Mirum Pharmaceuticals Inc Aktie

Good afternoon, and welcome to Mirum Pharmaceuticals First Quarter 2026 Earnings Conference Call. My name is Tracy, and I will be your operator today. [Operator Instructions]

I would now like to hand the call -- the conference over to Andrew McKibben, SVP of Strategic Finance and Investor Relations. Please go ahead.

Thank you, Tracy, and good afternoon, everyone. I'd like to welcome you to Mirum Pharmaceuticals First Quarter 2026 Earnings Conference Call. For our prepared remarks, I'm joined today by our Chief Executive Officer, Chris Peetz; our President and Chief Operating Officer, Peter Radovich; and Eric Bjerkholt, our Chief Financial Officer. Our Chief Medical Officer, Joanne Quan, will be joining us for Q&A.

Earlier this afternoon, Mirum issued a press release reporting our first quarter 2026 financial results. Copies of the press release and our SEC filings are available on the Investors section of our website.

Before we start, I'd like to remind you that during the course of this conference call, we will be making certain forward-looking statements based on management's current expectations, including statements regarding Mirum's programs and market opportunities for its approved medicines and product candidates and financial guidance.

These statements represent our judgment and knowledge of events as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed. We are under no duty to update these statements. Please refer to the risk factors in our latest Form 10-Q and subsequent SEC filings for more information about these risks and uncertainties.

With that said, I'd like to turn the call over to Chris. Chris?

Thanks, Andrew, and good afternoon, everyone. We have a number of important updates to cover today, but I'd like to start by grounding in the vision we set when we founded Mirum in 2018. building a company focused on bringing forward medicines for overlooked rare diseases. This quarter reflects the progress we've made in turning that vision into a durable growing business.

Our start was based on LIVMARLI. And today, we are a broader rare disease company with 3 approved medicines and a pipeline positioned to deliver multiple new therapies over the next 2 years. These high-impact programs are grouped across 2 focus areas: rare liver disease, where we have built clear leadership and rare genetic disease, where we are establishing a second growth platform, each with distinct commercial capabilities. Across both, we've built a financially self-sustaining business that can support continued investment in the portfolio. Our strategy is driving compelling results.

Starting with rare liver disease, uptake of LIVMARLI remains strong, driven in part by performance in PFIC, which continues to exceed expectations. Based on that demand and continued performance across all brands, we are raising our full year revenue guidance to $660 million to $680 million. More importantly, we are now seeing the next phase of our rare liver disease business take shape.

Our recent clinical readouts in PSC and hepatitis delta represent important potential expansions for this business, extending beyond our pediatric foundation into larger patient populations with significant unmet need.

In PSC, the VISTAS study of volixibat showed a significant improvement in pruritus, reinforcing the potential for volixibat to play an important role for these patients who currently have no approved medicines. This is a major advance in PSC research and positions volixibat as a potential first approved medicine for patients in the U.S.

And in hepatitis delta, results from the Phase IIb portion of the AZURE 1 study further support the potential for brelovitug in a patient population where treatment options are extremely limited. We look forward to the upcoming late-breaking presentations for both VISTAS and AZURE at EASL later this month.

Now in parallel to this expansion of our rare liver disease business, today, we are announcing another step in building out our rare genetic disease business with the addition of zilurgisertib recently licensed from Incyte. Zilurgisertib is a once-daily oral ALK2 inhibitor in development for fibrodysplasia ossificans progressiva or FOP, an ultra-rare progressive condition where patients develop bone and soft tissues. This accumulation of excess bone leads to profound physical immobilization with most FOP patients becoming wheelchair dependent by early adulthood and severely impact life expectancy.

Based on the strength of zilurgisertib's PROGRESS study conducted by Incyte, an NDA has been accepted for priority review with a PDUFA date of September 26 this year. If approved, we expect to launch by year-end. This is a strong strategic fit, aligning with our capabilities in rare genetic disease, where care is concentrated in a small number of specialized centers and requires deep engagement with patients, caregivers and physicians.

Stepping back, we built a company with multiple commercial growth drivers, a pipeline of meaningful upcoming catalysts and the financial strength to advance our portfolio independently. This foundation is translating directly into high-impact medicines for patients and into value creation as we deliver on our strategy.

And with that, I'll turn the call over to Peter to walk through the commercial portfolio and preparation for the 3 upcoming potential launches. Peter?

Thank you, Chris. The first quarter was another period of strong commercial execution with total net product sales of approximately $160 million. This included LIVMARLI net product sales of $84 million in the U.S. and $30 million internationally, with the bile acid medicines contributing $46 million.

Robust adoption in PFIC, particularly in adult patients, continues to be a strong point for LIVMARLI as education to increase awareness and recognition of genetic cholestasis among adult liver providers continues to be successful.

Additionally, we saw stronger-than-expected performance in Q1 international LIVMARLI sales as well as continued new patient adds in Alagille worldwide. The bile acid medicines grew in a manner consistent with their cadence over the last several quarters, highlighted by our rare genetics team continuing to identify undiagnosed patients with CTX.

Overall, we expect these dynamics to continue and as a result, are raising our full year 2026 net product sales guidance to $660 million to $680 million.

And as Chris mentioned, we are also beginning to see the next phase of growth in our rare liver disease business take shape. The recent results from the VISTAS study of volixibat in PSC and the AZURE-1 study of brelovitug in hepatitis delta represent important steps in extending our presence into larger, primarily adult liver settings, where patients have limited or no approved treatment options.

These programs build directly on the global commercialization platform we have established for LIVMARLI, CTEXLI and CHOLBAM, heavily leveraging our existing technologies, people and infrastructure.

We plan to expand our U.S. and international teams starting later this year to reach liver health care providers in adult settings, including GI liver providers, who manage PSC patients and hepatitis delta as well as other care settings like infectious disease and selected primary care providers, where we believe we can increase the number of diagnosed hepatitis delta patients.

In the U.S., our current 20-person liver field commercial team reaches about 1,500 health care providers with currently focus on pediatric liver providers and some higher volume adult providers. After our planned expansion to approximately 60 U.S. field commercial personnel, we anticipate being able to reach over 4,000 liver health care professionals, representing the vast majority of potential prescribers for our rare liver business.

Turning to our rare genetic disease business, we are very excited by the addition of zilurgisertib for the treatment of FOP, where there remains a desperate need for additional treatment options. FOP is a devastating relentlessly progressive condition in which soft tissues such as muscles, tendons and ligaments gradually turn into a second skeleton, leading to cumulative loss of mobility, severe disability in early childhood.

FOP is a highly concentrated ultra-rare disease with an estimated prevalence of about 1 per million, which translates to approximately 300 patients in the United States and around 900 patients globally.

Patients with FOP are largely managed by specialized tertiary centers, with most of these centers also managing patients receiving CTEXLI and CHOLBAM, allowing us to leverage our rare genetic disease team to commercialize zilurgisertib. And we've been impressed by the zilurgisertib data from the pivotal PROGRES study, in particular, the secondary endpoints, which form the basis of the NDA application, and we look forward to the presentation of the data from the PROGRESS study at an upcoming medical meeting.

The NDA for zilurgisertib has been accepted for priority review by the FDA with a September 2026 PDUFA date. If approved, we expect to launch zilurgisertib in the United States by the end of this year with expansion to additional countries starting in 2027.

We are excited about the addition of zilurgisertib, which we believe has the potential to become the cornerstone of our rare genetic disease business and reach peak sales of over $200 million. This high-impact medicine fits perfectly with our medical and commercial team's capabilities and passion for supporting patients suffering from ultra-rare diseases like FOP.

And with that, I'll turn it over to Eric to review our financial results. Eric?

[Technical Difficulty] and disciplined investment behind our pipeline, which remains on track across all programs. Today, I'll walk you through the financials for the quarter, including an overview of the impact of the Bluejay acquisition and the zilurgisertib transaction.

The net product sales for the first quarter were $160 million compared to net product sales of $112 million in the first quarter of last year. Cash, cash equivalents and investments as of March 31 were $421 million compared with $391 million at the beginning of the year.

In the first quarter, the cash contribution margin from our commercial business was in the mid-50s percent and cash flow from operations was about $2 million.

First quarter financials were significantly impacted by onetime expenses related to the acquisition of Bluejay Therapeutics, which closed in January of this year. The total net cash outflow related to this acquisition was $253 million, which was offset through net financing proceeds of approximately $260 million.

Total operating expense for the quarter ended March 31st was $949 million, which includes $761 million in expense associated with the acquisition of Bluejay, R&D expense of $98 million, SG&A expense of $96 million and cost of sales of $29 million.

Expenses for the quarter included stock-based compensation, intangible amortization and other noncash expenses of $64 million, including $35 million of stock-based compensation expense associated with the acquisition of Bluejay. The intangible amortization and other noncash item expenses are largely reflected in our [ company's ] results.

As Chris and Peter mentioned, we recently entered into an exclusive license agreement with Incyte. In return for worldwide rights to zilurgisertib, Incyte received an upfront payment of $16 million and is eligible to receive additional development and regulatory milestone payments, including $25 million upon U.S. FDA approval for FOP ownership of a rare pediatric disease priority review voucher, if awarded, as well as sales-based milestones and tiered royalties on worldwide net sales in the mid to high single-digit percent range.

As we've discussed previously, we expect R&D expense to step up in 2026 as we invest behind brelovitug ahead of the anticipated BLA submission next year. For example, R&D expense in the first quarter included $21 million related to the development of brelovitug. Importantly, this expense expected increase is fully funded.

We are continuing to scale the business with disciplined, balancing investment in growth with a strong balance sheet and financial independence. This approach positions us to advance our pipeline and execute on upcoming milestones without compromising our long-term financial strength.

I'll now turn the call back to Chris for closing remarks.

Thanks, Eric. Mirum is in a strong position after a very busy start of the year. What is most encouraging about the quarter is not just a number of positive updates, but how clearly they fit together. We continue to grow our commercial medicines. We're expanding our rare business into rare liver business into larger indications. We've added what we believe is a transformational medicine to our rare genetic business.

And importantly, this is all coming together within a high-impact scalable business model. We're excited about the progress ahead as we approach multiple pivotal readouts, potential regulatory submissions and potential new product launches. I'd also like to thank the entire Mirum team for all the hard work in getting us where we are today. Your dedication brings new treatment options to patients around the world. And with that, operator, please open the call for questions.

[Operator Instructions] Your first question comes from the line of Gavin Clark-Gartner with Evercore ISI.

This is Yesha on for Gavin. I just had one on FOP. Wondering your current view on the number of diagnosed FOP patients in the U.S. based on claims, patient advocacy and provider research. And then how many of those patients will immediately be treatable at launch? And then I have one follow-up on LIVMARLI.

Yes. Thanks for the questions. Yes, the -- we point towards the approximately 300 identified patients in the U.S. coming from patient [ advocacy ] group [indiscernible]. In terms of addressable patients, probably the main feature there is the NDA application inside filed as for age 12 and over. So that would be the main piece to consider, which would be the majority of the prevalent patients.

And then on -- in terms of LIVMARLI specifically on the guidance raise, wondering what's kind of driving the bulk of the increase? Is it due to the ex-U.S. expansion or kind of the continued PFIC ramp? And within PFIC, is the contribution still skewing towards those older patients?

Yes. Thanks for the question. I mean, certainly, LIVMARLI U.S. PFIC was the biggest driver and continue to see both pediatric and adult patients come to treatment. I think the older adolescents and adults really is the major driver, although we're still -- we think still in early innings.

We've made good progress educating adult providers on genetic testing, but still the minority of them are actually doing that. So I think there's probably more adult patients to find out there to potentially benefit from LIVMARLI.

And yes, on the international piece, in Q1, historically, we've seen a bit more seasonality and a little bit of a softer number in Q1. that just wasn't as much of a factor this year, somewhat in part of not only additional countries performing, but also PFIC starting to show up in that international number.

Your next call comes from the line of Josh Schimmer with Cantor.

Also on zilurgisertib, how are you thinking about its differentiation versus maybe some of the other programs in development, garetosmab, if I'm pronouncing that right. And so who knows that's number one.

Number two, are you planning to explore the program in other ossification indications disorders?

And then number three, I think I heard you say peak sales for the asset of $200 million, is that global or U.S.

Thanks, Josh, for the questions. Yes, just to clarify that peak, the $200 million plus is a global number for us. And then in terms of kind of positioning here, the programs that you covered there, those are the ones that we're tracking, Sohonos being approved and the other program being in registration phase. And for Sohonos, the data coming out of the PROGRES study here for zilurgisertib is a real step forward in terms of the overall activity profile and tolerability and safety profile.

So we see the clinical data here being quite meaningful advance on what's currently available in the market, which has quite a few limitations to it.

And then compared to the pipeline, this is an oral, which we see as a big advantage and particularly in the setting, where you can potentially drive ossification from injections and some of these other interventions. So having an oral, we see as a nice differentiator for the program.

Got it. And then plans for other ossification disorders?

We -- it's still early days in thinking about it. At this point, we want to stay very focused on getting this launched for FOP, but it's certainly something we'll consider as we get further down the road.

Your next call comes from the line of Jon Wolleben with Citizens.

A little unusual having something under review or I haven't seen any of the data for. Just wondering what you guys have been privy to make you comfortable with this acquisition? And then what would be the form for it to make sense to get this out into the public domain?

Yes. Thanks for the question, Jon and fully appreciate the uniqueness of the situation. In our review, we -- this is a conversation that actually has been going on for quite some time as is typical for a license transaction like this. So we've had full access to clinical data, to the regulatory correspondence and the NDA. So we feel quite confident in the profile for zilurgisertib and where they're at in the regulatory process.

From the Incyte side, where they've done a fantastic job putting together this program, and saw it fitting better in a rare disease company like Mirum, but the work they've done on it is quite strong. They want to have the data presented first at a medical meeting. So we're hopeful that's happening relatively soon. So once we get that presented, we'll be able to share more on the pivotal data and overall product profile.

And will you guys be eligible for a pediatric review voucher if approved?

So we do expect this to be eligible for a voucher under the terms of the agreement, Incyte will keep that voucher, and we will launch the product. So the way operationally, this works is Incyte is kind of given their mid-stride with the filing and review, they'll complete the primary role through approval, and then we'll take over sponsorship at the point of U.S. approval.

Your next question comes from the line of Mike Ulz with Morgan Stanley.

This is Rohit on for Mike. With the recent pipeline acquisitions, can you talk about how you're thinking about BD moving forward? And then also, can you just talk about how you're thinking about pricing in FOP?

I can start, and I'll hand it over to Peter. But I think as you've seen now for Mirum kind of over the history of the company, we see a priority in staying active on the BD front. That's how you find unique opportunities that fit and add value to the company. So we will continue to work to find good programs to bring into the team. Maybe have Peter kind of touch on the -- any more on that or the second part of the question?

Yes. I mean nothing more on the BD strategy on the zilurgisertib pricing. Obviously, we'll make a decision and communicate that closer to approval. But just I think for thinking about the U.S., I mean, you can look at the Niemann-Pick C products and other ultra-rare settings like that where you have a strong value proposition and similar AbbVie is probably get you in the ballpark.

Your next question comes from the line of James Condulis with Stifel.

Congrats on the quarter. Maybe one follow-up on HDV. I think where we've heard a couple of questions is maybe in the 900 mg monthly arm, specifically as it relates to the T&D virologic response is maybe a little bit of an outlier relative to like some of your prior data and other -- the rest of your sort of data set. Just like curious your perspectives here. And as you think about the commercial opportunity here, for docs in the real world, what do you think is kind of the most important measure as it relates to evaluating efficacy for these different drugs? Is it that T&D virologic response, other measures of virologic response, the composite? Just curious your perspective there.

Yes. Thanks for the question. I'll maybe make a couple of comments and then have Joanne speak to some of the data that we're seeing out of the AZURE-1 Phase IIb portion. And I think in terms of what we're focused on and what we think is most relevant for ultimate use and driving adoption here is that composite of virologic response and ALT normalization.

Those 2 factors are really what's pointed to in the FDA guidance and shows that you're not only addressing the viral load, but you're also addressing the liver inflammation that is part of the disease. So seeing both of those move means you're kind of going after both components of the -- both of the considerations for both the infection and the liver.

Maybe I'll ask Joanne to touch on the data we've seen to date.

Yes. And so Chris is talking about the composites, all very true. When we look at the curves in terms of the virologic response, we do see declines in everyone. So when you structure the endpoint, if you don't meet a certain point by week 24, then you're either on one side of the line or the other. But we do see decreases in all of the patients. There's certainly no evidence of lack of response or resistance or anything like that. So really, partly, it's an artifact of time. We do see deepening response with continued treatment. And again, this is a fairly small -- numerically fairly small group. We'll have a lot more information with the full AZURE-1 and AZURE 4 Phase III data sets to make a final call on that.

Your next question comes from the line of Brian Skorney with Baird.

Great quarter. I guess I'd love to also ask a question on FOP too. It seems like you're doubling down on making Ipsen your corporate nemesis. So I'm just wondering if you could kind of give your broad thoughts on where you think Sohonos' profile leaves an opportunity for another entrant and compare and contrast how zilurgisertib might address these. And the time line would put us right around mid-cycle review with the FDA right now. So I'm just wondering if you could say if that has already happened or is still pending.

Yes. Thanks for the question. On the review, yes, that has happened, and I'd just say things are tracking as expected. But maybe I'll ask Peter to comment on -- a little bit more on positioning.

Yes. And I think certainly, the feedback we've heard from stakeholders, patients, caregivers, physicians, others available therapy in the market today. There's just -- there's a lot to be desired in terms of both efficacy and safety. And we'll obviously be able to get into more details once we have the PROGRESS data presented at an upcoming medical conference. But from what we've seen in our review, the zilurgisertib profile, really exciting about what it can mean for these patients, both efficacy-wise as well as a convenient oral and well-tolerated regimen.

Your next question comes from the line of Lisa Walter with RBC Capital.

Maybe just some more details if you can share on the opportunity for FOP. Are there any overlap with your current call points? And did you disclose the deal terms with Incyte? And maybe just one more. Given the recent positive results in [ hep D ] and PSC, wondering if this has impacted your thinking on when Mirum could become a profitable company.

Yes. Maybe I'll ask Peter to kind of speak to the FOP points and then have Eric kind of give some financial forward-looking views.

Yes. great overlap with our existing team, our rare genetics team that's focused on CTEXLI, CHOLBAM. We mentioned that the majority -- the significant majority of the FOP patients, FOP patients are cared for in settings -- centers that also prescribe CTEXLI, CHOLBAM. Different prescribers most of the time, some overlap in medical genetics. FOP has the biggest prescriber there will be endocrinologists. So that's a new kind of physician target, but the center overlap is really high with our existing rare genetics business. So excited about adding this product to that team.

Yes. And then on the financials, we did disclose the upfront license fee was $16 million, and then the next milestone would be $25 million upon FDA approval. There's some other commercial milestones, but also a royalty in the low to -- well, mid to high single-digit range.

And we expect after launch that this product will be accretive very, very quickly. But your question was also about path to profitability, and I think that's much more driven by brelovitug and volixibat as well as our current commercial business. As we've said, we're spending a lot on R&D this year for both of those products. And so, profitability will be pushed out probably until '28 on a GAAP basis.

But I would reiterate that we expect to be operating cash flow positive next year.

Yes.

Your next question comes from the line of Jessica Fye with JPMorgan.

Can you estimate the contribution to first quarter LIVMARLI sales from Alagille versus PFIC?

And then another one on FOP, just thinking about that market. What do you see as the penetration for palovarotene? And would you envision the ALK being used in combination with that drug?

Jess, for the questions. I mean just briefly on LIVMARLI, we typically aren't breaking out by indication, but what we'd say is that PFIC is -- they're both growing, but PFIC is the bigger growth driver. Maybe pass the FOP question over to Peter.

Yes. And when we look at the U.S., the market where this medicine is available, palovarotene, it's probably a minority of diagnosed patients that are currently receiving it.

We can see from pharmacy claims data, and that kind of matches what we've heard in physician and caregiver interviews that can be tried, but it can often be difficult to tolerate and stay on.

Your next question comes from the line of Mani Foroohar with Leerink Partners.

You have Ryan on for Mani. Congrats on the quarter. Maybe just circling back to FOP. What's the latest thinking here on an OUS filing and when you guys would expect to launch there?

And then just going back to the peak sales of $200 million, we're just wondering, is that in the 12-plus age group that you guys would get approved in the upcoming? And how should we think about upcoming data for the younger age groups that are being tested?

Thanks for the questions, Ryan. On ex U.S. strategy, actually, a European filing is upcoming. So we could actually still have that in this quarter. Incyte is still driving those activities. And again, their team is doing a great job.

In terms of the overall peak estimate, that $200 million plus, that's the full brand in FOP over life cycle is the way we look at it. The younger age patients, we do expect that the label would launch with the 12 and older. There are 2 other cohorts in the study that are ongoing that would support potentially taking that age lower over the near term, frankly. So those are ongoing and enrolling now, so they're not too far out.

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

A couple for me. What's your strategy for identifying FOP patients in the U.S. and abroad and addressing a relatively high misdiagnosis rate for FOP? And do you anticipate any early line of sight into a substantial group of patients from Incyte's prior clinical studies or maybe a compassionate use program or something like that in FOP? And I have a follow-up.

Yes. Thanks for the question, Ryan. Yes, the -- I think that FOP patients often have a longer diagnostic odyssey than they should. There are patients get diagnosed at birth, but often I think the literature said the average age of diagnosis is 7 years, and so obviously, people that wait longer than that. I think that's improved with the availability of genetic testing.

But that's, I think, an opportunity to continue to raise awareness, just like all of our rare genetic diseases to try to shorten that diagnostic odyssey as much as we can.

We do think in the U.S., though, most of the -- a pretty substantial majority of the patients are identified with FOP, probably a different story in middle and lower-income countries [ interesting ].

And did you have a follow-up, Ryan?

Yes. I just was also wondering if there was anything notable so far in the VISTAS extension in terms of rollover discontinuation rates, pruritus or other patient metrics that might take a little longer to modulate over time.

Yes. I mean Incyte does have this PROGRESS study. It's enrolling well. And I think we'll be able to disclose more about what they've seen from that at the upcoming medical conference, but have certainly seen a lot of physician and patient interest in the program.

Your next question comes from the line of Joseph Thome with TD Cowen.

Maybe one on FOP. I guess the level of ALK2 inhibition you're seeing with the therapy, I guess, do you think that could be enhanced by garetosmab, Regeneron's Activin A drug? Or are these largely just going to be competitive therapeutics in the landscape?

And then second, when we think about the potential expansion opportunity for LIVMARLI in the basket trial that's going to be reading out later this year, I guess, how should we think about that in your overall projection for LIVMARLI, how much is this basket population?

I can make a quick comment on the garetosmab positioning, and it's probably best to get into more detail on this after our data is presented, so it can give a better -- a more complete picture.

But we think the profile for zilurgisertib and its clinical positioning is really strong as a convenient oral single agent and excited about bringing that forward. Maybe I have Peter take the follow-up.

Yes. And expand, we've kind of talked about that indication being about 1/3 of the at least $1 billion peak sales opportunity for LIVMARLI and still reiterate that.

Your next question comes from the line of Charles Wallace with HCW.

This is Charles on for RK. So for FOP, another question on that. How many patients from the PROGRESS study, I think there was 63 in that study, do you expect will -- could come on after launch? And do you expect to have some sort of bridging program?

Thanks for the question, Charles. And given the kind of the nature of the relationship here, we're going to wait until we have that data presented to give some of the detail on it. Overall, I think it's a really compelling profile and the feedback has been positive, but I just don't want to get into specifics ahead of having that data presented.

Okay. That's fair. And then I guess another question, if I may, on the sales force expansion. So you're growing it to 60 in the field. And I just wanted to maybe get a little more color on when you expect these -- the team to be fully on board? And also, when do you expect them to be fully functional?

Yes. I -- kind of prepared comment was starting this -- later this year. And so I kind of think early next year, we'd be kind of fully on board. And that team would cover both pediatric and adult settings, where not just Alagille and adult PFIC can be found, but also PSC and delta. So I think by early next year, they'd be active in all those areas. And of course, with the pipeline products, the activity would really start upon potential FDA approval.

There are no further questions at this time. I would now like to turn the call back to Chris Peetz for closing remarks.

Great. Well, thank you all for joining us today and for all the support and a great start to 2026. Have a great afternoon.

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

Good morning, and welcome to Mirum Pharmaceuticals Business Update Call. My name is Ben, and I will be your operator today. [Operator Instructions] I would now like to hand the conference over to Andrew McKibben, SVP of Strategic Finance and Investor Relations. Please go ahead.

Thank you, Ben, and good morning, everyone. I'm very happy to welcome you to Mirum's conference call to discuss our recent clinical readouts, including the top line results of our VISTAS Phase IIb study of volixibat in patients with primary sclerosing cholangitis, or PSC, and last week's announcement of top line results from the Phase II portion of the AZURE-1 study of brelovitug in hepatitis delta. For our prepared remarks, I'm joined today by our CEO, Chris Peetz; and our Chief Medical Officer, Joanne Quan. I'm also joined by our President and Chief Operating Officer, Peter Radovich; and our Chief Financial Officer, Eric Bjerkholt, who will both be available for Q&A. The call will begin with opening remarks from Chris, followed by Joanne, who will review the clinical data. After prepared remarks, we will open the call for Q&A.

Earlier today, Mirum issued a press release announcing the VISTAS Phase IIb study results. A copy of that release, along with the presentation summarizing these results is available on the Investors section of our website. Before we start, I'd like to remind you that during the course of this conference call, we will be making certain forward-looking statements based on management's current expectations, including statements regarding Mirum's programs and market opportunities for its approved medicines and product candidates and financial guidance. These statements represent our judgment and knowledge of events as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed. We are under no duty to update these statements. Please refer to the risk factors in our latest Form 10-K and subsequent SEC filings for more information about these risks and uncertainties. With that, I'd like to turn the call over to Chris. Chris?

Thank you, Andrew, and thanks to everyone joining our call today. It has been a busy couple of weeks for the Mirum clinical team. Today marks a defining moment for Mirum and more importantly, for patients living with PSC. We are very pleased to announce that the VISTAS study met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in cholestatic pruritus for PSC patients treated with volixibat. These results represent the first successful demonstration of a therapy addressing a core symptom of PSC in a controlled study and position volixibat as a potential first approved medicine for patients. PSC is a progressive and highly burdensome condition with no approved therapies.

For patients, pruritus is not a secondary concern. Along with fatigue, it is often one of the most debilitating aspects of the disease, impacting sleep, daily function and overall quality of life. These results highlight the potential for volixibat to meaningfully change the treatment paradigm in PSC. It is a transformational moment for Mirum as a company as this progress comes on the heels of the Phase IIb portion of the AZURE-1 study of brelovitug in hepatitis delta we shared last week. Our commercial team looks forward to the potential to bring both of these standard of care-changing medicines to patients. Before turning it over to Joanne to walk through the highlights of the VISTAS data, I want to also acknowledge the patients, investigators and advocacy groups who made this study possible. PSC is a challenging disease to study and their commitment is reflected in the strength of these results. Now over to Joanne. Joanne?

Thank you, Chris. I'm very pleased to review the results from the VISTAS study, and I will also take a few minutes to walk through the top line results of the AZURE-1 Phase IIb study we announced last week. First, I would like to extend my gratitude to the patients, investigators and study teams whose participation made this work possible. PSC is a chronic progressive cholestatic liver disease characterized by impaired bile flow, leading to the accumulation of bile acids and subsequent liver injury. Patients experienced fluctuating elevations in liver enzymes and progressive fibrosis, often accompanied by the development of biliary strictures and recurrent and unpredictable episodes of acute cholangitis that can require repeated endoscopic or interventional procedures to manage.

PSC can ultimately result in cirrhosis, liver failure and the need for liver transplantation. PSC is also associated with a significantly increased risk of cholangiocarcinoma. Importantly, beyond disease progression, patients carry a substantial symptomatic burden, particularly cholestatic pruritus and fatigue, which meaningfully impacts daily functioning and quality of life. As a reminder, VISTAS is a Phase IIb randomized, double-blind, placebo-controlled study evaluating volixibat in patients with PSC and pruritus over 28 weeks. Patients with moderate to severe pruritus at baseline were placed in the primary cohort and patients with mild pruritus at baseline were evaluated in the secondary cohort. All patients were included in the safety evaluation. All patients were randomized to receive volixibat 20 milligrams twice daily or placebo.

Baseline demographics and patient characteristics were well balanced across study arms in the primary cohort with a mean baseline itch score of about 6 out of 10, reflecting the severity of itch in this patient population. Consistent with PSC, slightly over 70% of patients had concurrent inflammatory bowel disease and baseline liver function tests were characteristically elevated and generally comparable across study arms. The primary endpoint evaluated the mean change from baseline in pruritus compared to the average of the last 12 weeks of treatment using a mixed effects model with repeated measures analysis. Pruritus was assessed using the Adult ItchRO, a once-daily 0 to 10 numerical rating scale with a score of 10 being the worst itch.

I'm very pleased to say that volixibat demonstrated robust and statistically significant reductions in itch. Specifically, treatment with volixibat saw a 2.7 point reduction in itch score compared to a 1-point reduction for patients receiving placebo. This translates to a placebo-adjusted improvement of 1.64 points with a p-value of less than 0.0001. We believe this is an outstanding treatment effect and the magnitude of improvement is consistent with what we have observed in other cholestatic indications and reflects a meaningful benefit for patients.

The safety profile of volixibat was consistent with the known effects of IBAT inhibition, characterized by gastrointestinal adverse events and changes in liver laboratory parameters such as alanine aminotransferase, ALT and total bilirubin. There were similar numbers of patients in both treatment groups with grade 3 or higher treatment-emergent adverse events, and there were no treatment-related serious adverse events. There were 8 patients in the volixibat group and 5 in the placebo who experienced serious adverse events. In general, these were reflective of the course of their underlying disease. There were 7 patients with treatment-emergent adverse events leading to premature study discontinuation in the volixibat group and 2 in the placebo group. Of the 7 patients in the volixibat group who discontinued the study, 3 were for diarrhea.

40% of patients on volixibat had treatment-emergent diarrhea compared to about 9% on placebo. Elevations in ALT, AST, ALP and bilirubin were observed more frequently in volixibat-treated patients than placebo-treated patients. This trial represents an important step toward bringing a potential first-in-disease treatment option to patients with PSC, and we are looking forward to presenting the full results as an oral late-breaking presentation at the EASL International Liver Congress at the end of May. We also plan to review these results with the FDA at a pre-NDA meeting scheduled for this summer.

Following this interaction, we plan to submit an NDA in the second half of this year. Finally, a quick reminder on the recently announced Phase IIb portion of the AZURE-1 study, which also met its primary endpoint. AZURE-1 is evaluating treatment-naive hepatitis delta patients randomized to 300 milligrams once weekly, 900 milligrams once every 4 weeks or delayed treatment with a 24-week primary composite endpoint of biologic response and ALT normalization. This is an earlier time point than the 48-week Phase II brelovitug data previously shared at AASLD. In the first 53 patients evaluated at week 24, brelovitug demonstrated robust antiviral activity across both dose groups. With 100% of patients in the 300-milligram arm and 75% in the 900-milligram arm achieving virologic response compared to 0 in the delayed treatment arm.

The primary composite endpoint was achieved in 45% and 35% of patients in the 300-milligram and 900-milligram arms, respectively, versus 0 in the delayed treatment arm. Importantly, we continue to see further reductions in ALT and hepatitis delta RNA beyond the 24-week time point. Brelovitug was well tolerated across dose groups with no treatment-related serious adverse events and very low rates of flu-like symptoms. Overall, these results reinforce a compelling profile for brelovitug as a potential well-tolerated convenient single-agent therapy for hepatitis delta and provide confidence as we look ahead to top line data from the Phase III AZURE-1 and AZURE-4 studies in the second half of this year. We look forward to presenting full results from the Phase IIb portion in a late-breaking poster presentation at EASL. With that, I'll turn it back over to Chris.

Thank you, Joanne. These results represent a major milestone for Mirum, advancing potential game-changing new medicines to patients. And stepping back, Mirum is entering a new phase of growth and value creation. We now have a high-performing commercial business that continues to generate strong and durable growth alongside 2 emerging therapies in adult liver disease, each with important upcoming milestones as we move towards potential registration. Looking ahead, our focus is clear. For brelovitug in hepatitis delta, we are on track with the AZURE-1 and AZURE-4 Phase III studies with top line data expected in the second half of 2026. For volixibat in PSC, our next step is this summer's pre-NDA meeting with the FDA as we prepare for a potential NDA submission in the second half of the year. And in parallel, we will continue to advance the VANTAGE study in PBC through its confirmatory stage with top line data now expected in the first quarter of next year.

For the balance of the pipeline, the LIVMARLI EXPAND study is on track for top line data in Q4, and we expect top line data from MRM-3379 in Fragile X syndrome next year. Taken together, we see a clear opportunity to extend our leadership in rare disease, building on the same foundation that has driven our success to date. Once again, thank you to the patients and investigators who participated in VISTAS and AZURE-1 and a huge thank you to the Mirum team who are working tirelessly to make these major advances in research possible. And with that, operator, please open the line for questions.

[Operator Instructions] Your first question comes from the line of Ryan Deschner with Raymond James.

Congrats on the data set. What have you learned from the baseline characteristics of the enrolled population and the placebo response in this study with regards to patient heterogeneity and how chronic or intermittent pruritus can be in the PSC indication? And I have a follow-up.

Thanks for the question, Ryan. Yes, I mean first observation on that. I mean we've enrolled this study for pruritus, and so that shows up in the baseline criteria. And one of the things that I think worked very well in the study design and give credit to the team here at Mirum is how we -- you see a quite low placebo response on those pruritus values. And so not only does that point to good study conduct, but also shows that the concept that has been talked about of intermittent pruritus and PSC is not really something that showed up in these patients that placebo arm, you see persistent itch throughout the study, which is, I think, kind of a new finding for a study like this being the first time we've looked at pruritus in this amount of detail in PSC. And what was your follow-up?

Quick question on the pruritus signal seen in the mild pruritus patients, statistically significant, which is impressive to see. Can you remind us what range is considered mild -- and if you can, the mean baseline itch score for this mild group?

Yes. We're not discussing the specifics of that at this point. But just to kind of reassure you that we did measure it carefully and then sort of the patients kind of based on the severity of their itch at that point. But essentially, based on the 0 to 10 itch scale, there's kind of less room to move when you look at the mild pruritus. And I think that actually makes the results pretty satisfying for us in that group as well. So we certainly didn't expect to see that statistically significant response, but I think that just shows you how well volixibat works.

We'll look to have some of that data presented at one of the upcoming conferences. But the baseline was really just over 2, it's about 2.3. So to move -- have a significant move from that baseline was a great finding from the result.

Your next question comes from the line of Josh Schimmer with Cantor.

Congrats on another positive trial. Did you kind of look at the interim analysis of the VISTAS study and how that compared to the final results since there may be some relevant read-throughs to how we interpret the interim from the VANTAGE trial. And maybe you can talk a little bit about why the magnitude of separation in PSC may not be quite as large as you've seen in PBC.

Thanks for the questions. Yes, we did see -- as part of the unblinding, we did see the results from the interim portion. Overall, consistent profile. And what I'd say is the way we designed the study, having the data monitoring committee make the dose decision and viewing the results all generally consistent with the final results, I think we would have made the same decision if we had been unblinded. So overall, again, pleased with how the study design and conduct played out here. And then in terms of the magnitude of change, we powered the study on a 1.75 change versus placebo. So really saw that coming very much in line with that. And what played out differently from a statistical standpoint was the variability of the data was much lower, so a much tighter response range and placebo performance that we talked about before that ended up with a higher significance from a statistical standpoint.

And in terms of the underlying disease biology, any reason why one would be more responsive than the other?

Yes, Josh. I think that's a good question. I think we have to remember that PSC and PBC are really different diseases. I know we're doing studies of volixibat in both of them, we consider them under the umbrella of cholestatic pruritus. But if you think about just the course of disease and the origin, they are quite distinct. With PSC really showing a lot of fluctuation, both biochemically as well as just in the clinical course, patients with cholangitis that can occur. Some patients have multiple episodes. They may have biliary strictures, require intervention. And so that fluctuating disease course with kind of underlying progression is a bit different than kind of the slower kind of monotonic progression that you see in PBC. And I think we see that as well in terms of labs and also just the -- how these patients behave during the course of 6 months.

So I think even though we have kind of lined them up side by side, and we're starting to look at that in 2 different studies, they are different disease entities. So I think it is difficult in different disease conditions. So to our view, I mean, this is really the only controlled study of itch in PSC that's out there. And I think the result is a robust...

Your next question comes from the line of Swayampakula Ramakanth from H.C. Wainwright.

Two quick questions from me. The first question is on the hepatic safety. Can you quantify the magnitude and reversibility of the ALT, AST and bilirubin elevations? Were there any cases of Hy's Law cases? And in terms of the discontinuations of 9.1%, can you help us understand what percent was LFT driven versus diarrhea driven? And the second question is on the breadth of the label. Obviously, the mild second cohort showed statistical significance, which is pretty good. Do you think you can get a label which covers all the way from mild to severe populations?

Yes. Thanks for the questions. I'll start with the label and then have Joanne comment on some of the safety profile questions. And overall, the labeling we've seen for IBAT as the class really just points towards pruritus being the indication cholestatic pruritus. So there's not really a concept of grading of severity. So that's kind of what we expect to play out here. I'd also say kind of on the labeling, this kind of [ reason for the ] safety profile here for what we see in this study. The results are pretty consistent across IBAT as well in terms of the liver safety and having monitoring labeling as part of the class. So expect that to be part of an eventual volixibat label as well. I'll have Joanne speak to the specifics.

Yes. Okay, thanks for the question. In terms of -- you asked about Hy's Law. I think you're aware that Hy's Law really was developed in the setting of having a normal liver. And obviously, these patients don't have a normal liver. And actually, we also know that PSC disease without volixibat or any other treatment by itself actually can be associated with fluctuations in some of the biochemical abnormalities that look just like DILI. So all of those things make it pretty difficult to kind of sort out all this. We're in the process of putting that together. We'll be reviewing it with some independent external folks to help us with that assessment. For today, I think really what's important to note is as you can see on the adverse event slide, I think, which is in Slide 10 of the deck, you can see some of those things reflected the underlying changes essentially in some of the what we viewed as clinically significant lab elevations like ALT, bilirubin.

And specific to your question on discontinuation, there was one patient who discontinued for lab elevations in the volixibat arm.

Your next question comes from the line of Gavin Clark-Gartner with Evercore ISI.

This is Yesha on for Gavin. I was wondering if you guys could speak to what you saw in the patient-reported outcomes, specifically around fatigue and sleep. Were you able to note directional improvements or nominal significance across any of the groups?

Yes, thanks for the question. We did see trends in fatigue and sleep in terms of improvements that favored volixibat. For fatigue, it was a trend and because of the way that we set up the hierarchical analysis, once we start missing something, then we're kind of technically not allowed to go further because the FDA kind of holds their feet to the fire for that.

The nominal p-value for sleep was actually significant, however. So I think this actually all kind of hangs together. It makes sense. We've significantly improved itch, trend in fatigue, trend in sleep. These were -- the fatigue and sleep were included in the study to kind of give us some insight into that. But obviously, the study itself is not designed to look for those improvements. So I think the overall data really kind of hangs together for what we expect.

Your next question comes from the line of Mani Foroohar with Leerink Partners.

You have Ryan on for Mani. Congrats on the data. How should we think about the differences in baseline characteristics, whether that be gender or serum bile acids and how that may have impacted the results between the 2 arms? And then maybe just one commercial one. Can you guys just talk about your launch expectations given this is moving into an adult setting and based on our channel checks, pruritus is not active or proactively asked about by physicians. So maybe just some initial launch expectations as well as we look into next year.

Ryan, thanks for the question. So your question was about impact of gender differences and serum bile acid differences. I'm not sure that, that has a big impact really. There was fairly -- the gender balance is really equal among both sides. I think in terms of the group, 46% versus 61% being female. I don't think that's that big of a difference. The study results is strong. So I doubt that, that has any impact on it in terms of that.

In terms of the serum bile acids, there is an imbalance at baseline. So the serum bile acids in the volixibat group is higher. However, both of those values are significantly higher than normal. So again, I think that reflects probably a few kind of outliers there. I'm not sure that we don't really read a whole lot into that. The study was not selected based -- patients were not selected based on serum bile acids. They were selected based on itch. And I think that's where we look to the interpretation is that we selected patients with pruritus and it demonstrated improvement in pruritus. So I think that's where we -- that's where our takeaway is. Obviously, we'll look more closely at bile acids and other [ provisions ] at some later point.

I'm going to ask Peter maybe to speak about the launch expectations.

Yes. Thanks for the question, Ryan. And I think it's an astute point. Certainly, if you do calls, you'll hear a wide range of clinical practices and estimates for pruritus, and it's not as front and center today as it should be perhaps because there are no approved therapies and nothing to offer these patients. So this will be our wood to chop as we move towards launch and not an unfamiliar exercise for Mirum. It's -- this is somewhat similar to what we had to do on the pediatric side over the last 5 years. And we will expand our team to have a larger footprint in adult care settings, but really excited about the opportunity to have the potential first approved therapy in the...

Your next question comes from the line of Joseph Thome with TD Cowen.

Congrats on the data. Maybe the first one, just a bit of bookkeeping. Can you comment if this is all you need from a safety database side of things for the NDA submission? Or do you need to follow these patients for any longer, and that might be gating to the H2 submission in any way? And can you comment a little bit in the real world, how often are these patients assessed for liver enzymes when they're seen with their physicians? And maybe last quick question. How do you think about any necessary changes to your sales force once hopefully that is approved and available to your team?

Thanks for the question, Joe. Yes, I'll start off, and then we'll pass it over to Joanne on monitoring and Peter on the commercial team. This overall on the expectations for the NDA submission, we do see this as everything we need from a clinical standpoint for the NDA. Given the size of PSC as an indication, this is a substantial safety database. And just as a reminder that this -- the conversation and expectation with FDA is that this will be submitted for a full approval with pruritus being the outcome for the basis of that approval and looking forward to discussing all that with FDA this summer. And then maybe Joanne can speak about kind of standard of care monitoring in PSC.

Yes. So these patients, because of their risks and just their clinical course are seen fairly frequently. I mean, the risk of cholangiocarcinoma is actually quite high. So I believe the AASLD recommendations that they're essentially monitored every 6 months or so. If they have cirrhosis, they're also monitored for hepatocellular carcinoma. And then as well, many of them have -- might have episodes of acute cholangitis, which bring them in as well, and they may need procedures for that. So this is a fairly closely monitored population just because of the complication rate of their underlying disease.

And in terms of our field force sizing, yes, as mentioned before, we will be expanding just to use the U.S. as a frame of reference. I mean, today, we have about 15 folks on the sales side doing the liver side of things, which gives us a strong presence across the board in pediatric care delivery settings as well as, I would say, the top decile, the biggest centers on the adult side, where we're finding adult PFIC patients. We'll expand into probably somewhere in the 60s total on the liver side. That will actually use that team to promote brelovitug, if approved, for hepatitis delta. That will allow us to get into the full kind of setting where PSC patients are taken care of and also hopefully find more adult PFIC patients out there.

Your next question comes from the line of Jessica Fye with JPMorgan.

I had a couple on volixibat and then one on brelovitug. On volixibat, do you expect that the 56% versus 26% 2-point responder secondary endpoint data could get on the label? Second, on volixibat, it's between the -- I think it was north of a 2-point placebo-adjusted benefit you saw at the interim in pruritus with PBC and the 1.64 point delta you saw today in PSC. Can you talk about your confidence in being able to deliver data in pruritus with PBC that would compare well to volixibat? And then on brelovitug, with the 300 weekly and 900 Q4-week data looking directionally different from the prior data, acknowledging the different time points? Is it your expectation right now that you'll likely file for both the 300 weekly and 900 monthly dosing regimen?

Thanks for the question, Jess. Yes, I'll touch on some of those. First on the label and what we'll be proposing for volixibat, again, the indication statement that we're proposing we expect to have is treatment of cholestatic pruritus in PSC. And then in the clinical trial description, there will be some discussion of the efficacy data. So ultimately, at this point, unclear whether that response rate is one of the specific data points that's in there. So a little early to be able to speak to specifically what would be -- what we think will end up in there. And then speaking on PBC confidence, given what we saw in the VANTAGE interim, what we're seeing here, I think we're in really good shape heading into the full analysis for the VANTAGE study.

If this is -- we're seeing now consistently with volixibat, really strong placebo-adjusted difference here. And in particular, with the PSC results, the VISTAS results, just as basically the ratio of placebo change to drug is really remarkable. And so I think that speaks quite a bit for the VANTAGE study as well in the first quarter of next year. Then kind of moving down to brelovitug, maybe you can have Joanne comment a little bit on the findings. But ultimately, in the Phase III study, both doses are in there in the final analysis, and we'll be able to make that determination when we have the data in terms of the filing package. But I'll let Joanne speak to kind of what we observed from those 2 dose levels.

Yes. Jess, thanks for the question. You're correct that directionally, they were a little bit different. But I think we're -- we have to remind ourselves that the data set is fairly small. And so we are running the Phase III studies for the Phase III for AZURE-1 and as well AZURE-4, and we'll make a final determination at the end of the year when we unbind those. I think it's -- we're hesitating for making too big conclusions based on the limited data set. Directionally, we feel confident in the results. So we're sticking with that, and we think this is actually overall, very consistent with prior Phase II data that we presented. No major differences there.

Your next question comes from the line of Mike Ulz with Morgan Stanley.

Congratulations on the data as well. Maybe just a follow-up on the significant benefit you saw in the mild patients, which I think was a bit of a positive surprise for us. I guess does that change your view on the potential market opportunity for volixibat? And then I have a follow-up. Thanks, Mike.

Yes, I mean, it certainly is nice to have that data. And our message with LIVMARLI has always been any level of pruritus is a signal and it deserves to be treated and to have that data in hand, I think will be kind of helpful for the launch effort. I don't know if it fundamentally transforms. I mean these are scales used in clinical trials in the real-world setting, it's unusual for someone to rigorously measure itch the way it's done in clinical trials. And I think what we've seen with LIVMARLI is that those patients do come to therapy, and we'd expect a meaningful proportion to do the same.

Got it. And then just for the upcoming pre-NDA meeting scheduled for this summer, anything specific you're looking to get clarity on from the FDA? Or what's going to be the focus there for you guys?

We see that as a pretty routine presubmission meeting just to align on a format of analyses and data sets. In terms of what's in the package overall, we've had good communication throughout the history of the PSC program and also as part of the post -- the PBC breakthrough designation conversation. We've been able to get good feedback and clarity along the way. So don't feel that there's really much to be debated, so to speak. It's really just the standard presubmission meeting.

Your next question comes from the line of James Condulis with Stifel.

Congrats on the data. Just wondering what we can expect at EASL in May in terms of like additional data? Is that where we may see things like fatigue and sleep? And then maybe one more sort of follow-up on the commercial side of things and totally understand it's way too early to be any sort of getting into specifics, but just curious if there are good analogs to look at here as it relates to things like pruritus and the launch as we approach a potential launch here.

Thanks. On EASL, a little early to comment on what specifically will be presented. Excited that EASL recognizes the importance of this data set and that we're having one of the headline late-breaker oral presentations, but we do plan to get deeper into some of the analyses in that presentation. And maybe I'll ask Peter to speak to the commercial analogs.

Yes. I think probably the best analog we can think of is right here at home at Mirum, LIVMARLI and Alagille syndrome, well-diagnosed disease, perception amongst providers of a variable pruritus phenotype. We're almost 5 years in from our first launch in the U.S. there, and we've talked about how we reached about a 50% penetration, but we continue to add patients every month, every quarter and have kind of clear line of sight to that being kind of the continuous adoption dynamic for the life cycle of the product. And as best we know, that's probably a pretty reasonable way to think about how a launch adoption curve looks in PSC.

Your next question comes from the line of Jonathan Wolleben with Citizens.

Just a couple for me. When you guys talk about the commercial opportunity in your slides, you mentioned that median worst itch score is typically around 8 and baseline here is more around the 6 level. So wondering if you captured the patients you wanted to in this primary group or if there's any difference in the population here than you would have expected?

Thanks for the question, Jon. Overall, I mean, this -- we see the VISTAS population is really representative of what PSC looks like out there, both in terms of the pruritus burden and what we see over time, kind of what we spoke to with the persistent itch on the placebo arm, the rough proportion on how people are scoring their itch between the moderate to severe and the milder patients. And then also just the underlying kind of complications that happen in PSC patients that we saw throughout the study, just that it's a really tough disease. So I do think we have a very representative population in the VISTAS study.

Okay. And then the diarrhea, it actually was a little bit better than we would have expected based on the VANTAGE interim. But I wonder if you could talk a little bit about categorization, temporal pattern and then if there was any difference in the IBD population as well.

Yes. Thanks for the question. So the diarrhea was all grade 1 or grade 2. So no grade 3 diarrhea in the double-blind portion. In terms of kind of onset, onset median within the first couple of weeks of starting therapy. And then duration in terms of the median is about a couple of weeks as well. So in most patients, not prolonged. We looked carefully to see if giving an IBAT with a known characterized adverse event of diarrhea could trigger exacerbations, and we don't see any evidence of that. There was a pretty careful look in patients with IBD if they develop diarrhea, so we collected fecal calprotectin to see if we could see evidence of increased inflammation, look carefully for C. Diff and all of those other kind of causes. Currently, we don't have any evidence that giving an IBAT to these patients actually increased IBD exacerbation. So I think that's actually very reassuring for us and also for patients as well.

Your next question comes from the line of Lisa Walter with RBC.

Congrats on the results today. Just 2 for me. Did the 80% of patients on UDCA background therapy have a greater improvement with volixibat added on versus those on monotherapy? And during your pre-NDA meeting with the FDA, do you plan to discuss potential for priority review for volixibat? Any color here would be helpful.

Thanks for the questions, Lisa. Yes, starting with the FDA conversation, we will propose priority review. I think this setting has a tremendous unmet need and really fits the profile for priority review. So that will be part of the conversation. Then kind of on UDCA response, initial look, we're not seeing really any difference in response across different criteria, but still early in cutting the data, but nothing really to speak to out of the top line results.

There are no further questions at this time. I will now turn the call back to Chris Peetz for closing remarks.

Great. Well, thanks, everybody, for joining the call this morning. Really excited about bringing volixibat forward for PSC patients, and we also look forward to providing our Q1 update later this week.

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

Good afternoon, and welcome to Mirum Pharmaceuticals Fourth Quarter and Full Year 2025 Conference Call. My name is Elliot, and I'll be your operator today. [Operator Instructions] I'd now like to hand the conference over to Andrew McKibben, SVP of Strategic Finance and Investor Relations. Please go ahead.

Thank you, Elliot, and good afternoon, everyone. I'd like to welcome you to Mirum Pharmaceuticals Fourth Quarter and Full Year 2025 Conference Call. I'm joined today by our Chief Executive Officer, Chris Peetz; our Chief Medical Officer, Joanne Quan; and Eric Bjerkholt, our Chief Financial Officer. Peter Radovich, our President and Chief Operating Officer, is unable to join us today as he is attending international commercial event.

Earlier this afternoon, Mirum issued a press release reporting our fourth quarter and full year 2021 financial results. Copies of the press release and our SEC filings are available in the Investors section of our website. Before we start, I'd like to remind you that during the course of this conference call, we will be making certain forward-looking statements based on management's current expectations, including statements regarding Mirium's programs and market opportunities for its approved medicines and product candidates and financial guidance. These statements represent our judgment and knowledge of events as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed. We are under no duty to update these statements. Please refer to the risk factors in our latest Form 10-K and the subsequent SEC filings for more information about these risks and uncertainties. With that said, I'd like to turn the call over to Chris. Chris?

Thanks, Andrew, and good afternoon, everyone. 2025 was a year of disciplined execution and growth for Mirium, positioning us for a pivotal 2026. On today's call, we'll recap some of the headlines we announced in January and open the call for questions. In 2025, we delivered $521 million in net product sales, exceeding the upper end of our guidance range. This was made up of LIVMARLI net product sales of $245 million in the U.S. $115 million internationally with our bile acid medicines also contributing $161 million. The strong finish was driven in particular by our continued leadership in Alagille syndrome accelerating PFIC uptake and growing demand in our international markets. Building on this performance, we are entering 2026 with confidence and expect to deliver net product sales of $630 million to $650 million for the year. Beyond commercial performance, we advanced our pipeline through important clinical and regulatory milestones, including the approval of [indiscernible] for CTX and a tablet formulation of LIVMARLI and enrollment completion of the VISTAS study of Volixibat in PSC.

We also meaningfully expanded our pipeline with the addition of the Phase III Brelovitug program for chronic hepatitis delta virus, a serious rare disease with limited treatment options. This addition to the portfolio is an excellent fit with our team and the upcoming potential Volixibat launch, creating substantial operating leverage. Since the closing of the transaction earlier this year, integration has progressed smoothly, and we've welcomed a team that shares our focus on disciplined execution and delivering high-impact medicines for patients with rare disease. With the addition of Brelovitug, we now have 4 potentially registrational clinical readouts expected over the next 18 months in areas of significant unmet need. Beginning in the second quarter, we expect to report top line data from the Volixibat VISTA study in PSC as well as interim results from the AZURE 1 study of Brelovitug in hepatitis delta. The broader Azure Phase III program continues to enroll well, and we expect full top line results from both Azure 1 and Azure IV Phase III trials in the second half of the year.

We're also seeing continued momentum across our other LIVMARLI and Volixibat programs, enrollment in the Phase III EXPAND study and additional rare cholestatic conditions as well as the VANTAGE study in PBC continues to exceed expectations, and we expect to report top line results from expand in the fourth quarter of this year and from Vantage in the first half of next. And finally, the BLOOM Phase II study of MRM 3379 in Fragile X syndrome is also on track for data next year. Taken together, Mirum is entering a pivotal phase of growth as a leading rare disease company with multiple commercial medicines and several near-term potentially registrational readouts. Our team's strength continues to be its dedication to understanding patient needs and translating that into important medicines. Through this team's insight and hard work, we have now built a portfolio with over $4 billion in potential revenue. And with that, I'll turn it over to Joanne to walk through our pipeline in greater detail. Joanne?

Thanks, Chris. 2025 was an important year for our pipeline, and 2026 will be even more significant as multiple programs approach potentially registrational readouts. As Chris mentioned, enrollment across all our clinical studies is on track or ahead of previously communicated time lines. Today, I'll focus on 2 of our near-term data readouts for Volixibat in PSC and Brelovitug and hepatitis delta. Starting with Volixibat in PSC, we are on track to report top line data from the VISTAS study in the second quarter of 2026. The primary endpoint, as aligned with FDA is pruritus safety, change in term bile acids and other symptoms and quality of life measures will also be evaluated. As a reminder, the study exceeded a prespecified threshold for efficacy at the blinded interim analysis in 2024 and has proceeded with a selected 20-milligram twice-daily dose. Collectively, the prior clinical data of IBAT inhibitors in PSC and the consistent treatment effects seen across other call aesthetic diseases, including PBC, all support IBAT inhibition as a meaningful therapeutic approach in PSC, a disease with no approved therapies. We look forward to sharing the top line results from this study in the coming months.

Turning to Brelovitug for hepatitis delta, I'm pleased to report that all 4 Azure clinical studies are progressing well. In the Azure program, Brelovitug is being studied as a single agent regimen in a broad group of patients with elevated ALT at baseline. Azure 1 and Azure for the 2 Phase III studies that will form the basis of our FDA registration package are expected to complete enrollment soon with 24-week top line data anticipated in the second half of the year. In the second quarter, we expect to report interim results from the Phase IIb portion of the Azure 1 study. This study is evaluating hepatitis delta treatment-naive patients, randomized to Brelovitug or delayed treatment using a 24-week composite endpoint of viral electric response and ALT normalization and endpoint aligned with FDA. The Phase IIb portion of the study will include the first 50 patients evaluated at the week 24 time point. The study is continuing to enroll an additional 150 patients for the Phase III portion, which has the same study design and endpoints.

The Azure I and Azure III studies are enrolling well. These are active controlled studies evaluating Brelovitug in the context of [indiscernible] and are designed to support European registration as well as provide additional long-term safety and efficacy data. Finally, for MRM 3379, our Bloom Phase II study in Fragile X Syndrome is off to an excellent start. The program recently received Fast Track designation from the FDA, and recognizing its potential to address a serious unmet need. We're on schedule and expect to report data from this study in 2027. We overall, we're very pleased with the continued progress across our pipeline and look forward to several important updates over the coming year. With that, I'll turn the call over to Eric to review our financial results.

Thanks, Joanne, and good afternoon, everyone. 2025 was a year of accelerating financial performance driven by growth across our 3 commercial medicines. Total net product sales in the fourth quarter of 2025 was $149 million compared to $99 million the year before. For the full year 2025, total net product sales was $521 million compared to $336 million the year before, representing 55% year-over-year growth. Total operating expense for the quarter and year ended December 31, 2025, was $153 million and $543 million, respectively. Full year operating expense includes R&D expense of $186 million, SG&A expense of $257 million and cost of sales of $100 million. Expenses for the year included noncash stock-based compensation, intangible amortization and other noncash expenses of $95 million. The intangible amortization and other noncash item expenses of $24 million are reflected in our cost of sales. Commercial cash contribution margin in 2025 was approximately 55%, a significant increase from the prior year.

We ended 2025 with $391 million in cash, cash equivalents and investments, up from $293 million at the end of 2024, reflecting our solid operating performance. In addition, we recently completed 2 private placements concurrent with the closing of the Blue Jay acquisition, generating aggregate gross proceeds of $268.5 million effectively covering the cash outlay to support the acquisition. In 2025, we achieved positive cash flow from operations. Looking ahead, we expect R&D expense to increase in 2026 driven primarily by investments in the Brelovitug clinical program and manufacturing validation and scale-up in preparation for the anticipated BLA submission next year. This increase in R&D spend is fully funded. We expect a return to positive cash flow in 2027. We have scaled the business while maintaining spending discipline and a strong balance sheet positioning us to advance our pipeline without compromising financial strength. I'll now turn the call back to Chris for closing remarks.

Thanks, Eric. To close, Mirium entered 2026 in a great position. Our commercial business has continued momentum and our financial position is strong. Our pipeline has 4 potentially pivotal readouts for the 18 months, each representing the potential to bring standard of care changing medicines to difficult treatment settings. It's inspiring to work with the team that can achieve this level of impact for patients, and it's going to be a very busy year. We look forward to several updates as we go. And with that, operator, please open the call for questions.

[Operator Instructions] First question comes from James Condulis with Stifel.

And congrats on all the progress. I actually wanted to ask 1 on Volixibat and specifically as it relates to the commercial opportunity, obviously, Volixibat is coming first and I think generally, a lot of people are thinking about pricing in the context of Volixibat around the PPARs in terms of the PBC opportunity. I'm just curious as you guys are getting closer to data and potentially commercialization kind of how you're thinking about the right way to price Volixibat? And if pricing specifically around the PSC opportunity is kind of on the table or it makes sense.

Thanks, James, for the question. This obviously is something we spent a lot of time thinking about. And kind of as you're saying in your question there, the PPARs in PBC really are good planning benchmark to think about, but that's not -- certainly not our final guidance or decision on it. We'll take that as we have data in hand and are closer to launch to make the final decision -- and one of the big factors to keep in mind here is that unlike in PBC, there are no other approved medicines. So really unique positioning for Volixibat, but we'll take that decision when we're at launch.

We now turn to Joseph Thome with TD Cowen.

Maybe one on the upcoming PSC trial. Are KOLs are hinting that maybe the itch associated with in PSC patients can be a little bit more episodic -- maybe do you see that as providing a little bit more risk into the study versus what you're seeing in PBC? And maybe what have you done in the study, whether in terms of the patients that you're enrolling or monitoring, do you think that can maybe help limit any variability there.

Yes. Thanks for the question there. A couple of things to comment on. I'll lead in, I'll let Joanne speak a little bit to the -- some of the study design elements. And what we find in market research that's more directed at patients and some of the advanced practitioners that maybe spend more time with patients. is a different perspective on pruritus than what you get from some of the top KOLs who may actually just be seeing the patient episodically when there are other more complicated factors. And in conversations with patients and some of the advanced practitioners, you do get a different picture, how persistent the pruritus can be and also just the proportion of patients that are actually dealing with it being quite different than might be the perspective of a KOL at a top center. But then on study design, I'll let Joanne speak to some of the things that we've seen from screening and the overall operational side.

Thanks for the question. A couple of things. Actually, we know that pruritus is an issue for a lot of patients. And then this is really from some work that we did with Chris [indiscernible], a few years back presented at EASL that a really high proportion of patients do complain of pruritus and fatigue as the main symptoms associated with their PSC. And then perhaps about half of them said that it's disrupted their daily life activities. So pretty significant. Within the study, we are enrolling patients with persistent pruritus. And so we're careful to have that as eligibility and therefore, we track the pruritus response throughout the city. So I understand kind of the basis for your question, but I think between study design and also understanding the patient population will be better. We feel comfortable that this is really designed to address a significant symptom for patients with a significant impact in terms of their day with lives.

We now turn to Joe Kim with RBC Capital Markets.

I wanted to dig more into the study design for PSC. If you could highlight some of the key similarities and differences between VITAS and the Vantage study designs. And you mentioned that you expect to enroll patients with persistent pruritus, but just wondering whether we should expect the baseline pruritus scores for the PSC study to be in a similar range to what we saw in the PBC interim data.

Yes. So thanks for the question. So I think the commonality is that we're really studying cholestatic pruritus which is something that we know well and have characterized with the other indications that we have for [indiscernible] for instance. So we know how to measure this. We know how to implement that within a clinical trial. PSC and PBC are different diseases in terms of the etiology. But we think the commonality here is the fact that there is cholestasis, intrahepatic cholestasis and then, therefore, cholestatic pruritus. So there's a lot of commonality in terms of how we implement it within trial. I think probably the best guide in terms of what the baseline pruritus is, is if you look at the PBC interim and that shows significant pruritus, I mean, with -- clearly, within the range of modes of your pruritus for baseline. So I think that's kind of our expectation. We're selecting patients with moderate to severe pruritus baseline to study in both of these studies.

Let me now turn to Jon Wolleben with Citizens.

Piggybacking on the PSC questions, can you talk a little bit about your interactions with FDA around safety database requirements for volixibat and what follow-up you'll need and what that means for timing of a potential NDA submission?

Yes. I can jump in on thanks for the question, John. A lot of this kind of goes back to some of the original pre-IND interactions we've had with FDA. And we've subsequently actually confirmed some of the safety database questions with them, in particular, around PBC in terms of what they want for overall safety database and with acknowledgment that PSC is smaller. And so what we do expect that the current VISTAS PSC study has the sufficient safety database for the setting. So the idea is after our top line data will have an interaction with FDA on the submission plan and think it will track to get it submitted in the second half of the year.

We now turn to Ryan Deschner with Raymond James.

Congrats on a big year looking forward to a busy cadence of catalyst this year. For the expand readout coming later in 4Q this year, how are you -- are you expecting to break out the data on pruritus by into other secondaries by indication? And are you looking at the pruritus bar here, how are you looking at the pruritus bar in general compared to what we've shown in PFIC and allergy?

Yes. I -- overall, there's the mix of patients in the study, just as a reminder, we think it's probably ultimately going to end up being approximately half biliary atresia and then a much longer tail of other settings. So we'll look at whatever the most relevant ways to break it out. Our biliary atresia is an obvious one. The others are just much smaller each of them individually. But I'd come back to the comment that Joanne was making earlier, just on the commonality here being these are settings with elevated bile acids and cholestatic pruritus. So we see kind of the treatment objectives and the potential for response that we've seen in compassionate use examples having more uncommon than different across various settings

We now turn to Mani Foroohar with Leerink Partners.

You have Ryan on for Mani. Maybe just sticking with and Chris, I'm curious, how you think a positive readout here kind of plays out in terms of like the label expansion, given it's more of a basket trial -- and when we think about biliary atresia and the other indications, like how well diagnosed are these? Or is this going to be more of a PFIC setting where you're going to have to improve diagnosis to really drive that additional growth?

Thanks for the question, Ryan. The thinking around indication statement in the label, as you point out, it has some nuance because it's a basket. It's really defined by exclusion, right? I mean we're the way that the protocol is written as it excludes the larger settings where you could run a stand-alone study to look at cholestatic pruritus in PSC, for example, as we're doing with Volixibat. So expect that to be reflected in the labeling. And could you run me on the second part of your question?

Yes. Just kind of like when you think about these additional settings, like how well diagnosed are these? Or do you think it's going to really take a lot of handholding and physician education to drive further uptake in these additional settings?

Yes. Actually, we think that -- I mean, what we're seeing, in particular in the pediatric settings is it's highly symptomatic. So it is diagnosed. And that's really what the origin for the study was a compassionate use request. So we see the demand is out there for something to help these patients. So I do see it as a pretty well tracked patient population.

[Operator Instructions] We now turn to Charles Wallace with HC Wainwright.

This is Charles on for RK. So I guess a question on the guidance for me. So in 2025, the sales grew about 55% and the guidance range implies a 21% to 25% annual growth, so I was wondering if you could provide some color on how much of this is driven by LIVMARLI versus the bile acid portfolio.

Yes. I mean the growth is definitely more legally driven, Keep in mind, though, that for Japan last year, we had $22 million in revenues, which was inventory buildup. And this year, we expect, therefore, lower revenues from Japan, although I should clarify that the launch in Japan is going as expected. In terms of the bile acid portfolio, we do expect continued growth, but it's more kind of steady growth, not accelerating the way the LIVMARLI growth has been in the last few years.

We now turn to Brian Skorney with Baird.

Congrats on a great quarter and year. I just wanted to revisit the EXPAND study -- are there any learnings that you've taken away from Embark that you're going to be applying here based on the high proportion of biliary atresia patients. And could you just kind of help us contextualize the market represented by the expand basket relative to PFIC and ALGS in terms of size as well as the dose you anticipate using in this population?

Thanks for the question. It's an important distinction from Embark actually to point out. As a reminder, the EMBARK study was looking at bilirubin levels in biliary atresia patients immediately after the Kasai procedure. So think of that as it's just a very acute setting where the goal would be to try to improve the immediate transplant rates. What we learned is in that very young infant setting after Kasai procedure, the surgical procedure directed at bile flow actually is most determinative of outcome in that -- in those young patients. Now what's different in expand and in the biliary atresia patients and expand is those are all patients that had a successful Kasai, and then over time, they have what seems to be just a much slower progressing or persistent cholestasis that is not the kind of acute transplant driving situation you see in the very young patients. So those -- the biliary atresia of patients that are enrolling into EXPAND are going to be thinking this toddler to school age that have a persistent post-kasai cholestatic pruritus. So from the learnings there, it really comes back to what we saw in compassionate use is that there are examples of patients being highly responsive to LIVMARLI treatment with that profile. So that's kind of what inspired us to pursue the study is seeing actual strong treatment responses in those older biliary atresia patients.

And in terms of bridging that to market size, because this is a basket, it's hard to -- you can't use traditional epidemiology so you can't look at literature incidence rates, so to speak, because this is a long list of different potential causes of cholestatic pruritus. From the work we've done in the pediatric setting, it's clear that there's readily at least 500 patients in the U.S. that would fit the profile of this potential for more. When we look at kind of the total peak LIVMARLI potential of that $1 billion plus that we see as the long-term potential for the brand, expand could represent 1/3 of that overall.

We now turn to Mike Os with Morgan Stanley.

This is Rohit on for Mike. Can you just talk about the current market for HDV and how you expect it to develop over the coming years? And then how much do you expect R&D to increase this year from the HCV studies?

Yes. I'll speak to the market and then pass it over to Eric to comment on the investment side. And for the current treatment landscape for HDV, there really is -- there is nothing specifically labeled in the U.S. And the 1 labeled medicine Hepcludex in Europe that actually has been performing well. We do expect that to evolve in the U.S. given from what we're seeing is that Hepcludex is up for review and potential approval in the U.S. and then also another dual agent regimen looking at HB surface antigen and sRNA approach in hepatitis delta. So this will be an evolving landscape. But what got us excited about Brelovitug as a potential for best-in-class profile is that with a single agent, you're seeing really impressive response rates and a very attractive safety profile. It's 100% viral response at week 48, that 65% to 82% composite end point has a chance to really set the bar for treatment options in Delta.

There will be -- we do expect to have other competitive agents in the market just excited about what Brelovitug can do compared to those. Pass over to Eric on the P&L.

Thanks, Chris. So the good news is the Brelovitug 4 Phase III studies are enrolling really well, which means that the will be somewhat compressed into this year. It also means we need to make significant CMC investments to prepare for a filing next year. So they are compressed and in total related to Brelovitug, we anticipate roughly $150 million increase in R&D spend types to this program with about half the CMC.

This concludes our Q&A. I'll now hand back to Chris Peetz, CEO, for any final remarks.

Great. Thank you all for joining today. We're really excited about the year ahead, and I hope everybody has a great afternoon.

Ladies and gentlemen, today's call has now concluded. We'd like to thank you for your participation. You may now disconnect your lines.

Great. Good morning, everyone. My name is Jess Fye. I'm a biotech analyst at JPMorgan, and we're continuing our 44th Annual Healthcare Conference this morning with Mirum. First, you're going to hear a presentation from the company and then we're going to go into a Q&A session. So for all of you in the room, if you do have a question, just raise your hand so someone can bring you a microphone for the webcast. And if you're listening online, you can submit questions to the portal, and I can read them off up here. But with that, let me pass it over to Mirum's CEO, Chris Peetz.

Thanks, Jess, and thanks, everyone, for your interest in Mirum today. A quick update that I'll be making forward-looking disclosures. So we refer you to our SEC statements for a more complete discussion of risk factors. In particular, right now, we're going to be talking about the proposed acquisition of Bluejay Therapeutics, which has not yet closed. But really excited to give an update on Mirum, one of my favorite topics to talk about. We are a rare disease company focused on delivering life-changing medicines to rare disease patients and heading into what is I see as a pivotal year for the company. So excited about much of what's going on across the business. And we find ourselves finishing 2025 with really strong commercial performance. So at the start of the week, we announced that we sold an estimated $520 million of total product revenue for the year and gave guidance for 2026 of $630 million to $650 million. So a track record of really strong commercial performance across our 3 approved medicines.

And that sets us up nicely for a slate of readouts of high-impact clinical-stage programs in the pipeline, namely 4 potentially pivotal programs reading out in the next 18 months. So a really exciting time for our pipeline as we head into the next 18 months. And behind that is a substantial potential for future revenue. So across our current commercial and pipeline programs, we see over $4 billion of potential across the Mirum portfolio. I'll use this pipeline chart as a bit of a table of contents of what we'll cover here. We'll spend some time talking about LIVMARLI. This is our lead program that was our first commercialization, now approved for 2 indications in Alagille syndrome, pruritus and Alagille syndrome and pruritus and PFIC. A third indication with a pivotal readout later this year. We just accelerated the time lines for the EXPAND study, which we'll touch on in a bit more detail, expecting top line data in Q4, so label expansion opportunity for next year.

CTEXLI and CHOLBAM are approved ultra-rare medicines that continue to grow nicely. And volixibat is kind of the next big catalyst that's up with top line data from the VISTAS PSC study expected next quarter and potential NDA filing in the second half of the year. A follow-on indication in PBC with the VANTAGE study, tracking towards completing enrollment later this year with top line data in the first half of next year, Fragile X program in Phase II behind that. And we'll touch on the exciting addition to the portfolio, the announced acquisition of Bluejay Therapeutics. The key program there that fits quite well with the Mirum adult hepatology program is brelovitug for hepatitis delta. So great synergy across all of our call points, not only for LIVMARLI currently, but for the anticipated expansion for volixibat into adult GI and hepatology which we'll touch on in a bit more detail.

We are set up in commercializing directly across North America and Western Europe. So all of these products fit nicely into a focused commercial team across these geographies. And have seen really great success using partnerships and distributors to expand to smaller countries, leveraging our team to geographies where not able to have a direct presence in smaller countries. As mentioned, the track record on the commercial side has been strong with an expectation of $630 million to $650 million in net product revenue this year. And breaking out some of the potential of the pipeline here at the bottom of the page with LIVMARLI having $1 billion-plus potential opportunity, volixibat and MRM-3379 also $1 billion potential brands and the latest addition of brelovitug, we see as at least a $750 million opportunity. So it's going to a bit more detail on LIVMARLI.

LIVMARLI is an oral, minimally absorbed IBAT inhibitor, and this mechanism of action reduces the overaccumulation of bile acids that's relevant across a number of different cholestatic settings. In particular, this has been a game-changing medicine in Alagille syndrome and PFIC, where we see from the clinical programs, rapid and dramatic reductions in serum bile acid levels and the associated symptomatic burden of disease with pruritus and fatigue improvements and over long-term comparison seeing an impact on the transplant rate in these pediatric settings. And it's been a strong growth driver for the company. So LIVMARLI in 2025, hit $359 million in net product revenue. You can see there's been a nice acceleration of growth over the past year. What's underneath these numbers is a steady pattern of growth from the Alagille syndrome indication where we've now been in market for 4 years.

And we've seen a continued accumulation of patients largely driven by pediatric patient starts that then has a quite high persistence rate given the symptomatic benefit of the medicine. And over time, these patients starting out with pediatric weight-based dosing do increase their dose over time. In 2024, we had a label expansion into PFIC. And this has been a really interesting acceleration of that pattern of the background growth from Alagille syndrome. In particular, a dynamic where we're finding that PFIC in particular, in adult settings is underdiagnosed. So we've been focused on building awareness of genetic testing and adult hepatology clinics where it has not been a standard practice to run genetics on a number of their cholestatic and pruritic patients. And we're finding this having an impact not only for LIVMARLI's growth but also having a new option for treatment of these cholestatic pruritic patients.

And all of these trends that we've seen throughout the year we see them as durable into 2026 as well. So a lot of that driving the guidance that we're quite excited about for the year. Beyond Alagille syndrome and PFIC, the EXPAND indication is another substantial expansion for the opportunity for LIVMARLI. We see this sized as at least the size of PFIC, potentially the size of Alagille syndrome in terms of its underlying epidemiology. A quick comment on the balance of the commercial portfolio, the bile acid replacement products CHOLBAM and CTEXLI, these are relevant across a number of different ultra-rare genetic synthesis disorders to replace the -- one of the missing bile acids that is disrupted by a mutation in the cascade for biosynthesis. We acquired these programs in late 2023, and have had a focus on bending the curve in diagnosis, in particular for CTX patients.

So we achieved a formal approval of CTEXLI for CTX last year and have seen an increase in diagnosis and treatment of patients driving this nice increase in the growth curve. We also see this as a durable trend moving into 2026. Some comments on the pipeline, and I'll start with LIVMARLI's EXPAND study. And the EXPAND study is a basket design that is -- really was informed by a surprising amount of interest for compassionate use across a number of very, very rare cholestatic settings for patients that presented with cholestatic pruritus as a result of some other background indication. And given the overwhelming interest, we designed a basket protocol to look at ultra-rare settings of cholestasis in the EXPAND study. EXPAND looks at 45 patients for LIVMARLI twice-daily dosing versus placebo. This is a 20-week study focused on pruritus oriented for a label expansion into other cholestatic pruritic indications.

The study is nearing completion of enrollment. We've been able to accelerate that time line to a Q4 top line readout and really interesting mix of different settings here and a lot of unmet need that we think that EXPAND will help address. Worth noting that a sizable portion of these patients may be just a bit less than half are biliary atresia patients that can have a persistent cholestasis after a successful Kasai procedure. So excited about what this can mean for an additional treatment option for those patients. Moving into volixibat. Volixibat similar to LIVMARLI is an oral, many absorbed ileal bile acid transport inhibitor. And we are studying volixibat in both PSC and PBC. These are larger adult settings of cholestasis where pruritus burden can be a substantial unmet need. So 2 programs ongoing for volixibat in these settings for PSC with the VISTAS study and PBC with the VANTAGE study.

In PSC, orienting on some of the U.S. epidemiology numbers, we see that there's likely about 30,000 patients and about 2/3 of them deal with pruritus as an aspect of their disease burden. It is hard to overstate what this can mean for a patient's day-to-day life to deal with the persistent pruritus and itching that is related to the elevated bile acid levels of the disease. Fatigue is also a big component of this and we've seen across the clinical studies, improvements in both itch and fatigue with IBAT in these cholestatic settings. So this means that we're orienting around -- at around 20,000 patients as the target launch population for volixibat in PSC of those patients with PSC and related pruritus. And there's strong evidence behind IBAT driving an improvement in pruritus in prior studies and compassionate use experience for LIVMARLI in patients with PSC.

This is data on the page here of the CAMEO study, which looked at LIVMARLI at lower doses on patients with PSC. And you can see there's a nice improvement in itch in those that had itch at baseline and reduction in bile acids. So we took this observation as well as some of the compassionate use experience and designed and are running the VISTAS study. VISTAS is an adaptive Phase IIb study, now fully enrolled that had an interim analysis in 2024. It's worth spending a moment on that interim analysis and design because it really informs how we see the readout coming up next quarter. And the study was designed to have a blinded interim analysis where a data monitoring committee reviewed the data in detail and had a minimum threshold that had to be met for the study to continue blinded. And that is the case. So the study remains blinded. So we're excited about what this can mean in terms of the outcome next quarter and expect to file an NDA in the second half of the year based on that top line data.

So next big readout for the Mirum portfolio coming up soon. Follow-on indication for PSC with volixibat is PBC and quite a bit in common between these 2 settings in terms of the cholestatic disease burden. PBC patients also suffer from elevated bile acid levels and pruritus. There's a bit more of a segmentation of the market because there have been recently new medicines approved in a second-line setting where patients can -- may not have biochemical control. So the recent approvals of 2 PPARs in this setting has been a nice advance for PBC patients, but leaves unaddressed a large number of those patients in the frontline setting who do not have a treatment for their pruritus. And that's a big part of what we're focusing on here with volixibat is going after those 31,000 patients in the frontline that have elevated bile acids and pruritus but may be controlled on their alkaline phosphatase.

And the VANTAGE study similar to VISTAS is an adaptive Phase IIb study, but we're targeting a larger population with VANTAGE. So we were able to conduct an unblinded interim analysis and present some of those data at AASLD and EASL at prior meetings. And it's quite striking results that I'll skip to here from the interim analysis. And you can see here the 2 doses of volixibat having a dramatic reduction in the pruritus levels versus placebo, a clear treatment effect that sets in early and is durable over the treatment time period. We've chosen the 20-milligram twice daily dose to take forward in both the VANTAGE and the VISTAS study. And we do see read-through across these settings. The dosing of IBAT inhibitors as we've looked across all of the different settings where we've studied cholestatic pruritus with an IBAT inhibitor, if you get to a sufficient dose level, you can drive a similar response across different settings.

So excited about what this interim results means -- what these interim results mean for both the VANTAGE PBC study and also the VISTAS PSC study working together as a program. Talk for a quick moment about 3379 and the Fragile X program before moving on to the acquisition of Bluejay. And the Fragile X program that we've designed with MRM-3379 is targeting males with a full mutation of Fragile X, which is estimated to be about 50,000 patients across the U.S. and Europe. This is kind of where the most need is in this setting across the males with the full mutation. And MRM-3379 is a PDE4D inhibitor that helps boost cyclic AMP levels. One of the key features of Fragile X as an indication is depressed cyclic AMP levels and the impact that, that has on neurodevelopment and cognition. And there's actually been a really compelling Phase II data set with another PDE4D inhibitor that inspired our program. And what we -- what attracted us to 3379 as a program is that it is highly CNS penetrant.

And so we think we can have an improvement in what's been seen in prior Phase II study by having more CNS exposure and driving an effect on cognitive scores in Fragile X patients. We've seen this play out in animal models of Fragile X. So recently presented animal data confirms that we can get to comparable levels of activity to another competing PDE4D program. with a fraction of the dose, and we've taken that into the BLOOM Phase II study. BLOOM is a dose-ranging study that just recently randomized its first patients on track for data in 2027. Looking at the NIH toolbox cognitive score domains. We've had an interaction with the FDA supporting this program and the use of this end point with validation for a potential approval in a subsequent Phase III study. So excited about getting this towards data next year.

Now we'll finish the pipeline discussion with an overview of brelovitug in HDV. And first for a little bit of context on the acquisition of Bluejay Therapeutics which we see as a unique fit with the Mirum pipeline and team. So hepatitis delta is a rare disease that's treated in -- primarily in GI and hepatology clinics. A lot of the same call points that are already prescribing LIVMARLI and will be target prescribers for volixibat, so high synergy to be able to bring this into the pipeline as we're moving into the volixibat launch. Hepatitis delta is a rare co-infection with HBV. We think there's about 15,000 diagnosed and insured patients in the U.S. So that's our target launch population, though prevalence rates are much higher in certain other countries. So in the U.S., we see this as a rare disease launch that fits really well with our commercial team.

And the Phase II data to date for brelovitug is very compelling. At AASLD last year, an update for a dose-ranging Phase II study were presented where brelovitug achieved 100% urologic response. So 2 log or greater reduction in hepatitis delta levels. And more importantly, on the right side of the page, the FDA's approval endpoint for the setting of virologic response with ALT normalization, you see a 65% to 82% response rate on the approval endpoint. So really compelling results here and a safety profile with a single agent regimen that is really compelling. Minimal rates of flu-like symptoms, which has been a real issue with interferon and some of the legacy treatments in this setting and a clean fully humanized antibody profile beyond that. And taking this forward, the AZURE Phase III program is currently enrolling and I'd say enrolling rapidly.

So AZURE 1 and 4 are the registration studies for the U.S. These are placebo-controlled, the valuations of brelovitug at either 300 milligrams weekly or 900 milligrams monthly. Looking at that composite endpoint of virologic response with ALT normalization, we expect top line data from the AZURE 1 and 4 programs in the second half of this year. That is the planned submission package for FDA. And worth noting that in Q2, we'll have an interim look at AZURE 1. So the first 50 patients in AZURE 1 will be evaluated in the interim analysis right around the corner. EMA, because there is another approved agent in Europe with Hepcludex has the AZURE 3 and 2 studies as the basis for approval there where you look at either a head-to-head or a switch of brelovitug versus Hepcludex.

So slightly longer time lines to get to those EMA endpoints. And so pulling it all together, Mirum is in a really strong position with a track record of compelling commercial performance guiding towards $630 million to $650 million of revenue this year. Our expanding pipeline has a lot of exciting readouts on the page here. And in addition to all of the readouts that we're heading into these 4 pivotals really of note with the VISTAS PSC top line next quarter, the brelovitug AZURE program the second half of this year, the EXPAND LIVMARLI study in Q4 and PBC data for volixibat in the first half of next year. It is just a pivotal stretch for the Mirum pipeline. And pulling this together with the financial performance, that's compelling as well. A well-financed balance sheet and expect to be cash flow positive in 2027 with all this investment across the pipeline. And so with that, I'll pause and turn to questions from Jess.

Great. [Operator Instructions] You started out talking about LIVMARLI and the growth that you've seen. So when we think about the growth that you're looking for in '26, what are the major sources of that growth? And just how are those sources of growth evolving, right?

So the growth patterns for LIVMARLI are largely consistent in 2026. I think there's a couple of things to note. And some of this just -- one thing I'd note is the seasonality for international. The tail end of the year tends to be a little bit stronger. So we expect to see that going into this year as well with the international markets, in particular, with some of our distributors have bigger orders in the back half of the year. But other than that seasonality, we do expect international to continue to grow. Our partner, Takeda, had a bit of inventory buildup in 2025. But other than that, all geographies, we expect continued growth. So Takeda, we do expect to be a little bit lighter into 2026. On the U.S. side, clear line of sight that the trends are continuing. So Alagille syndrome now for many quarters has had a steady accumulation of patients. You see some weight-based adjustments for the patients on therapy longer term. And the adult PFIC phenomenon and supporting patient finding in PFIC is having -- is a big driver of patient starts throughout 2025, and we expect that throughout all of '26.

We have a couple of audience questions. A couple of audience questions here. So sticking with LIVMARLI, can you say how many patients are being treated for Alagille and for PFIC?

We haven't broken out patient numbers. What I would say is that our U.S. revenue number is direct sales so there is no inventory in the U.S. number. So you can get a sense of patient numbers pretty directly by looking at the net revenue for the U.S. market. We have some of that broken out in our supplemental materials in the back of our corporate deck. So I invite you to go take a look at that. And in terms of -- we also get asked about indication breakdown between the 2, between Alagille syndrome and PFIC. Alagille syndrome to date is the larger component of that revenue. But PFIC really is the bigger growth driver over recent quarters. One of the ways to put some perspective around it over the long term, as we talked about LIVMARLI being $1 billion-plus brand, we see these trends taking LIVMARLI to that level. And it's probably roughly equivalent size between the 3 indications between Alagille syndrome, PFIC and EXPAND when you extrapolate out to that peak revenue number.

And another audience question here. Can you talk about the latest pricing for LIVMARLI in those 2 indications between Alagille and PFIC?

So Alagille syndrome on a net basis for the average patient, you have to keep in mind, this is weight-based dosing so there are patients that are well below the average and also patients above the average. But on a net basis, the average Alagille patient is in the mid $400,000 to $500,000 per year. PFIC has a higher dose. So the average price in PFIC can be as much as 2x that. And the EXPAND population has yet another dose level that's kind of in between the 2. So you think of that as the range of net price for LIVMARLI.

Great. And then another question here. Where are you on IP for LIVMARLI?

So LIVMARLI's IP, the guiding assumption we look at is the 2040 family of patents, many of them Orange Book listed. And those are directed at the unique dose response pattern in general for IBAT and very specific to LIVMARLI and the data that we've generated. Those are 2040 expiring family. There are many supportive families at other time points as well in addition to that. I note going all the way out to 2043 as our longer-dated IP for the tablet formulation of LIVMARLI, kind of didn't talk about that in the -- on the revenue page, but the tablet has been a big part of this growth story that we've seen, in particular for the older patients, teenagers and adults having a preference for that tablet formulation, so which has the 2043 IP time frame.

Okay. Maybe turning to EXPAND where it looks like we could hear an update on that before the end of this year, right? You mentioned that up to half of those patients are biliary atresia and there was some development history with LIVMARLI in biliary atresia. Can you just kind of like recap what the back story was in that setting and kind of how this development approach makes sense?

Yes. I'll give a little perspective on the disease setting as well as part of answering that question because this has been a learning over the time on developing LIVMARLI. So in biliary atresia, the -- these children are born with a disruption and really no connectivity of the biliary tree to the GI tract. So standard of care is to urgently upon diagnosis to complete a Kasai procedure, which establishes bile flow from the liver to the GI tract. So that's a life-saving procedure really important for these patients. And there are 2 different ways that IBAT has been studied after that procedure. One is which we looked at in a Phase II study, looking at the chance to improve outcomes after that Kasai procedure. And what -- which is different from what the EXPAND study is looking at which is improving pruritus much later than the Kasai procedure.

And what we've learned from these studies and from the compassionate use experience, is that, that Kasai procedure really determines the outcome near term. So the Kasai procedure surgically reestablishes bile flow. When it works, these patients have a very nice response on their liver parameters, their bilirubin. And when it works, it tends to work quite well and they stabilize nicely, at least in the near term. When it doesn't work, they move very rapidly to liver transplant because it can be fatal if they do not get satisfactory -- sufficient flow of bile into the GI tract. So in those earlier patients, when we -- which we studied in the EMBARK study, if they didn't do well, they went right to a transplant. And those that did well saw really no need for therapy in that acute setting. But what we see is, over time, they can start to develop more of a slower progressing cholestasis and the periodic burden can be quite substantial. I think of these children as kind of starting in the 2- to 3-year-old range, all the way out to as old as a teenager when they start to develop that profile.

Maybe switching to volixibat with the PSC readout coming up in the second quarter. Can you just expand on what specifically gives you confidence in a positive outcome? And maybe also to the extent like what are the risks for that trial?

Yes, many layers of evidence that we look at here for the VISTAS PSC study and really starting with the -- what we know about the class. IBAT as a treatment when you're dosing at a high enough level drives a very consistent reduction in bile acids and improvement in cholestatic pruritus. So we've seen now across all these different settings when IBAT is dosed sufficiently, you can drive a response on pruritus. Specific to PSC, we actually have IBAT data in the indication. So we know we have case studies and analysis of responders from other studies where you can see that there's an improvement in itch that those that have pruritus at baseline. And then kind of the third and probably the most direct evidence we have really comes from the study itself.

So the VISTAS study had the first portion where 2 doses of volixibat were evaluated versus placebo and the data monitoring committee had a dose selection algorithm as part of that. And for them to select the dose and leave the study blinded means that there was -- the treatment effect exceeded the minimum threshold for the study to continue. We wanted to be able to unblind the study and evaluate what needed to be changed if that wasn't the case. However, the study remained blinded. So we know that the data monitoring committee saw something, selected a dose and rolled the study forward to Part 2.

Does your conviction in the likelihood of success in PSC differ from PBC? And if so, why?

Not at all is how I would answer that. I mean across all of these settings, in particular, when you look at the PBC interim data, which we think informs what could be happening in that blinded PSC data, it is a highly active dose. So really confident that volixibat is a relevant medicine for both of these settings where while the underlying disease may differ, the commonality is that there is a restriction in bile flow causing cholestasis, they have elevated bile acids and pruritus. I think that another element to add on top of that conviction is the screening criteria, how we've enrolled these studies is common across the 2. So we're screening for baseline pruritus due to cholestasis, similar profile for entry criteria between the 2 studies.

This is sort of a different version, but similar question. So if we see positive data for PSC, should we read that across positively to the PBC study?

I do think that there is reason to extrapolate between these indications. We're excited to share that data when we get to it and share any findings that might be unique or change that view. But overall, IBAT in these settings has a really consistent response.

And what do you see as the kind of the market opportunity for volixibat in PSC and PBC and kind of how much of each market could volixibat capture?

Yes. There's a very unique market opportunity that is different between the 2. And I spend a little more time maybe talking about PSC because it is just a lot easier to get your head around. It's -- in PSC, there are no approved therapies, there is a desperate need for new medication, and pruritus is a burden across most of these patients. We think that pruritus is likely under reported, when you talk with patients and some of the advanced practitioner team versus physicians, it comes up to be as high as 90% of patients talk about pruritus as an element of their disease. So getting a new therapy out there will be high impact. And volixibat is really the only agent we see on the horizon with the near-term approval potential. End points have been really challenging for PSC.

And this is quite different than the PBC setting, where FDA and industry have not come up with adequate surrogate markers to use for approval in PSC. So the path kind of points towards a much longer outcomes approach, which is daunting. And with the VISTAS study, we found an alternate path. So we've been able to use itch as the outcome in a reasonable amount of time to get a new medicine approved for PSC patients. So it's a really unique positioning for what we're -- how we're approaching it and bringing it forward. And that plays through for a market opportunity that there's 20,000 addressable -- estimated addressable patients in the U.S., volixibat being the only approved therapy, we think there's a really high potential for volixibat in that setting. PBC is a little more competed. So there's some nuance in patient segmentation.

We talk about breaking up the PBC market into kind of the first- and second-line setting. First-line setting are patients that start UDCA and have control or a lowering of their biochemical measures, namely alkaline phosphatase. So an alkaline phosphatase level of normal or normal to 1.67x upper limit of normal tends to be how the first-line setting is defined. There are no other therapies approved in that setting other than UDCA. And UDCA has not been shown to address pruritus. So that's one of the treatment opportunities for IBAT inhibition. The second-line setting, PPARs are -- have been recently approved there. They can really target and address some of the biochemical disruption. They have reported some effect on itch as well, but frankly, at lower rates than what we see from the IBAT studies. So we see the evolution of the second-line market really being patient-by-patient consideration on how the PPARs and an IBAT might get sequenced or used depending on an individual patient's disease burden, symptomatic burden and some of the decisions they're making with their physician.

Yes, assuming positive data in PSC, how are you preparing for commercialization?

So a lot of what we already have in place overlaps with where we're going for volixibat, namely, last year, we already expanded our field medical team to cover the expansion into adult hepatology and GI. For LIVMARLI, we're already targeting some of the kind of the top adult hepatologists as well. So that overlap substantially with the KOLs and some of the prescribers for volixibat. We are planning to have a field expansion to get to more of the community physicians and GI physicians that see a large number of PSC and PBC patients and hepatitis delta. So it's really an expansion for all 3 of these indications for the 2 medicines in the pipeline. We -- current planning is probably about another 30 to 40 people in the U.S. field force, and we'll have kind of similar plans on a scale up across some of our direct Western European markets where it would be smaller numbers but kind of a similar scale of expansion.

So on the slide, it looks like both the VISTAS data and the AZURE 1 interim are coming in 2Q, which comes first?

At this point, I haven't clarified which comes first, but we'll have 2 great announcements on what I think are going to be really compelling data sets.

Maybe while we're on it, we can just expand a little bit on what specifically makes you confident in positive Phase III results for the Bluejay asset?

So for the brelovitug program, the Phase II data are just so striking. And so with that 100% virologic response, we do expect that to replicate across other settings and some of the aspects of the design of the Phase II program and frankly, of a competing program, which also has a Hep B surface antigen antibody in it where you're seeing consistent response on HDV viral load and ALT normalization. So we've seen this across multiple sequential cohorts with brelovitug itself in the Phase II program. So kind of replicating in independent cohorts as well as seeing in the telbivudine program that's been presented as well, showing another HB surface antigen that has driven some virologic response. So we know this is an active and relevant mechanism. Really confident in the dosing regimen for brelovitug that was chosen in the Phase III program. That's what was shown to be so active in the Phase II and really, as an antiviral, you see these data sets replicate quite well in most cases. So confident that we're tracking towards bringing brelovitug to hepatitis delta patients.

What is the addressable market for hepatitis delta in the U.S. and then in Europe and then elsewhere?

Yes. The -- in the U.S., we talk about this 15,000 diagnosed insured patients that we've analyzed from claims data, the prevalence is actually much larger than that. We think it's probably 40,000 but the diagnosis is really insufficient for hepatitis delta. It's a co-infection with HBV, and to date, there has not been kind of automatic reflex testing to test for delta if you are diagnosed with HBV. And we think that's an important step in guidelines to help bring better diagnosis to these patients. And there's actually been a recent experience in Europe that has shown that can change diagnosis rates moving from what today is more of a risk-based hepatitis delta testing paradigm to one that's reflex where you get a Hep B diagnosis, you automatically test for delta.

So working towards doing that in the U.S., we think, can expand from that 15,000 patients to more diagnosed and more brought to care. As you get into other geographies, the prevalence actually can be substantially higher. Some of the -- some of our direct markets in Southern Europe, we think, are going to be higher prevalence countries. And then as you get into Eastern Europe and parts of Asia, there are some very high prevalence countries as well. But in terms of our direct markets, North America, the U.S. numbers is what we're going after with the AZURE 1 and 4 program in the second half of this year. Subsequent studies will expand into those other settings.

Okay. Looks like we're about out of time, so we'll stop there. So thank you.

Excellent. Thanks for the interest.

Hello, everyone, and thank you for joining us today for Mirum Pharmaceuticals Business Update Call. My name is Sammy, and I'll be coordinating your call today. [Operator Instructions]

I'll now hand over to your host, Meredith Kiernan, Head of Global Corporate Communications, to begin. Please go ahead, Meredith.

Thank you, operator, and good morning, everyone. I'd like to welcome you to Mirum Pharmaceuticals conference call. I'm joined today by our CEO, Chris Peetz; our President and COO, Peter Radovich; our Chief Medical Officer, Joanne Quan; and our CFO, Eric Bjerkholt.

Earlier today, Mirum issued a news release announcing its proposed acquisition of Bluejay Therapeutics. The signing of the definitive agreement for this proposed transaction represents an important step in expanding Mirum's rare disease portfolio and advancing our late-stage pipeline. This news release can be found in the Investors section of our website. Speakers will be referencing a transaction announcement presentation that can be found in the Events section of our website.

Before we begin, I'd like to remind you that during the course of this conference call, we will be making certain forward-looking statements about Mirum and our programs as well as the proposed acquisition of Bluejay and Bluejay's programs. These are based on management's current expectations, including statements regarding Mirum's business plans, development programs, strategies, prospects, market opportunities and financial forecasts and guidance as well as Mirum's expectations with respect to the closing of the proposed acquisition and its expected benefits if completed. Mirum is under no duty to update these statements, and they are subject to numerous risks and uncertainties, and actual results could differ materially from the results anticipated by these statements. Investors should read the risk factors set forth in Mirum's latest 10-Q filing and any subsequent reports filed with the SEC.

I'd also like to remind you that the proposed transaction with Bluejay has not closed and remains subject to customary closing conditions. Prior to closing, Bluejay remains a separate company from Mirum, and both Mirum and Bluejay will continue to operate independently until after closing.

With that, I'll now turn the call over to Chris. Chris?

Thanks, Meredith, and good morning, everyone. Today marks another exciting milestone for Mirum, building on a year of strong commercial and pipeline momentum. I'm happy to announce that Mirum has entered into a definitive agreement to acquire Bluejay Therapeutics, which will add brelovitug, an anti-hepatitis B surface antigen monoclonal antibody being developed for chronic hepatitis delta virus, to our pipeline. This transaction will deepen our position as a leading rare disease company, purpose-built to bring forward breakthrough medicines for patients with overlooked conditions.

Hepatitis delta is a severe, rapidly progressive rare disease with high unmet need and no approved FDA -- no approved treatments by FDA. Brelovitug has compelling Phase II results and has the potential to become a foundational therapy in this setting. This proposed acquisition is highly anticipated -- pardon me. This proposed acquisition is anticipated to be highly aligned with our core strategy and capabilities.

First, we're following clear clinical data showing brelovitug has the potential to change the standard of care for patients. The recently announced results Joanne will highlight are outstanding and earn the program Breakthrough Therapy and PRIME designations in this severe, significantly-underserved disease. Second, hepatitis delta represents a highly synergistic fit for Mirum. It would be a natural extension of our rare disease expertise, and we look forward to continue to develop and potentially commercialize another breakthrough therapy following the closing.

And third, brelovitug's ongoing Phase III program will meaningfully expand our late-stage pipeline and will add a fourth potential registrational readout in the next 18 months with a potential BLA submission in the first half of 2027. And finally, the closing of this proposed transaction would build value within Mirum while maintaining our financial independence. With a solid balance sheet, the proceeds from the concurrent financing announced this morning and our growing commercial business, we are well positioned to support brelovitug through registration and launch.

Overall, this addition to the pipeline following the closing will bring the revenue potential of our rare disease portfolio to over $4 billion. What the Bluejay team has created is impressive and critically important to patients, and we look forward to welcoming this high-performing team to Mirum following close.

And with that, I'll hand it over to Joanne to walk through the clinical program and upcoming milestones. Joanne?

Thanks, Chris. We see strong promise in brelovitug for patients with hepatitis delta, a population with a severe burden of disease and few therapeutic options.

To start, I'd like to provide a bit of background on delta. Delta is the most severe form of viral hepatitis and only occurs in the setting of co-infection with hepatitis B. Patients with delta have a risk of hepatocellular carcinoma 3x that of HBV alone and nearly half progress to liver-related death within 10 years of diagnosis. The delta virus hijacks the hepatitis B surface antigen for its own viral envelope. Thus, targeting hepatitis B surface antigen is a compelling treatment approach for delta.

Brelovitug is a fully humanized IgG1 monoclonal antibody that binds to hep B surface antigen, thereby rapidly clearing virions and subviral particles and preventing infection and replication. The results of the brelovitug Phase II study presented at a recent AASLD plenary session highlighted on Page 7 of the presentation, show the potential for this treatment to substantially decrease viral load and improve liver function. The Phase II study in 47 adults with chronic hepatitis delta demonstrated 100% virologic response, defined as a 2 log or greater reduction or target not detected for HDV RNA. This was observed across all dose groups at 48 weeks, with nearly all patients achieving this response by 24 weeks.

Importantly, 65% to 82% of subjects achieved the composite endpoint of virologic response and ALT normalization, which is highly encouraging given the progressive nature of this disease. The safety profile was favorable with no grade 3 or higher adverse events, no serious adverse events, a low rate of flu-like symptoms and no ALT elevations or neutropenia. Based on this data, brelovitug has been granted FDA Breakthrough designation and PRIME designation in the EU.

Brelovitug is currently being evaluated in the global AZURE Phase III program, which is well underway. The AZURE program is designed to meet registration requirements in both the U.S. and EU using clear objective endpoints aligned with FDA and EMA. An overview can be found on Slide 8 of the presentation.

Both FDA and EMA agreed that meeting the combined endpoint of virologic response and ALT normalization in Phase III will support registration. As noted above, virologic response is defined as a 2 log or greater decline or target not detected for HDV RNA. Registration in the U.S. will be supported by the AZURE 1 and AZURE 4 studies with the primary composite endpoint of virologic response and ALT normalization. Each study is evaluating two doses of brelovitug, a once-weekly 300-milligram subcu dose and a once-monthly 900-milligram subcu dose. Each study also includes an extension period to support long-term safety and efficacy.

The AZURE 1 study will include 150 patients, randomized 2:2:1, treated open label in two dose arms of brelovitug versus delayed treatment for 24 weeks. There will be an interim analysis when the first 50 patients reach 24 weeks of treatment, and we expect this interim data will be available in the second quarter of 2026.

The AZURE 4 study is similar in design to AZURE 1 and will include approximately 80 patients, randomized 2:1:1, with a treatment delay of 12 weeks. Both studies are enrolling well and final data for both are expected in the second half of 2026 to support a BLA submission.

AZURE 2 and AZURE 3 will compare brelovitug to an active control, bulevirtide, which is approved in the EU. AZURE 2 and 3 are 48-week and 24-week studies, respectively. These studies are intended to support EMA registration as well as long-term safety and efficacy with final data expected by the first half of 2028. Altogether, the clinical data, regulatory alignment and program momentum give us strong conviction in the Phase III AZURE program's ability to advance brelovitug toward registration.

We're very impressed by what the Bluejay team has been able to accomplish in such a short time and are excited to welcome them to the Mirum team to advance the hepatitis delta program efficiently toward regulatory submissions. We see brelovitug as an important medicine to fill a critical treatment gap for delta, and we're excited to help bring it to patients.

With that, I'll hand it over to Peter to provide more color on our commercial approach to hepatitis delta and how brelovitug fits our broader strategy in rare diseases. Peter?

Thanks, Joanne. Hepatitis delta is a natural extension of our rare disease commercialization strategy. Bringing life-changing medicines to underserved and under-diagnosed patients is where Mirum excels. And brelovitug squarely fits this profile, adding to our portfolio another high-impact rare liver disease medicine with significant leverage on Mirum's existing commercialization capabilities.

Hepatitis delta is a rare disease with substantial morbidity and mortality, but limited treatment options. While there are an estimated 40,000 prevalent delta patients in the United States and over 230,000 in the U.S. and EU combined, most go undiagnosed. For example, in the U.S., we believe there are about 15,000 delta patients who are currently diagnosed, insured and under care. This estimate is based on claims data of hepatitis delta patients with multiple interactions in the health care system, which we see as a solid starting point for an initial U.S. launch population.

The rate of diagnosis is higher in Europe due to the availability of an approved treatment and the growing implementation of EASL-recommended delta reflex testing among hep B patients. And even with the low rate of diagnosis today, we see substantial revenue potential for brelovitug in delta. In our view, the rarity of the population and the severity of the disease, coupled with brelovitug's expected compelling clinical profile supports a global revenue potential of at least $750 million.

Operationally, we are in an excellent position to support the commercialization of brelovitug. Our global commercial operations are already in place, delivering $500 million to $510 million in expected 2025 worldwide sales and a brelovitug launch would heavily leverage our existing organization that commercializes LIVMARLI and the bile acid portfolio as well as our ongoing expansion for volixibat's expected 2027 launch in PSC.

While we expect to make modest incremental adds to our field teams to cover areas like infectious disease and selected internal medicine practices where delta patients are managed, we see launching brelovitug as highly leveraging our existing team, operations, expertise and relationships. In the U.S., for example, hepatitis delta is geographically concentrated with the majority of currently diagnosed patients located in seven states and primarily managed in urban centers. In important global markets for delta, our global commercial infrastructure is in place with deep and proven stakeholder relationships that we expect to leverage to drive broader geographic access for brelovitug.

Overall, we are excited about the impact brelovitug is expected to have for hepatitis delta patient community, and we are energized by the opportunity to deliver another high-impact medicine to a population in urgent need with limited treatment options. Together with LIVMARLI, CTEXLI, CHOLBAM and volixibat, brelovitug will strengthen our rare disease portfolio and extend the impact we can have across rare disease patient communities.

And with that, I'll turn it over to Eric to walk through the transaction terms and financial impact. Eric?

Thanks, Peter. Under the terms of the agreement, Mirum will acquire Bluejay for $250 million in cash and $370 million in Mirum stock priced at $71.21 per share with up to $200 million in tiered sales-based milestone payments starting at $500 million in annual sales. In addition, we've secured $200 million through a private placement financing from a syndicate of leading health care investors, which we'll fund concurrently with the closing of the proposed acquisition. We expect the transaction to close in the first quarter of 2026, subject to regulatory approval and customary closing conditions.

Operationally, we are well positioned to absorb the HDV program. There is no change to our 2025 guidance and with our growing commercial business, we expect to return to be cash flow positive in 2027. We expect that the incremental expenses associated with the brelovitug program will support the ongoing execution of the AZURE Phase III program and manufacturing validation and scale-up in preparation of the anticipated BLA submission in the first half of 2027 and subsequent commercial launch. As Peter mentioned, we anticipate significant synergies with our existing commercial efforts and would only expect a modest increase to our ongoing efforts supporting LIVMARLI and volixibat.

In summary, this transaction is consistent with our disciplined approach to capital allocation and business development. Without compromising our financial independence, we have expanded our rare disease portfolio with a high-value, late-stage medicine that features compelling data, a clear regulatory path and significant value potential.

With that, I'll turn the call back to Chris for closing remarks.

Thanks, Eric. I'd like to again express how excited we are to welcome the Bluejay team and the hepatitis delta program to Mirum following closing. We have created a potentially paradigm-changing medicine for delta, and I look forward to what we together will accomplish at Mirum. This proposed acquisition aligns with our vision as a leading rare disease company with a portfolio of transformative programs and will add meaningful strategic and financial value.

Our commercial business is strong and growing. We are entering a phase of accelerating value creation potential with four registrational-stage readouts in the next 18 months. Next up will be volixibat VISTAS PSC top line data in Q2 with the potential to bring the first approved therapy forward for PSC patients. This will now be followed by the brelovitug AZURE 1 and 4 results in the second half of 2026 before the LIVMARLI EXPAND and volixibat PBC data expected in the first half of 2027. It is an important catalyst calendar for both bringing forward new medicines for patients and to shape the next chapter of Mirum.

With that, operator, please open the call for questions.

[Operator Instructions] Our first question comes from Mani Foroohar from Leerink Partners.

Congrats on what looks to be another deal at a pretty attractive peak sales multiple. Can we talk a little bit about how you see the competitive dynamics? I know Hepcludex is not approved in the U.S., but [ to ] be filed. How about competitive dynamics and positioning?

And then one pushback we've gotten from Vir is being, well, could that being approved in the U.S. change some of the nuances of your registrational path forward or regulatory treatment? If you could address those two, that would be really helpful.

Mani, thanks for the question. I'll touch on the last part briefly and then pass it over to Peter to talk about the commercial dynamics. In terms of the registrational path and Hepcludex being potentially submitted, there's really clear buy-in from FDA on this program. So comfortable that AZURE 1 and 4 are designed and set up to support registration in the U.S. Kind of as you mentioned, there is a head-to-head component in the European studies, AZURE 2 and 3. But FDA has given clear feedback and buy-in on that AZURE 1 and 4, supporting filing in the U.S. But I'll let Peter kind of talk about how we see this playing out commercially once we get to a potential approval.

Yes. Thanks, Mani. I mean I think with regards to Hepcludex and Gilead entering the U.S., we see this as a real positive to develop the market. As we mentioned in our prepared remarks, we've seen what's happened in Europe over the last 5 years with the availability of an approved product and EASL changing their guidelines to do reflex testing. You could imagine possible similar dynamics may occur in the U.S. And with that product being approved, more and more patients being diagnosed and the market being developed.

Obviously, we're really excited about the monoclonal antibody approach targeting the surface antigen, hep B surface antigen. And I think that's kind of an approach that's distinguished itself as highly active in terms of the delta emerging treatment landscape. What we really like about the Bluejay program, it's a single drug, 100% virologic response rate, really compelling ALT normalization rates and a great safety profile so far, very low rates of flu-like symptoms. So feel really good about the profile here.

And if I can slip in one commercial follow-up. When we think about the adult side of the rare liver disease franchise, can you give us a sense of how to think about the evolution of operating margins going forward? You should get some operating leverage from these combination of agents together in the same bag, but that mostly depends on how tightly defined some of the call points are. So can you just give us a sense how to think about that?

Yes. I mean I think we expect the operating -- the commercial operating margins to continue to improve. The -- as you know, we're planning an expansion with the PSC launch in 2027. That will get us a little bit deeper outside of the tertiary kind of academic medical centers where LIVMARLI is prescribed today. With delta, we -- actually, the top KOLs for delta, many of them are already prescribing LIVMARLI today. Many of the delta patients are taken care of out in the community and private practice GI settings. Those are a lot of the same docs that take care of PSC patients and even some LIVMARLI and CTEXLI patients. And then we just have an incremental expansion on top of that into infectious disease, selected internal medicine. So overall, the high-level kind of story is continued margin expansion on the commercial side.

Our next question comes from Josh Schimmer from Cantor.

Congrats on the transaction. I believe there are royalties and some economics owed from Bluejay to Novartis. Can you summarize those? And then can you discuss your plans for potential international commercialization of the product?

Thanks for the question, Josh. On the Novartis kind of background license, pretty favorable terms there. So low single-digit royalty and some fairly minimal milestones back to Novartis. So attractive -- helps us continue to improve margin over time. And I'll turn it back over to Peter to comment on kind of international commercial opportunity.

Yes. As Joanne highlighted, the Phase III AZURE program is very well designed to support international commercialization, a direct comparison to bulevirtide, which would be quite helpful for international markets. We have a team at Mirum that directly commercializes LIVMARLI in several Western and Central European countries, U.S., Canada, distributor network that extends well beyond those countries, well north of 30 countries around the world with reimbursed access to LIVMARLI. So we plan to heavily leverage that group of people with kind of modest expansions to the on-the-ground footprint that we mentioned before to launch this product.

Our next question comes from Brian Skorney from Baird.

This is Charlie on for Brian. So really impressive results. Do you guys think at all just based on the competitive space, it's necessary to pair with an siRNA for any additional efficacy? And what are you thinking about in terms of the rest of Bluejay's pipeline going forward? Are you interested in pursuing the HBV functional cure pathway? Or is this more so wholly focused on HDV?

Thanks for the questions, Charlie. On the second part of your question first, we're very much focused on the delta program. That's where the data is clear that this is tracking towards being a standard of care medicine. So we don't plan to invest in the HBV pipeline, agents that Bluejay has. This is all about bringing focus to that -- to bulevirtide for delta.

And that kind of then leads into the answer to the first part of the question where the results that we see from the Phase II proof of concept already are hitting 100% virologic response, really high results on the FDA composite endpoint. So frankly, not sure that an additional agent is needed. You're driving really fantastic results with a single agent. So excited about the profile of how convenient this can be as a therapy to get really competitive response rates for patients.

Our next question comes from Gavin Clark-Gartner from Evercore ISI.

This is Yesha on for Gavin. Congrats on the acquisition. Just a quick question from us. For the at least $750 million worldwide peak sales number that you noted, how much of that do you envision coming from the U.S.? And then what would that correspond to for the number of peak U.S. patients treated? And then how does that kind of compare to what you found in the health care system from your commercial intelligence?

Yes. Thanks for the question. So yes, we would anticipate the majority of the peak sales would come from the U.S., kind of on the order of 2/3 or so. And yes, the question with regard to patient numbers, it does kind of assume roughly on the order of 2,000 to 3,000 patients at peak treated chronically. That's kind of in comparison to the 15,000 who are kind of diagnosed and under care and insured today. So we think pretty reasonable base case way of thinking about the product.

Our next question comes from Mike Ulz from Morgan Stanley.

Congratulations on the deal as well. Maybe just a follow-up on an earlier question, I think, was asking about a competitor out there that's also in Phase III. If you can maybe talk about some key points of differentiation for your program versus theirs?

Thanks, Mike, for the question. I think probably referring to the program of tobevibart and elebsiran, which also had Phase II results at AASLD. Really, again, a very active regimen and has the overlap of mechanism with the hepatitis B surface antigen targeted antibody. So we do expect to have another regimen that eventually gets approved for this setting coming out of that program.

We're really excited about brelovitug and its profile, namely what we see on the FDA composite endpoint, the 65% to 82% response rate for virological response with ALT normalization, that is among the most -- highest response rate on that endpoint that's been presented. So excited about what that means for the approval path and competitive positioning. And then having just the single-agent antibody and how clean that is from a tolerability and safety profile, we do see that as an advantage taking brelovitug to launch. So really what drove us to enter this agreement is that compelling data coming out of a single-agent regimen.

Our next question comes from Ryan Deschner from Raymond James.

Congratulations on the new pipeline expansion. A couple of questions. Curious if you could talk a little bit about the IP portfolio associated with brelovitug, when you expect LOE? And was this a competitive deal process?

Thanks for the question, Ryan. Yes, on IP, there's -- the composition of matter to 2041, which would be eligible for some potential extension beyond that. So great duration of exclusivity expected for the program. And would you remind me the second part of your question?

Was this a competitive deal process?

Yes. Talking -- a little bit of background on the transaction to kind of answer that where -- we do think that there was other interest in the program overall. But this is something that we've followed for well over a year. We identified this as a really interesting program from some of the early results presented even last year. And so it's -- this was a result of a long ongoing conversation, getting to know the program and the Bluejay team. I'm excited that we were able to get to something that works for both parties and adds a lot of value to Mirum.

Our next question comes from James Condulis from Stifel.

Congrats on the acquisition. Can you maybe just talk about this interim in 2Q a little bit in terms of kind of what are the outcome scenarios and how important is it? And looking ahead for kind of the full study, could you also just talk about powering and if you need both studies for approval? Any color there would be great.

Yes, James, thanks for the question. Just one quick comment, and I'll pass it over to Joanne to go into a little bit more of the detail. That the -- just to clarify, the FDA package is AZURE 1 and 4. So both of those studies tracking towards top line data in the second half of 2026. So that clear buy-in that both of those studies are the two Phase IIIs to support a U.S. approval. I'll have Joanne give a little bit of color on the interim and how the results play out.

Yes. Thanks, James, for the question. The interim is set up so that we get a readout when 50 patients in the AZURE 1 study reach 24 weeks, and that will be in Q2. We expect, given the strong results that we're seeing in the Phase II with a fairly limited number of patients there that this will be, again, a strong result.

The overall powering for the studies is really not for efficacy, given a highly effective agent, but it's really to have enough patients for the safety database. And that's really what drives the numbers for both AZURE 1 and AZURE 4 specifically for FDA. As you know, with a highly effective agent, you're often not powering for efficacy, you're really overpowered for that. And then you're really looking at the numbers of patients to be treated to meet requirements for safety database and characterization there. And that's exactly the situation we have here. So even with the strong interim results, then the studies would not stop early, simply because we need to collect additional data to support the safety database.

Our next question comes from Joseph Thome from TD Cowen.

Congrats on the announcement. Maybe one just on the overall addressable population. I guess what are sort of the main blocks right now to kind of increase that addressable market in the U.S.? Is it that patients aren't being seen by their physicians, or they're not being screened for delta? And maybe what can you do over the next couple of years before the drug is available to maybe increase that?

And then maybe just one point of clarification on the supportive AZURE 3 and 2 studies for Europe. Are these superiority studies? Or are these non-inferiority studies? Just kind of any color on that would be helpful.

Great. Yes. Thanks, Joe. With regards to addressable population in the U.S., the 15,000, yes, that is the number of patients in the U.S. who are diagnosed, insured, kind of under management, interacting frequently with the health care system today.

Yes, I think that the -- in terms of how to increase that and get it something closer to the prevalent population, which we and others estimate at about 40,000, I think the biggest lever you have there is to do reflex testing like they've implemented in Europe. If AASLD or others were to endorse that and physicians were to adopt that and do delta reflex testing in all their hep B surface antigen positive patients, I think you'd most likely see the diagnosis rate go up much like the Europeans have published. And then maybe I'll pass to Joanne to comment on the design for AZURE 2 and 3.

Yes. So AZURE 2 and 3 are both superiority studies. One of them is a switch study. So patients already taking bulevirtide for at least 6 months will either continue bulevirtide or switch to the brelovitug antibody. And the other one is a head-to-head in patients who have not been previously treated with either agent to -- bulevirtide versus brelovitug. So given the strong data that we saw with the high -- 100% virologic response rate and then also the high rates of reaching the combined endpoint, we feel pretty confident in terms of both of these studies having a positive outcome.

Our next question comes from Jon Wolleben from Citizens.

This is Catherine on for Jon. I have a quick question about the weekly versus monthly dosing regimen. In particular, how are you looking at the Phase III hierarchy? And any differential responses you guys are expecting? And then how important does it have -- both for the commercial launch?

Maybe just to comment on the last part and then pass it over to Joanne. We -- the data will speak for which regimens actually get submitted for approval. But either one of these would be a convenient option for patients. So we're comfortable with either one of them having a really compelling profile.

Yes. So when we look at the PK from either of these doses for -- from the Phase II study, they actually are fairly similar in terms of [ overall ] exposure. So there's probably a fair amount of overlap in terms of the actual antibody exposure to the patient with either of these regimens. The weekly subcu can easily be given at home. Currently, the monthly dosing regimen is actually given in the clinic. So both of these have been taken forward. But on balance, they're probably more similar than they are different, if that makes sense.

Our next question comes from Swayampakula Ramakanth from H.C. Wainwright.

This is RK from H.C. Wainwright. Congratulations on this acquisition. And I have a couple of quick questions. One of them is, obviously, the investment thesis here is heavily relying on the success of the Phase III asset. So what sort of data makes it -- gives you confidence for not only the clinical profile, but also the probability of success here? And then beyond the clinical program itself, what other execution risks are you kind of looking at to mitigate, especially things like manufacturing or competition or commercial readiness, et cetera?

Thanks, RK, for the question. I mean, overall, just to kind of recap some of the points made from the clinical data that gives us confidence here is the Phase II results that Joanne went through are just really impressive. You're seeing 100% virologic response and 65% to 82% on the FDA composite endpoint. So we feel really good about those Phase II results and what that means for the probability of the Phase III program reading through and also just what that means for patients to have a treatment option that's driving virologic response in 100% of patients, obviously, would be a game-changer for this setting.

And in terms of overall, like the risk going forward, I mean, that's a great question and a little bit -- I can speak a little bit to some of the diligence work that we did and really have to say that the Bluejay team has done a fantastic job setting up this program for success. So continuity of that team working on this program, given they have such momentum in the Phase III execution, that's one of the things we're focused on, on bringing that team over to help us continue to drive the program forward. On the manufacturing side, everything is lined up, a lot of good planning and investment that's gone in on that front. So we feel great about the status of the program and driving to that Phase III readout in the second half of next year.

If I may, another question, just on the strategy itself. So once you have this program onboarded, how does this change in the long term, your competitiveness within the rare liver disease landscape?

We see this as just a way to, I'd say, just double down on everything else that we're doing in the space. We already have strong relationships with all the key stakeholders here, and we're bringing really important medicines forward for them to treat their patients. So it only deepens that relationship and offering that we have over time.

We currently have no further questions. So I'd like to hand back to Chris for some closing remarks.

Great. Well, thank you all for joining the call this morning. We look forward to providing updates throughout a busy 2026 ahead. Have a great day.

That concludes today's call. We thank everyone for joining. You may now disconnect your lines.

Next up, we have the team from Mirum Pharmaceuticals. So we have Andrew McKibben from the IR side; and Eric Bjerkholt, who is the CFO, hopefully, I pronounced that correctly. Awesome. All right. So before we dive into it, let me just turn it over to you guys for introduction, overview of the company where things stand today.

Great. Thank you, and thank you to Evercore for inviting us to present here today. And as usual, we will be making forward-looking statements. So please refer to our SEC filings for risk factors. So Mirum is a rare disease company. We have 3 approved medicines for rare cholestatic and other diseases. Our guidance for this year is $500 million to $510 million in revenues, and we are cash flow positive, and we expect continued growth from all 3 medicines into next year. And we also have a full pipeline led by volixibat for adult cholestatic diseases, PSC and PBC and then MRM-3379 for Fragile X syndrome, where we announced yesterday that we enrolled the first patient in a Phase II trial. So -- very excited about what our commercial medicines can deliver and also our pipeline.

Awesome. All right. So let's actually start off on the Fragile X side of things, kind of go in reverse order from what we normally do. You've noted $1 billion-plus opportunity for Fragile X. How do you get there?

Relatively simply. I mean there's about 50,000 male Fragile X patients between the U.S. and Europe. From a pricing perspective, if you look at comps, that's -- you kind of get into the 200-ish range. I think that's pretty reasonable looking across other comparable disease settings. And we assume that there's -- while there's nothing approved today, Shionogi has PDE4D in clinic in a Phase III study. So a rough kind of competitive share and the math gets pretty simple. It's quite a sizable opportunity.

Okay. That makes sense. So I guess that's for every 5,000 U.S. patients, that's about $1 billion opportunity, give or take?

Give or take, yes.

Yes. I mean, still early. We'll have more to say, I'm sure in the future, but...

Yes. I mean once -- I mean we're just starting Phase II. So once we have a full understanding of the clinical profile and the competitive profile, all that stuff plays in. But rough math, that's correct.

Awesome. Do you actually know what's the latest with Shionogi's program? I mean on their last earnings, they said they've had the last patient out, but they're discussing the primary with the FDA. Do you have any speculation so what's going on there?

We do have speculation. But I think, generally speaking, based on their comments, it sounds like they're going through the typical motions of validating the NIH toolbox. So if you have a patient-reported outcome, the FDA does require a certain amount of validation for that. And that typically is conducted before you unblind the study. So it sounds like they're kind of going through those discussions right now, getting alignment on MCID and some of those other kind of anchoring measures that are important. But our general expectation is that we'll have a clear answer in Q1.

That makes sense. And you guys are doing an AH toolbox on the CCC domain specifically. I guess like from -- like on that last point, from an FDA clinical outcomes perspective, how validated do you think this measure is?

It needs to be -- I think it's -- there's a lot of great precedent and reason why this end point makes a lot of sense in the Fragile X setting. It does need to be validated, and that's pretty common. I mean we went through the same validation efforts with the ItchRO for the Observer score in the pediatric studies. We're doing the same thing in the adult studies. So pretty standard to do that in parallel in context of a registrational study. So nothing seems out of the ordinary on that front. And from what we've seen from this endpoint versus others, we think this is particularly well suited. And it seems like the FDA agrees with that.

Why did you choose this domain specifically? Maybe it's helpful to kind of walk through what the CCC is testing specifically?

Yes. I mean it's a crystallized measure, right? So it's looking at picture vocabulary, learning memory and some composites of those. What we like about it is that it's calibrated for individuals with cognitive impairment. So that's important. And I think a departure from where -- what you've seen in some of the historical Fragile X studies where you're looking at clinician or caregiver global impressions of change, which you have some real issues with floor-ceiling effects. Because this is completed by the patient, and calibrate it to whether they're getting answers right or wrong, it's a little bit more sensitive and feels particularly well suited for this population.

And I think [indiscernible] data on this measure was pretty strong, too, if I'm not mistaken?

Correct. Yes. I mean, yes, to be very clear, I mean they use this in their Phase II and that definitely informed our approach in terms of pursuit of this mechanism and design of our study.

Awesome. How do you power the Phase II?

Similarly to what we saw from the Shionogi Phase II just as a rough benchmark. I mean that's -- Phase II, the primary endpoint is safety and tolerability. The NIH toolbox is a secondary. And one of many, we're looking at a lot of different other end points, some of the clinician and caregiver change scales, some biomarkers. So we're trying to learn a lot from the study, which would inform subsequent Phase III.

That makes sense. For the 3 doses that you're testing, do you know how much CNS concentration, CNS inhibition, I guess, that you're getting compared to [indiscernible]? Specifically, I know [indiscernible] is using a 25-milligram dose in both of the studies, I think. Like, how do your 3 doses kind of bracket that?

We're, generally speaking, at their level or more exposure.

Yes. All right. That makes sense. All right. Over the PSC side then looking ahead to next year, which is going to be one of the big binary events. Maybe it's just helpful to kind of recap what you guys have said on powering and variability, kind of what you're seeing for the ongoing trial to set the stage there.

Yes. So we had an interim analysis about 1.5 years ago, which was blinded to us, but it was set up where the committee that looked at the unblinded data had the 3 possible outcomes. One was to continue the study without any change, and that would be the outcome if what they saw in terms of efficacy and safety exceeded predefined thresholds that would predict a positive trial.

The second option would be to supersize the study, increase the size. And the third would be to tell us to unblind because it wasn't working. And the outcome was the best possible, meaning the first option, which is they said, continue the study unchanged. We also, in the first portion, had 2 different doses plus a placebo, so 3 arms. And they were to select which dose to take forward, and they picked the 20-milligram dose as the one with the best therapeutic window.

Awesome. Have you talked about the baseline pruritus scores at all? I'm just trying to kind of mix and match versus the prior VANTAGE study, which is on the PB side for what you've shown. Like, was the baseline pruritus here generally similar seen there?

Yes. baseline pruritus in the VANTAGE study was -- for the interim was a little over 6 on a 0 to 10 scale, and I expect the same in PSC.

Awesome. What about minimal effect size from a statistical perspective, right? Because you talked about how you powered it, especially variability is tracking a bit on the lower side, which is good. Like, at what pruritus effect size do you start to run into troubles from the statistical perspective?

The limit of detection. I actually don't know the answer to that, but I mean in PBC, GSK had a positive study with a 0.7 difference, placebo adjusted. And I mean, they have more patients, but I don't think it would take a lot more than that to achieve statistical significance with our number of patients in PSC.

Makes sense. What about beyond pruritus, like the quality of life, fatigue, sleep, very important secondaries that you guys are measuring? Should we expect those to be statistically significant in this study? If they are statistically significant, what does that do for you commercially?

We didn't power obviously for these, right? I mean we've seen a really nice interesting signal in the PBC interim on fatigue. And just worth pointing out that fatigue and sleep are different things. Fatigue is not just being tired, it is characterized as a brain fog or kind of this inability to get off the couch, always wanting to sleep, but not the same thing as "I didn't sleep well last night." And is next to pruritus, one of the most burdensome symptoms that patients discussed in both PSC and PBC settings. So very encouraged by what we saw in the PBC side. It's certainly a nice to have if we can get it, and I think would be very meaningful for patients. But I don't think we've -- we didn't set the study around a stat sig for fatigue or sleep. But clearly, when you address the itch, you see improvements in sleep, that's been pretty consistent across the pediatric settings, and we'll learn more on fatigue when we see the final data.

Makes sense. All right. Thinking about the tolerability safety side, and this applies to PBC also. Just one investor question we've gotten, and I'll just paraphrase it, is if you have some rates of diarrhea, GI events that you've seen with just the IBAT inhibitor class, why trade itch for diarrhea? And I know it's not quite like that, but I'll phrase it to get your response.

Yes. I mean, I think this kind of minimizes how bad the patient experience is, and it's really important -- and we've heard this a lot, it is just itching. And when you actually talk to a patient and understand what this actually means for them and how much it impedes their ability to live a normal life, it is significant. The diarrhea that you see with IBAT is very much on target. That's how you clear the bile acids out of the body. And it's typically mild and transient. It's very easy to manage with simple imodium, if you even have to do that. So it is -- it seems to be a very easy trade. And if you just look at our studies and participation in the extension portions, the degree of participation we're seeing is indicative of a patient choice and that's, I think, important.

More importantly, I would say, look at our experience in real life, we have now many hundreds of patients treated with LIVMARLI and very, very rarely does somebody discontinue for diarrhea or other side effects.

Yes. That makes sense. It's just back to the quality of life and other measures beyond pruritus alone. If some of those other secondaries hit, does that change how you think about things from a pricing access perspective?

Maybe. I mean, the more attractive the profile is, obviously, the more value the medicine will deliver. And so we'll -- that would be one of the factors we consider when deciding what the right price is.

Yes. Switching gears, going over to the PBC side of things. For the VANTAGE study. How many patients are on UDCA or PPARs on that study?

Just about all patients are on UDCA. I mean, that is the kind of underlying therapy that if you have PBC, you are treated with UDCA. Very few patients end up intolerant to UDCA. So you typically see that as the mainstay. And for the portion of the patients where UDCA doesn't work that well, you typically layer on typically not PPAR, what used to be Ocaliva. So just about everybody is on UDCA. With PPARs, I'd say maybe a handful. I mean it's certainly part of the inclusion criteria that if you're on a stable PPAR, you can continue that into the study. We had several patients who were on fibrates in the interim, which I think is an interesting point. PPARs do have some benefit on price, but it's not universal. And seeing patients meet the inclusion criteria for Vantage while on a PPAR is kind of indicative of that.

So I guess with that said, how do you expect the label to read assuming it's a positive study per the last data that you've put out?

Treatment of cholestatic pruritus in PBC.

Yes. For like all backgrounds, different ALP status?

Yes, there's no alk phos cutoff for the study, so that we're agnostic.

Awesome. All right. Working our way commercial, but one before we get there on the expand side of things for the next expansion of LIVMARLI. Like what's the mix of patients that you're seeing come in to that study because you allow a few different groups.

Roughly half the patients have biliary atresia and the rest is a smattering of different extremely rare cholestatic conditions.

How is the age also skewing for the trial?

Well, we've got a pediatric cohort, and there's also a separate adult cohort. So the primary endpoint will be based on the pediatric cohort that's the ItchRO Observer Scale. So there's slightly different ways of measuring itch between peds and adults. So that's why you break them up. Typically, though, in the pediatric side, these patients are 7, 8, 9 in that range. I mean, there's a spectrum for sure, but I'd say, on average, pretty typical.

Maybe it's worth asking like given you're seeing a high mix of VA patients as expected, can you call out how that's different from the population that was studied to EMBARK?

Very different. Yes. I mean the EMBARK study was incident biliary atresia. So these are right after these children are born, they're diagnosed with biliary atresia. They have an emergency Kasai procedure and then would be enrolled in the study. This population that we're looking at and expand, these are patients who've had a successful Kasai, and 2, 3, 4, 5 years later, they developed cholestasis and the resulting pruritus. So you can't predict which patients who do have a successful Kasai will go on to develop cholestasis, but we do see a fair number that do -- and it's a fairly activated patient population, which is why we aren't surprised to see such a good participation and expand.

Awesome. All right. So turning to the commercial business. Thinking about 2026, maybe just kind of frame like if we step back on 2025, what drove so much growth? And especially in the PFIC side, was it more on the population being larger than you expected? Was it more that they skewed a little bit heavier, maybe there was a different pricing mix than you expected. Maybe it's a little bit of both. But really the question is, you'll have that base in revenue given your high retention that you've talked about before. What's the right way to think about growth heading into 2026?

Sure. So I mean we expect continued growth from all 3 medicines and also both U.S. and international. This year, the reason we so dramatically outperformed our original guidance at the beginning of the year was primarily related to PFIC, where we found more patients that were naive to treatment much more than we thought. And that's, I think, a combination of probably there being more PFIC patients. than we had originally thought, but also more patients that had yet to see treatment. And we've been very successful through our various efforts at getting a good share of those patients to treatment, and we expect that to continue.

I mean like next year, do you think there's still more upside versus your original expectations? Or do you think you've kind of recalibrated at this point to a more reasonable view?

It's hard to tell. We keep being surprised to the upside of how many patients we can get to therapy, and hopefully, that will continue.

Awesome. I think I asked this question at least once a year, maybe a good time to ask again. The reweighing dynamic that you see as patients stay on therapy as they get older and grow. What do you see on that front?

That's definitely a dynamic that's playing out, and we're seeing the average dose creep up, albeit slowly. And the reason it slowly is because on average, a patient will see a dose adjustment every other year. And the difference between each dose span or one dose span and the next is about 10% to 15%. So that's a dynamic. But we have some discontinuations usually to transplant is the most common. And those patients are then -- if you look at the whole pool usually replaced by infants that are diagnosed to Alagille syndrome, and they weigh a lot less and so bring down the average weight. But over time, as the pool of prevalent patients gets larger, you definitely see more of that dynamic play out.

Awesome. And then just on the Paragraph IV side of things. Maybe you could just like quickly frame your IP estate and like which patents you put more weight on internally? Like I know, for example, the 2040 method of use patent was something the company was founded on right out of the gates, and there's basically why you got the assets. So there's some interesting findings within that patent. But maybe you could just kind of walk through that.

Yes, that's definitely still our -- I think, our most important patent out to 2040. And this Paragraph IV filings were completely expected on the date, no surprises, and we were prepared for that. So we have a very good legal team ready to vigorously defend our patents.

Awesome. Well, it's right on time. So I think we'll wrap it up there. But thanks so much for joining.

Thank you.

Thank you for having us.

Hello, and welcome to the Mirum Pharmaceuticals Third Quarter 2025 Financial Results and Business Update. My name is Harry, and I'll be your operator today. [Operator Instructions]

I would now like to hand the conference over to Andrew McKibben, SVP of Strategic Finance and Investor Relations. Please go ahead.

Thanks, Harry, and good afternoon, everyone. I'd like to welcome you to Mirum Pharmaceuticals Third Quarter 2025 Conference Call. I'm joined today by our CEO, Chris Peetz, our President and Chief Operating Officer, Peter Radovich, a Chief Medical Officer, Joanne M. Quan; and Eric Bjerkholt, our Chief Financial Officer.

Earlier today, Mirum issued a news release announcing the company's results for the third quarter of 2025. Copies of this news release and SEC filings can be found in the Investors section of our website.

Before we start, I'd like to remind you that during the course of this conference call, we will be making certain forward-looking statements based on management's current expectations, including statements regarding Mirum's programs and market opportunities for its approved medicines and product candidates. These statements represent our judgment and knowledge of events as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed. We are under no duty to update these statements. Please refer to the risk factors in our latest Form 10-Q and subsequent SEC filings for more information.

With that said, I'd like to turn the call over to Chris. Chris?

Thanks, Andrew, and good afternoon, everyone. 2025 continues to be an outstanding year for Mirum. We've created a leading rare disease company, purpose built to create and deliver life-changing medicines to patients. Our success comes from that foundation. The team deeply connected to patients and families turning their insights into meaningful therapies and measurable performance. In the third quarter, we delivered strong commercial results, advanced our clinical pipeline and strengthened our financial foundation. I'm proud of the way our team continues to execute with focus and consistency.

First, on commercial performance. We reported third quarter revenue of $133 million, representing a nearly 50% year-over-year increase over the same period last year. This performance reflects the strength and breadth of our commercial portfolio, including continued momentum from the U.S. PFIC launch and expanding demand from our international markets.

Turning to R&D. We remain on track for three potentially pivotal readouts over the next 18 months. First up is the VISTAS Phase IIb study in PSC. With enrollment complete, we expect to announce top line data in the second quarter of 2026. With the successful interim analysis last year and a consistent body of supporting data with IBAT inhibitors across multiple cholestatic diseases, we're optimistic about volixibat's potential to become the first approved treatment in this setting.

We are also progressing well with our VANTAGE study of volixibat in PDC, the EXPAND study of LIVMARLI in ultra rare cholestatic conditions and our newly initiated Phase II study of MRM-3379 and Fragile X syndrome.

We've also taken meaningful steps to further strengthen our financial performance. This quarter, our cash balance grew significantly, and we recognized positive net income for the first time. This is an important milestone that highlights the operating leverage in our commercial model.

In sum, it has been another solid quarter of execution from Mirum. I want to thank the entire Mirum team for their continued dedication to patients. We built a high-growth cash flow-positive rare disease company with a broad pipeline and global footprint, and we're just getting started.

And with that, I'll hand the call over to Peter. Peter?

Thanks, Chris. Q3 was another excellent quarter for Mirum with total net product sales of $133 million. This was driven by continued robust performance of LIVMARLI in both the U.S. and international markets as well as steady contribution from our bile acid portfolio.

LIVMARLI net product sales totaled $92 million for the quarter. In the U.S., LIVMARLI demand remains healthy in both ALGS syndrome and PFIC with $64 million in net product sales. ALGS syndrome growth remains durable, and PFIC continues to contribute meaningfully, reflecting the real-world benefit of expanded diagnosis and increased genetic screening.

As we begin reaching into broader segments of the medical community, particularly adult-focused providers, we're finding that genetic testing is still less embedded in practice and often requires more education and dialogue. So we view this as an area where sustained engagement can continue to drive incremental gains.

Internationally, LIVMARLI demand continues to grow with $28 million in net product sales this quarter. Demand across our direct and partner markets remains robust, supported by expanding reimbursement and launches in new geographies. Q3 was the first full quarter of commercialization for our partner, Takeda and Japan, with in-market adoption dynamics generally consistent with LIVMARLI's U.S. launch.

Our Bile Acid Medicines, CHOLBAM and CTEXLI generated $41 million in net product sales this quarter, supported by increased CTX patient finding following CTEXLI's FDA approval earlier this year. And I'm happy to say that we now expect to land in the upper end of our prior full year 2025 guidance range with $500 million to $510 million in revenues.

This reflects the continued strength of our U.S. business in both ALGS syndrome and PFIC, steady contributions from our bile acid portfolio along with the typical quarter-to-quarter variability in international partner and distributor ordering patterns. Looking ahead, we continue to see substantial growth potential across our portfolio with peak revenue potential for LIVMARLI, volixibat and MRM-3379 each exceeded $1 billion.

And then with that, I'll turn it over to Joanne for an update on the pipeline. Joanne?

Thanks, Peter. I'm pleased to provide an update on the continued progress across our clinical pipeline, where we're seeing continued collaboration and momentum with physicians and patients across all of our ongoing studies.

Starting with volixibat, we completed enrollment in the Phase IIb VISTAS study and primary sclerosing cholangitis, or PSC, and expect to announce top line data in the second quarter of 2026. PSC represents a significant area of unmet need with no approved therapies and limited treatment options. We're deeply grateful to the investigators and the PSC patient community for their partnership in advancing this important study.

As a reminder, the outcome of the interim analysis of the VISTAS study last year was what we'd hoped for. The recommendation was to keep the current sample size, which we believe reflects a strong signal for the final analysis. It's worth noting that the study was powered using conservative assumptions, a placebo-adjusted treatment effect of 1.75 points and standard deviation of 3.

A case series is being presented at AASLD of 8 PSC patients treated with maralixibat under our [indiscernible] program, a continuation of a case series presented earlier this year at DDW. All of these patients had meaningful reductions in pruritus and 4 of the 8 had complete resolution. This data supports the role for IBAT inhibition as a treatment for PSC.

Turning to PBC. The VANTAGE study continues to progress well, and we expect to complete enrollment next year. Interim data presented last year demonstrated statistically significant improvement in pruritus, meaningful reductions in serum bile acids and encouraging improvements in fatigue. We're excited to advance this study through the informatory stage. Additional analyses from the VANTAGE interim will be presented at AASLD which highlights the decreases in fatigue and improvement in sleep, in helipad patients as well as showing a decrease in IL-31 in treated patients.

Our EXPAND study evaluating LIVMARLI in additional settings of cholestatic pruritus is also enrolling well. This study is designed to broaden access to patients across multiple rare cholestatic diseases who currently have few or no treatment options. It represents a meaningful label expansion opportunity and we're targeting enrollment completion in 2026.

Finally, I'm excited to share that we've initiated our Phase II study of MRM-3379, our brain-penetrant PDE4D inhibitor for Fragile X syndrome. The preclinical data we recently presented from a mouse FMR1 knockout model of Fragile X, showed that MRM-3379 reversed the disease phenotype across multiple behavioral assessments and increases our confidence in the importance of this pathway in [indiscernible]. Overall, we're very encouraged by the progress across our development programs and look forward to upcoming milestones in 2026.

With that, I'll turn the call over to Eric to discuss our financial results. Eric?

Thanks, Joanne, and good afternoon, everyone. We delivered another solid quarter of financial performance, highlighted by total net product revenue of $133 million representing a 47% increase over the prior year and reflecting growth across all our commercial medicines. This quarter included approximately $5 million in sales to our partner Takeda in Japan. We do not expect additional sales to Takeda in Q4 of this year. Total operating expense for the quarter ended September 30 was $130 million, which includes R&D expense of $43 million, SG&A expense of $62 million and cost of sales of $26 million.

Expenses for the quarter included noncash stock-based compensation expense of $18 million an intangible amortization and other noncash items of $6 million. Intangible amortization and other noncash items expense are largely reflected in our cost of sales.

Our cash operating margins continued to improve, and we delivered GAAP profitability in the third quarter, generating approximately $3 million in net income. While this reflects the strength and scalability of our business model, we view quarterly GAAP profitability as a milestone, not yet a consistent expectation as we continue to invest in growth. Cash, cash equivalents and investments were $378 million at September 30, an $85 million increase from the beginning of the year. We continue to be well funded and financially independent, providing us the resources required to expand our patient impact and grow our business.

With that, I'll turn the call back to Chris.

Thanks, Eric. Before we open the call for questions, I want to close by reflecting on what's been an incredibly productive quarter. Across every dimension of our business, commercial, clinical and operational, we continue to execute with purpose and discipline, anchored by the same patient-centric approach that's driven our success from the start. That's what's enabled us to become a high-growth cash flow positive leading rare disease company. Thanks again to the Mirum team, to the patients and families who inspire our work every day.

With that, operator, please open the call for questions.

[Operator Instructions] Our first question will be from the line of Jessica Fye with JPMorgan.

This is [indiscernible] on for Jess. We just have two questions. What are going to be the key drivers of LIVMARLI's performance as we look at '26? And can you talk about why the midpoint of the new guidance range now implies 4Q reps flat sequentially from 3Q? I don't think we saw that dynamic last year.

Thanks for the question. On key drivers in the 2026, I mean, we see a lot of basically what we have today rolling forward into next year. We expect that we'll probably give guidance early in the year next year on what that year looks like. But we are in early innings of the PFIC launch, both in the U.S. and internationally. So expect that to continue to build in over time. And I think for the guidance this year for Q4, maybe I ask Peter to speak to what we see from kind of the quarter-to-quarter dynamics.

Thanks, Chris, and appreciate the question. The main dynamic is tried to highlight in our prepared remarks. We see growth for LIVMARLI U.S. We see the bile acid portfolio continuing to do what it does. It's really the LIVMARLI international line where we expect variability as we move quarter-to-quarter, as we've talked about before, that business has periodic large orders from distributors, and we saw those come in Q3, we also mentioned that we had Takeda revenue in Q3, which we also had Q1 in Q2 that we don't expect in Q4. So there's a fair bit of inventory build there. So that's really the dynamic is in the LIVMARLI international line.

The next question will be from the line of Josh Schimmer with Cantor.

Maybe I have two quick ones. First, what trends are you seeing in terms of adoption of the solid tablet formulation of LIVMARLI and what percent of sales are for that versus the liquid? And then for volixibat, what are you thinking in terms of the appropriate price analogs, especially after we've seen a significant increase in rare orphan disease prices perhaps over the last year, particularly for conditions that perhaps are less prevalent than PBC and more aligned with PSC.

Thanks for the questions, Josh. Yes. So in terms of the solid tablet just launched in the U.S. in mid-June, so this is really our first full quarter with it. And what we've seen a very encouraging kind of uptake and really switches from the liquids. So if you look at the prescribing information, patients are eligible to switch if they're at least 25 kilos.

I think what I could say is that substantial proportion of those who are eligible based on their weight, are switching. So certainly excited about what that can mean long term in terms of persistence and adherence and an easier single tablet per dose format that will be preferred by these adolescents and adults. So excited about that dynamic.

And then yes, if you look about pricing. Obviously, I haven't made a final decision there to monitor those dynamics that you're talking about. We've kind of base case thinking you can look at the other -- PPARs and the other products that are kind of approved in PBC at [ 130 to 15 ]0 in, but we're still analyzing. I think it's kind of too early to say what the right pricing strategy is for [indiscernible].

The next question will be from the line of Gavin Clark-Gartner with Evercore.

Just had one. What's your expectation for Paragraph IV filers. Maybe just helpful to lay out your confidence in your whole IP portfolio, especially around the method patents and including [indiscernible].

Gavin, thanks for the question. Overall, I mean, the -- we're in the window where we could potentially see that in kind of all routine from this point in the life cycle for LIVMARLI, and really quite confident in our overall IP position. In particular, you mentioned the method patents that are specific to dosing of LIVMARLI in these indications. So we've seen this has been really the key fundamental observation that's made all of Mirum possible and the IP behind it, we see is quite strong and a great position and prepared to defend it. So more to come if and when we do see any filers, but nothing today.

The next question will be from the line of James Condulis with Stifel.

This is Mark on for James. So recently on earnings, I know you seem to suggest it's still an open question around sort of what exactly the best endpoint is for the Fragile X study, I wanted to see if you guys had any perspectives on that and sort of the implications for program that you initiated this year.

And then we had a second question on PSC and these patients typically kind of have inflammatory disease sort of like morbidities and we know that IBAT inhibitors by nature, sort of have some of the GI side effects. So curious your thoughts on the safety risks there. And if you can see sort of anything in the blinded data on like GI side effects, and whether those look any materially different than, say, PBC or ALGS.

Thanks for the question, Mark. I can't really speculate too much on -- is update on what's going on underneath that. But let me turn it to Joanne to talk a little bit about our endpoint strategy and what we're -- our approach on our programs.

Yes. Thanks for the question. We feel that we're in a good spot at this point. The preclinical data in terms of this pathway -- the importance of this pathway in Fragile X is quite strong. We recently presented some preclinical data with our compounds in a mouse model, mouse knockout model, which supports efficacy and us moving forward.

And then we've also had very good engagement with the community with patients and with physicians, we also had a very successful and engaging pre-ND meeting with the FDA earlier this year and they're entirely aware of the range of endpoints that we're looking at, and we're well aware of the types of validations that are needed for these types of outcomes. So I think we're actually in a pretty good spot. A lot of interest in the community, and we're looking forward to conducting the study and seeing what we see.

And then on the PSC safety standpoint, actually let to Joanne for that.

Yes. And so with regards to that for the PSC study, we've had a data monitoring committee following with us. And so no issues have been raised, no [indiscernible] modifications to the protocol. So we feel pretty comfortable there's no big safety issues here. I feel pretty comfortable with moving forward with the way the protocol was initially designed. So it's not -- no issues have emerged there.

Profile overall is consistent with what we know about IBAT at this point. Thanks for the questions.

The next question will be from the line of Joseph Thome with TD Cowen.

Congrats on the progress. Maybe on the PSC study now that, that one is fully enrolled, are you able to talk a little bit about the baseline criteria of the patients that were enrolled, especially as it relates to the population that was studied in the interim analysis population. And maybe second, can you also discuss a little bit the importance of hitting on quality of life measures or bile acid in addition to ITCH, and will that -- those secondary endpoints be provided in the top line release in the second quarter?

Thanks, Joseph, for the question. I think overall, we've not plan to present or analyze some of the baseline criteria at this point. What we know from -- and we can take it more generally from the enrollment criteria and what was in the interim, is the patients are selected through ITCH. So we do have quite elevated baseline pruritus scores. And it's -- from what we're seeing, it's quite representative of the PSC population in terms of background disease, background medications, things like that. So overall, kind of in line with what we expected for the population.

And shifting to the question about endpoints, the focus from a regulatory standpoint is 100% on that pruritus endpoint being the outcome that we've discussed with FDA. We do expect to -- are excited about and expect to see based on other settings. We expect to see movement on things like fatigue and the bile acids. Bile acids, obviously, being a key mechanistic marker fatigue being a really important measure for patients. But again, those are secondary for a reason. The regulatory path is entirely through that pruritus endpoint. Thanks for the question.

The next question will be from the line of Ryan Deschner with Raymond James.

Congrats on the quarter. Can you remind us what went into the decision to offer BID dosing for the EXPAND study? And how would you expect the dosing instructions to look on an expanded label in cholestatic pruritus patients? And then I have a follow-up.

Thanks, Ryan, for the question. I mean the simple answer is empirical, right? So this is based on observations we've had in compassionate use settings, at dose levels that have explored across a range in this kind of all in the bracket of these elevated dose levels from the Alagille label up to the PFIC label. And empirically, this is where we've seen really great response stories from compassionate use examples.

How big of an impact has the government shutdown been so far for things like genetic screening programs and other programs related to Alagille and PFIC.

To date, no impact that we've seen across kind of all of our interactions with customers and really across the business.

The next question will be from the line of Mani Foroohar with Leerink Partners.

You have Ryan on for Mani. Can you just talk a little bit about the pace of new PFIC adds that you guys saw in the third quarter compared to the second quarter. I know you talked a lot about genetic testing and new patient diagnoses. And then maybe more broadly, as you guys start to see consistent positive cash flow and you have several launches on the horizon. Maybe just talk through your BD strategy about adding more products to the pipeline.

Thanks for the question. I'll turn it over to Peter to jump into those.

Yes. In terms of the pace of PFIC ads, it continues to be healthy. It continues to come from a broad patient population, everything from infants to adults that we've kind of commented on that is a dynamic where the paradigm is really being changed with adult providers to think about kinetic cholestasis as kind of a clinical entity to be suspicious about. So that's kind of a educational efforts. And some of the major medical centers are on board with that and they're looking into genetic causes of cholestatic liver diseases in the patients they can't explain with other diseases, but most aren't, right? So that's just kind of a gradual effort and but it's continuing to bear fruit in Q3

Than the second -- do you want to...

Sure. I mean, thing we'd say on BD is since the beginning of the company, that's really been at our cores looking for underappreciated programs. So we continue to do that and expect to always be active doing that, but we're in just a fantastic position where the -- there's no urgency and no need. So we have a very high bar. And as you can see from the programs we've brought in since the start of the company, look for good value creation opportunity. So that will continue to be the standard we take going forward. And plenty in the company to grow and build and optimistic about adding more down the road. Thanks for question. .

Next question will be from the line of Mike Ulz with Morgan Stanley.

This is Rohit on for Mike. Just with the recent [indiscernible] about PDUFA announced for GSK, how do you see the competitive dynamics playing out in PBC?

Rohit, thanks for the question. I think two overarching things to think about for the competitive landscape in PBC. One is just kind of a reminder on lines of therapy and where the volixibat program in place. And in the VANTAGE study, there is no baseline outline passing [indiscernible] criteria. So our program incorporates both first and second-line PBC settings to those that have stable upline phosphatase on UDCA that likely wouldn't be a treatment candidate for some of the PPARs that are recently launched, but still have ITCH. That's a candidate for volixibat study and we expect ultimately looks at market treatment.

And then with respect to linerixibat as a competitor, we're very excited about the interim data that we saw from the VANTAGE study and what it means for the dose level that was selected the placebo-adjusted difference that we saw on ITCH in that data set is striking, it led to breakthrough designation, it's really everything that we had hoped to see from all that we've learned about dosing of this mechanism in these settings. So quite excited about the competitive profile of volixibat given that highly active dose level.

The next question will be from the line of Jon Wolleben with Citizens.

Wondering if you guys are anticipating seeing similar disease-modifying effects over time with volixibat as you saw with LIVMARLI in PSC and PBC. And if so, what would be the time frame? And do you think that would be a point of consideration for adoption and use over time?

Jon, thanks for the question. I mean, the overarching first thought there is the first readouts here, we think are probably too soon to be looking at that and focused on the ITCH endpoint and really see that as the -- that's the launch profile. But I'll turn it to Joanne to talk through some of what we'll be looking at and what we'll be able to see over time from the burden.

Yes. Thanks for the question. As Chris alluded to, the whole discussion, especially with the regulators has been around how do we get something in PSC approved. And clearly, that's with pruritus or with the pruritus point. At this point, in the field of PSC, that's really the only approval end point. Obviously, we'll look at other things. Look, longer term, we do expect those types of endpoints may take quite a long time to evolve. We'll continue to follow these patients. And obviously, we'll continue to engage with the agency in terms of appropriate endpoints.

But we do think a concrete path forward is with pruritus and we're pretty confident in terms of the ability of [indiscernible] to affect that in a positive way for patients.

And with no further questions on the line at this time. I would like to hand the call back to Chris Peetz for some closing remarks.

Great. Thank you again, everyone, for joining us today and for your continued support. We look forward to updating you next quarter. Good afternoon.

This will conclude the Mirum Pharmaceuticals Third Quarter 2025 Financial Results and Business Update. Thank you to everyone who is able to join us today. You may now disconnect your lines.

All right. Good morning, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Michael Ulz, one of the biotech analysts here. And it's my pleasure to introduce Chris Peetz, CEO from Mirum Pharmaceuticals.

Before we get started, I just need to read a quick disclaimer for important disclosures, please see the 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. And with that, I'll just turn it over to Chris to give us some introductory comments for people that might not be familiar with the story.

Mike, thanks for having us. I'm going to kick off with also forward-looking statements being made here by me. So I refer you to our SEC filings for full risk factors disclosure.

But a quick highlight of Mirum. We are a rare disease-focused company, have 3 approved medicines on track for $490 million to $510 million in revenue this year. So a really strong growing Commercial business, and a very active pipeline in the near term here. Just this morning announced completion of enrollment of the VISTAS Phase IIb study of Volixibat and PSC, and position that as 1 of 3 potentially pivotal studies that we have coming up over the next 18 months with the VISTAS PSC being the first one, expect top line data 2Q next year. .

And behind that, a follow-up indication for Volixibat in primary biliary cholangitis and label expansion opportunity for LIVMARLI with the EXPAND study, and Fragile X program behind that. So a lot going on in the company overall. LIVMARLI is really the highlight of the commercial performance recently and with a recent label expansion for PFIC, the second indication for LIVMARLI, we've seen a really nice step-up in growth overall driven by new patient finding, new patient diagnosis and a really strong profile for LIVMARLI, positioning it now as we see line of sight to $1 billion plus for the brand. So exciting moment for the company and really happy with how these high-impact medicines have been rolling out.

Well, great. Thanks for that introduction, and a lot going on. Congratulations on getting your study fully enrolled. And I thought though maybe we could start just with LIVMARLI. Obviously, that's your revenue driver. You touched on this in your prepared remarks that you're seeing some really nice growth there. And a big part of that is PFIC. So maybe just dig into that a little bit more and what's happening there?

So for LIVMARLI, PFIC is what's new. I'd start with actually Alagille syndrome because this is a great base to the LIVMARLI product profile. And what we've seen for LIVMARLI in Alagille syndrome, since its approval, is now a pretty steady pattern of new patient accumulation, really great performance in the U.S., and that continues. So there's a good baseline support from the Alagille syndrome business.

Internationally, that's really what's driving most of the performance. It's still Alagille syndrome with PFIC in its early days internationally.

In the U.S., the PFIC dynamic since we had that label expansion last year, we've actually been pleasantly surprised about how well we've done from a patient finding standpoint. Unlike Alagille syndrome, there's probably a bigger under-diagnosed pool of patients with PFIC. So we put a lot of focus on getting conversations going about cholestatic patients that maybe haven't had genetic testing, trying to get some of those diagnoses confirmed.

And then also, it was kind of worth noting that with our LIVMARLI's flexible formulation, we have a liquid solution for younger patients. Now have recently approved a tablet. It's one tablet per dose for older patients, that's played into some of the performance as well, where for a newly diagnosed patient, that liquid formulation is a little easier and then also a simpler administration for older patients that might want a tablet.

Just for PFIC in terms of identifying the patients? Are you doing anything unique than what you've done sort of in the past with Alagille, for example? Or is it just maybe you underestimated what the initial patient numbers might look?

There's a little bit of each of that, right? So I do think we absolutely underestimated what was the actual patient population out there. And for Alagille syndrome, we're highlighting a difference in presentation where Alagille syndrome is typically better -- we think better diagnosed and earlier diagnosed because of the multi-systemic nature of it. There's facial characteristics, they tend to be more jaundiced in younger age. And so we do think they get picked up more regularly. So the Alagille syndrome population is pretty well defined from what we're seeing.

And for PFIC, which really is -- it's a simplifying term for a number of distinct genetic mutations in bile acid-related transporters. So, say PFIC kind of oversimplifies what's going on there. And for some of the specific subtypes, there can be a later onset presentation. So there are a lot more of patients out there that maybe weren't picked up in childhood and start to present with elevated bile acids, elevated liver labs and itch later on in childhood or even in adulthood. And so that's -- so that was kind of what we underestimated.

What we've been doing proactively is much more supporting the diagnosis. So we have -- a lot of this through a field medical team, have supported kind of broader awareness of the availability of genetic testing, starting to get, in particular, some of the older patients, the why behind testing for the adult hepatologists, and we're seeing some of the impact of that.

Makes sense. You also mentioned sort of the strength in your international markets. So maybe talk about some of those markets you recently launched? And then sort of looking ahead, what are the additional markets you'll be looking out for?

International performance has played out nicely. I think we still, as mentioned, early days because what we're seeing to-date is largely Alagille syndrome-driven. I note on how we approach the international commercialization. We're direct in a shorter list of countries. So Canada and Western Europe. That's where it's Mirum people on the ground. So we call those our direct markets. And beyond that, get closer to global reach using distributors and partners, so kind of the partner markets.

And what we see in the direct markets, really echoes a lot of what the U.S. is seeing for Alagille syndrome. So a nice steady growth over time and new patient starts. And distributor markets, we continue to get access in new countries. So we're now over 30 countries with reimbursed product. Real highlight from the second quarter, first and second quarter, frankly, is Japan. So our partner Takeda is off to a great start with their recent approval. That was a big factor in our Q2 numbers, some of their first orders get recognized. And so more to come from the international rollout as we get more distributors up and rolling and then also ahead, we'll have a PFIC expansion as well for the international markets.

Great. maybe we can just flip back to Alagille syndrome for a minute in the U.S. and kind of that's been sort of your initial launch there. So it's been several years. You keep growing that. Sort of where are you in that sort of process and how much room is left, I guess?

So when we're thinking about the patient population here that we think LIVMARLI can be it applicable for, there's both the prevalent pool of patients that, as mentioned, we do think are pretty well diagnosed. And we think we're probably about half penetrated into that prevalent pool of patients.

But on top of that, new diagnoses every year, call it about 100 is what is typical new Alagille cases diagnosed. So 100 infants that present in any given year. And so those -- we think we do even better than that 50% because the treatment decisions are just a lot more straightforward, frankly, at that new diagnosis time point.

And the question that always follows is like, so where is this going? Like how high does that 50% go? And we certainly see it moving higher. So we do continue to see new starts in the prevalent population even this far into the launch.

And what's behind that, that we've talked about before is the physician-patient conversation and decision on who's a patient for eligible for treatment and who's a LIVMARLI treatment candidate. A lot of that's somewhat subjective conversation about what is the burden of my pruritus, what is my symptomatic burden that I'm dealing with. And so there's a lot to unpack to get those conversations to happen from both the physician side and from the patient or family side. So that's how we see that 50% continuing to go higher over time.

Makes sense. And in your sort of introductory comments, you sort of mentioned you recently increased your sort of peak sales expectations for LIVMARLI to $1 billion plus. Maybe you can just talk about, maybe a different components of that and I don't know if you're willing to go there, but the breakdown of those components?

Happy to give a very high-level picture of it. It's not something that we've really kind of detailed out by indication. But the three big pieces here, Alagille syndrome which we now have a clear line of sight, steady trends, kind of have a good view of where that's going. That's certainly the biggest component from how we look at it, so call that roughly 40% or so of where we see the peak getting to. And then the other two pieces probably somewhat equivalent as well. So between PFIC and the EXPAND indication. So we'll note that we're still learning as we go on those two pieces.

So PFIC, as noted, there's been more out there than we initially thought. For EXPAND, we're starting trying to be pretty conservative in terms of what that population is. It's a long tail of different causes of cholestasis. But initial performance from the clinical study, enrolling and conversations with investigators and physicians, it's at least the size of PFIC in terms of patient population.

Maybe in terms of the EXPAND study, if you can just sort of remind us, the rationale there and how you started to head in that direction for those rare conditions?

It's an interesting program. So the EXPAND study is a basket study. And there are several different causes of cholestasis. So different diseases or postsurgical complications or implications that cause cholestasis. And with that comes elevated systemic bile acids, the pruritus that shows up in Alagille syndrome and PFIC, quite similar in how it develops in these other causes of cholestasis. And so we were initially seeing a lot of just compassionate use demand for patients that kind of fit in the long tail. These could be older biliary atresia patients. That's a big portion of it. Secondary sclerosing cholangitis, a number of kind of more rare occurrences of cholestasis, that are secondary to other diseases.

And given the volume of compassionate use that we saw, FDA actually requested us to put a protocol together around it. That kicked off a conversation to develop this protocol and strategy, to gather these otherwise hard to study indications because each one on its own is just too rare to run a stand-alone study. So that allowed us to put them into a pooled population. So call it, at least 500 patients in the U.S. that fit the criteria that we have here and on track to complete enrollment next year.

Okay. And how, I guess, enrollment is tracking sort of as you expected? Or is it faster maybe or...

Yes, as expected, I mean the -- in terms of what we're seeing out there, the patients are there, and it's really about getting sites open and the families engaged with the clinical trial. It is a study that's open to children and adults. Worth noting that the focus analysis and the real primary endpoint is in the pediatric patients. So we do see adult interest in it as well. So our screening and enrolling adult patients into it. So the target 45 patients that we talk about is in the pediatric population.

Got you. And maybe just last question on LIVMARLI before we move on, maybe just touch on current IP? Or is there more IP coming that we should be looking out for? Or what's the status there?

For IP, we point to a key family of patents that are 2040 family that are directed towards LIVMARLI indications and dosing. There is more around that, including formulation and some other applications that extend a bit beyond out to 2043. But as we look at it, we plan on 2040 is really the key patent family.

Great. Maybe we can move on to just the bile acid portfolio. You had 2 programs there. You added them a few years ago, and you're seeing some nice growth. So maybe just give us a little background and kind of what's driving the growth there?

Yes. So Cholbam and CTEXLI are the 2 bile acid replacement drugs that we acquired a couple of years ago now. And we've been able to do quite a bit with them, really across both brands on identifying patients as well as the real highlight of the work we've done has been getting to the approval of CTEXLI. A lot of great work started from Travere, the company that we acquired these from, and we were able to go to the final NDA to get CTEXLI a formal label for the treatment of CTX.

So what we've been doing to grow these products has been execution on patient finding for CTX, in particular, pretty substantially under-diagnosed. So we've been iterating on different programs on supporting genetic testing in different specialties. These patients do present in a number of different settings and generally can be quite advanced into adulthood, before they're found.

So that's where we've been seeing early traction. I expect it to be continued build over time as we iterate through some of these different programs. And we've done really well. When we -- our first quarter with these, they were about $25 million a the quarter and recently, Q2 was at $40 million. So a lot of good impact over time and see it growing -- continue to grow in the future.

Yes, definitely making nice progress there. And maybe now we just shift to Volixibat. And maybe just start with PSC since that's sort of more advanced in development, maybe talk about the market opportunity there and the unmet need?

So Volixibat for primary sclerosing cholangitis, PSC. Really exciting program. PSC is one of the larger adult cholestatic indications and really historically has been really challenging from a drug development standpoint, where there's not really been an attractable surrogate endpoint. It's a lot of work on trying to find different alternatives, but unlike some of the other liver settings, there isn't as predictable of serum measures that you can use for drug development.

Now what we've done with the approach for Volixibat is to target symptoms. And that actually gives us an attractable near-term outcome that can be used for registrational purposes. So the VISTAS study for Volixibat in PSC is the primary endpoint of pruritus in patients with PSC and designed to use that as the registration pathway, similar to what we've done in the pediatric setting.

Now I mean what the -- how that maps on to the patient population and the impact we can have there, probably about 30,000 PSC patients in the U.S. Those that have itch is probably about 2/3 of that. And when you start to have conversations to understand what the impact of this means for patients. It's a potential game changer for them. The day-to-day burden of itch and fatigue as well, is another one of the symptomatic burden that's a real highlight in this setting is the day-to-day burden of this disease that these patients are facing. So feedback we've gotten from response stories from Volixibat, and LIVMARLI as well, I should note have some case studies. Feedback has been very positive on what that means for the patients day-to-day.

You mentioned coming up with an endpoint for this disease has been a bit challenging. You sort of focused more on the symptoms and you've seen some nice impact there. But I guess from a regulatory perspective, are there any issues or hurdles you need to sort of clear to sort of make that an approvable endpoint? Or is that -- are we there already?

It's a pretty straightforward approach and using a itch endpoint with the 0 to 10 NRS scale, and that's what the ItchRO scale is in this study. It's a pretty typical approach. There's a standard validation work that goes into any PRO endpoint, and that's all baked into our program. And so otherwise, while it's novel for PSC, it is otherwise a pretty standard approach to using itch as an outcome.

Makes sense. And I think it was last year, you gave some sort of interim analysis. So maybe walk us through that and kind of how to think about that.

Yes, the interim analysis design for VISTAS, part of what gives us -- makes us so excited about where we're at now. And I'll tie in a little bit of the VANTAGE PBC study here because these were designed really to help inform each other. And last year, we conducted interim dose selecting analyses for both of these studies. For the VISTAS study in PSC, it was designed to help the independent monitoring committee follow an algorithm to make a dose selection decision and keep the study blinded assuming all was within the target effect size. So for the VISTAS study, interim analysis stayed blinded. There was a potential outcome there where the effect size was close to the boundary that we had designed. There could have been a recommendation to upsize, that didn't happen. So it makes us feel confident on where we're at and that was designed to be predictive of a positive outcome for the overall study. So really kind of an interim analysis designed to give us confidence in the final primary data that we're going to see next year.

For VANTAGE, however, because PBC is a more common indication, and we're targeting overall a larger safety database, we could unblind that data. So the VANTAGE study had an unblinded interim analysis that was announced and subsequently presented. And that gives us confidence in the dose selection as well. So both of these selected the lower dose to move forward and the unblind VANTAGE analysis, we think, helps us understand what was potentially happening in the VISTAS study.

Have you mentioned what the threshold was in VISTAS for the interim on pruritus or...

It was designed as a threshold based on the statistical effect size. So think of it more as a curve. We haven't disclosed what the exact numbers are, but it's basically a curve looking at the placebo-adjusted difference, the variability within the data set. So -- and with that curve then, there was a boundary area. We know we were above the boundary area.

And then maybe just on pruritus in general, like what's considered a meaningful difference? And then remind us what you showed in the VANTAGE?

So this measured on, as mentioned, is 0 to 10 scale, and it's expected that a 2-point change would be clinically meaningful. And in the VANTAGE analysis, we saw a 3.8 change from baseline. So really strong, clinically meaningful effect coming out of that interim analysis.

Great. And maybe just sticking with VISTAS and again, you complete enrollment that you announced today, and now you're heading towards data in the second quarter of next year. So maybe just talk a little bit about what to expect from that readout and kind of what you're looking for and what's sort of a positive readout in your view?

So the study was designed to really look at the pruritus as the primary outcome. As mentioned, from looking at VANTAGE, I think that this dose level is highly active. So we're confident that we'll be seeing -- that effect size that it's going to be meaningful for patients. The analysis is really just looking at placebo adjusted difference on that itch score, so that the top line, expect to be announcing that.

And from the tolerability profile, at this point, we have a pretty good handle on what IBAT looks like in clinic. And the most common treatment-related effect is actually mechanistic, right? So there is a diarrhea related to flushing the bile acids out of the body. And we found that if you're coaching and helping patients expect it, it can be very manageable. So it's not something that we see as a real barrier, in particular, if there's good awareness around it. So that's another thing we'll be looking at, is the headline kind of GI adverse event rates.

Okay. And then maybe just shifting to PBC and maybe just a similar questioning market opportunity there, unmet need?

Yes. So for PBC, it's a much larger indication, but it's busier from a competitive standpoint, where PSC because of the endpoint issues, there are no approved therapies. In PBC, there has been a surrogate using alkaline phosphatase as an endpoint for recent approvals. So to break it down, think about in lines of therapy and probably about 100,000 patients in the U.S. roughly is the rounded way to make the math is pretty easy to follow. And in that -- of that 100,000, maybe 1/3 or 40% have progressive alkaline phosphatase levels. So they are eligible from these more recent approvals of Seladelpar and Elafibranor, the PPARs that were recently out there. And the Volixibat's role really goes across all of these lines of treatment.

So we see pruritus in PBC really happen at similar rates in both first line and second line. So we kind of are approaching the market segmentation quite differently from the recent approvals. That means that in the first-line setting, right now, there's no other approved therapies. We have one other IBAT that has a PDUFA date next year. So there will be one other product out there that we can surely touch on their relative positioning. The IBAT role in PBC really cuts across all lines of therapy. Similar to the other indications, probably about 2/3 of patients have pruritus. So that's nearly 60,000 patients roughly is the target market for launch.

And just for the VANTAGE study, can you just remind us the current status there in terms of where you are in enrollment and kind of time lines around that?

Yes. So expect to complete enrollment next year. We -- and that would put us on track for top line data in the first half of '27. We'll look to try to refine that as we get closer, but that's the rough guidance that we have at this point. And study conduct is going well. As mentioned, for PBC, we're looking for a bigger total safety database. And so it just takes a little bit more time than the VISTAS study to enroll to get to that target patient number.

And I'd point that out because the size of the study really is not about efficacy powering right? As we saw from the interim analysis, it's highly significant, even with only a 30-patient analysis. So this is really about sizing up for the safety database.

And maybe you can touch on the competitor in the space or the recent data we've seen and kind of how you're positioned there?

So the other IBAT that's been developed in PBC is coming out of GSK, and they have a PDUFA date next year, first half of next year. What they saw from their Phase III data really looks like an IBAT, right? So they're seeing improvements in pruritus. Their approval strategy and kind of patient population is really similar to kind of how we're approaching it. But in some of their -- from what we've seen from their dose selection, they did not take their highest dose forward. And we think that really shows up in the headline effect size.

The VANTAGE study in its interim analysis, the effect size we saw there was just really striking. And so I think that puts us in a position, assuming it holds up in a similar range in the final data set be a fast follower with a much stronger effect size.

Makes sense. Maybe we can just shift quickly to your [ FXS ] program. Maybe just talk about that a little bit, how it's differentiated and kind of next steps there?

MRN-3379 is the PDE4D that we're starting a Phase II study now for Fragile X. Really unique program here. And again, we're going to come back and talk about endpoints is kind of what's got us excited about diving into this program.

So in Fragile X, there's been a number of different studies, largely looking at behavioral tools, so surveys from the caregivers. And these studies because of the -- we think in large part to the end point, have had a lot of noise in the final data sets. And there was a key data set that actually came out of Shionogi from a competing program where they used a cognitive tool called the NIH toolbox. It was really designed for settings of cognitive impairment. And so it adjusts to provide a scale for the level of where the patient's at. And that resulted in a pretty striking Phase II result for their program.

We think the MRM-3379 program has a differentiated CNS penetrant. So it gets more of the drug where you want it to be and is a compelling profile compared to that program, and looking to play that out in the Phase II study.

And maybe just quickly remind us where you are in the Phase II. Is it started yet? Or when will you start it?

We just cleared the IND. So after in-licensing the program, we did some work on having formulation and drug product ready to go conversation with FDA confirming their view on endpoints, what they wanted to validate this NIH toolbox. I feel great about that being the viable registration endpoint. So we want to have all that squared away before we started the study, and kicking it off now. So it'll be 3 doses versus placebo, to do that dose-ranging work to understand where we're at on playing out this, we think the stronger drug profile for 3379. I want to make sure we do the dose-ranging work to figure that out.

Maybe in the last few minutes, we can talk about some of these macro issues. We're asking a couple of questions to all our companies at the conference. So maybe if we just start at the top with the first question, China's rise in biotech innovation, how are you thinking about your competitive position here? And will this influence your R&D or BD strategy?

So overall, I mean, the most relevant for BD strategy for us, where the more potential drug candidates out there, that's our business model is to go find kind of underappreciated programs, and maybe reposition a mechanism or find something that data set was misunderstood that we can take it forward. I'd say from rare disease competition, we haven't seen as much of that out of China.

They've been -- these companies have been focused on bigger indications. It doesn't mean that might not happen over time. But what the result of that is more product candidates that are available for us to go try to bring into the company.

Maybe next question, how are you currently leveraging artificial intelligence or thinking about AI's future disruption potential in your business?

Yes. So all the Mirum employees out there listening, make sure you're logging in and using it. That's the -- we've been trying to roll it out for really a lot of kind of first round drafting of documents, as all the work that we're doing here, there's a lot of writing on the regulatory side, on data review, on analytics and having some of these tools as a first path to add efficiency, we think will help us helps out quite a bit. And it's really about adding efficiency for the team we have. We're ambitious about bringing in more programs and doing more. So it's not necessarily that we're trying to replace people's jobs, just trying to make our strong team even stronger.

Got you. And then maybe last question, just what's been most impactful for Mirum on the regulatory side in terms of would it be FDA? Would it be MFN, if you have any impacts there or tariffs?

Mostly, it's been about how much time we have to answer questions about it. That's been the biggest impact for us so far.

With Mirum -- from how our business is set up, I feel like we have somewhat less exposure on a lot of these topics. And we certainly track them. But for the FDA interactions, continue to be constructive and direct our teams that we deal with are all here. We've had 2 approvals and recent interaction on multiple programs. That's all gone smoothly. So no impact there.

On the other ones, MFN, I think hard to tell where that one goes. But our relative pricing in the European markets, it's really not that far off of where our U.S. government price is already, frankly. So overall, we're -- I think we're pretty well positioned.

Great. Looks like we're just about out of time. So why don't we end it there. Chris, thanks so much. Appreciate it.

Yes. Thanks for the time.

Hello, everyone, and welcome to the Mirum Pharmaceuticals Report Second Quarter 2025 Financial Results and provide Business Update. My name is Carla, and I will be coordinating your call today. [Operator Instructions].

I would now like to hand you over to your host, Andrew McKibben, SVP of Strategic Finance and Investor Relations, to begin. Please go ahead when you're ready.

Thanks, Carla, and good afternoon, everyone. I'd like to welcome you to Mirum Pharmaceuticals Second Quarter 2025 Conference Call. I'm joined today by our CEO, Chris Peetz; our President and Chief Operating Officer, Peter Radovich; our Chief Medical Officer, Joanne M. Quan; and Eric Bjerkholt, our Chief Financial Officer. Earlier today, Mirum issued a news release announcing the company's results for the second quarter of 2025.

Copies of this news release and SEC filings can be found in the Investors section of our website. Before we start, I'd like to remind you that during the course of this conference call, we'll be making certain forward-looking statements based on management's current expectations, including statements regarding Mirum's programs and market opportunities for its approved medicines and product candidates. These statements represent our judgment and knowledge of events as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed. We are under no duty to update these statements. Please refer to the risk factors in our latest Form 10-Q and subsequent SEC filings for more information.

With that said, I'd like to turn the call over to Chris. Chris?

Thanks, Andrew, and good afternoon, everyone. 2025 is shaping up to be another outstanding year for Mirum, a second quarter that underscores the momentum behind both our commercial medicines and our pipeline. Mirum was founded in 2018 with a vision of bringing life-changing medicines to patients with rare disease around the world. Today, we have 3 approved medicines with reimbursed patients in over 30 countries and a pipeline that is rapidly advancing opportunities in still larger settings, highlighted by 3 potentially pivotal studies reading out over the next 24 months.

Our strategy is rooted in commercial execution, scientific innovation and financial discipline, and we're proud of the continued progress on all 3 fronts that we will cover today. On that note, on second quarter results, we are excited to share another strong update for Mirum with total revenues reaching $128 million or 64% growth over the second quarter last year. Livmarli is a key driver of these results and is continuing to bring substantial benefit to patients and to build a differentiated position with physicians. As the top line suggests, we are reaching more patients than we initially anticipated. Given the growth we are seeing across our medicines, we are raising our full year guidance for 2025 to be $490 million to $510 million, positioning us for another year of close to 50% top line growth.

Turning to the pipeline, the progress we are making is setting the stage for an exciting 2026, where we have a clear path to 3 late-stage milestones. In particular, the VISTAS Phase IIb study in primary sclerosing cholangitis or PSC, is on track to complete enrollment this quarter with top line data expected in the second quarter next year. Now this program passed its interim analysis last year and the consistent precedent data for IBAT inhibition across other cholestatic settings gives us confidence in the potential of volixibat in PSC. Exciting steps lie ahead to potentially bring this much-needed treatment to PSC patients.

We are also seeing excellent momentum in our VANTAGE PBC and EXPAND studies and are looking forward to starting our Phase II study of MRM-3379 in Fragile X syndrome now that we have FDA feedback on the program, which Joanne will tell you more about shortly. I would also like to say thank you to the Mirum team, whose dedication to bringing high-impact medicines to patients has made all this progress possible. I'm proud of how this group has come together to create a high-growth, cash flow positive rare disease leader with an exciting pipeline.

And with that, I'll hand the call over to Peter to walk through the commercial performance in more detail. Peter?

Thanks, Chris. Q2 was another strong quarter for Mirum with total net product sales of approximately $128 million, driven by continued momentum across Livmarli in both the United States and international markets as well as solid performance from our bile acid portfolio. In the U.S., Livmarli demand remains strong with -- in Alagille syndrome and PFIC with approximately $57 million in net product sales for the quarter. Notably, we are seeing more PFIC patients than we had originally anticipated, which we believe is due in part to increased disease awareness and broader use of genetic testing, leading to more PFIC diagnoses in patients with later onset cholestasis.

While PFIC is often associated with clinical presentation in infants, we're increasingly seeing PFIC patients presenting later in childhood, adolescents or even adulthood. An expanding recognition of this variability and highlighting the importance of genetic testing across age groups has been a core focus of our launch strategy.

We're also seeing real synergy between the approved Alagille syndrome and PFIC indications with providers increasingly viewing Livmarli as a preferred treatment across these settings of pediatric cholestasis. The combination of these factors is translating into a meaningful uptick in volume growth. Importantly, our recent U.S. launch of the single tablet per dose formulation in June adds meaningful convenience for patients, though I'll note that Q2 results reflect the performance of our oral solution.

Internationally, we are seeing durable Livmarli growth across both direct and partner markets with $31 million in net product sales. This was driven by expanding reimbursement and growing demand as well as strong performance in our partner markets. In Q2, our partner, Takeda, secured reimbursement in Japan and launched Livmarli in June with promising demand observed in the initial days of commercialization. Under our license agreement with Takeda, we received large periodic orders for Livmarli, creating quarter-to-quarter variation in international product sales. We also saw strong performance from our bile acid portfolio with CTEXLI and COBACHOLBAM contributing approximately $40 million in revenue.

These medicines continue to benefit from steady demand and increased engagement following the CTEXLI approval earlier this year. Given the momentum across our medicines, we are raising full year revenue guidance to $490 million to $510 million, driven largely by Livmarli's strong performance, particularly growth in our international business, steady increase in Alagille demand and our PFIC launch in the U.S. It's an exciting time for realizing Livmarli's potential. Looking long term, with the current trends in Alagille syndrome and PFIC and the label expansion opportunity in ultra-rare cholestasis, we aim to unlock through the EXPAND study.

We believe Livmarli ultimately has the potential to be a $1 billion-plus revenue brand. We're excited about continuing to execute to realize that potential and prepare for potential launches ahead of our clinical pipeline.

And for an update on the pipeline, I'll turn it over to Joanne.

Thanks, Peter. I'm pleased to share updates on the continued progress of our clinical pipeline, where we're seeing strong interest and engagement across all studies. Starting with volixibat, we're very encouraged by the momentum in our VISTAS study for patients with pruritus due to PSC. The last patients are in screening now, keeping us on track to complete enrollment this quarter and on track for expected top line data in the second quarter of 2026. With regards to PBC, the VANTAGE study is proceeding nicely, and we expect to complete enrollment next year. The EXPAND study evaluating Livmarli in additional settings of cholestatic pruritus is also progressing well, and we expect to complete enrollment in 2026.

Finally, I'm excited to share more on MRM-3379, our brain-penetrant PDE4D inhibitor for Fragile X syndrome. We had the opportunity to discuss the program and endpoints with the FDA in a pre-IND meeting earlier this year, and our IND has recently cleared. We are on track to initiate the Phase II study by the end of the year. Our study will enroll approximately 52 male participants aged 16 to 45 with Fragile X syndrome.

We will enroll males who are confirmed genetically, what is called full mutation, as these patients are known to be most severely affected from a cognitive standpoint and therefore, have the greatest unmet need for new therapy. This is a randomized, double-blind, placebo-controlled study evaluating 3 active doses in order to identify the optimal dose. An additional open-label cohort will include approximately 8 younger patients, males aged 13 to less than 16 at the lowest dose to evaluate PK and allow us to move into younger populations in subsequent trials.

The primary endpoint is safety and tolerability and the key secondary efficacy endpoint is a change from baseline at week 12 on the NIH toolbox crystallized cognition composite, a well-recognized cognitive measure also used by other programs in the space. Based on FDA feedback, we do anticipate that this ultimately will be the primary endpoint in Phase III. We're excited by the pace and engagement across our pipeline and look forward to sharing further updates in the coming quarters.

I will now hand the call over to Eric to discuss our financial results for the quarter. Eric?

Thanks, Joanne, and good afternoon, everyone. We delivered another solid quarter of financial performance, highlighted by total net product revenue of $128 million, representing a 64% increase over the prior year and reflecting growth across all our commercial medicines. Total operating expense for the quarter ended June 30 was $133 million, which includes R&D expense of $46 million, SG&A expense of $63 million and cost of sales of $23 million. Expenses for the quarter included noncash stock-based compensation expense of $18 million and intangible amortization and other noncash items of $6 million.

The intangible amortization and other noncash items expense are largely reflected in our cost of sales. We were operating cash flow positive for the quarter and expect to continue to be cash flow positive for the full year. Our cash operating margins continue to improve. For example, our cash contribution margin from our Commercial business exceeded 50% in the second quarter. Cash, cash equivalents and investments were $322 million at June 30, a $29 million increase from the end of last year.

We continue to be well funded and financially independent, providing us the resources required to expand our patient impact and grow our business.

With that, I'll turn the call back to Chris.

Thanks, Eric. I want to take a moment again to acknowledge the incredible efforts of the Mirum team. The progress we've made so far this year, both commercially and across the pipeline reflects our continued commitment to delivering life-changing medicines for patients with rare disease. We are operating from a position of strength and the opportunities ahead make this an exciting time for Mirum. We have a clear strategy, the right team in place and a growing impact on the lives of patients and families around the world.

And with that, operator, please open the call for questions.

[Operator Instructions]. And our first question comes from Gavin Clark-Gartner with Evercore.

Congrats on another great quarter. First, I just wanted to ask on Livmarli. What are you seeing for overall therapy persistence rates? And has that changed at all over the last couple of years? And then on the pipeline, for the ongoing VISTAS PSC trial, is there anything you're seeing on a blinded basis that gives you increased confidence? Maybe it's blended pruritus variability tracking within expectations, baseline characteristics continuing to come in as expected? Or anything else you can give us there would be really helpful.

Thanks, Gavin, for the question. I'll let Peter speak to the persistence question and then let Joanne comment a little bit about how VISTAS conduct is going.

Yes. Thanks for the question, Gavin. In terms of persistence, our information is most stable from the Alagille indication where we've got patients that have been on several years or some of them approaching a decade. And if you think about persistence, probably 70% to 75% are on after 1 year. So that's the kind of attrition in year 1. And then in subsequent years, the attrition is much less than that. So that's probably the way to think about it analogy. And then PFIC, it's just probably a bit too early to comment.

Gavin, this is Joanne. Thanks for the question. With regards to your questions about VISTAS, we're feeling pretty confident. And part of it is that the standard deviation that we powered the study on was pretty conservative.

So our best estimate is the standard deviation should come in less than that. So given that we powered the study, assuming a treatment difference of 1.75 with a standard deviation of 3, probably it's closer to 2. So I think that gives us added confidence. And I can also share with you that the baseline characteristics in general reflect the PSC population. So I think these are all points that give us some good confidence kind of proceeding forward as we're getting the last patients in the screening [ going forward ].

The next question comes from Jessica Fye with JPMorgan.

This is [ Bill ] on for Jess. Congrats on the quarter. Can you provide details on the expected revenue distribution between Livmarli and the Bile Acid business for the remainder of the year?

Thanks for the question. We're not breaking down guidance by specific products. But one thing I would say is that some of the trends that we've seen year-to-date, we expect those to kind of, in general, continue moving forward. So that's kind of the best color I can give on how it breaks down in that $490 million to $510 million range.

The next question comes from Ryan Deschner with Raymond James.

Congrats on the quarter. I wanted to ask what main drivers are you attributing to the growth that we're seeing in Livmarli sales? And then also how meaningful of an impact on script volumes are you seeing specifically due to the availability of the tablet format in Livmarli?

Thanks, Ryan, for the question. I'll give a first comment and let Peter add on to it. I think one of the -- there are several dynamics going on here. I think one in general that we've noticed is really just as PFIC has been added in the U.S., building awareness of availability of genetic testing and the concept of later onset PFIC diagnoses, which -- to be honest, when we got the label expansion and we're initially starting out in PFIC, we thought was pretty minimal. What we're finding is that it is -- it's just -- it's more -- there are more of them out there than we originally expected. So that's one of the drivers that we've actually deployed against over the past 12 months.

Yes. I think that is one of the main drivers, really growing the pie and PFIC, if you will, the total market for the class in that setting. Also happy with the continued growth in Alagille syndrome and certainly, the international business has performed well. In terms of your question about the tablet, that was introduced in the month of June.

So obviously, part of our comments there at the outset that didn't have an effect this quarter, but certainly encouraged. We had a lot of positive feedback from patients and providers who have chosen to go to the tablet since then.

So the next question comes from Brian Skorney with Baird.

This is Luke on for Brian. Two on Livmarli. Can you discuss any inventory impacts in the second quarter? And also, could you provide a little more insight on the Takeda order cadence? Do you expect it to be more of a seasonal trend? Or would it be more regular than that?

Yes. Thanks for the question, Luke. As far as inventory, it's really only relevant in so far as Japan and Takeda goes. No inventory in the business in the U.S. or Europe anywhere else. With Takeda, it is kind of large periodic orders that happened from time -- from -- we expect there'll probably be another one this year, but we don't have perfect line of sight into it.

There's variable consideration placed on it when the order comes. So that's why in subsequent quarters, the estimate can change, but that's kind of the best color we give to you. We'd expect quarter-to-quarter variability there.

Yes. And specifically, in Q2 It was -- $11 million was the number of the Q2 number.

The next question comes from Mike Ulz with Morgan Stanley.

Congratulations on the quarter as well. Maybe just a question on Fragile X. It sounds like you made some nice progress interacting with the FDA on the trial design. Just curious if there's anything else you need feedback on or from the FDA or any next steps before you start that study in the fourth quarter?

Yes. Thanks for the question. So we're actually good to go. We have the clearance from the IND, so we have a Study May Proceed letter. We've engaged a lot with the patient community and also the physician community to make sure they -- we've incorporated their comments into the design of the study. So we feel pretty good in terms of where we are and certainly on track to enroll the first patient by the end of the year.

The next question comes from Mani Foroohar with Leerink Partners.

You have Ryan on for Mani. Congrats on the quarter. Just curious how well penetrated do you guys think you are in the Alagille and PFIC markets, kind of looking at your commentary that Livmarli can be a $1 billion product. Wondering how you see that broken out by Alagille and PFIC. And then just one on the pipeline. I know Fragile X design is pretty ironed out, but are there any specific elements you're particularly interested in from Shionogi's update later this year?

Yes. Thanks for the question. I can touch on the last point first and then pass it over to Peter to talk about some of the sizing for the various components for Livmarli. In terms of the Phase II precedent data from the Shionogi program and the upcoming Phase III a couple of thoughts that we have on it. First, the Phase II is great proof of concept out there and kind of what got us excited about 3379 and the ability to have a potentially wider therapeutic index, get more of the drug into the CNS. And in terms of kind of what we are looking for out of the Phase III, that differentiated profile that we have, I think, kind of makes us really interested to run our proof of concept kind of regardless of the outcome. Expect we're not going to learn a lot from any top line release, but we'll kind of be looking closely and see if there's anything to incorporate into the future studies in the program.

And in terms of your question, Ryan, about penetration and opportunity. If you think about the U.S. in Alagille syndrome, we think we're approaching 50% penetration, but still every quarter, including Q2, adding patients in both infants as well as kind of older patients who are more prevalent in that prevalent addressable pool.

So still see the potential to keep growing Alagille further and further in subsequent quarters as we have and grow that business. PFIC has been really interesting, as Chris mentioned in his comments, we're growing the pie right now as we speak. I think traditionally, the field and others in the area thought about PFIC is really an infant onset disease. And if it's not that scenario, then it's not PFIC. And I think what we've shown through our education and genetic testing efforts is that there's a lot more there than was previously thought.

So we have kind of less visibility than kind of how big that could be. I think historically, we thought about PFIC as being about 1/3 of Alagille. Quite frankly, that's probably an underestimate at this point. So excited to define that as we move forward.

And I'd add on the one other component of when you think about the total Livmarli potential, the $1 billion-plus number that we're looking at, the EXPAND study also is a big contributor there, where the EXPAND patient population is really at least the size of PFIC and that kind of the conservative view of it. And all of these dynamics kind of continuing to build over time, the patients on therapy and ultimately, the size of the brand.

The next question comes from Josh Schimmer with Cantor Fitzgerald.

One for me on the EXPAND study. I was wondering if you could share if any of those eligible patients are already on Livmarli through compassionate use or other exceptions?

Yes. Thanks for the question. I'll let Joanne speak a little bit to the background of how we thought came upon designing the EXPAND study kind of speaks to that question.

Yes. Thanks for the question. So really, the EXPAND study came around because we had a lot of requests for [ compassionate ] use in these patients with cholestatic pruritus from these other settings. And so we're taking patients who have not previously been treated in order to assess the treatment response in this setting. So, so far, we're encouraged by the engagement we've heard from sites and also just the interest from patient populations as well.

The next question comes from David Lebowitz with Citi.

I know a few years ago, $500 million was viewed as kind of the peak for Livmarli. This is obviously a dramatic shift. How much of it comes from potential from the new indications versus PFIC and ALGS, new potential indications?

Yes. Thanks for the question. The $500 million, I think you're referencing is we used to kind of give a size for the indication of Alagille in the U.S., just kind of the market sizing. So this is kind of the first time with these indications that we've put out guidance on where we think Livmarli can ultimately get to. So a slightly different lens than kind of indication sizing.

And really, a lot of the confidence in doing that is just how much we're seeing come together across all these different settings. So the 3 indications, Alagille, PFIC and EXPAND in the U.S. quite sizable. What we're seeing on the international side, also kind of running ahead of where our expectations were. So a lot of this is kind of a change in what we've seen so far this year in terms of uptake and things that we're doing directly as well as distributors and partners and the success that they're seeing.

[Operator Instructions]. The next question comes from Jonathan Wolleben with Citizens.

Two for me. One on PSC. You guys estimate that there's about 65% of the population with active pruritus. I'm wondering if there's any evidence that that's due specifically due to excess bile acids or if there could be any other drivers of pruritus in that group? And then second one, just wondering on CTX, if you guys have seen any inflection now that you can promote and what you expect for that long term?

Yes. Thanks for the question. I'll pass this over to Peter and Joanne to speak to the 2 components, and let Peter lead off with CTX.

Yes. We're certainly excited about the FDA approval now, first full quarter since that here. A lot of our efforts are on patient finding across different specialties where patients present. Not expecting -- I think it's a gradual steady build in CTX. Patient finding is laborious, but excited about the potential there to grow [ this ] longer term. Joanne?

Yes. Yes, thanks for the question. Regards to PSC, we do think that bile acids do have a role here. However, the pathophysiology is a bit different than some of the other diseases like Alagille and PFIC that we studied in the past.

In reality, what we're treating is cholestasis. And therefore, there's an intrahepatic component to it that we don't measure. What we think is that what we're measuring in serum bile acids is really kind of spillover. And so we think that the serum bile acid level is probably less important when we're thinking about a disease like PSC, probably more important when you're thinking of Alagille and PFIC for instance. So I think slightly different disease pathophysiology, but still kind of the important central feature here is cholestasis.

So the next question comes from Swayampakula Ramakanth with H.C. Wainwright.

I have 2 of them. The first one being on Livmarli. So you made some remarks regarding how Takeda is managing the Japanese part of the collaboration. Any remarks on how you're going about in Europe? And also within Europe, what sort of efforts are you making to increase your penetration? So that's question number one.

And the question number two is on the -- based on the EXPAND study, what sort of additional population -- patient population can you bring to Livmarli?

Great. Thanks for the question. And I can make a couple of comments on kind of end market Livmarli and then have Peter speak to the opportunity [ and ] expand. And so commentary on Europe and kind of where we're at, what I'd say is the European performance to date is largely Alagille syndrome. So kind of what's to come and most exciting in some of our direct European markets is now bringing forward the PFIC indication and adding that in. It's right now kind of coming through it's the reimbursement steps for adding that indication. So that's what's kind of on the horizon in Europe. And maybe speak to expand.

Yes. And in terms of expanding, a lot of different ultra-rare patient populations individually when you look at the underlying kind of etiology cause of the cholestatic pruritus that could pull in. Certainly, biliary atresia patients with cholestatic pruritus will be a portion of that, but there are also several others. And we hear about these, as Joanne mentioned earlier, through compassionate access requests and from sites who have these patients in their clinics, and they don't have anything to offer them. So excited about the potential to study them and potentially have an option for them.

And that was the final question. And that does conclude the Q&A portion of today's call. So I will hand back over to Chris Peetz for any final comments.

Great. Thanks again for joining us today and for your continued support. We look forward to updating you in the quarters ahead. Have a great afternoon.

This concludes today's call. Thank you, everyone, for joining. You may now disconnect. Have a great day.