leverage the scale, the operating scale, the commercial footprint that we have at BioMarin to expand this product as quickly as we are able to. Do we expect to generate more switch moving forward? We absolutely do. That is the intention here. And importantly, that is going to be driven in large part by the continued experience with Pompe out there in the field, but also importantly, with the continued data generation that demonstrates that this is a really important option for patients as they progress.

And thank you. With regard to the manufacturing question. I mean, obviously, this is part of what we need to do in terms of the integration planning period. We're going to evaluate the long-term manufacturing strategy for these important products. We do have a really compelling manufacturing capability at BioMarin with plants in both Ireland and the United States and an ability to manufacture enzyme therapies reliably and at high quality. So we think this is a very, very interesting part of how we can add value to all stakeholders. But again, our first priority is continuity, and we will be working to understand the current state of contract manufacturing organizations and our priority will be continuity of supply.

Your next question comes from the line of Mohit Bansal of Wells Fargo.

On the deal as well. Just trying to double-click on enzyme replacement therapy and the longer tail here. So I mean enzyme replacement therapies tend to have longer tail. I mean we have learned that from Sanofi enzyme as well as you guys as well. If you think about oral Galafold, the 2037, do you think there is a future beyond 2037 as well given that it's an oral? Or is the other drug which probably has a longer tail than IP here?

Thanks, Mohit. Thanks very much for the question. I mean it's very, very important. Obviously, the IP settlements that Amicus negotiated that really provide really clarity through to 2037 with regard to Galafold. I do think at that point, it's a long, long way into the future, rare disease, these sorts of conditions. I don't think you'll expect to see the same level of generic erosion that you would see with oral therapies in other disease states. But again, that's a long, long way into the future.

And then I would just actually -- I mean, you can take a little bit from our own experience with Kuvan, where we've actually -- the erosion rates have not followed the traditional oral path. They're a good example, and I would encourage you to look at that as an analog. Should Mohit your modeling out to 2037, I'm very, very impressed. You could probably use that as a basis.

Your next question comes from the line of William Pickering of Bernstein.

On the deal. Could you speak in relative terms about the magnitude of upside you see from geographic expansion as opposed to execution in existing markets for Galafold and Pompe? And a second question would be how you see the full commercial organization fitting into BioMarin's existing EU structure.

Thank you for the question. So at this stage, we're not providing guidance. We're not going to quantify the numbers, but I'm happy to say that we really do see opportunity here in terms of the level of expansion and being able to really build upon where we are currently in our country footprint of nearly 80 countries.

Now Galafold is already in 40 or so countries. So you can imagine there that the uplift will not necessarily be the same given where it is in the maturity of its life cycle, but also importantly, the penetration it has already in some of the countries. But I will say the important value driver in Galafold isn't only the expansion, but it's also importantly our ability to continue to drive diagnosis rates as well as treatment rates. And we believe that there is opportunity there, both for naive patients as well as for some switch patients moving forward.

Now Pompe is in a different phase of its life cycle. And it's, as I mentioned earlier, only reimbursed in 15 countries. So we see great opportunity here to expand it. So not only deepen in the markets that it currently is, but importantly, expand it. And this is going to take us some years as we've learned with our own enzyme therapies. So I don't want to promise that that's going to happen overnight.

But you can imagine throughout the integration planning, we are doing some very deep dive into looking at what that launch timing will be across our global footprint. We see this as a brilliant fit within our Enzyme Therapies business unit. This is an area that we feel that we've been historically very successful at. And again, that's about finding those patients, starting them on treatment and then importantly, continuing to drive high adherence rates, which Amicus has already been very successful at, and we believe that we can do that as well as we move forward. So we're very excited, as you can hear in our voices about the integration. And I believe that there is a lot of expansion opportunity.

Thank you. That concludes our Q&A session. I will now turn the conference back over to BioMarin's CEO, Alexander Hardy, for closing remarks.

Thank you, operator, and thank you all for joining us this morning. We believe this transaction represents a compelling rationale for all of our stakeholders, patients, employees and shareholders. It creates significant strategic and financial value immediately upon close and well into the future. With the second significant public company acquisition this year for BioMarin, we have strengthened our financial outlook and position BioMarin for an exceptional 2026 and beyond. Thank you very much for joining us, and happy holidays.

This concludes today's conference call. You may now disconnect.

Day 2 of our London Healthcare Conference. Great to see everyone. Always really appreciative of the attendance. My name is Akash Tewari. I'm a pharma and biotech analyst here at Jefferies. I have the pleasure of hosting the BioMarin management team.

Alexander, why don't I hand it off to you for some intro remarks, and we'll get started.

Great. Excellent. Thank you very much. Can folks hear me okay? Good. So thanks very much for joining us. Thank you for your interest in BioMarin. So actually, at the beginning of next month will be my 2-year anniversary as CEO of BioMarin. I just wanted to -- this is always a period where hit a milestone like this of a degree of reflection. We've done a lot of things, made a lot of changes. I think we're in a period of execution now of those changes.

So what are the things we've done? We've reorganized the strategy around 3 pillars, around growth, driving growth from our existing portfolio, innovation, our pipeline, supplemented by business development and then value commitment, realizing greater returns, increasing profitability, cash flow -- free cash flow from improving our operations. We identified $0.5 billion of cost transformation. A lot of that we've dropped to the bottom line to improve that cash flow and strengthen the balance sheet. But we've also reinvested into the growth drivers into that pipeline.

We're now, as I said, into execution phase, growing that current portfolio. But we're entering now a really interesting -- it's great to have Greg here, the Head of R&D, 14 months into the role. We're now into a period of pipeline readouts. So what can you look forward to in that? We've got 351 for Duchenne's muscular dystrophy, where we're on the verge of -- by the end of this year, we'll be sharing the top line results of that program.

At the beginning of next year, we've got the readout of the Phase III data of hypochondroplasia, Voxzogo, which will be another growth opportunity, the fourth of 5 additional indications that we're pursuing for vosoritide or Voxzogo. We have the Phase III readout for the 401 program. This is the program that we acquired as part of the Inozyme acquisition. And in addition, we have the pending approval by the FDA with an FDA action date of February 28 of next year of Palynziq in adolescents, which is an exciting additional growth opportunity for Palynziq. Palynziq is already growing at about just over 20% this year. So this will be another additional growth leg for that.

So there's a lot to talk about. Akash, I'm looking forward to hearing your questions.

Thank you. And actually, I'm going to start -- we'll get to the guide, we'll get to the products. But I wanted to talk a bit about the unique BD environment we're seeing right now. I've had 2 companies where there was a public offer and then there was a topping bid, and it is annoying for me to deal with, but nonetheless, you don't see that typically. I think the question I have for your team is there is this kind of dynamic of people who have cash and you have about $2 billion in terms of flexibility. But then you might be competing against a mega cap company where they might have a limitless balance sheet seemingly in terms of getting an acquisition done. How does that concern apply to your team? Because your new Head of BD has come in, you guys have talked out external acquisitions. Do you feel like it has been more difficult for you to identify assets that you find compelling and pay a price that makes sense? Or actually, that's not the case.

Yes. I mean we have built a world-class BD function. We do think that BD is a real opportunity for future growth to supplement our internal innovation. The space we're playing in, I mean, let's be really clear, we're focused on genetically defined conditions. We've defined that. That is an absolute requirement for anything we look at from an external standpoint. And that is a segment that we see little -- relatively little competitive pressure in terms of other people hunting after the same assets. They require very specialist expertise. Just for the very nature, these end up being a little bit smaller opportunities or smaller opportunities that will move the needle for the big pharma players that are the actors in the play that you're watching and enjoying watching. So we don't see that same context with the companies and the assets that we are going to do right now.

Understood. And to me, you're kind of thinking about like peak sales and risk adjustment. I can't help but think, Alexander, you're thinking, give me a Palynziq, Voxzogo like opportunity that fits into this business unit approach, right, genetic disorder, skeletal muscles -- skeletal conditions and then enzyme replacement. It seems like that's the kind of sweet spot and then either pre-commercial or just launch. I mean, is that the right framework we should be thinking about in terms of external BD.

Yes, we've largely got it spot on, Akash. I mean we're -- BD is about, for us, supplementing the growth rates in the medium term. That's what we're focused on doing. We don't need to buy revenue. We don't have any large loss of exclusivity events. But we believe that actually assets are worth more in our hands than where they're sitting right now. There's lots of under-resourced genetically defined disease or rare disease companies. And why do I say that? Well, actually, the prevalent populations for these genetic conditions sits outside the United States and Europe. This is a footprint that we're in 80 countries. It's absolutely remarkable. We've built that up over 20 years and occupied it with our enzyme therapies and Voxzogo. That's where the patients are. And these companies don't have that sort of geographic presence.

I'll give you the example of achondroplasia, which is Voxzogo's first indication. 68% of patients are outside the United States, Europe, Australia, Canada and New Zealand, 68%. So you need that geographic footprint. We have that, others don't. And that is just one element of the capabilities. Our capability advantage is across research and our deep genetics capability, our development, our ability to design studies, regulatory endpoints for these sorts of conditions, manufacturing. Again, many of these small rare disease companies use contract manufacturing organizations. We have our own manufacturing capability across multiple modalities. So we can do that more efficiently and effective. And I've already mentioned the commercialization footprint. So I hope that this investor audience can see that there's a real value proposition. As we announce deals, you'll be able to understand the value proposition of how this is going to actually be really good for the growth prospects.

Maybe just a point on that because I remember last year, there was this question of would you do -- you have your long-term guide, would you do a deal that would impair that. And I think your answer was like, look, in general, we want to keep our long-term approach. We think that's really important. If there's an asset that we think is super compelling, we're going to have to go for it. But I think lost in that kind of nuances and especially in what you just said, it's about acquisitions that are earnings accretive, right? Talk to me about the importance of if you are in-licensing assets, how does that change the long-term financial profile of the company? And how coherent is that with your long-term guide as well?

Brian, do you want to.

Yes, sure. I can start. First, maybe thanks for the question, Akash. Just to start on the financial elements of our transformation itself, those are on track. There's largely 2. First is executing on revenue, which we've been doing the last several quarters. And then second was cost, where we've always had a sense of prioritization. It was important through this transformation to fully get costs under control, which we have. That comes with disciplined investments in the right places as well as operating efficiency, which we're executing. We're, as Alexander mentioned, 2/3 of the way through here now on $0.5 billion cost transformation.

And importantly, it's not just investments prioritization and efficiency. During this time, we've been able to make actually incremental strategic investments across all parts of the business, whether it be global sales and marketing, within the business units or to accelerate the pipeline assets. So this was not outright cost reductions, but strategic investments. So that's on track, targeting 40% non-GAAP operating margin next year. That would be more than doubling of our operating margin back in 2023, which was 19%. Excluding our in-process R&D development charge this year, our operating margin is 33% to 34% target. So that's a substantial improvement.

But to your question, when faced with the choice of shareholder value creation and those long-term profitability targets, we'll choose creating shareholder value. So that could adjust where we land long-term margins, but these targets are solidly ahead of many benchmarks within the peer group. So we think we can balance both achieving and sustaining profitability and reinvesting in the business. That's the goal.

Okay. Understood. Now maybe just kind of stepping back. And as a part of that kind of revised tweak guidance, I think there's a bit of confusion about Voxzogo's trajectory both into next year and 2027. And this -- I'm just kind of thinking out loud. Would you agree, if I were to say, I'm very confident, a, Voxzogo is going to grow in terms of just net patient adds year-over-year in a manner that's quite similar to 2025. And then number two, in 2027, there are scenarios that we can easily imagine that patient adds in achondroplasia -- sorry, hypochondroplasia more than offset any competition you face in achondroplasia. How crazy is that framework for you?

I would say that we believe that Voxzogo is going to continue to grow over the next several years. There's still a lot of growth opportunities in achondroplasia, both in the U.S. and in that global footprint. And then as you mentioned, in '27, if we're approved, we have the hypochondroplasia launch. So we think there's sources of growth and plenty of opportunity for the drug to continue to grow through this time frame.

With regard to the -- you didn't directly ask the question, but with regard to the '27 guidance, there's a lot happening, obviously. This is the big question is the competitive question around Voxzogo. There's a lot happening over the next several years. We thought it was useful. We had this '27 guidance rather than saying that's a point estimate, there's a whole range of scenarios. And we decided the most useful thing was to communicate a range. And that low case scenario is not a scenario that we believe is the most likely. But we said, okay, what if there are 2 competitors that take substantial share from Voxzogo. What does that mean? And obviously, also backing out things like ROCTAVIAN. That translates to a number which is really in line actually with your own perspective on '26. That's our low case. That's not what we believe is going to happen. We're confident back to the first part -- your question and the first part of my answer. We're confident that actually Voxzogo will grow over the next several years.

Understood. And actually, I'm just thinking about this, there seems to be kind of a -- what I find kind of amusing, maybe a little sad is you have other CEOs that are entering in the space, and they are convinced that there's going to be this kind of explosion for their programs. And it almost implies not only is Voxzogo's share just going to go to 0 in a way that I just don't think maybe makes logical sense, but there's also just that -- there's just patients out there that we're not seeing, right?

From my perspective, there seems to be kind of consistent patient adds we see in achondroplasia. And in a lot of your markets, you're going from kind of a prevalence to an incident type of framework. So you've done a good job talking about 70% of your patients are ex U.S. But if you were to tell me, like roughly speaking, how much of the markets you're going in an incident market where you have a 0 to 2 label versus a prevalence market where there's still kind of room to expand. Help us understand that.

Yes. So there are obviously different markets in different stages. We're still launching. We're now in 55 out of the 80 countries. Again, that's part of how we're still growing. So obviously, those sorts of markets where new patients come from all different age groups. But in more mature markets, this is very much an incident market. The majority of patients with achondroplasia in many countries are diagnosed actually, in some cases, before birth, but within days or weeks of birth. It's very evident, unfortunately, the disease presentation. And we will be -- we have the 0 to 2 indication and to be determined how long it will take the competitors to get that indication. But that -- in many markets, that is the incident population. So competitors will have to switch in the more penetrated markets. They will have to switch existing patients.

And as you know, and I think you're intimating with your question, switching patients that are doing well on a treatment as they are on Voxzogo. This safety profile is very well established. There's a lot of confidence amongst prescribers and caregivers around the profile of the product is not a straightforward proposition, I would say. And I think this is a topic that the implied valuation has got wrong. This is not a zero-sum game. Again, in our low case scenario, which is not the one that we believe is the most likely, we've taken that into account and it sits right on top of consensus that the reality is going to be somewhere in between. And yes, there will be some patients to switch, but there will be many that decide to continue because they've seen great results with Voxzogo.

So I'm going to dig into that, and I think it's quite important as we get into the Ascendis approval. And that decision is coming up soon. Look, again, I have a horse in this race, but I can't just help but think. It's hard for me -- like I look at the multidisciplinary review for Voxzogo. There are age-match analyses that were done. There are ways that the FDA cuts the data and some of those analyses end up reflecting what's in the label. And we're in this kind of, I think, surreal scenario where if it's 0.3 or it's 1.5 -- or 1.3 versus 1.5, there's a perceived meaningful difference in terms of impact to your franchise. Do you feel like there are scenarios where the Ascendis label could show efficacy that looks numerically worse than Voxzogo on an age-match basis? And then Greg, I'd love if you could comment on this in terms of switch. What is the label that you anticipate them getting given that they did run a different clinical trial?

Yes. It's always a little bit tricky, and I never like to speculate on what -- how the regulators are going to view data sets. But you're correct, they will be looking at individual patient level data, both with regard to efficacy, but also with regard to safety analysis and how preferred terms are bundled, for example.

Our experience would suggest that for accelerated approval, for example, the indication statement that we've received is probably the most likely regulatory outcome, though. Again, I don't want to speculate, again, where the regulators will end on that. Beyond that, again, what we have in Voxzogo is we have almost 10,000 patient years' worth of data at this point. That means, of course, not only are we talking about 1 year or 2 years of efficacy, but we can extrapolate that out to 7, 8, 9 years, we can talk about tibial bowing in a meaningful way, interpedicular distance for hopefully prediction and prevention of spinal stenosis. That's a data set that we want to continue to publish on. We want to own the information that we have. Voxzogo is a safe and effective drug. And all of that data is something that we think will be valuable, certainly to patients and physicians, absolutely to payers.

Okay. So just to hit on that, we got into this question of full approval for Voxzogo and final adult height and whenever -- when does that end up getting reached. Could you potentially make an argument to the FDA that we shouldn't just look at final adult height when you're thinking about that decision, but maybe more holistically, looking at some of these other kind of secondary biomarker-driven endpoints as a part of a full approval decision? And could you be having that discussion with regulators right now?

This is absolutely something that's on our mind. Final adult height is driven by a mathematical calculation and negotiation with regulators. Any time we engage with regulators, it's an opportunity to put in front of them the totality of our data, which we think, again, will help prescribers and patients make an informed decision. We have a wealth of data from that 10,000 patient years' worth of safety and including following up on many efficacy endpoints. So what you can be assured of is that those are going to be active discussions, and we're very much looking forward to having those discussions with regulators around the globe.

Okay. Understood. Maybe just lastly, there is a regulatory and IP discussion to be had here. You guys have seen my research. I'm personally a little skeptical that you had a citizens' petition that perhaps a citizens' petition would be able to block a competitor product from getting on to the market. And to us, we dealt with this with Jazz and Avadel, where you had a once-nightly and that still got approved. But I think one of the things that maybe doesn't get caught in that discussion was there are 2 separate decisions that get made by the FDA, right? There is a separate division that makes a decision on granting both exclusivity and designation. And then there's a separate part of the FDA that actually grants approval.

I think if we look back at the Avadel scenario, there was a delay in outright approval as you waited for the actual ODE decision. Is that an angle we should be thinking about here with the citizens position? It's not just as binary as launch or not, but maybe potentially a delay.

Again, just like Greg, I don't really want to speculate on what the FDA will or will not do. You are correct. It is a separate part of the FDA. And I think we're all professional -- we've always been professional FDA watchers, but trying to understand kind of how decisions are made at the FDA right now. What I would -- I would sort of reframe this that this is -- we feel convicted in the importance of the orphan drug exclusivity to incentivize companies like us. We've now had 6 first-in-disease treatments. We know how important orphan drug exclusivity has been for the business case for ourselves and for others to make progress. And we think we made a strong argument. We will only know, obviously, that outcome at the point of approval. We'll find that out at the same time as you do. But it's not the only arrow in our quiver. We also have ongoing litigation in front of the International Trade Commission with regard to the U.S. We've got traditional IP litigation as an option in the United States on a point of approval.

And in Europe, there is also the possibility of additional IP litigation around new patents, which are pending at the European patent office. So we've got -- I think primarily, the focus of this conversation has been competing in the market with very satisfied patients, additional indications driving additional growth, our global footprint, our indication 0 to 2. In addition, we have this myriad of ongoing litigation, which I think investors should keep one eye on.

Understood. Now maybe going into hypochondroplasia. Can you talk about the size of that population relative to achondroplasia because there are degrees of severity with hypochondroplasia. And then number two, the Dr. Dauber data so far, I mean, it looks just as good in hypochondroplasia as it does in achondroplasia. Can you give us directionally your powering assumptions for that trial and what you expect on average growth height velocity?

And then maybe lastly, what investors love to know, is there warehousing? Have you identified patients? Could this be a bolus launch? Because it's the same doctor. So how immediate is that commercial opportunity for you, let's say, if you get approval in 2027?

Okay. I think there's three questions there. I'll take the first and the third, and you take the second. Okay. So with regard to the first, in terms of the size of the population, we think the genetic prevalence, and we have quite a good level of expertise here, is approximately the same as achondroplasia. So achondroplasia is about 24,000 patients globally. However, to your point, these patients present later. And we think it's likely that it's going to be a more severe subset of these patients, which are really the addressable population. So we would encourage you to use a figure of 14,000 patients. That's what we use internally is the addressable market.

The work that we have underway right now is to really create awareness and understanding of the disease. People talk about this relative to achondroplasia. I think the important thing is to talking about this relative to patients without those genetic mutations. There's around 3 to 5x the level of health care utilization. These kids aren't just shorter, but they have a myriad of health issues.

With regard to your third question, there are clearly -- this is the same prescribing universe, pediatric endocrinologists as achondroplasia. They're very excited about the prospect of a first-in-disease treatment for hypochondroplasia. They do have patients that they have tried in some cases in the United States to get reimbursement for and have been unable to because there's no approved indication. There will also be, just like we're now seeing with achondroplasia, the older patients are under the care of pediatricians in the community. So the ability to reach and connect with those patients. This is a capability we have that we've developed over multiple drugs using it in achondroplasia, where you get a ping of a diagnosis in a claims data saying that there is a hypochondroplasia patient, a particular pediatric practice. And then we go into action and encourage that patient to be referred into the specialists to get treated -- they're already diagnosed, but to get treated.

And very quickly, the study is powered to look for an AGV delta similar to what's seen with achondroplasia, 1.5 centimeters per year. And that is conservative compared to the Dauber experience, which saw more like 1.8 centimeters. I'll also add that the most powerful predictor of AGV change is AGV that you walk into the study with. So if you're a slower grower, you have the chance to grow faster. And we have refined for patients who are minus 3 standard deviations or less. So hopefully, that will, again, make the powering conservative for what we're looking.

We're out of time. I'm going to sneak one more question, and I think it's quite important. Greg, can you just comment on how to do an apples-to-apples comparison with your DMD corrector data versus the Dyne and Avidity datasets? I think it's quite important.

I think it's important to look at other Exon 51 skippers. So that would be Dyne. Dyne has reported the 3.2%, again, not adjusted for muscle or fat content, but that 3.2%, they recently, I believe, commented that they believe over time that, that will go up to about 4% at their next level. We will be looking similarly at an earlier time point than steady state. Our goal is that we have a level that will predict 10% at steady state. It's a different dynamic. It's a different timing with the phosphorothioate chemistry. It takes almost a year or more to reach steady state. A level of between 3% and 5% at 6 months will predict a 10% level out at steady state.

Got it. Thank you so much. I appreciate it. Thanks, everyone, for joining us. Thank you.

Thank you.

Hello, and welcome to the BioMarin Pharmaceutical Third Quarter 2025 Conference Call. [Operator Instructions]

I would now like to turn the conference over to Traci McCarty. Please go ahead.

Thank you, operator. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, such as 10-Q, 10-K and 8-K reports.

In addition, we will use non-GAAP financial metrics as defined in Regulation G during the call today. These non-GAAP measures should not be considered in isolation from, as substitutes for or superior to financial measures prepared in accordance with U.S. GAAP, and you can find the related reconciliations to U.S. GAAP in the earnings release and earnings presentation, both of which are available in the Investor Relations section of our website. Please note that our commentary on today's call will focus on non-GAAP financial measures unless otherwise indicated.

Beginning on Slide 3 and introducing BioMarin's management team joining today's call, Alexander Hardy, President and Chief Executive Officer; Brian Mueller, Chief Financial Officer; Cristin Hubbard, Chief Commercial Officer; and Greg Friberg, Chief R&D Officer.

I will now turn the call over to BioMarin's President and CEO, Alexander Hardy.

Thank you, Traci. Good afternoon, everyone, and thank you for joining us on today's call.

Turning on Slide 5. I am very pleased with the strong results across the business, leading us to raise full year total revenues guidance at the midpoint and reaffirm our VOXZOGO revenue outlook for 2025. In addition to top line performance, BioMarin has delivered expanding profitability and significant growth in operating cash flow, bringing our cash and investments part to approximately $2 billion at the end of the third quarter. We are focused on finishing the year strong, positioning ourselves to achieve record commercial results for the full year.

To date this year, we have delivered 11% increase in top line growth year-over-year. These strong results are driven by the performance of our global Enzyme Therapies and skeletal conditions business units as we deliver for patients around the world. We have built the Enzyme Therapies business unit into a $2 billion-plus franchise over the last 12 months with continued growth anticipated. In the skeletal conditions business unit, our first indication with our first product, VOXZOGO, the treatment of achondroplasia is expected to generate more than $900 million in revenues this year, leading us to reaffirm our full year 2025 VOXZOGO outlook and representing 25% growth at the midpoint of our guidance range. As the established standard of care in achondroplasia, VOXZOGO revenue has increased 24% and year-to-date compared to 2024.

Now in the fourth year of its global launch, VOXZOGO has represented a breakthrough therapy for families seeking treatment for their children with achondroplasia. Building on this innovation, we are excited to bring VOXZOGO's second indication forward for the treatment of children with hypochondroplasia. We have high confidence in the upcoming pivotal data readout fiber chondroplasia expected in the first half of next year, based on proof-of-concept data and more than 10,000 patient years of safety and efficacy data in achondroplasia.

Building on the rapid and successful global commercialization of VOXZOGO in achondroplasia, now available in 55 countries, we are well positioned to execute a strong global launch in hypochondroplasia, targeting 2027 should the data be supportive. Cristin and Greg will provide more details in a moment.

Turning now to our broader strategic objectives. Over the past 18 months, we have undertaken a series of initiatives designed to prepare BioMarin for future growth and expansion. As part of this effort, we have made difficult decisions including the discontinuation of multiple research programs that did not meet our criteria for advancement. Accordingly, today, we are announcing the decision to pursue options to divest Roctavian and remove it from our portfolio as we focus on the business units aligned with our strategic priorities. Roctavian is an innovative gene therapy that holds potential within the treatment landscape for severe hemophilia A. As a result, we are working to find an alternative that will allow for Roctavian to reach its full potential by ensuring access to those interested in gene therapy treatment. In the meantime, Roctavian will be commercially available in the United States, Italy and Germany. Throughout this process, we will support and monitor patients who've received Roctavian as their well-being is our top priority.

As we look to the future, we are pleased that our breakthrough medicines are in high demand and reaching thousands of patients around the world. Our financial performance so far this year reflects strategic investments in the Enzyme Therapies and skeletal conditions business units, both of which remain central to our growth strategy along with increased business development opportunities and our own advancing internal pipeline. Building on this momentum, we look forward to the many data readouts and potential new approvals ahead along with new business development opportunities as we focus on the next stage of BioMarin's growth.

With that, I will now turn it over to Brian.

Thank you, Alexander. Please refer to today's press release for a detailed third quarter 2025 results including reconciliations of GAAP to non-GAAP financial measures. All 2025 results will be available in our upcoming Form 10-Q, which we expect to file in the coming days.

Starting on Slide 7, strong global demand across our portfolio of innovative medicines drove a year-to-date total revenue increase of 11% compared to the same period in 2024. Revenues from VOXZOGO and Palynziq each increased by more than 20% on a year-to-date basis. As we shared last quarter, we anticipate VOXZOGO revenue in Q4 to reach its highest level of the year due to the timing of contracted orders as well as increasing numbers of patients on therapy, and we expect full year 2025 VOXZOGO revenue of between $900 million and $935 million.

We are pleased with 8% year-to-date growth of the Enzyme Therapies business unit led by Palynziq. Due to large orders for Naglazyme and Vimizim in the second quarter, we note that Enzyme Therapies revenue was lower in Q3 quarter-over-quarter. And compared to Q3 2024, Enzyme Therapy revenue in the quarter was relatively flat primarily due to a higher volume of Aldurazyme quarter last year. Given the strong top line performance so far this year and our expectations for the fourth quarter, we are raising the lower end of our full year 2025 total revenue guidance to $3.15 billion, with the midpoint of the range representing double-digit year-over-year growth.

Now moving to Slide 8. Q3 2025 results include a charge of $221 million for acquired in-process research and development, or IP R&D. On a pretax basis related to the Enzyme's Pharma acquisition completed on July 1 of this year. This acquisition-related expense represents an approximate impact of $1.10 on a per share basis. The IT R&D charges significantly increased both GAAP and non-GAAP R&D expenses in the third quarter. And along with higher SG&A investments, across our skeletal conditions and Enzyme Therapies business units resulted in lower year-over-year operating margin and diluted earnings per share both on a GAAP and a non-GAAP basis. However, looking past the IP R&D charge, BioMarin's underlying strong revenue performance and operational efficiencies drove increased year-to-date GAAP and non-GAAP diluted earnings per share. Further, we recognized lower tax expense during the third quarter due to the timing impact of the Enzyme IP R&D charge on our quarterly estimated tax rate as well as some tax benefits from the recently enacted tax law.

Taking these dynamics into account, alongside our expectations for strong revenue growth and continued operational execution in Q4 2025, we are updating full year 2025 non-GAAP operating margin guidance to between 26% and 27%, and non-GAAP diluted earnings per share guidance to between $3.50 and $3.60. BioMarin continues to generate robust operating cash flow, reaching $369 million in the third quarter, $728 million year-to-date attributing to the company's total cash and investments balance of approximately $2 billion at the end of Q3. We expect this momentum to continue, both solidifying the sustainability of our profitability and cash flow and building incremental capital to invest in future growth through business development.

Now moving to Slide 9 and to summarize, we have updated our full year 2025 guidance across total revenues, non-GAAP operating margins and non-GAAP diluted earnings per share, incorporating the impact of the Q3 IP R&D charges. This update reflects a net improvement in our expected financial performance net of the IP R&D charge of about $0.15 per share through non-GAAP diluted earnings per share. We are executing on our business plan so far this year and today's guidance updates reflect both our year-to-date performance and our confidence in strong top line and profitability growth in the final quarter of 2025.

Finally, we are sharing an update on our previously provided 2027 revenue outlook given the high level of interest. Based on the many unknowns and variables impacting our revenue over the next 2 years, mostly the impact of VOXZOGO potential competition. We recognize that there are a range of outcomes from which a single scenario cannot be predicted with enough certainty at this point in time. We have developed a number of scenarios and will share that the lower end of our range of estimates is in line with current 2027 top line consensus per FactSet, excluding Roctavian. And on the higher end of the range of estimates, there are scenarios that reach $4 billion in total 2027 revenues, also excluding Roctavian. But again, given the many unknowns between now and then, we are not providing a specific estimate or more narrow range. Going forward, we will continue to execute on our strategy and monitor the most impactful variable. However, we do not plan to provide additional estimates of 2027 revenues, and we plan to follow our usual process of providing full year guidance at the beginning of each year with the usual quarterly updates.

Thank you for your attention, and I will now turn the call over to Cristin for a commercial update. Cristin?

Thank you, Brian. I want to begin by acknowledging the exceptional work from our teams across the world. This dedication has delivered strong year-to-date results for BioMarin's commercial portfolio.

Now moving to Slide 11. We are pleased that Palynziq's strong performance resulted in another quarter of more than 20% growth, reflecting more patients reaching efficacy and adhering to therapy. Palynziq's sustained growth demonstrates the PKU community's continued belief in its unparalleled efficacy profile and the importance of reaching normal fee levels for effective treatment. We are pursuing approval of Palynziq for adolescents aged 12 to 17 in the United States and Europe in 2026, potentially enabling this younger group of people to have access to therapy during an important period of transition to adulthood. Beyond Palynziq, year-to-date revenue growth across our Enzyme Therapies portfolio reflects increased new patient starts across all products and strong adherence to therapy, reinforcing the durability and high penetration of these treatments, despite quarter-to-quarter order timing dynamics.

Now moving to Slide 12. VOXZOGO for the treatment of achondroplasia was available in 55 countries as of the end of the third quarter, with new launches across multiple geographies. Global expansion and demand drove year-over-year VOXZOGO revenue growth of 15% in the third quarter and 24% year-to-date, with growth in patient numbers quarter-over-quarter. For the remainder of 2025, we expect large contracted OUS orders, deeper penetration across our growing VOXZOGO footprint and quarter-to-quarter new patient starts to result in Q4 being the highest of VOXZOGO revenue for the year. Outside the U.S., with a large majority of children eligible for VOXZOGO are located, our global footprint remains a powerful growth engine, and we saw strong uptake across key large markets during the quarter. With approximately 75% of year-to-date VOXZOGO revenue generated outside the U.S., we expect significant opportunity ahead as we open new countries and more deeply penetrate countries that currently have access.

Leveraging VOXZOGO's best-in-class evidence package of health benefits beyond height, international treatment guidelines recommending treatment as early as possible and broad age label, we are focused on increasing access to VOXZOGO for more children around the world and keeping them on therapy to realize the greatest health benefits.

In the United States, the team has been laser-focused on initiatives to expand VOXZOGO treatment. These efforts drove new patient starts across all age groups during the third quarter, but the majority of new starts from children under 2 years of age, and we expect that trend to continue. Due to the geographical dispersion and management across a range of specialties for older children in the U.S., we have implemented initiatives to address slowing uptake in that age group, noting that the initiatives will take time to show results. We have expanded this prescriber base across the country and increase the number of children on therapy across all age groups in Q3 versus Q2. Importantly, the strong adherence rates observed among families with children receiving VOXZOGO remain a key indicator of the product's value proposition.

Now moving to Slide 13. We look forward to building on the momentum we have established with the breakthrough treatment of achondroplasia as we pursue the next 5 indications in our skeletal conditions business unit. Achondroplasia represents the first of 6 indications we are pursuing for treatment with VOXZOGO and/or BMN 333, our long-acting CMP. With the pivotal data readout just around the corner in hypochondroplasia, we are preparing for a strong global launch should those data be supportive, and I'll share more about that in a moment.

We are also advancing our Canopy clinical studies with VOXZOGO across 4 additional indications, including Phase II studies in idiopathic short stature, Noonan syndrome, Turner syndrome and SHOX deficiency. These skeletal conditions represent a total addressable population or TAP, of approximately 420,000 patients. Acknowledging our focus will be on the most severely impacted subset of these children, representing a modest proportion of the total TAP.

We are expanding our leadership position in skeletal conditions building on VOXZOGO as the standard of care in achondroplasia with future potential indications, the second in hypochondroplasia and 4 follow-on indications across the Canopy trials. Our next-generation product, BMN 333, offers the promise of even greater efficacy, not just the convenience of the extended dosing interval, and we look forward to starting our Phase II/III study in the first half of 2026.

Now moving to Slide 14. Our experience launching VOXZOGO for the treatment of achondroplasia has given us a strong foundation to scale globally. We built the infrastructure, the relationships and the expertise to execute effectively as new indications come online, and VOXZOGO for the treatment of hypochondroplasia represents a potential significant breakthrough for patients. Hypochondroplasia is underdiagnosed because children with growth delays often do not receive a full diagnostic workup for various reasons, in part because hypochondroplasia presents with a wide range of symptoms and no single sign confirms the diagnosis. And families often face a complicated referral process and barriers to genetic testing, which slows down the path to diagnosis. These challenges mean many children go undiagnosed for too long, and that is why one of our priorities is improving early diagnosis for hypochondroplasia worldwide. We're driving initiatives like genetic reclassification, clinician education and patient and caregiver awareness, all aimed at driving earlier diagnosis. We're also optimizing diagnostic pathways so that in the future, children can potentially access therapy as early as possible.

Importantly, we're seeing robust engagement from health care providers across multiple specialties. That enthusiasm reflects growing recognition of the unmet unhypochondroplasia. This positions us well for the next phase. Phase III program in hypochondroplasia is progressing, with data expected in the first half of 2026 and a potential launch in 2027.

I'll now turn the call over to Greg to provide an R&D update. Greg?

Thank you, Cristin. Now moving to Slide 16 and to provide a little more color, hypochondroplasia is a serious condition with a potentially broad impact on the health and daily life of those affected. Children and adults with hypochondroplasia and face significantly higher rates of comorbidities and procedures when compared to the general population, covering areas like respiratory, orthopedic; ear, nose and throat and mental health. As a result, they often undergo more surgeries adding to the overall burden of the condition.

Beyond the medical challenges, the condition can affect quality of life in very real ways, making everyday tasks harder in creating social and emotional strain. These insights reinforce why it's important to advance treatment options for hypochondroplasia, a condition for which no approved therapies are broadly available today.

Now moving to Slide 17. At ASBMR in September, we presented important spinal morphology data for children under 5 years old with achondroplasia. These children were treated on our Phase II Canopy study with either vosoritide or placebo. Spinal morphology is one of the factors that contributes to spinal stenosis, a leading cause of morbidity in achondroplasia. Spinal stenosis, particularly in the lumbar region is a serious and all too common medical complication in achondroplasia, resulting in pain, muscle weakness and reduced mobility in the most severe cases.

Since measures of spinal canal reached near final size by age 5, early intervention is essential to prevent complications. Radiographs of the spine and our CANOPY study, demonstrated that children who received VOXZOGO experienced improved spinal measurements across all lumbar vertebrae and an overall improved curvature of the spine after just 1 year of treatment. As a reminder, these improvements were seen as compared to placebo rather than simply describing the natural history of growing children.

As these anatomic measures are often predictors of complications later in life, we intend to follow these patients in our Canopy extension study to confirm that they translate to reduced morbidity or need for surgical correction. Importantly, with these results, VOXZOGO is the only approved therapy with data showing a positive impact on spinal morphology, and these findings add to the extensive body of evidence supporting VOXZOGO's health benefits beyond improving growth.

Now moving to Slide 18 and BMN 333. We will focus on our next-generation therapy for achondroplasia. Last call, we shared that multiple cohorts from our Phase I study had demonstrated superior pharmacokinetic measures of 3 CNP as compared to another long-acting CNP agent. We're advancing the program and are targeting initiation of Phase II/III in the first half of 2026. We have a strong conviction that the multifold increases in free CNP AUC that we observed with the BMN 333 can translate into clinical benefit. That confidence comes from 3 pillars: Preclinical data showing roughly double the attributable growth versus VOXZOGO at high free CNP exposures; human genetics, where natural CNP pathway over activation leads to extreme height without unexpected safety issues and clinical dose response data from other long-acting CNP agents, suggesting that additional growth may be possible at higher exposures.

BMN 333 is the right agent to test this hypothesis. And in our Phase I study, we observed multiple cohorts, which met our modeled PK requirements to deliver superior growth. From a design standpoint, the upcoming study will include a dose-ranging Phase II portion, followed by a Phase III comparison against Voxogo, assessing safety, growth and resulting functional outcomes.

Our goal is clear. BMN 333 is designed to deliver superior efficacy versus VOXZOGO without additional safety signals. We've engineered the molecule to safely achieve these higher free CNP levels and our target product profile reflects that ambition. We've aligned with regulators on this approach and our strategy is to establish a new standard of care for achondroplasia. BMN 333 represents a major opportunity to build on VOXZOGO's success and further strengthen our leadership in skeletal conditions.

Finally, on Slide 19. Here's a snapshot of a few highlights expected across the pipeline through the coming quarters. As mentioned, in our skeletal conditions portfolio in the first half of next year, we're excited for the Phase III data readout for VOXZOGO in hypochondroplasia as well as the initiation of our Phase II/III registrational enabling study for BMN 333 in achondroplasia. For Enzyme Therapies, we look forward to extending Palynziq access to younger populations with a potential approval in 2026 of the Palynziq label extension for adolescents aged 12 to 17. In the first half of 2026, we also expect Phase III data for BMN 401 in children aged 1 to 12, providing a potential first in disease medicine for an ENPP1 deficiency.

Our earlier-stage pipeline is also advancing, and we plan to share a clinical update by the end of the year for BMN 351 for the treatment of exon 51 skip-amenable Duchenne muscular dystrophy. At this next update, we intend to share whether data from our 6- and 9-milligram per kilogram cohort, supports our stated ambition to reach mean muscle dystrophin increases of 10% at steady state. And a reminder, this is without additional adjustment for muscle content. Safely achieving this target defines our go criteria for a potential registrational study.

In summary, we have multiple data readouts and regulatory milestones ahead, and we look forward to keeping you updated as we execute on these opportunities to drive growth and deliver value for patients.

Thank you for your attention today. We will now open the call to your questions. Operator?

[Operator Instructions] Your first question comes from Phil Nadeau with TD Cowen.

Question is on the 2027 guidance. Can you talk a little bit more about the scenarios you see? And maybe more specifically, why are you rescinding the guidance now? What has changed over the last year since it was initially issued?

Phil, this is Brian. Thanks for the question. I'll take that one. Since we shared the original $4 billion 2027 outlook last year, we've had a year to assess the various factors that have arisen since then, including the impact of potential VOXZOGO competition. There's other puts and takes. We've got our acquisition of Enzyme and the potential for BMN 401 to launch in the pediatric indication in '27. We've also incorporated today's announcement that we're pursuing options to divest Roctavian. We've developed a number of scenarios to capture what we believe are different outcomes across these key variables, across the entire portfolio. But given the many unknowns and their impact on predicting 2027 revenue, instead of taking an official position on those key assumptions, what we've done is outlined the range of our lower case estimates and our higher case estimates. I'll share that in the lower case estimate, that reflects the scenario with 2 competitors successfully launching and taking significant share by 2027. And I'll share in the high case, that reflects the scenario where there is a significant delay in the competition, for example, successful intellectual property for BioMarin. And again, in between there, there are a number of outcomes highly uncertain at this time and therefore, narrowing the range or coming up with more specific point-in-time estimates at this time isn't appropriate. Again, I'll just finish by saying reiterating my comments in the prepared remarks that in that lower case estimate for BioMarin, we are still at consensus for 2027.

And maybe just a follow-up. I think when you issued the guidance a year ago, you were -- you suggested that competition aspect into the guidance. Do you now have a different appreciation or a different concern about how that share that competition as -- specifically in...

Yes. Thanks, Phil. We did the initial work last year following Investor Day when the competitor data was released and at the time, modeled some competitive impact. There was some ability to absorb that into our original forecast at the time, and we did have some other upside last year. We have taken a different view. We've observed trends in the marketplace, both what we are experiencing in these markets as well as, again, different potential competitor scenarios. And this is not a single point in time estimate. It is not our forecast. We merely wanted to reflect what the range of outcomes could be from our view.

The next question comes from Salveen Richter with Goldman Sachs.

Can you speak to why VOXZOGO sales were down quarter-over-quarter? And then also -- just help us understand here the business development strategy, just given that there seems to be so much of a focus on VOXZOGO and how that plays out, but you're kind of stuck from just given all these various dynamics competitively, when can we start to see that business development lever or levers kind of emerge to really add to your portfolio?

Salveen, this is Brian. I'll take the first part of the question on Q3, VOXZOGO. And yes, slightly down quarter-over-quarter. Looking back to the remarks that we made back last quarter when we signaled that we were expecting VOXZOGO revenue for the second half of the year to be back weighted to the fourth quarter. We noted a couple of specific larger orders where there were true timing shifts, but also just market-by-market forecast for Q3 and Q4. What ended up happening in Q3 is that, that was just a bit more exacerbated and the timing shifted a little more. I'll point you to 2 things. One, reaffirming the total VOXZOGO range today for the year of $900 million to $935 million, again, just timing between Q3 and Q4. Hesitantly and most importantly, steadily adding patients across all markets and all age groups in Q3, which, again, just that's the key indicator of long-term demand, and we're going to continue to experience some of these quarter-to-quarter order timing fluctuations.

Salveen, thank you very much for your question. It's Alexander. I'll answer the part of your question around business development. First off, I would say, we've got strong underlying business performance in both Enzyme Therapies and its scale conditions. I mean 11% year-to-date growth across both business units. But we are also producing significant cash flow. Our balance sheet is very strong, and we have conviction that assets are worth more in our hands than they are right now. So business development is a very important part of our strategy right now. We have a number of deals that we're in pursuit of. We've always been a company focused on early-stage collaborations, but what is different or how has our strategy has evolved is we're also looking at Phase III pre-commercial and commercial assets because, again, we think we can add value to all stakeholders with those in our hats. So we have a number of deals in the works and in sight. And obviously, business development is never completely within your control, but it remains a very high priority for us, and we're looking forward to sharing more information when we have that.

The next question comes from Cory Kasimov with Evercore.

I guess I have a follow-up on two questions that were asked. First of all, Brian, I appreciate the commentary you made on the previously issued '27 guidance. I think the way you framed it is helpful. However, I'm curious if you have any qualitative commentary you could also share in your prior long-term mid-2030s guidance with regard both to the opportunity for VOXZOGO as well as the anticipated CAGR for the Enzyme Therapies business? And then a follow-up for Alexander's capital deployment commentary. Given the pretty big cash balance and good operating cash flow generation you alluded to, have you given much consideration to share buybacks? Or are you really just holding that capital for other uses like BDs you were talking about?

Thanks, Cory. This is Brian. I appreciate the question. And it's a similar analysis, as I shared with the '27 range of estimates there. We are absolutely planning on continued sustainable growth across the business. I'll share that we are still targeting high single-digit sustainable growth rate for the Enzyme Therapies over time. VOXZOGO, we do plan to continue to grow the brand by deepening patient penetration across all markets, plus the indication expansion opportunities where we will always have a lead. However, the offsets to that, most notably being potential competition are still very uncertain at this time. So we and the investor community will watch all of these variables very closely and we'll keep you updated in terms of what we're seeing along the way. But again, we feel it's prudent to avoid taking an official position on a forecast with so many uncertainties. So not quoting a long-term growth rate at this time for that reason.

Cory, this is Alexander. I'll answer the second part of your question with regard to capital allocation. It's obviously something we discussed with our Board frequently. It's very, very important, obviously, that we're really effective stewards of the significant capital we've generated through the success of our business. We actually think that business development is the greatest opportunity for us to drive significant incremental growth rate on the top line, and that's the most highly correlated stock appreciation. .

We have this strong financial profile. We have this capability in rare diseases, whether it's in research, development, manufacturing, commercialization. And we're convicted that assets are worth more in our hands and where they are right now. In an environment that we have right now in the U.S. with biotech stocks, there are many rare disease companies that are undercapitalized and under resourced. And those assets are worth more in our hands. So we are -- as you can tell, we're very convicted that business development is the best use of our capital. That remains our priority, but it's something that is a board we constantly look at.

The next question comes from Joe Schwartz with Leerink Partners.

Great. For the upcoming BMN 333 PK data, what specific exposure levels would give you confidence that you can achieve clinical superiority over VOXZOGO? And as you move into a head-to-head superior trial against VOXZOGO, what is the minimum annualized growth philosophy delta over VOXZOGO that you believe could be required to demonstrate clear clinical superiority, drive patient switching and reestablish a standard of care in the face of potential competition?

Thanks, Joe. This is Greg. I'll take a stab at both of those. With regard to the exposure levels, the stated level that we were looking for from our Phase I PK study was while we were looking at the free CNP level. So in the case of VOXZOGO, of course, that's the drug itself. In the case of other molecules, it would be the release active quantity. We were looking for increases of at least 3x on the AUC. And as I mentioned in our prepared remarks, we actually saw 3 different dose levels where we achieved that in that ongoing Phase I study. So in our dose ranging, again, we'll have an opportunity to test a variety of levels that met that criteria.

With regard to the change in AGV over VOXZOGO, not ready to comment today on an actual number. Sorry to disappoint you there. I will add, though, that we have looked at this very closely, spoken with both clinicians as well as patients, and we've determined a level of differentiation that we think will be not only clinically meaningful, but also has the potential to pull through to the end points that really count, which are not just linear growth, but are all of those measures of health and wellness and function that we think, again, these patients deserve from a next-generation therapy.

The next question comes from Jessica Fye of JPMorgan.

I had a couple on the guidance and a couple on the pipeline. On the guidance, I don't have FactSet. What is the 2027 FactSet consensus, excluding Roctavian just we know what that lower bound is? And then the second one on the guidance -- maybe just asking about the other 2 elements of the longer-term targets that I don't think Corey mentioned. Should we still expect 40% non-GAAP operating margin starting in '26 that could expand to the low to mid-40s and the greater than $1.25 billion of CFO starting in 2027? Or were those sort of top line dependent and more in question now? And then the 2 on the pipeline. For 351, my understanding is look at 6-month biopsy data for the 6-milligram cohort. What should we expect for the 9-milligram cohort? And second one, the pipeline is for hypochondroplasia, can you remind us of the powering for that trial? And is that sig, sufficient in your mind? Or is there some minimum delta on efficacy you want to see to meet your target product profile?

Thanks, Jess. This is Brian. I'll speak to those first couple. So first, just to clarify that FactSet math for you. We are showing FactSet total revenue consensus for 2027 of $3.725 billion, and that includes $75 million of Roctavian so that without Roctavian consensus would be $3.65 billion in '27. And then with respect to the 40% operating margin target next year that does remain our target, just a reminder that we've grown profitability and operating margin significantly over the last 2 years due to our strong underlying execution and the focused cost transformation. We do expect that to continue heading into next year and hold that 40% target. I will say that our operating margin objective is rooted in driving efficiency in the business through cost, cost and process transformation, but without compromising value-creating activities. So any of that in the lower-end scenario over time if we do face a trade-off in this next year or more beyond, if we face a trade-off between preserving those value-creating activities and hitting the 40% margin, we will prioritize value creation to maximize long-term shareholder value. But right now, cost transformation and the target for next year is on track, we'll be prepared to update that again when we issue 2016 guidance early next year.

Thanks, Jessica. This is Greg. Let me take your 2 pipeline questions. With regard to 351, just as a reminder, what you can anticipate as a top line result that will be a combination of all the safety data that we have. That will be the 6-milligram and the 9-milligram per kilogram cohorts as well as the early data that we have. We'll be looking at the 12-milligram per kilogram, which is currently enrolling. What we will be also looking at is biopsy results and dystrophin levels from muscle biopsies in both the 6- and the 9-milligram per kilogram cohort. Our goal again is to have a level that predicts a steady state that we would be hitting this 10% level, which is a quite ambitious target. That's not correcting for fat and muscle content. That is a level that has yet to be seen in programs targeting exon 51.

With regard to hypochondroplasia, we powered the study to measure for an HEV delta similar to what's been seen with VOXZOGO with achondroplasia. Though as a quick reminder, the Dr. Dauber data would suggest that growth in hypochondroplasia maybe on the order of 1.8 centimeters per year a little bit more, which gives us confidence, again, that this is a well-powered study for hypochondroplasia.

Sorry, Jess, this is Brian. I'll come back again because I realized you had another part to your question about that '27 cash flow and that greater than $1.25 billion. So I'll use your word there. That was top line dependent. And therefore, in the lower case scenarios would be somewhat proportional to the overall revenue scenario. But I will say, again, we're generating significant operating cash flow today, almost $370 million this quarter, over $700 million year-to-date. We've got a number of working capital optimization initiatives that we're introducing across the enterprise over the next 2 years, as Alexander touched on with respect to capital allocation strategy and business development, this cash balance these cash balances and the sustaining cash flow that we're building have the opportunity to be -- opportunity to be deployed as growth capital going forward. So it's a top priority for the company, but in short, that $1.25 billion was tied to the...

The next question comes from Paul Matteis with Stifel.

This is Julian on for Paul. You talked about how your views have changed on the market as well as -- and thinking about some of these best case scenarios and some of these more bearer scenarios. Can you talk about the contributions of potential commercial competition versus the risk to some of these competitors entering the market? And how much do you think could be attributed to your overall view on being able to have a positive outcome and litigation? Just curious on what you think about that. And then further on the DMD program, can you just talk a little bit more about the 10% bar that you're sort of setting for yourselves there. Obviously, I think a lot of investors believe that the bar for regulatory approval is meaningfully lower when thinking about exon skippers that are currently approved. So just thinking about what sort of informs that view? And if there's any sort of outside case that you could push a program forward, that doesn't meet that bar?

Thanks for the question. This is Brian. I'll start with just outlining those bookends of the lower case estimates and the higher case estimates again. And then I'll hand it over to Cristin to make a couple of remarks on the specific market trends we're observing. So for the sake of making these assumptions and developing these -- the lower end of these estimate scenarios. Again, we took the assumption that -- two competitors come to market and that by the end of 2017, they've been successful with their launch and take significant share. And then in the higher case estimates, and there's a range in between outcomes, of course, that includes either less competition or success with our intellectual property defense. And again, neither of those are official forecast, we are illustrating what the revenue impact of those potential outcomes could be over time. And again, at the lower end, comfortable with consensus today. In the higher end, we can build back to $4 billion. And again, this is excluding Roctavian. Cristin, do you want to comment on?

Thanks, Brian. So -- yes, so looking at the overall trends, I just want to note what Brian, you said earlier and we said in the prepared remarks, and that is that we have continued to add patients on treatment with VOXZOGO quarter-over-quarter, and that is worldwide. Now if we dig a little bit into the U.S. market, in particular, we do see that the majority of those new patient adds is for children under 2 years old. And we want to see that, right? This is patients getting on treatment early, the international guidelines also reiterate the importance of this. And what we see is our adherence rates are remaining strong. And importantly, we are expanding the prescriber base primarily or mostly in the pediatric endocrinology specialty. But what we've also seen in the U.S., and this is not unexpected for something that's fourth year into launch. We are seeing a slower rate of growth in the older patients. Now we expected this to some extent. One, many of these patients are geographically dispersed and in different parts of the country and, therefore, harder to find. Not to mention, they're being managed by different specialties. But I will say that the team has been very focused on drawing out initiatives that will target these patients, and we expect that those initiatives will take a little bit of time to play out. But it's really important that we note that the U.S. is 25% of our overall revenues and really looking to the ex U.S., which comprises 75% of the revenues, we do reiterate our guidance of $900 million to $935 million this year alone. And if we look into the future, we continue to see VOXZOGO as a strong growth engine for us. This is a product that, as Brian has said, has been first to market in achondroplasia. We expect the same in hypochondroplasia, and we have a robust life cycle management plan behind it, launching a new indications over time, not to mention our asset BMN 333. So an important growth engine for us, but it's important to note the trends and the dynamics that we're seeing in the markets today.

Thanks, Julien. This is Greg. Just if I could tackle the DMD question, if that's okay. Yes, we have set a pretty ambitious bar with the 10% level. Just to back up a little bit, of course, -- muscular dystrophy, the name of the game is opening a therapeutic window in these patients and delivering meaningful results. We've made some choices with the way we've engineered this molecule. We've chosen to use so-called phosphorothioate chemistry instead of what most exon skippers use, the Morpholino approach is. That opens this opportunity, again, to open a large therapeutic window for what we think will be a potentially dramatic effect. There are some challenges associated with that as well, though. Weekly administration is required. And the reality is that steady state because of the very long tissue half-life will be out of a year or more. And so what we've done is we've set an ambitious target. We know that we're looking at biopsies at the 6-month time frame. Now as a quick reminder, if we see something between about 3% and 5% at 6 months, that will translate in our model to 10% at steady state. We chose that number because of the human genetic data that suggests dramatically improved functional outcomes in patients that reach those sorts of levels, similar more to a Becker's muscular dystrophy. And we think in the face of some of the characteristics of this molecule, we think that, that's sort of doubling of dystrophin as compared to some of the data that's been produced with other exon 51 skippers would be an undeniable advance in the field. And so while we also will be looking, of course, at functional data, we'll look at the totality of the data, that 10% bar is our true north right now to deliver something meaningful for patients.

The next question comes from Chris Raymond of Raymond James.

Just two actually for me. Brian, I heard what you said about '27 not being guidance, just to sort of range of outcomes. But so I won't say it this way. But -- is it safe to say you're more concerned about TransCon CNP than infigratinib? And I guess it is -- when you talk about that FactSet number being sort of the low end, is it your assumption that Ascendis gets first cycle approval with just 1 year's worth of data when their PDUFA date comes next month? Or does that even -- does that factor into your thinking? I know it's a little bit removed from 2027, but just kind of are you getting that granular in your thinking?

And then maybe an M&A question, Alexander. You guys; talk about wanting assets that are under resourced and could be better served by the BioMarin infrastructure. For the Enzyme asset 401, can you maybe talk about how you have leveraged and approved upon Enzyme's efforts in terms of patient identification, outreach, other things that you've done to make that asset better?

Thanks, Chris. This is Brian. I'll start. I appreciate the question. With respect to the two potential competitors, first, I'll say I don't think we're going to comment on them versus each other, one versus another. But I will say this is, I think, at the heart of your question. What we've assumed in those lower case estimates that I referred to in that lower end of the range, we have assumed middle-of-the-road assumptions with respect to that -- those companies communicated time lines for their approvals, one of which has a PDUFA next month, as you know it. And then following those action dates and communicated approval and launch time lines by those other companies, we then model what a successful launch for those competitors could look like, and that's where we get this point of the lower end estimate where VOXZOGO remains a growth product for us over these next 2 years. But I think that's all we'd have to say at this time.

Chris, I'm going to -- I'll take the first part of the question and then hand it over to Greg because obviously, 401 is very much in the development stage right now. But overall, what Amarin is now is we were executing rare disease at scale. I mean we're in 80 countries with an incredible muscle and we're confident that's going to magnify the potential impact and ability to reach patients with these genetic conditions all around the world. Our capabilities, the ability to find patients to start them on therapy and then keep them on therapy. These are capabilities we've built over 20 years. So very confident that should this product be approved, we'll be able to leverage that and achieve significant things for 401. But right now, our focus is on the execution of the clinical program, and I'll hand it over to Greg.

Thanks, Alexander. Yes, Brian, just as a quick reminder, again, the deal closed on July 1. So we're not quite 4 months into the integration at this point. It's premature to cite, I think, too many examples of the impact that, that scale of our capabilities and resources can have on the totality of the program. It is very early days. But I will reassure you again that we're leveraging all of our capabilities, whether it's interacting with regulators around the world, whether it's looking for additional indications. And that first sign, I think that we'll be able to talk about in future calls will be our preparation that's ongoing for an adult indication in this ENPP1 deficiency area. We're very much looking forward to taking this asset that the Enzyme team, quite frankly, did a remarkable job being able to recruit these very difficult to find patients, difficult to reach patients onto a pivotal study, and we're looking forward to turning the card over for the ENERGY III study in the first half of next year.

The next question comes from Sean Laaman with Morgan Stanley.

Just get your latest thoughts on orphan drug exclusivity, kids under 5 and what you think about the potential switching to a competitor is the first one. And the second one, if I'm getting a narrative for without business development, BioMarin, a capital accumulator. Just to get your thoughts on what you think your balance sheet capacity is and what you see as an efficient balance sheet structure?

Sean, this is Cristin. I'll take the first question. And I think it really comes down to that element of a patient switching. So assuming we're -- as we're looking at there being a potential for more therapies on the market for the treatment of achondroplasia, we do think that there's a distinct difference between patients that are new to therapy that are naive and the choices that they will make and importantly, those that are already on therapy and seeing great efficacy. So what we hear in both our market research and in our conversations with physicians and families alike, we hear that the majority of patients when they are looking at the opportunity to switch if they are satisfied with their treatment, they will more likely than not remain on therapy. Now of course, some will choose not to. But that is irrespective of orphan drug exclusivity. That is just a decision that a physician, caregiver and patient are likely to make in that moment.

We do think that the adherence rates that we see on VOXZOGO, which remain really high are a testament to the product's efficacy and safety for that matter and the impact that patients and families are seeing. And so it really does come down to that element of a decision made between the physician and the family at that time as to whether or not a switch is appropriate. But we think that, that's going to be a different decision than for those that are naive to treatment.

And I'll answer the fire power part of your question there, Sean. This is Brian. We estimate that our total firepower is between $4 billion to $5 billion. We're just reporting $2 billion of cash investments on hand, a significant portion of which is available to invest in future growth. And then with our current and growing EBITDA profile, we do have a chance to leverage our earnings and assuming a reasonable ratio we believe that in total, we've got $4 billion to $5 billion to deploy as growth capital.

Sean, I just want to jump in. Did you -- was your question around orphan drug exclusivity as well?

Sure. It was.

Okay. I apologize about that. Yes, I mean we've submitted a petition to the FDA concerning the drug exclusivity of VOXZOGO assert that. The planning of that is we'll find that out at the time of PDUFA. So we feel evicted the status and the importance of the incentive with regard to innovation in these orphan diseases, and that's very much in process right now.

The next question comes from Akash Tewari with Jefferies.

This is Aki on for Akash. So you talked about how the lower end of your 2027 scenarios is basically in line with top line restore consensus in part due to the changing competitive environment, which includes a sadist, which had positive data shortly after your initial guide. And now it sounds like we're kind of revising the case estimate ahead of pending Phase III data from Bridge. So number one, why not just wait until the BridgeBio data comes out first half of next year? I mean should we assume that the lower end of your '27 case is the most conservative case that has seen superior efficacy versus for Bridge? And then in the most bullish scenario, it sounds like you are either modeling at most $4 billion or lower in red. Just wanted to confirm that I have that correct.

Thanks for the question. And yes, I tried to capture the primary take away from this exercise, which is that we've modeled a significant level of scenarios across all of our portfolio, across all markets and given the various key assumptions. We did that given the significant level of investor interest on the topic. We appreciate that. When we gave the original $4 billion guidance at Investor Day last year, that was before seeing the first competitor data here and have made some updates along the way. But really outlining the full range of outcomes and including a lower case that has 2 competitors launching successfully, but yet our revenue is still landing at current consensus for '27, we thought would be useful. I'm not characterizing that as a worst case scenario nor am I characterizing the $4 billion is the best case scenario. We just decided to share with you a range of lower case estimates in our higher case estimates. And on the upside, that would include, I mentioned as an example, intellectual property defense success, but it can also include success across the entire portfolio. We're competing successfully.

That concludes the Q&A portion of the call. I will now turn it back to BioMarin's President and CEO, Alexander Hardy.

Thank you, operator. We are pleased with the third quarter results across the business, leading us to raise full year total revenues guidance at the midpoint, reaffirm our VOXZOGO revenue outlook for 2025. We have delivered expanding profitability and significant growth in operating cash flow, bringing our cash and investments balance to approximately $2 billion as of the end of the third quarter. Financial performance so far this year reflects strategic investments in the Enzyme Therapies, skeletal conditions business units, both of which remain central to our growth strategy. Building on this momentum, we look forward to the many data readouts potential new approvals ahead along with new potential business development opportunities as we focus on the next stage of BioMarin's growth. Thank you for joining us today. We look forward to speaking with you all soon.

This concludes today's conference call. Thank you for joining. You may now disconnect.

Good morning, everyone, and welcome to this good morning. Welcome to Morgan Stanley Global Healthcare Conference. I'm Sean Laaman, Head of the SMid-Cap Biotech Equity Research team here at the firm. Before we commence, for important disclosures, please see Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have the pleasure of hosting BioMarin, our President and CEO, Alexander Hardy and CFO, Brian Mueller, welcome to the both of you. Alex, would you like to make some opening comments? Or do you want to go straight to Q&A?

No, I'd love to make some brief opening comments. First off, thanks very much, everybody, for joining us at this very busy conference and Sean, thanks for hosting. .

Welcome.

Yes, I've been at BioMarin since December 2023. It's been a very busy period, maybe a lot changes to the company to strategy, the structure, the pipeline, the portfolio. I'm very proud of the progress we're seeing. The execution is, I think, has been really, really good quarter after quarter. particularly excited about this last quarter.

And why do I say that? I mean, in prior quarters, we've seen strong financial and commercial performance. We saw that this last quarter with 16% revenue growth and leverage many times that to the bottom line. But what was exciting for me after a period of structural change to see the organization across the board performing and executing. So we saw really good important news with regard to our pipeline with 333, which is our long-acting CNP, a very, very important product in our pipeline.

We communicated the results that we've seen positive Phase I results. Importantly, why is Phase I results important? Because we were looking to see what levels of free CNP we can achieve with our goal of actually raising the bar from an efficacy standpoint. And we saw those results sooner, and those results are stronger than we even hoped for. And we announced we are moving into a Phase II, Phase III design program. And then in addition, we talk Palynziq in adolescents and making progress there with the new indication we just released the results last week at a meeting actually in Japan. So it's good to see the pipeline.

And the last thing sort of the trifecta is business development. And we basically went from start to finish on a deal in 1 quarter. And coming in, that was part of our strategy is to elevate the focus on BD at BioMarin. We needed to have a clear strategy, and we needed to have that capability in place. We've now got it and to have identified a deal and done it in 1 quarter and execute it and now integrated it. And it's a really, really nice deal. This just makes me very proud. I think we're really delivering on what we said we were going to do.

Sure, sure. Thanks for those comments. Maybe just to talk about the macro for a little bit or we're doing this with all that comes in. I'd love to have your view. So with China's rising biotech innovation. How are you thinking about the competitive dynamic? And does it influence your R&D and business development strategy?

Yes. Well, having spent time in China in a prior role, China is a formidable force. And we should be very [indiscernible] as a U.S. R&D enterprise, we should all be very much focused on China. I think it's a very, very important topic. When we look at specifically the space that we're in a genetically defined conditions, we don't see the level of activity or the level of I think the progress there that we see in other therapy areas.

I mean, clearly, in oncology, immunology, cardiometabolism sure you're hearing this from other people. And you can see it with the deal flow. In genetically defined conditions or orphan diseases, there's much less activity in China. It's something we're watching. But at the moment, the leadership role is in the United States, and it's our intention at BioMarin to continue to do that, but we're clearly watching what's going on. And we have, particularly from the BD side, very, very vigilant watching certain Chinese companies right now.

Sure, sure. It's our view too. It's rare disease in euros, more or less untouched at the moment at the visible levels at least anyway. So the third question on the macro. So what's been the most impactful -- sorry, second question on the macro. How are you currently leveraging AI or thinking about AI as a disruptive technology?

Yes. So this is, I think, like most companies, this is a big topic in the leadership team and with the Board. I see that AI has potentially transformative potential. At BioMarin, we've been making a lot of changes to fundamentally across the different parts of our business. AI is now something that we're really now focused on. Our strategy is we're kind of a -- we're very realistic. We know where we're starting from. A lot of the big companies have been investing in this very significantly for a number of years.

We really want to learn from what's working and what isn't. So our initial phase of our strategy is very much a fast follower strategy until probably now until '27 and then we'll move into an area where we'll have an ambition, particularly I'd say in these genetically defined conditions to be in a leadership position when it comes to leveraging AI. Now that fast follower doesn't mean that we're not doing it. We're doing it across the value chain.

So from an R&D perspective, just to give you an example, we're developing right now in hypochondroplasia should be the next indication we hope for our biggest drug, Voxzogo. And there, we've leveraged AI to explain what were previously variance of unknown significance and actually tied then to hypochondroplasia, increasing the prevalent population of the disease. That helped us actually recruit the study even faster. So that's really, really cool. I mean, AI is just really well suited in genetically defined conditions.

We're dealing with huge data sets to be able to mine that. So that's from an R&D standpoint. On the regulatory side, we're using AI to draft our first pass regulatory documentation. We're using in manufacturing, in terms of supply chain optimization, predictive maintenance in our plants. And then on the commercial side, another, I think, a really exciting use of AI.

I mean a large part of our business model in genetically defined conditions is finding patients. And we're using AI to predict where patients are likely to be in remote geographic areas, we can do hotspot analysis, and the AI can say, you know what, representatives should go to this city, in this town, you've seen these other cases it's highly likely there's going to be another case there, and we can focus our efforts in those areas. So hopefully that gives you an idea of how sort of a mid-tier company is starting to really leverage AI.

Yes. Fantastic. Thank you. And last question on the macro piece. So what's the most impact the most impactful thing to BioMarin on the regulatory side? Is it being MFN, has it been tariffs? Has it been changes at the FDA.

Yes. Well, I mean, if it's okay, Sean, I'll just go through each of them one-by-one. I would say from the FDA side, there's been a lot of very positive commentary in the head of the FDA and [ Carie ] has been doing his listening tours. He's been very particularly pointed out rare diseases is an area where the FDA can lean in and continue to innovate in terms of our regulatory approach.

Those are very exciting words. We're excited to see what that translates to. Our interactions in the meantime on a number of different areas has been positive. We've not seen any issues with staffing levels at the FDA up to this moment.

Again, it's something we're watching. But we got regulatory alignment with the FDA on the pivotal program for 333, the line in CNP that I talked about in the Phase II, Phase III, that was really, really important to get that clarity. It gave us good alignment and good feedback on the Voxzogo canopy program, which is the 4 subsequent indications, hypochondroplasia and then on the Palynziq adolescents. So, so far, we're seeing good traction from the FDA.

On the tariff side, we're all waiting for the 232, the result of the investigation, the 232 investigation. BioMarin's manufacturing footprint for those that don't know is we have a U.S. footprint and the European footprint. So we are in Ireland and the U.S. We're a net exporter from the U.S. So we export bit more than we import and we are quite well positioned and 2/3 of our revenue is ex U.S., 1/3 U.S. If the 15% tariff the EU holds, I think that will be a scenario which will be the lower end of potential impacts for us.

And if that was to be implemented tomorrow, we would be pretty confident, right, Brian, with regard to our 2025 guidance. So it's something we're watching. We'll have to see what the Q3 looks like. We have a whole range of mitigations that we could employ depending on how the fact.

All right. And then MFN. MFN is of course, is very much in movement right now. I think we're entering into a really critical time to see how the administration approaches this. I think from BioMarin's perspective, again, that ex U.S., U.S. revenue split plays in our favor compared to most companies in the sector. So 2/3 of our revenue is outside the U.S., 1/3 in the United States. Rare diseases and our own experiences, we have much tighter pricing corridors than most companies.

I think the thing we're specifically watching is MFN in Medicaid. Again, being in rare diseases, we have very little exposure to Medicare. Medicare is less low single-digit percentage of our population in the U.S. is covered by Medicare. Medicaid is really important for these genetically defined orphan diseases. There's very high levels of disability. The Medicaid is about, 1/3 patients are covered by Medicaid and very concerned if MFN was applied in Medicaid, what it would create in terms of this incentive to invest in developing for rare disease drugs.

So we're very active in trying to make sure that MFN doesn't happen. And specifically, MFN in Medicaid would be a setback, I think, for innovation. BioMarin has a number of hedges but we'll just have to navigate as we see fit.

Awesome. Thank you for such candor that was great. On to more specifics on BioMarin...

Coming from an Australian, when somebody says candor. That's good. That's a high bar. Great. Showing you off your game here.

I'm right on it. Don't be fooled by the relaxed nature. Could you talk about the recent Inozyme acquisition and why it was a good acquisition, how long have you been evaluating it? And do you foresee those or when do you foresee those revenues being a meaningful contributor to BioMarin?

We're very excited about the Inozyme acquisition as a new CEO coming in, people are watching your first deal we -- as part of our strategy, we really saw all for BD in the future of BioMarin is being supplementing the internal innovation with, I think, a really compelling proposition to all of our stakeholders. And I would say to investors, we have this geographic footprint in 80 countries. We have this capability set that we believe that assets are worth more in our hands than where they're sitting right now because in many cases, it's rare disease companies undercapitalized, underresourced if they're lucky, 1 or 2 assets that are focused very much on the U.S.

But the prevalence of these diseases are generally outside the U.S. and Europe, take achondroplasia, for an example, which is what our drug Voxzogo is indicated for 70%, almost 70%, 68% of patients are outside the United States, Europe, Australia, New Zealand and Canada. I mean, almost 70% of patients. So you need that geographic footprint. And we have that. We built that up over 20 years with our Inozyme therapy business. So when it came in, we started looking at Inozyme.

We liked the first indication that they're working on, ENPP1. We think it's a promise with other indications, but they had proof of concept ENPP1 but didn't have the capital to complete the Phase III. We didn't like the value at the time. We waited our time and process was then started. We executed really well in that process and a $270 million for a first-in-disease asset. There were no competitors in development with peak sales potential of $500 million to $600 million for the $270 million in outlay. We're the first readout from the pivotal studies in 2026. So we could potentially have the first approval in 2027.

So you can see why I was particularly excited about this deal. It's been well received as well, and we aim to do more.

Okay. Wonderful. In your Q2, you noted that the company plans to provide updates to the $4 billion FY '27 revenue guidance later this year and also the '25 guidance currently does not incorporate IP R&D expense associated with the recently -- with the Inozyme acquisition. Can you provide any more color on those 3.

Yes, John. I'll take that one. We are working through a comprehensive review of all the assumptions at the product level within our portfolio in terms of current 2027 expectations. There's been a lot that's changed, both internally within BioMarin and externally. And we just want to take full account of all those assumptions and work them back to our models.

And more importantly, almost the revenue expectation of '27 itself is, we want to provide more clarity and transparency around some of the assumptions, again, at the franchise or product level so that it can be better understood by investors. We appreciate that last year when we talked about that 1 big number, $4 billion in '27, it was an outcome of our full strategic review. We tried to give some clarity with the growth rates at the business unit level, but we don't think it was enough to fully understand how given all the circumstances that are out there, we think we can continue to grow revenue for BioMarin.

So we're doing that work, and we'll...

Wonderful, thank you. Maybe to go product specific on Voxzogo .So it's been launched in 51 countries, I think, more recently, up from 49 in 1Q. Where do you stand on near-term country additions and reimbursement wins? And how should we measure progress against your longer-term ambitions?

Yes. So the growth opportunities that we have in front of us for Voxzogo in achondroplasia. I mean clearly, we've got these 5 subsequent indicators that we're working on too. Hypochondroplasia being hopefully the next one. But with achondroplasia, there's really 2 key growth opportunities. that are ahead of us. One is fully penetrating the U.S. market.

We've been really devoting additional resources there. It was a slower launch in the rest of the world, but it's the largest single market that we have of that 10% of prevalence. So that is very important. And we've been pleased with the progress we've been making there. But the other part is fully occupying the full global footprint. So in these underpenetrated markets. And we're still -- you mentioned 51 markets now. The most recent launches have not been in small markets.

We're still launching in reasonable sized markets and making really good progress. It was one, I think we've got -- I'm not going to mention names and markets because clearly, we want to, from a competitive standpoint, be confidential around that. But in market, I think we got approval last year. We've already achieved a penetration of about 1/3 of the patient. We should be aiming for about 60% by the end of this year.

So this is not a small market. And it's really exciting that we're still on the sort of interesting seeing the sort of rare disease dynamics that it's a pretty short ramp to peak, but they start when the country comes online. And we're still filling out that footprint.

Again, we're in 80 countries, now 51, aiming for 60 by '27. And that's another large part of the growth. And from a competitive standpoint, that's a real competitive advantage is that geographic footprint because a competitor is going to have to be successful in many, many countries outside the United States and Europe.

Sure, sure. And could you talk...

I was going to say just to add, that shows up in our current revenue profile today. So our Voxzogo revenue guidance for 2025 is $900 million to $930 million, roughly 75% of that revenue is from outside of the U.S. back to the competitor standpoint, we're talking about a competitive space and a smaller fraction of our total Voxzogo revenue and, of course, portfolio revenue.

Sure. And I guess we stand back and look at where the share price is and everyone seems to think it's worth double where it's trading at least on the sell side. And so the overhang seems to be Voxzogo what happens with TransCon CNP. So just to get your agreement on that, if that's what you think that the major overhang is.

And then maybe sort of walk us through your competitive positioning of Voxzogo and your early indication on an age-related basis, your geographic spread and maybe why you might not necessarily think there is a material risk to Voxzogo?

Yes. I mean that is the big thing that we hear that's standing in the -- again, we're executing, delivering significant revenue growth and profitability. And we're doing the things we set out to do and said that we were going to do and hitting those marks. But still, the stock price doesn't reflect that. And the big overhang is this Voxzogo thing. I would say that it's 1/3 of our revenue. And if you look at the implied valuation, basically, people are giving us no credit at all for Voxzogo.

The Inozyme therapy business is growing what we said it would grow high single digit very, very consistently. And we're just seeing the beginning of the benefits that we move structurally to a business unit structure to allow focus on these different segments, and it was underappreciated internally and externally. When it comes to Voxzogo, 1/3 of our business, that dominates so much of the investor perception. I think there's real reasons to be more confident than the external world is giving us credit for.

The first is this geographic footprint where we've already talked about the presence in all these countries where that's where the patients are. That's where our revenue base is 75% is outside the United States. And we've built that over 20 years. We're very, very good at commercializing outside the United States. The other aspect is that achondroplasia in the guidelines say, diagnose and treat children as soon as possible after birth.

The majority of children in the United States are actually diagnosed prenatally and often, the decision to treat is made prenatally. We will have for a while, we're the only one that's indicated in infants. Competitors are going to have to produce that data and get regulatory approval. So they will mainly be dealing with the switch market because we will have the incident market will be predominantly in many of these developed highly penetrated markets will be in the younger age group.

And switching dynamics in pediatric rare diseases if the patients are doing well, then this is not something that is going to happen across the board. There will be some patients. I think this is misunderstood. We're not saying that no patients will be switched. But we're also not saying, and it's not credible to say that all patients will be switched. Reality is somewhere in between, and that's still a very viable and growing golden conditions franchise for us.

And then on top of it, we obviously are bringing 333 forward which we already touched upon. We're aiming there to actually surpass the efficacy of Voxzogo, which so far nobody we're going head-to-head against our own drug in our Phase II, Phase III design. And that will be a reason why patients will be interested and caregivers will be interested in switching patients is for additional growth velocity and most importantly, benefits beyond height. right?

So think about the, I guess, sort of maybe prevention of switches, but the Canopy clinical trial program, maybe you touch on that as something that you think whether investors are focused on or not focused on. Maybe that is a defense strategy, if you like, if you did lose in achondroplasia and try and net that off if that makes sense.

Yes. Yes. I mean just to put this into perspective, so we're developing -- we're already indicating in achondroplasia, we're now indicating -- or pursuing indications in 5 subsequent indications. The total addressable patient population that we're aiming for across all of those 6 indications is 420,000 patients. Achondroplasia is 24,000. So the way I think of this is, I mean, certainly in Achondroplasia, we have got a lot of growth ahead of us still. But Voxzogo, overall, with all of these indications, we have much, much more growth in these indications.

And we're aiming to be in those indications and to establish that leadership position well ahead of any competition. It's important to note that some of the other MOAs like FGFR3s will not -- scientifically, there's not a strong hypothesis for them to work in many of those indications. So we should have some white space we'll certainly have time, we believe, to get ourselves established. And those are large patient populations. Those studies are recruiting. As I said, hypochondroplasia is finished recruitment, and we're now waiting for the results and we're recruiting the Phase II studies for those -- for them for subsequent indications.

Got you. And maybe move to a little bit more longer term, but on 333, which is showing extraordinary promise with the data that you released, you talk through getting to the registrational study and sort of looking at sort of longer-term potential launch plans like how far are we potentially thinking?

Yes, yes. So I mean, why do we make such a big deal over Phase I clinical study? I mean, obviously, we wanted to see the safety profile as you would expect in a Phase I, but we are very interested to see the PK data in the healthy volunteers. We have this hypothesis that we would be able to achieve 2x to 3x the free CNP levels that have been hither to shown by other low-acting CNP agents. And that's what we've seen already in that Phase I. We're still going through the dosing cohorts.

So we declared success after 3. 2 of them exceeded where our target was, and that was enough for us to go with green light from Phase II, Phase III. You asked then about the approach now for the registrational study. So it's an operationally seamless Phase II, Phase III study. This will take 3 the dosages from the Phase I study into the Phase II study, together with the control arm of Voxzogo.

Again, we're aiming for superiority. Will then select 1 of those dosages and move it into the Phase III. We'll carry the sites through, so there will be a minimal delay. As I already mentioned, we already have FDA alignment on the design of the Phase II/III study and the endpoints. And we think that this study will be really compelling from a recruitment standpoint because, again, the control arm is Voxzogo, the standard of care. And we think there'll be a lot of patient and investigator interest in it.

The time line is at the moment, we're saying publicly 2030. As you can imagine, after the superiority from an efficacy standpoint, that's the next most important thing for us is speed to get this to patients as quickly as possible to raise the bar really meaningfully from an efficacy standpoint. So we'll give you -- we'll keep you updated. But at the moment, we're saying 2030 was with a lot of ambition to move that up.

Wonderful. Wonderful -- thank you, Alex. On Palynziq, so some strong numbers, 18 to 25, and I believe there's some more data around on adolescents. So potential utilization of that data to further accelerate sales.

Yes. So there's a lot of interest in the overall PKU space. There's a lot of buzz and noise right now. It's an important part of our Inozyme therapy business and our franchise. We've been the leaders in PKU. We've had Kuvan and now we've had Palynziq. We saw -- you mentioned briefly that Palynziq is growing extremely well. So it is -- it's grown in the first half by 21%. And we're really seeing strong patient enrollment in the second quarter. we're confident of its competitive profile. It's really dealing with a very different target patient population than any of the new entrants. So this is for the severe patient has really unsurpassed effect on fee levels.

You just saw that adolescent data almost 50% reduction in [ fee ] levels for those analysts and population and an opportunity to significantly improve diet. So quite a few patients that achieve an unrestricted diet, which is obviously -- approaches normal life for these patients. So we really think they're very different segments that any competitors are going to come, and we're pretty confident that Palynziq is going to continue to grow.

Wonderful. And are there any steps getting the supplementary BLA submission in U.S. and EU?

And what sort of revenue contribution would you expect from the label inclusion to 12- to 17-year-olds.

Yes. Well, I encourage people to look at that data, as I've already mentioned, was published last week after a meeting in -- or was released last week at a meeting in Japan. This represents about a 10% increase in the patient population, which is meaningful. There is the vast majority of patients, though, in PKU are still untreated. So this is another growth opportunity, but we're still, even without this, we're nowhere near fully penetrated with Palynziq.

This will just add to that. And I think it's exciting to have the prospect, the adolescence. Children are generally quite well controlled with diet and parents overseeing that kid. When it comes to adolescence, this is really an important stage to try and get these patients well managed before they're sent off to college and into the world. And now we have the prospect should the drug be approved be able to offer it in this segment.

There's a lot of excitement amongst the treatment community and the patient community about this. Well, thank you. And I believe there's a recent approval in the PKU space that changed your view on the competitive dynamic market share assumptions. As I mentioned, I think this will really be a different patient population with the new competitor coming in. I think they can have a very successful launch and Palynziq can continue to grow because really our sources of patients are very, very different.

They're more likely to cannibalize Kuvan, which is not a significant product for us as it's already after its loss of exclusivity. So I think that's where they're going to be the majority source of their patients, and we're going to be more focused on the severe segment or sort of taking a step back and looking at the investment case.

So there's I think you mentioned 30% of the revenue is coming from Voxzogo when you've got sort of a balanced portfolio across the rest of the business and for biotech companies sort of cracking profitability and generating cash flow and I think you've talked about setting the business into operating units. But I guess a lot going on in the R&D pipeline, but what's your rethinking from here is invested? Do we think about enough appetite in your current R&D portfolio to suck up cash flows? If you think about the business development opportunities, do you think sort of mid- to longer term formal capital returns? How do you put all those pieces together?

Yes, maybe I'll start and then hand over to Brian. We're focused on long-term sustained high levels of growth on the top line. And we think we've got the ability to do that. The modification of our strategy is internal and external innovation, as I've already covered it. we think that we can deploy capital really effectively to supplement our growth rates as an established player with that geographic footprint and that capability and with the cash flow, we think we can do deals. And those deals we be worth -- those assets will be worth more in our hands.

So that's our primary goal with our capital allocation. to have a blend of both internal and external innovation, continue to be an innovation-driven company, but delivering sustained high levels of profitability, which we -- I think we've already demonstrated we can do.

So Yes. Maybe I'll just back to the investment thesis part of the question. We think we're uniquely positioned because we believe we can continue to grow our existing commercial franchise. We also believe we can continue to innovate and invest in research and development, but also increased profitability and operating cash flow.

And then as we improve and accumulate cash flow, it becomes a virtuous cycle and then you can just reinvest that back in the business as well through external innovation, which gets the capital allocation in Alexander's noted it well we believe that investing in long-term growth over return to shareholders has the opportunity to create more value for shareholders over the long run. We look at all mechanisms and vehicles for capital allocation, and we discuss it with our board regularly. But even at current price levels, we believe that investing in future revenue growth and thereby profitability and cash flow is the best growth opportunity.

Wonderful. One final question. Is there anything that I didn't ask that I should have?

We didn't go further into the pipeline around 351 or 349. So maybe on another time, we would love to talk about that. Innovation is pretty very much the lifeblood and highly innovative drugs that really make a big difference for these diseases, genetically deploying conditions. That's what we're really excited talking about.

Wonderful. Well, we're out of time but at another time. But thank you, gentlemen, for your time today, it's been great.

All right. Thank you very much. Thank you.

Thank you.

All right. Thank you very much for joining us today. My name is Mohit Bansal. I am one of the biotech pharma analysts here at Wells Fargo.

And this is my first session of the morning. And I'm very happy to have, from BioMarin, Greg Friberg with us. Greg is the EVP and Chief Research and Development Officer at BioMarin. Thank you very much for being here.

Yes. No, thanks for the opportunity to join you.

Great. So I mean before I get to specific questions, I would love to know, it has been how long for you at BioMarin?

It's been a year.

It has been a year, right? So yes, I mean, I think BioMarin, from the science point of view, is a great company. I mean so many rare disease drugs you have developed.

So can you talk a little bit about your experience last 1 year and what investors should look forward to from the R&D engine side of the company?

Yes. No, thank you for the opportunity to be here and talk about what I love most, of course, which is the science.

I've been at BioMarin for a year now. And of course, when our new CEO joined about 18 months ago, we began an organizational transformation. A lot of focus on operating margin, but also an attempt to make sure that we're focused on the most high-priority programs, opportunity to make the biggest difference for patients, and really a focus on genetically defined conditions.

We've had a lot of wins over the last couple of months and we have some activities looking -- we're looking forward to. In particular, our BMN 333, our long-acting CNP program, I would love to talk about a little bit. We just released some data publicly about a month ago at our earnings call.

Similarly, we have 3 events coming up. One, a filing for adolescent expansion for our PALYNZIQ project for PKU. We are turning over a card with our newest member of the stable of assets, BMN 401. This is the Inozyme program, a first-in-class -- first-in-disease therapy for ENPP1 deficiency. We'll turn over a card for the so-called ENERGY 3 study in the first half of next year. And finally, for VOXZOGO, the hypochondroplasia program, which recruited about 5 months ahead of schedule, we saw that as a very good sign, we'll be turning over the card for that pivotal study next year in the late second half as well. So more to come there.

And again, it's not just about internal innovation. Part of our evolution, James Sabry joined our organization just 1 week after I joined, and we're thinking about R&D not simply as sourced internally, but really internal and external innovation are going to be part of our future. We'll judge external science just like we judge our internal science, make tough calls when we need to. But business development is a large part of our activities right now.

The Inozyme transaction was the first of what we hope will be many, not only in the early space, but also looking at some late-stage assets. So more to come there. But it's busy times. And it's good, of course, we now, based on some of the transformation we've been going through, we've got cash and we've got free cash flow. So it's a good time to go out and try to find additional innovation to bring into the stable.

Great. One question I want to ask is that, in the last 18 months, the company has gone through a lot of rationalization of R&D in terms of what makes sense, what doesn't make sense. And you were part of some of those processes, and some were in place before you joined as well. So can you walk us through like what -- when you look at prioritizing an asset and deprioritizing, what do you really do?

Well, that's the magic that we do in R&D, we try to pick winners. But it's humbling. You have to be -- you look at the science, but also look at what the needs of the world are and the realities of where a medicine you'll be bringing forward will plug into that world.

So we apply not only rigorous scientific standards to our program, but we also develop target product profiles. We do market research. And we make sure at very early stages that that cross-functional dialogue is happening and that the molecules we're bringing forward have a chance to be embraced by society.

I would say that there's no one size fits all. You can only know so much about what the world is going to look like in the next 10 years. But when we go through that process, when we apply those rigorous filters, I mean there are some examples in the last 18 months where we've deprioritized and terminated programs. Partially, a few of them, we just thought were not good bets, they weren't going to deliver what patients wanted and needed. Others, regulatory endpoints or the time that it would take to get from here to there were just going to be too long. And we have a fixed, of course, R&D budget, it grows every year. But we want to make sure we're spending those research dollars, the time and effort and the patient time on molecules that we think will bring the most value.

The only truism, I would say, that we hold really steady to and don't waver from is that we are a company that focuses on genetically defined condition. We develop medicines for them. But we also help shape the way that those diseases are defined and the way medicine is practiced. And so we're continuing in that space. But beyond that, again, lots of opportunities both internally and in the business development realm.

Got it. So I mean, on that, I mean, something that can really be helpful for the patients. I mean 333, the recent data you generated, it wasn't healthy volunteers, but at the same time -- can you talk a little bit about the significance of that? Also, like I mean, you have VOXZOGO, but then there is a longer-acting CNP competition coming soon. The context of how the field could be in 4 to 5 years, what is the significance of these data?

So if I could take VOXZOGO first, if that's okay. VOXZOGO is a safe and effective therapy for achondroplasia. As I mentioned, we're hoping that the related but distinct condition of hypochondroplasia, we'll be turning a card over soon. And we're continuing to develop data both in those settings as well as new indications.

What I would say with VOXZOGO is we see it as our duty to leverage the 6,000-plus patient years of experience in now 52 countries around the globe, and growing, to make sure that we communicate and patients understand the value of the therapy. This isn't a drug that's simply meant to stimulate growth. We talk about growth a lot, we talk about annualized growth velocity. But that's not what the patients care about. They care about their health and their wellness.

And that means we need to do a better job, and we will continue to do so, analyzing, developing, publishing our data with regard to those angles of health and wellness. This is tibial bowing, this is spinal stenosis, this is looking at angles of the spine, looking at facial morphology, looking, of course, at quality of life, all of the health and wellness factors that we're familiar with that unfortunately achondroplasia patients can suffer from.

We're going to continue to develop that data. We're going to develop the molecule further as well. We're developing a citrate-free formulation. And we're going to continue to spread around the globe. We see, again, tremendous unmet need in other countries, and we're going to continue to find those patients.

But we're not going to stop there. We're thinking about this molecule as the beginning of a franchise, the CNP franchise. Now we pioneered the biology here. CNP 39 is -- the 39 amino acids are something we're quite proud of, that elongate the half-life beyond what natural CNP, which has a half-life only of a few minutes can provide.

Now by not stopping there, we've also generated a long-acting molecule in BMN 333 that uses an albumin binding peptide and essentially creates almost like a molecular depot effect where low levels of CNP will be released into the blood stream.

What that accomplishes is you avoid the very high C-maxes, where we can see excursions in heart rate and blood pressure that we want to be avoided. They're not life threatening, but they certainly are to be avoided. And it also allows us to increase the AUC exposure of CNP to levels that, in animal models, are giving us continuing increases in growth when we increase AUCs beyond what's seen with VOXZOGO and beyond what's seen with other long-acting CNP agents.

What we predict from the mouse models is that an AUC of roughly 3-fold or higher can unlock growth on the order of twice as much attributable growth as compared to the comparator arms. Will we see that in humans? To be determined.

But what we have in 333, the new data that we've discussed, is we have the right reagent to test this hypothesis. The animal models suggest that there's more growth to be had. There's genetic data from human systems. There are very rare individuals with high CNP levels or activations of NPR-B pathways that grow to be 7 feet tall or more without nonskeletal side effects also. So it appears like, other than at the bone, these are going to be areas that could be quite safe.

And then, of course, looking at other long-acting CNP agents that are on the market, there does appear to be a dose response relationship as you march up the curve. The question that hasn't been tested, the final question, is, does that curve keep going in humans when you have higher AUCs? We believe that that's a good bet, and we now know that we have a molecule that, in multiple cohorts, we've seen AUCs above 3x. It's a 6-cohort study. We mentioned in both cohorts 4 and 5, we had met that criteria for moving forward, and 6, of course, just completed.

So in that regard, starting as a combined Phase II/III program in the first half of next year, off to the races in achondroplasia. The hope is to have a superior growth profile. It will be -- there'll be a comparative effectiveness study directly against VOXZOGO as the Phase III portion. And we hope to have that program available with data to be on the market by the 2030 time frame. We're going through a lot of exercises to try to speed that up, but we're committed to the 2030 time frame as we speak, with the goal of beating that as well.

Got it. So let's just -- I want to talk a little bit about this AUC aspect of it. Do we know -- so when you say 3x of AUC, it is compared to the long-acting CNP, not with VOXZOGO, right?

So it's compared to both simulated long-acting as well as VOXZOGO. When we lock those into the animal models, we see in a linear fashion, as we go up on AUC, there's more growth to be had. The 3x just happens to be a threshold where we saw significant growth as well.

Got it. So did you see higher AUC for the longer-acting CNP, the comparator CNP, versus VOXZOGO?

When you -- well, so the short answer is yes. But if you take the AUC of the spike-shaped profile of VOXZOGO and you multiply it times 7 doses, the AUCs are actually in a similar ballpark. I don't know if that's really a useful math exercise. The concept of VOXZOGO, of course, is that there's pulsatile activation of the pathway, kind of like running the first 100 meters of a mile race and then maybe walking the rest of it. Whereas long-acting is more of a smooth jog over the course of the whole mile.

The biology, at least looking at the published data for long-acting versus VOXZOGO, it looks quite similar in terms of growth...

Right. The data are too, right?

Yes. And so I think that that gives us confidence that we're not going to see, say, like with parathyroid hormone, dramatically different biology from pulsatile versus continuous. Though I suppose with long-acting, again, longer follow-up, all we have is 1-year data, longer follow-up and additional time points are needed. Clearly, with 333, we believe that that's a good bet. And we believe that there's going to be so-called more meat on the bone here. There's an opportunity to continue to go higher, and we hope that that benefits patients.

We talk a lot about growth, we talk about it in the animal models, it's what we can measure. But the implication is that we're pulling through to those measures of health and wellness as well.

Got it. So this is the other question, is that these patients have at least the trial, you enroll about 4 centimeters of growth velocity by 1 year on the baseline. The baseline, and these drugs can actually get to 1.5 centimeter extra per year. How much more you can extract out of this mechanism? Could it be like 2, 2.5 centimeters? Like what is the normal, 6, 6.5?

Well, so when I talk to pediatric endocrinologists, they remind me that teenage boys in their growth spurt can reach 10 or even 12 centimeters a year. So again, physiologically, there are opportunities there.

But what we're looking for is to improve upon VOXZOGO. We know VOXZOGO, roughly, a 14-year-old boy with achondroplasia probably has an 18-inch growth deficit compared to normal stature peers. If you extrapolate out over the course of their entire life, VOXZOGO probably can achieve about 10 centimeters -- I'm sorry, 10 inches of growth, of that 18. Clearly, we'd like to do better. We'd like to be able to restore to average stature. So there is additional growth to be had.

The challenge, of course, is that not all growth is linear in these patients. There are 2 particular growth sinks, so to speak. One is at the time of birth, these patients are -- achondroplasia patients are already growth-deficient. And they don't have a typical growth spurt also in the teenage years. So to make up for that, we know something north of the 1.5 centimeters is needed. It's hard to know where the top is. But clearly, something between 1.5 and the growth curves of a normal stature individual, that's what we're looking for.

Got it. And I want to bring in the question about the growth hormones as well. So I mean, I think competitor shared some data in combination with growth hormones. Basically, the thought process, the new growth hormones, the way they work, they actually give you a nice growth initially, right? And then -- and that's -- like you can see the difference. While VOXZOGO and all, I mean, because of the mechanism [ is like over a slope of your ] time. Do you see a reason to use a CNP in combination with growth hormones or?

Yes, it's a tricky question. If I ask the question slightly differently, why don't -- why does the world not use growth hormone in achondroplasia, with the exception of Japan? And the answer has historically been that growth hormone is great in growth hormone deficient condition. This is not a growth hormone deficient condition. Growth hormone is also not a targeted therapy. There's a variety of downstream effects.

And in achondroplasia patients, historically, you can uncork additional growth, but it doesn't tend to last. Over the course of 1 to 2 years in achondroplasia, you tend to see a waning effect in terms of growth velocity increases. When you look at final adult height, a variety of publications, you also don't see a dramatic difference with growth hormone in achondroplasia. So hypothetically, the concern here is that you're accelerating bone growth, but it's at the expense of bone age and perhaps closing the growth plates earlier.

These are the, I think, the concerns that will only be alleviated by looking at longer endpoints. Six months is not going to be enough time to see, is this a persistent increase? Are there accelerations of bone age? So additional time is absolutely going to be needed.

What I believe these patients need and what the future will ultimately bring forward are more rational combinations. We're, again, as we develop the data, I think we'll get a better idea of phenotypes and genotypes of patients that are responding more favorably or less favorably, whether it's the CNP or FGFR3. And thinking about a future with rational targeted combinations, rational targeted sequences, I don't believe growth hormone is going to necessarily be the major player there, though again more to be seen and we'll have to see.

Growth hormone also comes with other side effects and challenges. The pediatric endocrinologists are well aware, and can handle the intracranial pressure increases, but soft tissue hyperplasia, there are a variety of cardiovascular effects. Again, we're talking about children, children who are going to be on these therapies for years at a time during their formative years. These drugs can be used, but we should ask the longer-term safety questions when we think about adding a second drug like growth hormone.

Makes sense actually.

Thanks for the water.

Of course. Just talk a little bit about the plans for a registrational study. I mean you are planning to start it in next year.

For 333?

For 333. You are talking about there could be a superior profile to VOXZOGO, but again...

That's the ambition. Yes.

That's the ambition. So how do you design a trial like that? And do you go for CNP-naive patients, you go for experienced patients? Because I mean, by that time, there will be a lot of patients already on CNP, right? So like I say, it reminds me of Alexion, right, back in the day, they were trying to develop...

[ Telling us it's ] 100%.

Right? So how do you think about this?

First and foremost, we think asking patients to sign up to a placebo-controlled study is a tall order. So we've designed a study that has no placebo arm. We've been able to model the data that we have. We also want to make sure, whatever our control arm is, that we buttress it, we supplement it. We'd borrow, statistically, as much data as we can from VOXZOGO. And we've been working with regulators again to design that study.

The study we're envisioning -- it's not locked in yet. Again, a study concept, of course, has been reviewed with a variety of regulators around the globe. The study we're envisioning is a combination Phase II/III study. The Phase II portion, which will begin in the first half of next year, will look at up to 3 doses of BMN 333, call it, high medium and low, to be determined.

And there'll be a fourth arm which will be a VOXZOGO control arm. We will run that in achondroplasia patients, look at 6-month AGV, and again, then pick the winner moving forward. And ultimately do a bake-off, a straight-up comparative effectiveness study of the chosen dose of 333 against VOXZOGO.

That study would be powered again to look for superiority. We believe, again, that's what the marketplace wants. That's what patients want. That's what they demand. We're envisioning again weekly dosing at this point. And that is really to optimize the AUC profile. Theoretically, you could spread out the doses more, but that's not what we're highlighting right now.

And through this study, again, we're hoping to have a registration package that would be available for approval in 2030. And of course, we're pulling all the levers that we can to move that as quickly as possible. Right now, we're committed to 2030.

And regulatory landscape seems to have changed as well around 1 year now, right? I mean so people -- FDA is probably looking for 1 year at this point rather than 2 years, or?

I believe the FDA has a bit of regulatory flexibility here. With regard to the pivotal study, it appears that 1 year is now acceptable for a filing package, if you have supportive data from other studies from other areas of longer-term efficacy. There also are always opportunities and post-marketing commitments that could be put in. But yes, 1 year appears to be a reasonable endpoint at which we could engage the agency after a Phase III study.

Got it. And non placebo-controlled trial will probably help with the enrollment speed and [indiscernible].

Yes, we're really hoping. And from that standpoint, it will be important for us to pick the sites and the countries appropriately. Of course, again, a switching study would be planned as part of the overall package, pediatric plan, a hypochondroplasia plan. But to be determined. It all begins though with this dose ranging in achondroplasia.

I just want to take a step back. We're moving from single-dose healthy volunteer and jumping directly into multi-dose patient Phase II. That's been agreed upon. And I think it reflects, again, the comfort level that physicians, patients, regulators have with the CNP pathway. They understand the biology here and feel comfortable moving into patients at this point.

Great. So how about we talk a little bit about like moving away from 333 now and talk about the other new assets, the DMD assets at this point? So I think you are trying to share some data by end of this year. So can you talk a little bit about what to expect there, what data will be shared?

So this is -- we call it BMN 351. It's an antisense oligonucleotide. It's targeting exon 51 skip amenable Duchenne muscular dystrophy patients. So it's not a gene therapy. And very sad, the news with the AAV therapies. This fortunately can avoid that, though ASOs have their own safety challenges. When you dose up a high enough mass of antisense oligonucleotides, inevitably, whether it's kidney tox, liver tox or platelet toxicity, those are expected to be seen, and I would call them even class effects.

Now inherent in what I just said though is that the goal for Duchenne muscular dystrophy is to find that therapeutic window. Put in enough skip products, generate enough surgically altered mRNA product that produces near full-length dystrophin, not microdystrophin, but near full-length dystrophin. That's the goal of the therapy.

And we've designed the molecule, it's a non-morphilino chemistry, for those who are organic chemistry aficionados. But it also targets a skip induction site that we think will be a much more potent producer of the skip product. So the strategy here is not that we have a biodistribution engine to the muscle per se, but that the drug that gets there will be able to do its job better and produce more product.

One of the downsides of that is that takes a lot of time. The tissue half-life of this program is such that we don't expect to reach steady-state dystrophin levels till out at a year or more. So we're not going to sit around and wait for that. We're running a study in patients with Duchenne.

They are treated at 1 of 3 dose levels, 6 milligrams per kilogram, 9 milligrams per kilogram or 12 milligrams per kilogram. It's weekly dosing. And we were pleased that, again, the 12-milligram per kilogram opened recently, the DMC allowed us to do that. But the 6 and the 9 have completed dosing, and we're waiting to get all the biopsy data results back.

We are looking for a fairly ambitious dystrophin level. We are looking for a 10% non-adjusted dystrophin level in the muscle of patients. Now what does that mean? Well, it means actually, at the 6-month time point, you'll probably be in the 3% to 5% range, but you'll be on the way up the curve to the 10%. That's what success would look like to us.

And the question becomes, is that achievable with these programs? We will have that data in those first 2 cohorts by year's end and we'll make some sort of announcement release of that data. We'll also certainly have combined safety data in the products. And we will have a first look, though this endpoint takes even longer than dystrophin, we'll have a first look at our stride velocity 95C data.

I would say that the data produced by Dyne is probably the best benchmark for what good looks like in this space right now. That 10% target that we have would be equivalent to a 3.2% with Dyne. Their 8% number is fat muscle adjusted. We're not using that as we talk about the math. So we'd be looking for dystrophin levels that are superior to what Dyne has shown. And again, the stride velocity 95C data that they've seen, which is quite encouraging, we'd hope to be able to see something superior to that as well.

The question, of course, will be whether or not we can achieve that, and that's what we'll be turning the cards over and getting our first look at. This is a weekly therapy. So we want to make sure that, if we're asking patients to undergo that sort of therapy, that we have the right efficacy and safety profile. So more to come, but we're right at the precipice of being able to turn some cards up.

Awesome. So this will be a 6-month data. The goal is to get to 10% by 1 year. So this -- you should not expect 10% here.

Correct.

3% to 6% is what you are looking for. And Dyne has showed 3.3% at the same time frame, roughly?

A little bit -- yes, roughly the same time frame, but with a much shorter half-life, short tissue half-life. And also a muscle distribution engine that just the pharmacokinetics will look different.

Got it.

I'll again say the Dyne data is great for patients. Great to see the breakthrough designation as well. Suggests that the FDA agrees that those sort of levels are meaningful for patients. Those sort of functional data are meaningful for patients. Our goal is to have a product that, again, will have some superior profile.

Got it. And for stride velocity, we should not expect anything at 6 months in terms of...

I don't think we can expect anything at 6 months. It usually is an endpoint that would pull through and take several quarters after you reach steady state. But we will be measuring it, and want to, again, tip my hat to some of the pioneering work that's been done by others. That appears to be a quantifiable, reproducible and a good measure of how these children are doing with regard to their functional aspects, their mobility.

Better than 6-minute walk as well?

Better than 6-minute walk. Yes. Well, it's like an Apple Watch for your ankle. And so you can imagine it's sampling through the whole day. So if you take the slice of the quickest velocity of 5%, it's going to be -- similar to 24-hour blood pressure monitoring, better than spot checks.

Got it. Very helpful. So can you help remind us what did eteplirsen show at that time from...

So we picked the 10% -- let's see if this is what you were asking, because we've looked at genetic databases and seen that if one has a 10% level or higher, their phenotype behaves much more like a Becker's muscular dystrophy, where ambulation is -- and we can look at this with codes and Medicare and U.K. database system, ambulation is maintained into the 30s and 40s, and the patients live into their 50s and 60s. That's very different than Duchenne's where ambulation, sadly, in their early teen years, is the loss of ambulation would be the norm. And of course, patients are coming to their illness in their 20s and 30s. Devastatingly different.

The hope is, again, near full-length dystrophin at this 10% level, we would hope that that would unlock a very meaningful change in the course of disease. We'd have to prove that. But again, it starts by having a reagent that can deliver that kind of a profile.

Got it. Very helpful. And then what about the safety side of it, right? I mean it should have the ASO level safety or...

Yes. We do expect that there will be class effects on the ASOs. This is a phosphorothioate chemistry. Again, a prior molecule was able to, at the 6 milligram per kilogram level, have a profile that had no irreversible renal toxicity. We, of course, have studied 9 and now 12 milligrams per kilogram. The Data Monitoring Board has looked at a whole variety of kidney toxicity measures and has agreed to move forward and allowed us to go to 12 milligrams per kilogram. We see that as a good sign.

But we are watching very carefully, both liver and the kidney for potential toxicity. We expect that ASOs at some level will reach these. And so the question, as with gene therapies, as with other ASOs, will be, can you thread that needle? We're hoping with the PK profile that we have, this loading up of the tissue, long tissue half-life, will again allow us to open up that window. We don't have to give big boluses once a month. We're giving weekly doses in order to be able to open that window.

Got it. That's very helpful. Maybe last few minutes. So quickly, if I want to talk about how should we think about the hypochondroplasia data when they come out? What is the bar for success?

Hypochondroplasia is a short stature disorder, short stature condition, that actually is a mutation in the same receptor as achondroplasia. It's different mutations that has a slightly different pull-through of phenotype. Children are often diagnosed later, more like 5 or 6 years old, rather than achondroplasia where it's often in-utero diagnosis.

But there is a misconception that hypochondroplasia is just mild achondroplasia. It's not actually true. Number one, we've refined for a population that are more severely affected. Most of the patients will be minus 3 standard deviations in height, or less. That means more negative.

And we've done some epidemiology work. Hypochondroplasia patients actually are 5x as likely to have orthopedic complications in their life. They're 4x ENT. And sadly, they have an increased risk of mortality over their lifetime, increased hospitalization, health care utilization. Building the evidence around that urgency-to-treat hypochondroplasia will be part of our story here.

What we could expect out of VOXZOGO, I think there's 2 sources of reassurance that we're going to see a safe and effective drug for this indication. Number one, Dr. Dauber, one of our collaborators, has run an investigator-sponsored study, and again, saw that not only does VOXZOGO work in these patients, but probably to a greater degree than what we see with achondroplasia. The hypothesis being that the less dysplastic of the growth plate, so the more orderly progression of the chondrocytes, the more responsiveness there may be to CNP. That's one data set.

And then again, I would say that just from a medical standpoint and, of course, with the receptors being the same, there is a belief that these indications will behave quite similarly. That's why we didn't have to do another dose range in Phase II, we could jump right to Phase III, even though all we had was achondroplasia data before we started that study.

The study recruited about 5 months faster than we had anticipated, again, speaking, we think, to the unmet need and the desire to have a therapy. And the study is powered to look for a size, a growth velocity acceleration similar to VOXZOGO. We're hoping it will be larger than that. Dr. Dauber's data would suggest that it will be larger than that. But the conservative assumption is that it can measure a difference similar to achondroplasia.

Awesome. So a similar topic for BMN 401, like we'll have data for the top line next year. So I mean what should we expect there?

So ENPP1 deficiency is rare and it's devastating particularly in infants. There are 3 phenotypes of the disease. There are the infants where, again, only about half of them even live outside -- 40% to 50% can live beyond the first year, strokes, really terrible burden of illness there. There are children where rickets, soft bones, hearing loss tend to be the major phenotypic pain challenges.

And then there are adults who have more osteomalacia, again, soft bones, pain, calcification in joints. Because when this enzyme is missing, there's a double whammy of effects. Not only do bones get soft, but paradoxically, the calcium goes where you don't want it to go. It goes to arteries, it goes to other tissue beds.

And so this is a product, it's an ENPP1 enzyme replacement. It's an Fc fusion, so it can be manufactured pretty easily. Great work by the Inozyme team to get us here and show us that, across a broad variety of indications, all those age groups, you can increase these biochemical markers. Pyrophosphate normalizes in days to a couple of weeks. And the pull-through to functional endpoints is what the ENERGY 3 study will be studying in children. This is the 1 to 12-year-old. We'll be turning over that card in the first half of next year.

And that will be the beginning. We are going to run an adult study as well. We're working on the Phase III protocol right now. We have infant data that will be certainly showing to regulators and getting their opinion on at any engagement that moves on. The first shot on goal is Energy 3. We may have the opportunity to extend that study if additional time or additional dosing work is needed. Bottom line is, though, we feel very confident that we can normalize pyrophosphate across all these different groups, including some we didn't talk about like calciphylaxis and ABCC6 deficiency.

There'll be more to come here. We closed the deal on July 1, and I'll just tell you that the integration is going well. Thrilled to have this molecule. We think it will be an important part of our stable moving forward. And really, it's a BioMarin drug. It fits with what we do right on top of our Inozyme therapies. And again, we see real value for patients and for stockholders and for BioMarin.

Awesome. On that high note, thank you very much for joining us. You have a lot going on.

Yes. Thank you.

Thank you.

Okay. Great. Hey, good morning, everyone. My name is Olivia Brayer. I'm one of the senior biotech analysts here at Cantor Fitzgerald. Thank you so much for being up early with us this morning to kick off our conference. And we are really excited to start the day with someone special from BioMarin, Chief R&D Officer. We have Greg Friberg.

Greg, thanks so much for making the trip out here to the East Coast.

Thank you for the invite. It's great to be here.

A lot going on at BioMarin these days. So maybe just to kind of set the stage, give us a sense of top priorities heading into 2026. Again, there's a lot of R&D going on these days. So maybe just set the priority list, right, in terms of what matters most to the company. And then as you think about shots on goal, where do you feel like you guys have the best chance of success with your current R&D engine, so to speak?

Well, thanks for the opportunity to share what I think is some pretty exciting progress in our pipeline. When I think of, again, our priorities, certainly, our BMN 333 program, our long-acting CNP for achondroplasia is one that I want to make sure that we talk about. That being said, we're actually turning over some cards when it comes to the pipeline over the course of the next year as well. Really excited to see the hypochondroplasia data for VOXZOGO in the first half of next year.

Similarly, we're filing both in the U.S. and Europe, our data in adolescents for PALYNZIQ, a big opportunity to expand the label there and again, give patients something that we think is of real value to them.

And last but not least, in terms of near-term news, we'll be turning over a card with regard to BMN 401, which was acquired from Inozyme. This is a first-in-class, first-in-disease therapy for ENPP1 deficiency. And the first study, the so-called ENERGY 3 study will be turning over its card also in the first half of next year.

When you think about the internal pipeline activities, I would be remiss also not to point out that we have a lot of enthusiasm in the business development space going on right now. We're in a fortunate position where we have cash and we're looking for opportunities, not just for early assets, but also for late-stage assets to be able to replenish the pipeline there.

And again, we feel that the financial environment that we're currently in, puts us in a good position given that we have those resources, and we're certainly preparing for those opportunities as well.

Yes. And maybe just to start with BD, because you mentioned it. How do you guys think about the business development strategy? I mean, you did do a deal this year. Is it one deal a year? Is it really not that frequent? Is it not really about the quantity, but it's about the quality of the assets? And then, I assume rare diseases has obviously been the company's wheelhouse. So are there certain indications or certain areas of rare disease that maybe you guys are more interested in exploring when it comes to BD?

So it's more of the latter strategy, looking for quality opportunities. Yes, we want to pick our shots, but we also want to be opportunistic in the current environment. I would add that there is no quota in terms of number of deals that would be done. The Inozyme deal was one we're incredibly proud of. The work that Inozyme has done is great to get that molecule to where it was. And we think, of course, as BioMarin that we can add significant value bringing that forward. That being said, it was on the small side.

We do have the opportunity and the firepower to look for larger opportunities as well. And they fall into a variety of bins. One would be the areas that we think we have strength already, certainly in the skeletal conditions as well as enzyme replacement therapies, which is a big bucket. But those are two areas that we're always on the lookout, making sure there are opportunities. There are adjacent opportunities as well in other indications in neuromuscular and pediatric neurologic indications, benign hematology, where we're continuing to look.

But that being said, the strategy is really one to look for genetically defined conditions. What that means to us, of course, is germline genetics, opportunities to use our strength, not just in terms of our financial strength, but in terms of our technical strengths. We have a footprint and foot boots on the ground in 70 countries around the world, reaching patients with so-called rare diseases, but again, genetically defined conditions.

We think that our ability to locate, find and then ultimately treat those patients is something that gives us an engine that if we plug in additional molecules, we can really capture the value of those and do so at a speed that perhaps other organizations would struggle. We've been doing this for decades. And again, we want to bring these sorts of therapies to the world.

Yes. And you led earlier with BMN333. So maybe we'll start there. Maybe just talk about -- and this is the long-acting CNP candidate that BioMarin is developing. What makes this asset different or unique or special? And then maybe just remind us where that program sits today? I know, you had some early -- or you had some initial healthy volunteer data. Can you talk about some of the highlights from that data set or at least what you've disclosed so far? And then what's next for that program?

So the CNP ecosystem is one that the biology is rapidly evolving. Native CNP, it's 22 amino acids. It's got a half-life measured on the order of minutes. VOXZOGO was created vosoritide, it's CNP-39, engineered to have a half-life on the order of an hour, again, given subcutaneous and daily, and we've seen certainly that this is both a safe and effective drug in Asia, helping a lot of patients right now, continuing to work to see whether or not VOXZOGO can help patients with additional short stature conditions. And so that work is ongoing.

We're also thinking of the CNP biology as giving us an opportunity to develop franchises. And so, we've engineered a molecule in BMN333 that offers an even longer half-life and a PK profile that will allow us to get more CNP on board. There's a nuance here, which is that when you have a short half-life molecule, you're often limited in the amount that you can give patients by what's called the Cmax.

And there's a very well-known side effect with blood pressure drops. It's not life-threatening, but it's measurable with tachycardia, particularly in adults that one can see when you get up to high Cmaxes. A longer half-life will allow you to avoid those Cmaxes and yet increase rather than a sawtooth pattern, increase in a broad stroke, the AUCs that one can see.

We've taken the CNP that we described, CNP-39, and we've attached it to an albumin binding peptide similar to other molecules that are out there. And that is BMN 333. Think of it as like a depot form of CNP, where slowly CNP is released in the blood stream.

We're running a Phase I study right now, and we've announced that in these healthy volunteers, single dose study that we've been able to see not just equal, but we've seen in multiple cohorts, 3x the AUC that other long-acting CNPs have been able to achieve.

Why 3x? Well, in the animal models that we've seen 3x appears to provide a meaningful increase in linear growth as compared to 1x with a simulated long-acting CNP as well. So the study has got 6 cohorts. We've completed all 6.

As we mentioned in the earnings call recently, when we reached Cohort 4 and 5, they had already reached our 3x threshold. Cohort 6, we haven't announced yet, but we just completed it. And so from that standpoint, this molecule will really exceeded our expectations with regard to the PK profile.

We believe that we have the right reagent in hand to test the question of whether higher exposures will deliver higher growth. That's a hypothesis supported by a couple of different sets of data. One would be the animal models that I mentioned. Another would be human genetics, where if you have activations in these pathways, those patients get quite tall.

And interestingly, it appears that the only side effect they have when those very high CNP levels are skeletal related. So no off-target, no off-skeletal toxicities which is reassuring.

And finally, these levels of AUC have not been tested in humans before, but there does appear even with the other long-acting CNP agents to be a linear relationship between dose and growth.

The question is, does that curve continue upwards? We think it's a good bet, and we think we have the right reagent to test that in BMN 333.

Yes. And maybe just contextualize that 3x AUC. I mean, I imagine 3x AUC isn't necessarily equal to 3x growth, right? It's not a linear relationship. But what are you all expecting to see in terms of the impact on growth? I mean, maybe not necessarily a number that I'm asking for, right? But as you think about the relationship between growth and AUC?

And then, maybe as a follow-up to that, and I'm sure you'll get to it on your own. But why AUC, right? Why is that a more important metric at this point than Cmax?

Yes. Very fair questions. So with regard to the amount of growth we're looking for, I can say that in the rodent models, the 3x AUC plus doubles the amount of attributable growth in the model that one sees as compared to a healthy dose of VOXZOGO or a similar dose of the 1x long-acting.

Will we see that in humans? To be determined. But what I would say is that, we've talked to physicians and patients and we're designing studies that would have a meaningful increase over what's been seen with VOXZOGO previously.

With regard to the targets, I would add that, the animal models tell us that increasing levels of AUC do appear to have a linear relationship with the amount of growth that can be delivered. One of the reasons we can't do the same thing with Cmax, we can't run the same experiment as you run into the Cmax related toxicities.

It's similar to the analogy, my pre-clinical colleagues remind me of running a race. If you got to run a mile, are you going to sprint the first 100 meters and then -- and jog it in the rest? Or are you going to have a nice brisk run for the entire period? Different measures. But clearly, you can't sprint the whole way.

And so if you could continue to increase the AUC as the metaphor continues here, the goal is that we would be able to unlock more growth. And the goal is to maximize the effect that CNP can deliver and to have a really best-in-class CNP to not only unlock that profile, but even in a future state where there might be rational sequences or combinations that this would be the drug of choice that would want to be partnered in those for these patients.

Yes. And you guys have spoken publicly about wanting to move into a Phase II/III and even running it as a superiority study versus VOXZOGO. What can you tell us at this point? I mean, what -- have you decided on the trial design, are you still engaging with regulators about the trial design? Where are you at? And what can you tell us at this stage about that Phase II/III?

So this is -- it still remains a dynamic process. We're engaging with regulators. Now when we engage with the regulators, we have what's called the study concept design. It's not a full protocol. It's not locked in, but it has all the elements that we're speaking about here. What we've envisioned and what we've agreed upon for the path forward is a combined Phase II/III study. This would give us an opportunity to move immediately into patients. So there's no multi-dose study in healthy volunteers that's needed.

We'd immediately move into achondroplasia patients, and we would offer them a Phase II study that would have potentially 4 arms, high and medium and a low dose of BMN 333 and a control arm of VOXZOGO. No placebo there of note. That would allow us in short order to determine, again, what we think the go-forward dose should be.

Of course, we want it to be as effective as possible. Effective meaning not just linear growth, that is what we can measure. It's what we can measure at 6- and 12-month time frames. But what we ultimately want to deliver is better health and wellness for these patients. So we'll be measuring other factors along the way.

We were leveraging the data that we have from our ongoing VOXZOGO program to, again, preclude the need for a placebo arm. We can model that arm, and that's been acceptable thus far to regulators. And of course, from a statistical standpoint, we're using as much borrowed information from VOXZOGO to try to limit that arm as well.

And once we've had that dose, we'll immediately move into a Phase III, which would be a head-to-head study in achondroplasia of a chosen dose of BMN 333 versus VOXZOGO. Again, no placebo here. We think that, again, in this world, not only would that be attractive to patients, they wouldn't necessarily have to sign up for a placebo-controlled arm. But we also think this is what the marketplace wants. Not just a me-too drug, not just a convenience lever, but they're going to want something again, that offers them more value, not just in linear growth again, but also in the health and wellness.

So we're continuing to show that in -- with VOXZOGO, again, the first generation molecule, this isn't just about growth, this isn't just about final adult height. We're seeing tibial bowing improve in these patients. We're going to be presenting next week some data with regard to spinal alignment, spinal canal width. We're seeing facial morphometry improvements, which, of course, are a surrogate for things like Eustachian tube abnormalities, ENT abnormalities.

We want these patients to live their best lives with the most wellness that they can. And again, we think it's part of our job not only to develop new agents, but take the agents we have and show as much data as we can and be transparent on what that value is.

And what gives you confidence that you think you'll show superiority over VOXZOGO?

So there's three data sets. I mentioned the animal data set. Of course, we mentioned before the genetic data that suggests, again, people with activating mutations of NPRB or of high levels of CNP, have quite a bit of growth that can be uncorked. And quite frankly, if you just look at the clinical data that's out there with long-acting CNP agents, there is not a suggestion so far that there's a data point where the efficacy seems to flatten out.

So continuing that curve upwards on the AUC, we think this is a very good bet. We suspect it will be a very safe opportunity and our goal to prove that and ultimately, to measure that in patients with achondroplasia.

Next step is to be in patients in the first half of next year, and we're moving with urgency to be able to deliver that.

Okay. Great. We're looking forward to that study kicking off and the data that's coming out from the healthy volunteer study.

A lot going on outside of achondroplasia too. Obviously, hypochondroplasia Phase III, VOXZOGO data coming next year. But even beyond that, there are a number of other short stature indications. And I know you've talked about wanting to move into Phase III with VOXZOGO, but also the potential now for BMN 333. So maybe just walk us through the thought process in terms of the development path forward for some of those additional indications. I hate to ask the question about time lines, but when will we get the next update? And then how do you think about now that you are -- that you do have these two molecules that you could potentially move forward with development?

Yes. And it's important not to put the cart ahead of the horse here. And of course, achondroplasia and hypochondroplasia are fairly related conditions, even the regulators allowed us with hypochondroplasia to move right into Phase III without dose ranging.

For additional short stature indications, whether they're proportional with idiopathic short stature or disproportional with, for example, Noonan, Turner and SHOX syndrome. We are doing and looking forward to seeing data from dose-ranging studies with VOXZOGO. We have publicly stated that, that data will allow us to make a decision to start Phase IIIs in those indications in 2027.

Now that happens to line up quite nicely with our dose ranging that we will see coming out of our BMN 333 as well, where in achondroplasia will have an idea again of dosing schedule, effect size and so forth.

I mentioned schedule, it's planned for weekly at this point for 333. There could be an opportunity to elongate that, but that's not our goal right now. That data will line up in the 2027 time frame, and we'll be able to look at not only the efficacy and safety, but also the totality of data from the three programs.

We're also considering other indications. The nice thing about CNP is, it's not dependent on an FGFR3 mutation in order for it to have its activity. It is a master regulator of growth. And by administering it to patients with a variety of conditions, we do believe there would be an opportunity to address their underlying condition.

That being said, the dose and schedule and the effect side may be very different in indications that are not as so-called dysplastic as hypochondroplasia and achondroplasia. And as a result, doing the dose ranging is going to be a very important part, not just from a regulatory standpoint, but also from a safety and appropriateness standpoint in order to choose those doses.

We're going to have a lot of data in that 2027 time frame. And I think, again, we're going to be in a good position to be able to make an evidence-based decision.

Yes. And of those additional indications, right? I mean you have Turners, Noonan, ISS, et cetera. Are there certain -- is there a higher probability of CNP mechanistically yielding successful results in one over the other? Or is that not necessarily the right way to think about it?

It's hard to say. I think, when you think about the success in different indications, I mentioned the growth plate biology. And there are certain indications where the orderliness of the progression at the growth plate is disturbed.

Achondroplasia and hypochondroplasia are one of the extremes there. There are shades of gray in the middle for some of the other monogenetic disorders. There are also collagen deficits in some of the disorders as well. And it brings up, I think, the larger order question that, will the biology be the same in all these indications. The best data we have right now is from Dr. Dauber's investigator-sponsored study. He's looked at a variety of indications.

And again shown that, yes, there is growth that can be unveiled in a variety of Noonan, Turner, SHOX, hypochondroplasia, ACAN deficiency. The question will be what's the right dose, and is the profile one that the benefit burden we can stand behind.

That's what's being explored right now in our randomized studies in our Phase II studies. And the hope is that we would have an opportunity to expand the use of VOXZOGO, potentially next-generation agents. But we got to do the experiment at this point. I do think it's a good bet. And in particular, the patients that are most burdened by comorbidities other than just height, that's where we really would want to make sure that we can unlock opportunities to offer them something, again, of value for wellness and health.

Great. Well, why don't we talk a little bit about your Inozyme deal that you all, I think, just closed maybe a month or 2 months ago. That's BMN 401. Maybe just give us a rundown of why you all decided on that company, on that program, what gives you conviction in it? And what have seen you so far in that clinical profile that you're excited about?

Yes. So the deal was announced in May and July 1 we closed. That's a nice proof point.

Busy summer.

Nice proof point that we're acting with urgency. The Inozyme molecule formerly called INZ 701, now BMN 401 is a molecule. It's an Fc fusion. It's an ENPP1 enzyme replacement for patients with ENPP1 deficiency. This is a devastating illness in infants. It's a genetic disorder where sadly 40% to 50% of the infants die for their first birthday. And those that live, unfortunately, are burdened with a variety of comorbidities.

The biology is such that when you're missing this enzyme, you have low levels of what's called pyrophosphate and AMP. And the end result is you get rickets, osteomalacia and [indiscernible].

And paradoxically, calcium rather than being deposited in the bone is deposited in your arterial beds, so you can have things like mesenteric ischemia strokes. It's quite devastated.

Now in the older patients, the 1- to 12-year-olds, there's a little bit less of the arterial endpoints though they still have challenges there and the bones become a little bit more of a focus pain, hearing loss, of course, bowing of the legs, classic rickets that you think about.

In adults, the phenotype is a little less severe, but it's still with pain and bone softness can become a challenge. The study that's ongoing right now, the ENERGY 3 study is in this middle group, this 1- to 12-year-old group. And the study is designed not only to look at, can you normalize the biochemistry. So this is the pyrophosphate levels, inorganic phosphate levels and so forth.

But it's also asking the question of whether there's a functional impact on the bones, looking at radiographic scoring indexes. When your growth plates are open, that's a very effective way to ask, are you reversing rickets. The study will turn over its card in the first quarter of next year. We're excited to see the results.

And we see that as really the tip of the spear. The largest indication would be in adults, about 75% of the opportunity. And so from that standpoint, we're designing a pivotal adult study right now, working with regulators and hope to get that study up and running the ENERGY 4 study next year.

What makes me most excited about the Inozyme molecule is that, it works to do what it's designed to do. Weekly subcutaneous injections, normalize the biochemistry very rapidly in almost all the patients at a variety of dose levels. We see pyrophosphate normalize. We can see inorganic phosphate start to normalize as well.

In the adults, we even saw the FGF23 levels, which is sort of a marker of phosphate wasting from the kidney normalize. So this is an opportunity from a biochemistry standpoint to really normalize what's going on in the patients. The question will be, can we get that dose and schedule right to pull through to the functional endpoints. And that's what the study is looking at right now.

We are incredibly humbled and pleased to see what the Inozyme team has been able to deliver up to this point. We think that this is an indication and a biology that really fits so nicely into the BioMarin portfolio.

Smack dab on top of our enzyme replacement therapy unit. In fact, many of these physicians, I don't call them call points, because I'm an R&D guy, but many of the physicians I meet with are for VOXZOGO, in fact, I was at a meeting when the deal was announced and it just so happened that our VOXZOGO investigators were the same investigators on the study.

So pediatric endo and genetic -- medical geneticists are a lot of the same physicians that we work with. So it fits very nicely into our portfolio. From a deal perspective, it was a somewhat small disease, but we think it will have a big opportunity to help a lot of patients and in our hands. Again, with that 70 country footprint, we think that we can get this molecule to a world in the fashion that others would struggle to do.

And so for that Phase III, is it powered to meet a prespecified delta on some of the endpoints?

It is on both. Now it's a fairly small study. Again, these are super rare diseases. 29 -- I'm sorry, 27 patients. And it is powered to look at a delta for pyrophosphate, and it has a powering level as well for the radiographic index.

Okay. Great. And then, once we get those data in first quarter, maybe just an overview of the granularity of what we should expect obviously, both primary endpoints, right? But anything beyond that, that you all are planning to publicly disclose?

Sure. I think, our philosophy is that we absolutely recognize we're a publicly traded company, and we want to make sure that for our stakeholders, we discharge any confidential information. Did the study need its primary end points? Did we see any unexpected safety? What I would expect is beyond that, that most of the details will be saved for an academic presentation thereafter. So that the totality of the data can be seen by the audience that we intended to be seen from a technical standpoint. That being said, again, we're committed when these cards turn over to make sure that we share that with our stakeholders in the financial community.

Okay. Great. And then, next steps for additional age groups. I know you've talked about the adults. Have you thought about going into infants as well there?

Thanks for the question. So adult study designing, I hope to launch that, initiate it next year. Infants...

And that will be a Phase III...

Yes. So that would be a dedicated Phase III study. Studies in infants that are already ongoing. There are single-arm studies. There's both Phase I data as well as an expanded access program. As we mentioned, this is really a devastating condition where the lives of these infants are certainly at risk. We would, as part of any filing strategy, we would include that data in the packages, sharing with our regulators.

Inozyme had previously stated, they believe that this would be part of the first approvals. Again, these will always be review issues and we're engaging with regulators to make sure that they see the totality of data not just safety but efficacy data, including from infants as well.

Okay. Great. Well, unfortunately, we're out of time. But Greg, thank you so much. Really appreciate it. Great discussion.

Thank you.

Good afternoon. My name is Audra, and I will be your conference operator today. At this time, I would like to welcome everyone to the BioMarin Pharmaceuticals Second Quarter 2025 Conference Call. Today's conference is being recorded. [Operator Instructions]

At this time, I would like to turn the conference over to Traci McCarty, Investor Relations at BioMarin. Please go ahead.

Thank you, operator. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, such as 10-Q, 10-K and 8-K reports.

In addition, we will use non-GAAP financial measures as defined in Regulation G during the call today. These non-GAAP measures should not be considered in isolation from, as substitutes for or superior to financial measures prepared in accordance with U.S. GAAP and you can find the related reconciliations to U.S. GAAP in the earnings release and earnings presentation, both of which are available in the Investor Relations section of our website.

Please note that our commentary on today's call will focus on non-GAAP financial measures unless otherwise indicated.

Introducing the BioMarin management team today on the call, we have Alexander Hardy, President and Chief Executive Officer; Brian Mueller, Executive Vice President, Chief Financial Officer; Cristin Hubbard, Executive Vice President and Chief Commercial Officer; and Greg Friberg, Executive Vice President, Chief R&D Officer.

I will now turn the call over to BioMarin's President and CEO, Alexander Hardy.

Thank you, Traci, and thank you all for joining us today for BioMarin's second quarter update. Now moving to Slide 6. We were very pleased with our Q2 performance across all aspects of the business, including strong growth, exciting progress across the pipeline and delivery of our business development strategy.

Starting with our strong growth in the second quarter, leveraging our business unit structure to drive focus and accountability, BioMarin achieved double-digit year-over-year revenue growth and significant profitability expansion.

Turning to pipeline progress. I'm excited to share that BMN 333, BioMarin's low-acting therapy for children with achondroplasia achieved our target profile. Our goal is for BMN 333 to demonstrate superiority to VOXZOGO and set a new standard for the treatment of achondroplasia. We plan to advance the program to the next stage of development and expect to begin a registrational Phase II/III study in the first half of next year. Greg will provide additional details in a few moments.

Moving to our business development strategy. We successfully completed the acquisition of Inozyme on July 1, broadening our enzyme therapies portfolio. We executed the transaction with precision and focus, moving from agreement to close in less than 2 months. A lead program BMN-401, formerly known as INZ-701 is a treatment for ENPP1 deficiency, a condition with high unmet need and no approved treatment options, and we look forward to the pivotal data readout from this program in the first half of 2026. Greg will provide an update on some anticipated milestones with BMN 401.

Moving to Slide 7, our outlook for the remainder of 2025. Building on the strong momentum so far, we will continue to execute on our 2025 priorities with urgency to deliver value to our stakeholders. Looking ahead and building on the momentum, we expect continued strong growth throughout the remainder of 2025, leading us to increase our full year guidance for total revenues, non-GAAP operating margin and earnings per share. We are progressing our pipeline as announced today with BMN 333 advancing BMN 401 pivotal data expected to read out next year and a number of other updates anticipated over the coming quarters. And building on the Inozyme acquisition, we plan to continue to augment our portfolio with strategic business development transactions to diversify our growth strategy. In conclusion, with the first half of the year now complete, I'm pleased with our progress and remain enthusiastic about our potential to deliver for patients, employees and our shareholders through the remainder of 2025 and beyond.

Thank you for your attention. I will now turn the call over to Brian to provide our financial highlights for the quarter. Brian?

Thank you, Alexander. Please refer to today's press release for detailed second quarter 2025 results, including reconciliations of GAAP to non-GAAP financial measures. All 2025 results will be available in our upcoming Form 10-Q, which we expect to file in the coming days.

Now moving to Slide 9 and starting with revenue. We were very pleased with our strong performance in the second quarter of 2025. Total revenues grew 16% in the quarter and 15% in the first half of 2025 compared to the same period in 2024. These results were driven by the underlying strength in global demand and new patient starts across the portfolio. Looking ahead, BioMarin is positioned for continued growth in the second half of this year.

Revenue highlights in the second quarter include VOXZOGO revenue increasing 20% year-over-year to $221 million, fueled primarily by the ongoing success of the product's global expansion. Midway through the year, as I previously noted, we expect second half VOXZOGO revenue to be higher than the first half. And further, we expect second half revenue to be weighted to Q4 and due to both the impact of our strategic [ skeletal ] conditions business unit initiatives and order timing outside of the U.S. Therefore, with better line of sight into the dynamics in the U.S. and outside of the U.S. For the remainder of the year, we are targeting full year VOXZOGO revenue of between $900 million and $935 million. Inozyme Therapies revenue rose 15% year-over-year to $555 million, reflective of both strong demand and order timing from regions across the globe. With PALYNZIQ, we continue to see strong year-over-year growth with Q2 marking 2 consecutive quarters of 20% growth. VIMIZIM was also a strong contributor to second quarter growth, increasing 21% year-over-year. Roctavian revenue was $9 million in the second quarter, led by contributions from the United States and Italy. All of these factors contributing to our strong Q2 revenues give us confidence to bring up the lower end of full year 2025 total revenue guidance to $3.125 billion, with the midpoint of our guidance range representing double-digit year-over-year growth.

Now moving to Slide 10 and operating expenses in the second quarter of 2025. Non-GAAP R&D expense in the second quarter was lower compared to Q2 2024, benefiting from focused R&D investment in prioritized assets following last year's strategic portfolio review. Non-GAAP SG&A increased in Q2 year-over-year, mostly due to our investments in the company's enterprise resource, planning system implementation and business unit strategic initiatives. As mentioned in our first quarter update, we expect both non-GAAP R&D and SG&A expense to increase over the second half of 2025 due to our historical spend patterns, incremental operating expenses related to the Inozyme acquisition and continued advancement of our clinical programs and commercial initiatives. These investments include R&D expense for VOXZOGO new indications and BMN 333 as well as expansion of commercial initiatives in our skeletal conditions and enzyme therapies business units. Non-GAAP operating margin expanded significantly in the second quarter as compared to Q2 2024, driven by strong performance across the P&L, including underlying revenue growth and current operating expense trends. We anticipate that higher operating expenses in the second half of 2025 to support our business unit initiatives will decrease second half operating margin as compared to the first half of the year. Further, as just outlined with revenue being back weighted to Q4, together with the expense timing, we expect profitability to be lower in Q3 as compared to Q4. All in all, continued strong revenue performance and underlying cost discipline enables us to raise full year 2025 non-GAAP operating margin guidance to between 33% and 34%.

Now moving to Slide 11 to highlight BioMarin's increasing profitability and operating cash flow. The bottom line continues to outpace top line growth at an impressive rate. In the second quarter, non-GAAP diluted earnings per share of $1.44 increased at more than 3x the rate of revenue growth, reflecting the flow-through of strong operating margin performance to the bottom line. Looking through the remainder of 2025 and as with operating margin, we do expect increasing business unit investments to result in lower earnings per share in the second half of the year as compared to the first half with the decrease concentrated to the third quarter due to timing. Supported by the strong first half performance, we are raising full year 2025 non-GAAP earnings per share guidance to between $4.40 and $4.55. In addition, BioMarin's increasing profitability continues to generate significant operating cash flow, reaching $185 million in Q2, a 55% increase versus the same period in 2024. Increasing operating cash flow is expected to continue going forward in support of our innovation expansion opportunities and future growth.

Now moving to Slide 12 and to summarize, we are pleased with our financial performance across the business in the second quarter and today's full year 2025 guidance update reflects our expectation of continued strong growth and value creation for shareholders. Separately, with the Inozyme acquisition completed on July 1, and we expect to account for the transaction as an asset purchase and record the impact of the acquired in-process research and development or [ IP R&D ] expense in our financial results in the third quarter of 2025. Today's guidance updates do not yet reflect the IP R&D, and we will update full year guidance when we report Q3 as the transaction is reported.

Thank you for your attention. And I will now turn the call over to Cristin Hubbard for an update on commercial activities in the quarter. Cristin?

Thank you, Brian. Now moving to Slide 14. I'd like to acknowledge the contributions from across the global teams that led to the strong second quarter performance from BioMarin's portfolio of 8 innovative therapies. .

Starting with VOXZOGO, 20% year-over-year revenue growth in the second quarter across a combined 51 countries was supported by new patient starts as well as strong treatment adherence. We were pleased to see strong uptake in the 0- to 4-year-old cohort in the U.S., new initiatives in the U.S., including increasing the field force as well as investments in digital promotion to drive VOXZOGO expansion are working. As a result, we doubled the number of leads generated year-to-date year-over-year, which translated to an increase in net new U.S. patients. With these initiatives firmly in place, we expect U.S. patient uptake over the remainder of the year to be strong, while noting that the revenue results from these initiatives will be realized over the coming quarters.

Now outside the U.S. VOXZOGO expansion came from deeper penetration into existing countries as well as good adherence from children on therapy with incremental contributions from newly added countries. In summary, we are pleased to expect VOXZOGO's full year 2025 revenue growth of 25% year-over-year at the midpoint.

Now moving to Slide 15 and turning to hypochondroplasia, the next indication we are studying for VOXZOGO treatment. Apachondroplasia is a rare skeletal condition characterized by impaired bone growth leading to disproportionate short stature along with a wide range of medical complications and functional challenges. The comorbidities are highly varied and can look like any combination of disproportionality,[indiscernible] ear, nose, throat and musculoskeletal-related issues. Because hypochondroplasia is a clinically and genetically heterogeneous condition, it may be diagnosed late or not at all. Unfortunately, there is significant unmet need as the condition has no approved treatment, except for growth hormone in Japan. People with hypochondroplasia can face significant health burden and reduced quality of life. To date, data from Dr. Andrew Dauber's investigator-sponsored study has provided encouraging proof-of-concept results with VOXZOGO and hypochondroplasia. Enrollment pace in BioMarin's pivotal study exceeded internal expectations, giving us a good indication of demand for the treatment of this condition. We are leveraging our established capabilities to raise awareness of the upcoming Phase III hypochondroplasia data set, which we plan to share in the first half of 2026 to support a potential launch in 2027. And at this stage, we are actively engaging with the medical community to advance education on disease awareness and management. Through strategic partnerships with health care professionals, including achondroplasia thought leaders, advocacy groups and academic institutions, we aim to improve early diagnosis and hypochondraplatia to shape future treatment decision-making with VOXZOGO.

Now moving to Slide 16 and our Inozyme Therapies business unit. In the second quarter, combined products delivered 15% growth year-over-year. PALYNZIQ's strength in the quarter was driven by greater numbers of patients titrating to their daily maintenance dose and strong adherence. Incremental new patient starts were encouraging in the quarter, and we look forward to them achieving their maintenance dosing over the coming quarters to realize the full benefits of PALYNZIQ. And if approved, we look forward to the opportunity to make PALYNZIQ available to adolescents in the U.S. and Europe based on its demonstrated ability to lower fee into the normal range and allow for an unrestricted diet even in people with the most severe form of PKU. We believe these 2 attributes will be particularly transformational for those preparing to transition into adult. VIMIZIM was also a strong performer during the quarter, growing 21% in year-over-year revenues and benefiting from ongoing patient demand globally as well as the timing of large orders in certain regions. Across Inozyme therapies, we expect strong trends to continue through the second half of 2025 despite potential quarter-to-quarter fluctuations due to order timing as we've observed historically. In summary, the team delivered another quarter of strong performance across the globe. Despite the significant macro challenges many companies in our sector are facing, the essential nature of our medicines, our strong patient support programs and BioMarin's global reach keep these important therapies available for the people who need them. I want to thank the team for their continued commitment and perseverance.

I'll now turn the call over to Greg for an update on R&D progress in the quarter. Greg?

Thank you, Cristin. Now moving to Slide 18. We're very pleased to share the first clinical update on BMN 333, BioMarin's long-acting CNP candidate for the treatment of achondroplasia. Today, we announced that we have observed encouraging PK results from our healthy volunteer study where BMN 333 demonstrated free CNP levels more than 3x greater than the AUC levels reported for another long-acting CNP as described in the British Journal of Clinical Pharmacology from June 2022. This profile represents a potential best-in-class molecule with the opportunity to drive even greater improvements in growth parameters versus available therapies and by extension, to further improve measures of health and wellness in children with achondroplasia. Our own preclinical data, along with publicly available dose response data for long-acting CNP agents, suggest that additional growth should be achievable with greater CNP exposures. We believe that safely achieving these PK results with BMN 333 means we have the right agent in hand to immediately test this hypothesis. Based on these results, we're planning to initiate the dose-finding arm of our Phase II/III registration-enabling program in the first half of 2026 with a targeted approval in 2030 should the data be supportive. .

The Phase I study continues as planned with ongoing monitoring of safety and pharmacokinetics at our sixth and final planned cohort. We anticipate sharing this full data set publicly at a conference in the first half of next year. We are very encouraged by these results thus far, and we'll continue to look for opportunities to accelerate the program.

On Slide 19, moving to our next regulatory filing. We're on track to submit applications an age extension for PALYNZIQ to include adolescents with the U.S. and EU applications planned for the second half of this year. Recall that our PALYNZIQ adolescent study, similar to our previous adult study, required participants to have sustained fee levels greater than 600 [ micromole ] per liter despite available dietary and pharmacologic treatment. This is a more severe population than those in which the BH4 analogs have been routinely used. Beyond simple fee lowering, the promise of PALYNZIQ is that it may offer adolescents the potential to consume more native protein during their formative years and to decrease or eliminate the need for medical food. We plan to share the complete data from our Adolescent Study at a scientific congress in the second half of this year, and we look forward to the possibility of expanding the PALYNZIQ label into adolescents with potential approvals in 2026.

On Slide 20. Now turning to another Phase III asset. We're very pleased that the Inozyme acquisition was closed so rapidly, allowing us to carry forward BMN-401 for the treatment of ENPP1 deficiency. TPP1 deficiency is a rare, serious and progressive genetic conditions that can affect blood vessels, soft tissues and bones in infants, in children and in adults. BMN 401 has the potential to be the first genetically targeted medicine for ENPP1 deficiency. We look forward to sharing a first look at the pivotal data from the ENERGY III study in 1 to 12 year olds in the first half of 2026 and and the progressing clinical development in other age groups once we finalize the integration and determine the most efficient path forward.

In addition to this initial focus on ENPP1 deficiency, we are already evaluating other potential indications with BMN 401, and we will share more details as they become available.

Finally, on Slide 21. Here is a snapshot of a few highlights expected across our pipeline through the next 6 quarters. Following today's healthy volunteer PK update for BMN 333, we look forward to the start of our Phase II/III study in the first half of next year. Also in the first half of 2026, we'll be sharing pivotal VOXZOGO data in hypochondroplasia with submissions planned in the second half of 2026 to support a potential approval and launch in 2027. We plan to submit our PALYNZIQ adolescent data before the year's end in support of potential launches in the U.S. and Europe in 2026. BMN 401, as already mentioned, is expected to read out the ENERGY III study in the first half of 2026 in 1- to 12-year olds, followed by a potential regulatory submission in that age group in the second half of next year with the goal of launching in 2027.

With BMN 351 for the treatment of Duchenne's Muscular Dystrophy, our study is progressing as planned. In addition to previously discussed 6 and 9-milligram per kilogram cohorts, which have fully enrolled. The study data monitoring committee recently approved escalation to a third preplanned cohort of 12 milligrams per kilogram, which should complete enrollment by the end of the year. We remain on track to share a more detailed clinical update by the end of this year. BMN 349 for alpha-1 antitrypsin deficiency is also progressing in the clinic, and we're planning a Phase II study start in the first half of 2026. .

In summary, we have a number of exciting readouts and regulatory filings on the horizon, and we look forward to sharing updates as they progress over the coming months. I want to thank you for your attention today. We will now open the call to your questions. Operator?

[Operator Instructions] We'll take our first question from Paul Matteis at Stifel.

I had a couple of questions on BMN 333. I just wanted to clarify that the competing program you're referring to is [ TransCon ] CNP relates to the comparison to AUC data. And then as it relates to the data itself, can you just confirm the safety profile that you're targeting and whether or not increased exposure is running into any increased risk of hypotension or other side effects?

So Paul, this is Greg Friberg. I can confirm that the agent you're referring to is in that reference that we commented there. With regard to the profile we're seeing with 333 from a safety standpoint, absolutely nothing unexpected, though we have to remember this is a healthy volunteer study. It's in adults, not in children. That being said, nothing unexpected. And again, we also look at the genetic data in this disease, where -- from the standpoint of patients who either have inborn mutations that cause them to have high CNP levels or activated receptors, nature has shown us that those patients -- the only problems that they tend to have in their lifetime is that, number one, they're quite tall and there are skeletal complications of being over 7 feet tall. But reassuringly, those patients don't have challenges in other organ systems. So again, we're hopeful that, that read-through will again be recapitulated when we pharmacologically go to higher levels of CNP.

We'll go next to Cory Kasimov at Evercore.

Great to see the continued execution in the preliminary 333 data. On the achondroplasia front, I'd be interested in your thoughts on the evolving competitive landscape here. with the recent data showing a long-acting CNP in combination with growth hormone and how you think that could impact the market down the road?

Thanks, Cory. This is Greg Friberg, again. I'll take a stab at that. When the early data -- the growth hormone combinations card turned over, it was not surprising to see that there was added growth at a very early time point when growth hormone was added to CNP. Being able to achieve small or at least short-term increases has never been the problem with growth hormone. On the contrary, it's been whether or not those accelerations of growth can persist over time. Of course, achondroplasia is a condition which is not growth hormone deficient. And long-term follow-up of these patients particularly even the Japanese patients where it's approved in Japan have only shown a couple of centimeters an increase in final adult height. Similarly, the kind of evidence beyond growth that we're seeing with CNP affecting facial morphology, looking at tibial [indiscernible], all of these evidence of improving the patient's well-being and health. Those haven't been as profoundly documented with growth hormone. So the question with the growth hormone combination, there are a few of them. One would be, is this something that's achievable over time. Secondarily, do we see mechanisms that accelerate bone age, do we see those? You won't see those in the first 6 months. So we'll want to -- as a -- I think as field, we'll want to see additional data before the story is written as to whether that combination will add anything significant for patients with achondroplasia. .

Next, we'll move to Salveen Richter at Goldman Sachs.

This is Tommie on for Salveen. Just on the VOXZOGO guidance, which was slightly adjusted. Could you lay out the contributions of the various factors as you think about ex U.S. order timing, demand and your U.S. expansion initiatives?

Yes. Thank you so much for the question, Tommie. So as we had mentioned, we are expecting higher revenues in the second half relative to the first half of the quarter. And really, when we think about it throughout the quarter, this is primarily due to some of the shifting of large OUS orders that we see that we expected later in the quarter that will shift out a little bit, some into the beginning of 2026 as well, which will, therefore, kind of bring down the number a little bit. Not to mention we are coming closer with only 5 months to go in the year, and we just have a much better sense of kind of what we're trending toward and what we can forecast throughout the year. So what we did, as you see, is we brought down the top end of the range from [ $950 million to $935 million ] but I want to emphasize that, that still represents 25% year-over-year growth.

We'll go next to Jessica Fye at JPMorgan.

This is Adam on for Jess. I just wanted to ask, can you walk us through when we should expect the next updates from the ITC proceedings?

Yes. Thanks very much for the question. With regard to the ITC update, we're expecting that has been publicly communicated that we're going to see the initial determination on the beginning of June, actually June 8, 2026, then a completion date, the target date for the completion of the investigation of ITC of October 8, 2026. So those are the time frames that have been publicly communicated. There is a possibility of a summary determination for that time, but these are very much what has been communicated by the ITC at this point.

We'll go next to Akash Tewari at Jefferies.

Can you just give us a little more detail about the design of that 333 superiority trial? Because when I look at the VOXZOGO Phase III, you had about 55 patients per arm. You're 90% powered to get a 1.75 average growth velocity delta. I feel like if you have the same powering per arm and you're going for superiority, you're probably looking at like a 0.8 to 1 centimeter improvement between 333 and VOXZOGO for that trial to hit on superiority. Is that the right way to think about efficacy? And like what gives you the confidence you can do that?

And then maybe number two, can you talk about the potential to pursue maybe beyond weekly dosing with the profile that you showed in [ Helly ] volunteers?

Thanks, Akash. Just dissecting your questions one by one. From the standpoint of the Phase III study, we're not going to go into details on powering today. But we do have confidence that this is biologically a very reasonable hypothesis test. Of course, we have the preclinical data and the mice where, again, in terms of attributable growth, we were able to almost double the amount of skeletal growth that we saw in those models using the kind of doses with 333 that we've now been able to show at least in the single-dose study or safe in humans. Similarly, we mentioned the human genetic data on the safety side. We also know that those individuals born with activating mutations in the pathway, they grow quite substantially, almost a 7 feet tall or farther. But finally, if we look at the available data that's published for another 1 acting CNP agent, marching upwards to the highest dose, there is proportionately an increasing amount of growth at each step along the way. By being able to then in our minds, continue that curve upwards with increased exposure, we feel we confidently have the right molecule to test that hypothesis with 333. I'll just add that we have -- we mentioned we're in our sixth cohort right now. We've completed 5 and 2 of them have met our criteria. So again, we feel like we have on the PK side, quite a bit of headroom and feeling very good about the results that we've seen.

With regard to the amount of attributable growth that we're going to look for in the Comparative Effectiveness Study. What I would add is that we certainly have talked to patients. We've talked to physicians, we've talked to their caregivers. And again, we've come up with an amount that we think again would be meaningfully differentiated in the marketplace. And I would be remiss if I didn't add that this -- while this is a story where we talk about growth, and talk about the number of centimeters, we also want to pull through to, of course, the markers of health and wellness. Spinal stenosis, of course, is something that we're following very closely. The additional skeletal facial morphometry studies, all of those, we would be measuring and we would hope to see meaningful improvements in the quality of life of these patients, these individuals who have this condition. So with that regard, we'll be sharing more information over time on the study design. I'll just simply add that from -- as you can extrapolate from some of the AUC comments I made, we would have the opportunity if desire to consider less frequent intervals than weekly. The question becomes, which parameter do you want to prioritize? And for us, increasing efficacy, increasing the ability to drive health and wellness in the patients is what we're prioritizing at this point.

We'll take our next question from Joseph Schwartz with Leerink Partners.

I'm Joori Park going in for Joe. I know you're working on BMN 333 with the goal to launch in 2030, but in the meantime, how predictive is your low discontinuation rates for VOXZOGO in an environment where there is no competition. How do you think about the discontinuation rates when there are other options, including once weekly or once daily oral prior to the availability of BMN 333? .

Yes. Thank you so much for the question. This is Cristin Hubbard from commercial. And just speak to the adherence rates that we know today. We continue to see that the vast majority of children that are on therapy really do adhere to their daily dosing, and this is true across the globe. And we are really expecting that many of the new initiatives that we've started will continue to ensure this high compliance going forward. Now I will say that this is something that we've invested in, in terms of patient support programming. We think it is incredibly important that patients do adhere to their therapy. And so we've definitely put some support programming in place that will aim at driving adherence and really ensuring that we have an improved experience, in particular, in some of those more high-risk populations where we're truly seeing strong results in terms of adherence. And I do think that this is something that is 1 of BioMarin's core strength at large across our portfolio. It's truly about finding patients through diagnostic efforts, it's about starting patients on treatment. And then importantly, it is really important that we keep patients on therapy because we know this is the most important thing for long-term outcomes. That's what we're investing in and continue to do so. .

We'll go next to Sean Laaman at Morgan Stanley. .

Just thinking a little forward to your $4 billion revenue aspirations in '27, I think it is. Just wondering how important other indications for VOXZOGO are after that? And what sort of contribution do you think they might make? And even going beyond hyperchondroplasia indications such as [indiscernible] and in [ Terna ], when might we expect those?

Sean, this is Brian Mueller. Thanks for the question. I'll take that one. So first, some remarks on the $4 billion revenue target in 2027. Given the many developments since we unveiled our new corporate strategy and 2027 guidance of $4 billion last year. We are taking full account of the latest information and plan to provide an update on our 2027 revenue guidance and our long-term targets by the end of this year. So stay tuned on that, we will revert shortly. I would answer the other part of your question that in the previous guidance, hypochondroplasia was the only indication expansion for VOXZOGO that was launching in that 2027 window. So there's a modest contribution from hypochondroplasia in that original number.

We'll take our next question from Gena Wang at Barclays.

I also will ask about the 333 program. So Greg, you said that now you already dosed the sixth cohorts. What are the thoughts when you go into the patient population? Is the aim is to maintain area on the curve over 3x, any upper limit you will be looking for regarding the safety. And then the -- if you can remind us the VOXZOGO low-dose, high dose. What was the area under curve comparison. We do understand the CMAC could be very different. But when you look at the area under curve, what was the difference between the low-dose and the high-dose of VOXZOGO?

Thanks, Gena. And let me take those in order. With regard to the data we have in hand for 3333. We feel that it's going to give us a totality of evidence that will allow us to pick relatively speaking, a low, a medium and a high dose at least several of those will be, again, at this 3x or above is what we're anticipating, though picking those final doses will require us to finish the study and do the formal pharmacokinetic analysis. As we mentioned, this sixth cohort, while recruited hasn't completed in terms of its data collection. So that is ongoing.

With regard to the original VOXZOGO studies, the AUCs because the half-life was 30 minutes to 60 minutes as you note, the calculations of AUC in terms of precision, we don't have a whole lot of confidence that comparing the 15 to the 30, for example, is going to give us all that meaningful data. But those numbers were much lower than the AUCs that we're seeing with the long-acting, which has a half-life on the order of days instead of a half life on the hour of minutes in the 30 to 60 minutes. Beyond that, I can't give you any more details in terms of the numerics, but if you have any specific questions afterwards, be happy to follow up with you offline.

We'll move next to Ellie Merle at UBS.

This is Jasmine on for Eli. Just another one on 333, trying to understand why the 3x greater AUC proceeding means, from your preclinical work, can you give any more color on what this level of CNP exposure translates to in terms of growth?

And then secondly, given the data that you've now seen how this impact your thinking on prioritizing 333 versus VOXZOGO for other growth disorders going forward?

Thanks for the question. With regard to the 3x growth, at least from a numeric standpoint, the preclinical model is probably the best because, again, there's a case where actually we were able to recapitulate this sort of increase in exposure. So the control animals had -- were treated with a very healthy dose of VOXZOGO. And again, all of the growth that, that could deliver, followed by increasing titrating doses of 333. And what we saw was at roughly -- what we're projecting are 3x margin compared to, again, what's been published for other long-acting programs that we were able to unlock additional growth. And so the 3x, again, is what we believe is a meaningful difference in exposure compared to what we've seen before. And in the animal models, again, we know that there's additional growth there. The question is going to be just how much is there. What we know for sure is that we have, what we believe to be the right agent in hand to test that hypothesis. We believe that we're going to be able to test multiple doses at that threshold or higher in the dose-ranging Phase II and that before, certainly, the initiation of the comparative effectiveness study, we're going to have a good handle on how much growth is there to be at. That being said, it is an unanswered question. the preclinical, the genetic and the data from other long-acting CNPs can only get us so far. And so having the right agent to test is the next step, and we're thrilled to be moving forward. We're excited about 333 beyond just achondroplasia. We're putting together our hypochondroplasia plan as we speak. All of the additional indications do require us to do a dose-ranging study. So doing that as quickly as possible is the key to unlock that. And again, having that arrow in our quiver is also going to allow us to think about additional indications where we might want a best-in-class CNP -- long-acting CNP agent. And again, that's what we're hopeful that we have in BMN 333.

We'll take our next question from Olivia Brayer at Cantor.

Can you give us an update on where you are with the citizen position? Have you had any back and forth dialogue with the agency? And maybe just any comments on how confident you are that there will be action taken by the FDA here?

And then just wanted to follow up on some of the comments made around the long-term guidance metrics. Is there something in particular that you're waiting to hear about before having better visibility into what those numbers could look like?

Thanks very much for the questions. I'll take the first one. This is Alexander. So with regard to the [ systems ] petition, we have submitted that to the FDA. The FDA [indiscernible] that during the review process for the competing molecule with regard to determining the validity of our orphan drug mentioned. So we do not expect to hear anything from the FDA until PDUFA. As you know, that is November 30. So that's all the information we have to share right now on the situation with regard to this system competition.

Now I'll hand it over to Brian to handle the second part of your question.

Yes. Thanks, Olivia. On the $4 billion in 2027, there is not a specific event that we're waiting to pass before we give that updated view. It really is just working through our collective refreshed view across everything that's changed over the last year. There's puts and takes. We're considering recent trends in market research across our portfolio. We completed the Inozyme acquisition this quarter. And of course, the VOXZOGO IP litigation is still ongoing. So we're working through that. And once we do, we'll share the perspective.

Next, we'll move to Konstantinos Biliouris at BMO Capital Markets.

Congrats on the progress. Maybe some more color on some comments you made earlier on the 3x difference between AUC -- can you please clarify how exactly you performed the comparison? Was it 3x -- at least 3x across all doses you compare or only in the highest dose or only in some doses.

And the follow-up is on Cmax. Does Cmax matter at all here maybe for safety or efficacy? And how does your Cmax compare with [ TransCon ] CNP.

Thanks for the question. With regard to the ongoing study, just to repeat something I said up, but I might have gone through too quickly. We've completed and analyzed 5 escalation cohorts. It's a healthy volunteer single-dose study. And 2 of those cohorts already have met our AUC criteria of being greater than 3x. That is greater than 3x the AUC, of which is published and we put the reference in our slides for the other long-acting CNP agent that's been discussed. From that standpoint, again, we have a sixth cohort that's running right now. All of these have been avoiding the kind of Cmax ranges where with VOXZOGO, we knew that we started to see a very predictable effect on the vasculature, which was the drop in blood pressure and some tachycardia in patients. That is Cmax that is well understood from the preclinical models and from our own experience, and we're still almost tenfold away from that with regard to what we're seeing. Nothing is for free, and of course, as your AUC goes up, so does your Cmax. And so from that standpoint, the Cmax, we predict will be greater than the other long-acting CNP out there. The question is, is that problematic? And so far, it has not been problematic. We're moving forward. And again, this is why we will, in patients do a dose ranging of a high, medium and low, that's a relative term, but a high, medium and low dose of BMN 333 moving forward in order to test not only what kind of growth and effects on health and wellness that we can see, but also to make sure that, that is safe in those patients.

We'll take our next question from Jason Gerberry at Bank of America. .

One just follow-up on the HCH opportunity and the commentary about getting to the patient earlier. I guess we observed with ACH or achondroplasia that getting the below 5 indication was really key commercially in a number of geographies. And with ACH, at least in the prior Phase II work, I think the average age was about 6 years of age, your enrollment criteria is 3 years. So I wonder given it's a milder disease, the motivation to treat and sort of the risk, I guess, from a patient perspective, they're going to come on later in life and may not get the sort of lifetime benefit that they see in HCH. So just wondering if you can maybe expound upon some of those efforts and how you see that evolving.