Mirum Pharmaceuticals Inc Aktie

Good morning, and welcome to the Mirum Pharmaceuticals Business Update Call. My name is Kelsey, 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, Kelsey, and good morning, everyone. I'd like to welcome you to Mirum's conference call to discuss top line results from the Phase III EXPAND study of LIVMARLI or maralixibat in ultra-rare settings of cholestatic pruritus. For prepared remarks, I'm joined today by our Chief Executive Officer, Chris Peetz; and our Chief Medical Officer, Rob Myers. Also joining us for the Q&A portion of the call are Peter Radovich, our President and Chief Operating Officer; and Eric Bjerkholt, our Chief Financial Officer.

Earlier today, Mirum issued a press release announcing these results. A copy of that release and our SEC filing, along with the presentation summarizing the data 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 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, I'd like to turn the call over to Chris and Rob for some brief remarks before we open the call for Q&A. Chris?

Thanks, Andrew, and welcome, everyone, for another great update from the Mirum pipeline. Today marks another important milestone in our effort to bring LIVMARLI to more patients living with ultra-rare cholestatic liver diseases. We are excited to announce that the Phase III EXPAND study demonstrated a statistically significant and clinically meaningful improvement in pruritus.

In addition to meeting the primary endpoint, the study met all secondary endpoints, including showing a highly significant reduction in pruritus in biliary atresia patients. Results in biliary atresia are notable as there are no approved medicines in this setting, and we estimate about 2,000 biliary atresia patients across the U.S. and Europe suffer from pruritus. Our next step is a planned supplemental NDA submission in the first half of next year.

Stepping back, EXPAND is a great example of how we think about building Mirum. We start with patient need, pair it with scientific potential and then apply efficient execution to bring meaningful medicines to those patients. That approach has now translated into our fourth positive study readout this year. And we see continued opportunity for the Mirum business model ahead. Today, fewer than 5% of rare diseases have an approved treatment. We believe focused companies like Mirum can play an important role in changing that.

And finally, before I turn it over to Rob, I'd like to thank the patients, investigators and study teams around the world who made EXPAND possible. Rob?

Thanks, Chris. My first few weeks at Mirum have been exciting, and I'm thrilled to be here. From the outset, the rationale behind EXPAND was straightforward. Many patients suffer from cholestatic pruritus due to rare liver diseases that are simply too uncommon to support traditional disease-specific development programs. As a result, many of these patients have historically had little or no opportunity to participate in registrational clinical trials.

EXPAND was designed in alignment with and at the request of the FDA to address this challenge. Rather than studying a single disease, the trial enrolled patients with different rare cholestatic liver diseases that share common underlying biology and a symptom that can profoundly impact quality of life, cholestatic pruritus driven by impaired bile flow.

This innovative approach allowed us to generate meaningful data in patient populations that might otherwise never be studied individually. Importantly, the results strongly support that strategy.

The primary efficacy population in EXPAND included 46 pediatric patients with moderate-to-severe pruritus across a range of ultra-rare cholestatic liver diseases. Approximately 1/2 of enrolled patients had biliary atresia and patients were randomized to receive maralixibat or placebo during a 20-week placebo-controlled treatment period.

Now let me walk you through the results in more detail. Starting with the primary endpoint. EXPAND demonstrated a statistically significant and clinically meaningful improvement in pruritus with maralixibat. Pruritus was assessed using a caregiver reported scale ranging from 0 to 4 corresponding to no itch and very severe itch, respectively. Across weeks 13 through 20, patients treated with maralixibat experienced a mean reduction in pruritus of 1.81 points from baseline. Putting the magnitude of this reduction in context of the 2.65 mean baseline value makes it particularly impressive. This reduction with maralixibat compares to 0.83 points for placebo, representing a placebo-adjusted treatment difference of 0.98 points and a p-value of 0.0004.

The secondary endpoints further reinforce the primary efficacy findings and the biologic rationale underlying maralixibat's mechanism of action. Serum bile acids were reduced by 70% with maralixibat compared with 3.5% with placebo, corresponding to a treatment difference of 69% and a p-value of less than 0.0001. Taken together, these findings demonstrate meaningful improvement in a symptom that matters greatly to patients and their caregivers, supported by substantial reductions in the bile acids believed to drive cholestatic pruritus.

I want to spend a little more time on biliary atresia, where there are currently no approved treatment options. This was the largest patient subgroup in EXPAND and the results closely mirrored the positive results observed in the overall study population. In the prespecified biliary atresia subgroup, maralixibat achieved a mean reduction in pruritus from baseline of 2.15 points compared with 1 point for placebo, corresponding to a placebo-adjusted treatment difference of 1.15 points and a p-value of 0.0002. Importantly, the treatment effects observed in patients with biliary atresia were highly consistent with those with other cholestatic liver diseases enrolled in EXPAND. Across both groups, we observed meaningful improvements in pruritus accompanied by substantial reductions in serum bile acids.

Now turning to safety. Maralixibat demonstrated a safety profile in EXPAND that was consistent with our prior clinical experience and no new safety signals were identified. Treatment-emergent adverse events were reported in 96% of patients in both the maralixibat and placebo groups. Serious treatment-emergent adverse events occurred in 20% of maralixibat-treated patients and 18.5% of placebo-treated patients. There was one discontinuation from the study in the maralixibat arm and none in the placebo arm.

Consistent with the mechanism of IBAT inhibition and our prior clinical experience with maralixibat, the most reported adverse events were diarrhea and abdominal pain, occurring in 64% and 20% of maralixibat-treated patients, respectively. Importantly, no patient discontinued treatment due to diarrhea.

Overall, we're very encouraged by these results. EXPAND met its primary endpoint and all prespecified secondary endpoints, while maralixibat demonstrated a safety profile consistent with our prior clinical experience. More broadly, EXPAND adds to a growing and remarkably consistent body of evidence supporting IBAT inhibition as a therapeutic approach for cholestatic pruritus. Across 5 positive clinical studies in multiple cholestatic liver diseases, we continue to see meaningful reductions in pruritus accompanied by improvements in bile acid biology.

Taken together, these findings reinforce our belief that targeting bile acid biology can deliver clinically meaningful benefit to patients suffering from cholestatic pruritus, regardless of the underlying disease.

Now I'll turn it back to Chris.

Thanks, Rob. And we're very pleased with these results and excited about the potential to bring LIVMARLI to these additional settings. From here, our focus turns to the planned supplemental NDA submission in the first half of next year. This label expansion opportunity comes on top of the continued growth we're seeing in LIVMARLI in patients with Alagille syndrome and PFIC. And today's update adds to an already remarkable year for Mirum's pipeline. The Atebrioz launch in FOP is on track to kick off this month, and we're excited about early feedback on the approval. This is an exciting growth opportunity for Mirum's rare genetic disease business.

And Brelovitug's recent positive AZURE-1 readout gives us confidence in the upcoming AZURE-4 study readout later this quarter. Those two studies will be the basis of the planned BLA in the first half of next year. And volixibat provides further opportunity for the rare liver business. The VISTAS results earlier this year in PSC were granted breakthrough designation, and we're moving forward with our strategy to interact with FDA ahead of an NDA submission planned in the first half of next year. Further, the VANTAGE study in PBC is on track for top line data next quarter. We're closing out the year with a lot of momentum and very excited about what lies ahead for Mirum.

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

[Operator Instructions] Your first question comes from the line of Yigal Nochomovitz with Citigroup.

We will take another question instead from Ryan Deschner with Raymond James.

Congrats on the readout today. On the roughly 70% reduction in serum bile acids, specifically regarding the biliary atresia patients, how clinically meaningful do you interpret this result to be? And I have a follow-up.

Thanks for the question. I would interpret that roughly 70% reduction as being very clinically meaningful. We have observed across multiple cholestatic liver diseases now that this degree of reduction is associated with improvements in pruritus that are also clinically meaningful. And we've observed the same thing here in the overall population and in these biliary atresia patients as well.

Appreciate it. And where do you expect pricing on a per patient basis to shake out relative to LIVMARLI in Alagille and PFIC? And could this be in a situation where revenue could grow over time, specifically driven by the actual growth of the patients?

Thanks for the follow-up, Ryan. First comment is no change in the pricing strategy for LIVMARLI, but pass it over to Peter to talk about launch expectations.

Yes, Ryan. The price for LIVMARLI is already established. So the unit pricing is kind of set. Therefore, the kind of indication pricing is a function of dose and consumption. So this would be about a 50% more dose than the Alagille indication, which is about [ $400,000 to $500,000 ] net annualized per year. So that would be the kind of EXPAND dosing for the protocol. And yes, you would expect to see weight-based dosing and dose changes over time with weight gain.

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

We will take a question instead from Kalpit Patel with Wolfe Research.

Many congrats on clearing the study. A couple from us. One, for the label, what's the minimum and maximum ages that you're planning to seek a label for? And then second, have you looked at the percentage of pediatric patients who achieved a sustained 1 point or greater reduction from baseline over weeks 13 to 20? And if you have done that analysis, can you break that out for the BA and non-BA patients?

Thanks for the question, Kalpit. First on label, expect from an age perspective, this to be pretty similar to what we see for Alagille and PFIC, where there's a lower end defined in basically infancy to a young childhood with no expectation on an upper end is how we expect this to be the case here. And just as a reminder, the inclusion criteria is our best indicator of how that indication statement plays out, which is effectively a definition of exclusion. So cholestatic pruritus, excluding some of the larger indications. And then will pass it over to Rob maybe to talk about what we've seen on some of the response rates on itch.

Thanks, Chris. Yes, we saw remarkably consistent results in terms of itch response. But in answer to your specific question, in the biliary atresia subgroup, roughly 90% of patients had at least a 1-point improvement in pruritus. And in the [indiscernible] population, this was about an 80% response rate. So quite clinically meaningful improvement with maralixibat treatment.

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

This is Adam on for Jess. Just could you elaborate what are the remaining steps between now and the sNDA submission, please?

Thanks for the question. Pretty typical post readout where we'll be compiling this data, putting it into a write-up with all the follow-up analyses to a supplemental NDA filing, really straightforward overall in getting to that in the first half of next year.

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

Congrats on the data. I wanted to get your thoughts on the non-biliary atresia opportunity here. You enrolled about 50% of the study in non-BA, and I think BA should be a pretty well diagnosed population. So I guess, was there any stratification in the study to think about? Or do you think that there would be sort of 50-50 in terms of patient flow in the commercial setting of addressable BA patients and non-BA patients? And -- do you have any thoughts on sort of the penetration of diagnosis of the non-BA ultra -- orphan cholestatic patients? Do you think it could be greater than the 2,000 BA patients when all is said and done once more diagnosis is pushed?

Yes. Thanks for the question, Brian. I mean it's a really good question. I mean the way I would think about it here, I mean, this study had 24 sites from U.S. and around the world enrolled for a little over a year. And as you note, about half the patients were biliary atresia, half the patients were other. These were pediatric investigators. So I think that's important to know. It's kind of representative of kind of the practice dynamics and setting there. So in terms of how large that other bucket could be, the non-biliary atresia bucket could be, I think that the actual study enrollment here is probably the best guide.

As far as diagnosis, yes, biliary atresia is very well diagnosed. Substantially all patients are diagnosed as infants. The basket of other, I think it's pretty variable depending on the indication. But certainly, we'd be hopeful that as you see often in new product introductions as awareness of a new product -- grows and there's something to do about pruritus and high bile acids, then hopefully, recognition and diagnosis would increase in those settings.

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

Congrats on the data. Maybe just now we have the data out there and you did mention the updated PFIC patient metrics on the last quarterly call. How are you seeing the breakdown in contribution between Alagille, PFIC and this sort of other cholestatic disease bucket in your $1 billion plus LIVMARLI expectation from a revenue perspective?

And then second, if you could just talk about your expectations for how quickly this could come to market? Would this be a priority review situation there or kind of what's the base expectation given your interactions with the FDA?

Thanks for the question, Joe. Yes. On the latter part of it first, we would see this as a candidate for priority review, just given the unmet need in the setting. And I'll pass it over to Peter to talk about the breakdown of the $1 billion-plus peak.

Yes. I think the first message overall is -- this readout really gives us confidence in the plus part of that $1 billion-plus peak guidance that we have here. You see a lot of different ways to get there from these components. The update we're providing in the materials today, if you look just at the biliary atresia component of the EXPAND study, it's about 1,000 addressable patients in the U.S., 2,000 U.S. plus Europe, that's comparable to Alagille. Actually, when you think about the addressable population of Alagille, maybe the two differences from Alagille, the dose here is different. It's about 50% higher. So that does play through the price. And then, of course, no competition in biliary atresia, although we've had pretty limited effects of competition in Alagille syndrome. So I think as you think about peak sales, the biliary atresia opportunity would be at least as large as the Alagille.

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

Congrats on the data. Maybe one on the epi here. I think historically, you maybe have pointed some more like 1,000 across the U.S. and EU. And -- is that right? And can you talk about sort of what drove that sort of revision upwards to this 2,000? And then a second question here, just sort of on this other non-biliary atresia subgroup. In the real world, do you expect those patients to be adults or pediatrics? Obviously, the study, you mentioned enrolled pediatric patients. But just like curious in the real world, is that sort of representative of what that other cholestatic bucket may look like?

Yes. Thanks for the question. One kind of initial comment, and then I'll let Peter speak a little bit more to it. The way we're talking about the epi here really is just a little bit of a shift in framing it because with the results in biliary atresia being so strong, you can look at this from a more traditional kind of epi standpoint on looking at a specific disease, just being the biggest component of it versus the others, which is really a long tail of less common presentation. Peter, maybe speak to the adult versus pediatric and some of the thoughts on the dynamic in the other.

Sure. Yes. The -- I think this -- in terms of the other patients in this study and is that representative of pediatric or adult. I think it's well representative of pediatric, right? These were 24 sites. They were all pediatric investigators. So I think if you're looking at the list of diseases on the corporate deck, I think it's a pretty good representative -- representation of what you'd expect in the pediatric setting. The adult dynamic is probably a little bit different. That's -- we're encountering some of that as we go search for adult PFIC patients. And the -- as we've talked about before, there's a pretty good group of other idiopathic cholestatic pruritus patients in adult practices, a decent proportion of them have a PFIC gene, but probably more don't. And so I think that -- but that's sort of a different population than was enrolled in the study.

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

Great. Just a quick question on the open-label extension study. I guess when can we expect to see that data? And do you plan to share the results broken down by other patient subgroups like the other disease indications or perhaps by adults and pediatric subgroups in the OLE results? Any color here would be helpful.

Yes. Thanks, Lisa, for the question. Really pretty rich publication plan opportunity here. And I'll let Rob speak on some of the different cuts we can expect to see from the OLE and the primary therapy.

Yes. No, thanks, Chris. The OLE part of the study is ongoing, and we will have another data cut there after 20 weeks of additional treatment. What I can tell you is that patients who have rolled over into the open-label extension are having similar responses to what we observed in the double-blind period with maralixibat treatment.

In terms of disclosing results for the individual diseases, in general, these are small Ns in each group of anywhere from one to two patients for most of these categories. So it'll be somewhat difficult to present data for every subgroup. But we feel very confident about the data in the biliary atresia and overall non-biliary atresia subgroups, and they look quite similar.

Our next question will be from the line of Joe Schwartz with Leerink Partners.

Congrats on the strong data. First, on the patients with biliary atresia, can you talk about them in a little bit more detail given liver transplant is pretty common, but the patients here averaged about 6 years old with near-normal bili. So they look like successful Kasai patients who still itch. Is that the population behind the label in the 2,000 patient figure? And how long do you expect patients to take LIVMARLI before transplant? And then outside of BA, I think there were 4 diseases you said. Has the FDA said whether the label would name those conditions or be a broad label that covers other diseases that weren't in the trial?

Thanks for the questions, Joe. On the dynamic in biliary atresia, the way you're thinking about it is kind of what we've seen in the study and how we expect kind of the overall natural history to play out for those patients that have cholestatic pruritus, they're post the successful Kasai. They've gotten through the very young age where you tend to see a lot of transplants happening quite young. And throughout childhood can suffer from that cholestatic pruritus. So we expect similar treatment duration and profile to what we see in Alagille syndrome, frankly.

And then on the label, it's premature to really know what the precise label language would be. A lot of back and forth with FDA on the design of the protocol, but we don't really speculate on the label or indication statement at that point. So I expect that to be part of the sNDA review.

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

This is RK from H.C. Wainwright. One quick question in terms of trying to identify patients and how to think about launch economics. How concentrated are the -- or potential patients within the existing LIVMARLI prescribers? And in terms of expenses, what incremental patient finding commercial investment do you need to outlay as you get this EXPAND label over the next year or so?

Thanks for the question, RK. Yes, highly concentrated in the same prescribers that currently prescribe LIVMARLI in Alagille syndrome and PFIC. And then to your second question, no incremental economics. It's the team we have out there now [indiscernible] these patients.

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

This is Catherine on for Jon. I just have another follow-up question on the opportunity. So you're saying 1,000 patients -- pediatric patients with BA. I'm wondering how many of those patients do have the option identified that have itch? Or does that number include patients that have itch? And also, when you say the opportunity is similar to Alagille syndrome, do you mean in size or in like the opportunity given the increase in price [indiscernible] BA patients?

Thanks for the question, Catherine. I appreciate the opportunity to clarify that. Yes, it's really addressable patients. So the 1,000 patients in the U.S. for biliary atresia, those are biliary atresia patients post-Kasai with their native liver and that have pruritus. So those are truly the profile of patients that you saw in this study that we'd expect to have on a label versus an overall sort of prevalence number. And likewise, for Alagille, that is 1,000 addressable patients -- Alagille patients with their native liver who have pruritus that would kind of fit in the current Alagille syndrome label. So that's what we mean. We're really comparing truly addressable patient numbers for both.

Your next question comes from the line of Yigal Nochomovitz with Citigroup.

Great. Hopefully, you can all hear me now. So maybe you could address one of these. I'm not sure exactly what was already asked, but could you comment on the -- how you're going to handle the 6 adult patients, if you haven't discussed that already, how that's going to work its way into the sNDA? If that was addressed, if you could comment briefly on the diarrhea. Was there any prophylaxis like loperamide or anything like that done or was that not necessary? And then -- if that was already discussed, then if you could comment briefly on the -- just this EXPAND population, how much are they concentrated already within the liver centers where LIVMARLI is prescribed or if it's going to require some additional market diligence to gather those patients?

Yigal, thanks for the question. I'll touch on the last part first and pass it over to Rob. In terms of the identifying the patient population and where they're at, it was actually the interest and demand from investigators and prescribers initially that drove the study design and the interest to do the study. So it was from compassionate use and off-label interest that kind of led to the EXPAND design. So just an example to say that these patients are with the same prescribers for Alagille and PFIC, and in particular in the pediatric setting. And so very efficient in terms of being able to get to them and identifying those treatment candidates. But maybe to talk about some of the diarrhea treatment and the adult patient dynamic, pass over to Rob.

Thanks, Chris. In general, I'd say, the diarrhea profile is consistent with what we observed in the past with maralixibat and other IBAT inhibitors, roughly 60% of patients did have diarrhea. This typically occurred early on in treatment and was short-lived. All of these cases were mild to moderate and no patients actually discontinued due to diarrhea.

And in answer to your specific question, we did not use prophylaxis with loperamide for this.

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

Great. Well, thanks, everyone, for joining today. And again, a big thank you to the Mirum team for making moments like this possible for the company and importantly, for patients living with rare disease.

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

Good morning, and welcome to the Mirum Pharmaceuticals Business Update Call. My name is Hillary, 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. Andrew, please go ahead.

Thank you, Hillary, and good morning, everyone. I'd like to welcome you to Mirum's conference call to discuss top line results from the Phase III portion of the AZURE-1 study of Brelovitug in chronic hepatitis delta, along with 48-week data from the Phase IIb portion of the study. For our prepared remarks, I'm joined today by our Chief Executive Officer, Chris Peetz; our Executive Vice President of Clinical Development, Nancy Shulman; and Peter Radovich, our President and Chief Operating Officer. Also joining us for the Q&A portion of the call are Rob Myers, our Chief Medical Officer; and Eric Bjerkholt, our Chief Financial Officer.

Earlier today, Mirum issued a press release announcing these results. A copy of that release and our SEC filing, along with the presentation summarizing the data 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, I'd like to turn the call over to Chris. Chris?

Thanks, Andrew, and thank you for joining our call this morning. Today marks another defining moment for Mirum and more importantly, for patients with hepatitis delta. We are excited to announce that the Phase III portion of the AZURE-1 study demonstrated rapid, statistically significant and clinically meaningful improvement on the primary endpoint with Brelovitug. To put these results in context, hepatitis delta is the most severe form of viral hepatitis with the potential for rapid progression to cirrhosis, liver cancer and liver related death.

In AZURE-1, Brelovitug treatment at 24 weeks led to virologic response and ALT normalization in the majority of patients. These results represent the first pivotal Phase III readout of the AZURE program, and they position Brelovitug as a well-tolerated single-agent human monoclonal antibody with potential to treat a wide range of hepatitis delta patients. We continue to expect top line results of the Phase III AZURE-4 study in the fourth quarter, keeping us on track for a planned BLA submission in the first half of next year.

Now this news comes just days after another important milestone for the company announced last Friday. The FDA approved Atebrioz tablets to reduce the volume of total new heterotopic ossification in adult and pediatric patients aged 12 years and older with Fibrodysplasia Ossificans Progressiva or FOP. Atebrioz is now the fourth commercial medicine at Mirum. We brought Atebrioz into the rare genetic disease portfolio only in the second quarter this year. So this is fast progress and credit to the Incyte team, who did a fantastic job leading this through regulatory review.

For today's updates, Nancy Shulman, EVP of Clinical Development, who designed and leads the AZURE program, will walk through the results. Peter will also provide comments on launch preparations for Brelovitug and the newly approved Atebrioz. And I'm happy to welcome Dr. Rob Myers, who joined us last week as our Chief Medical Officer for the Q&A portion of the call.

Rob is a widely recognized hepatologist and physician scientist with more than 2 decades of experience in developing novel medicines. He joins us from OrsoBio, where he was Chief Medical Officer and Head of Development. And before that, he spent a number of years at Gilead. He joins us at a busy time for our pipeline as we look to transition 3 programs from clinic to commercial in the near term. And finally, before diving in, I'd like to say thank you to the patients, investigators and study teams around the world who made AZURE-1 possible.

Now over to Nancy. Nancy?

Thank you, Chris. I'm very pleased to review the top line results from the Phase III portion of the AZURE-1 study, and I'll also walk through the top line 48-week results for the Phase IIb portion of the study. Like Chris, I'd like to extend my gratitude to all the participants, investigators and the dedicated Mirum study team who made this possible. As a reminder, hepatitis delta occurs only in the setting of hepatitis B virus co-infection because the hepatitis delta virus relies on hepatitis B surface antigen for viral assembly, entry and dissemination.

Hepatitis delta is the most severe form of viral hepatitis and relative to chronic hepatitis B alone, delta is associated with the more severe liver disease and more rapid progression to cirrhosis, liver cancer and liver failure. Brelovitug is a fully human monoclonal antibody that binds hepatitis B surface antigen. It works by clearing hepatitis delta from the circulation and by preventing entry into liver cells.

Before getting into the data, it's worth discussing the combined approvable endpoint recommended by the FDA, which includes both virologic response and ALT normalization. HDV RNA measures the degree of viral suppression, while ALT reflects ongoing liver inflammation, both are important. Although viral suppression generally leads to reductions in inflammation, a virologic response alone does not necessarily mean that liver inflammation has resolved. Liver inflammation is the key driver for progression to fibrosis, cirrhosis and liver cancer. In this setting, ALT is the most practical and widely accepted biomarker for assessing inflammatory activity within the liver.

Now turning to the Phase III results. The Phase III portion of AZURE-1 enrolled 153 patients globally randomized approximately 2:2:1 to receive Brelovitug 300 milligram once weekly self-administered by subcutaneous injection at home, Brelovitug 900 milligrams once every 4 weeks administered in clinic by subcutaneous injection with an additional loading dose at week 2 or third arm with delayed treatment starting at week with a crossover at week 24 to the 300-milligram once-weekly regimen.

We enrolled a broad patient population with meaningful disease burden. There was no upper limit on ALT for study participation. And at baseline, we had 18% who had ALT above 5x the upper limit of normal. 41% had cirrhosis and 20% had clinically significant portal hypertension. I'm very pleased to say that at week 24, Brelovitug met the primary endpoint. I'm going to focus on the results for the 300-milligram once-weekly dose, but the numbers are highly significant for both arms.

For the 300-milligram dose arm, 56% achieved the combined endpoint compared to 0 in the delayed treatment arm with a highly significant p-value. Virologic response was achieved in 86% compared to 0 in the delayed treatment arm. HDV RNA below the limit of quantification with our assay, this is 10 IUs per ml was achieved in 25% compared with 0 in the delayed treatment. And this includes 17% who were at target not detected.

ALT normalization was achieved in 63% of patients compared to 0 in the delayed treatment arm. Brelovitug was well tolerated with a safety profile consistent with the previously reported AZURE-1 Phase IIb results. There were no treatment-related serious or grade 3 adverse events or discontinuations and low rates of flu-like symptoms.

Now turning over to the 48-week data from the Phase IIb portion of AZURE-1. As a reminder, the Phase IIb portion included the first 53 patients enrolled in the study. At EASL earlier this year, we presented the full week 24 results. Here, we provide an update out to week 48, which showed continued deepening of viral suppression and increasing rates of ALT normalization with ongoing treatment. A highlight is the proportion achieving HDV RNA below the lower limit of quantification, which again is 10 IUs per ml. Remember, the average HDV RNA levels for these patients at baseline was around 0.5 million. So dropping these to less than 10 is a significant reduction.

Finally, we also expect to present 2-year data from our original Phase II study showing continued improvements in ALT and HDV RNA in the cirrhotic patients at an upcoming medical conference. Overall, these results reinforce the compelling profile for Brelovitug as a well-tolerated, convenient single-agent potential therapy for patients with hepatitis delta, including those with advanced disease.

With that, I'll turn it over to Peter.

Thanks, Nancy. Hepatitis delta is a natural extension of our rare disease commercialization strategy, bringing life-changing medicines to underserved and underdiagnosed patients is where Mirum excels and Brelovitug fits that profile. Let me start with the opportunity. We believe there are approximately 15,000 patients with hepatitis delta in the United States who are diagnosed, insured and under care today. Over the course of 2026, Mirum has supported several hepatitis delta disease awareness initiatives and engaged with hepatitis B providers from a broad array of clinical settings to better understand the delta diagnosis paradigm and disease burden.

Through our disease state conversations, it's clear to us that delta testing in the United States has been extremely low and that most of the burden exists in nonacademic community settings. Thus, we believe the true U.S. prevalence is considerably larger with the significant majority of patients undiagnosed today. And given our confidence in Brelovitug's robust single-agent profile shared today by Nancy, we are updating our peak sales guidance to at least $1 billion.

We believe one of the strengths of the Mirum model is the efficiency of our commercial organization. Today, our rare liver team supports LIVMARLI in pediatric and adult liver care settings. Over time, we expect to leverage this capability, utilizing the same team to support 3 commercial medicines, LIVMARLI, Volixibat and Brelovitug.

Now turning briefly to Atebrioz. Atebrioz is a once-daily oral ALK-2 inhibitor designed to target the disease-driving pathway at the center of FOP biology. As Chris mentioned, we received FDA approval late last week, and our rare genetic medicines team is ready to go. We're excited about the label and believe it can facilitate broad access for FOP patients aged 12 and over. With product launch in October, we expect revenue to begin in the first quarter of 2027. This launch leverages the Mirum Rare Genetics team already in place supporting CTEXLI and CHOLBAM as the physicians who care for FOP patients are concentrated in many of the same specialized centers. And most importantly, we are both grateful and enthusiastic about the opportunity to bring another high-impact medicine to a rare disease patient population in desperate need of treatment options.

And with that, I'll turn it back to Chris. Chris?

Maybe we'll have Eric wrap up.

Yes. Chris seems to be muted, so I will read the last section before we open it up for Q&A. Thanks, Peter. Today's updates are exciting for both patients and Mirum. I'm proud that we've built an industry-leading team in rare disease to deliver moments like this with a new approved therapy for FOP patients and strong Phase III results in hepatitis delta, and our strategy is positioned for continued growth. Today, fewer than 5% of rare diseases have an approved treatment and even where treatments exist, significant unmet need remains.

The upcoming launch of Atebrioz is an immediate opportunity to put our business model to work to help patients with FOP. For hepatitis delta, these are the first pivotal Phase III results from the AZURE program. The week 24 results reinforce our excitement about what Brelovitug can mean for patients with hepatitis delta as a highly active, well-tolerated potential medicine for a deadly disease.

Looking ahead, we expect top line data from AZURE-4, a second Phase III study with a similar design to AZURE-1 in the fourth quarter, which keeps us on track for a BLA submission in the first half of next year. Once again, thank you to the patients and investigators who participated in AZURE -1 and a huge thank you to the Mirum team who are working relentlessly to bring these important medicines forward.

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

[Operator Instructions] Your first question comes from the line from Yigal Nochomovitz from Citigroup.

Congratulations on the -- both the approval as well as the data this morning. So just curious if you could speak a little bit with regard to the read-through to AZURE-4. Obviously, the endpoint there is a little bit more stringent. So could you just comment on how you see that playing out given the results in AZURE-1 with obviously very strong 86% virologic response, although a lower T&D rate of 17% at week 24. And then just related to that, in terms of the filing, what's the latest commentary from the FDA with respect to needing both AZURE-1 and AZURE-4? Is there a pathway where if it's just AZURE-1 for whatever reason, you would still be in a good position to file?

Thanks for the question, Yigal. A couple of quick comments, and I'll pass it over to Nancy to speak about the difference in study design and AZURE-4. But the one thing I'd say is overall, alignment with FDA on the AZURE-1 and 4 being part of the filing and AZURE-4 is just around the corner. So we expect to be bringing those results in the fourth quarter and on track for that first half BLA submission. But Nancy get into some of the details on AZURE-4.

Yes. Thanks, Chris. So actually, the endpoints are quite similar. AZURE-4 is a 24-week endpoint for the Brelovitug. It is the comparison, we are comparing 24 weeks to 12 weeks. As we see here, the control arm doesn't really improve from 12 to 24.

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

Congratulations on the strong readout. Are you seeing continued improvement in ALT and ALT normalization at time points later in the 48 weeks in the Phase IIb portion of AZURE-1? And I have a follow-up.

Yes. Just to put a couple of things in context, and I'll let Nancy speak again to the data. Here, we are providing the Phase III update, that's a 24-week endpoint. The long-term follow-up from the Phase IIb at week 48. And we have additional analyses out to 2 years planned from the Phase IIa. So painting a nice picture overall, but I'll let Nancy speak to some of the trends that we're seeing.

So the short answer to your question is yes. We do see continued reductions in ALT even when they're below the upper limit of normal.

Got it. And then what do you attribute the lack of mean reversion on the primary endpoint or ALT normalization, particular to in this readout compared to the Phase IIb portion of AZURE-1?

Yes, that's a great question. So remember, there's 20 -- approximately 20 patients in each of the Brelovitug arms in the IIb. And so these are -- remember, these are point estimates, and they have confidence interval around them. And if you look at the confidence level, they still overlap. So we think they're not really different.

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

Congrats on the results. I guess considering the community setting for HDV patients, how might that impact your overall commercial strategy, if at all? And maybe you can elaborate on some of the efforts you're planning to undertake to continue to identify new HDV patients.

Thanks for the question. Pretty active on this front. I'll let Peter kind of share what we've been up to.

Yes. Thanks for the question, Josh. Yes, indeed, many of the HBV patients and therefore, delta patients are not in gastroenterology, hepatology, many of them are infectious disease or even primary care settings and kind of select areas often where in urban areas where population reside. But we do actually have a team out in the field now doing disease state awareness, scientific exchange, 10 or so folks out there now interacting with those people, raising awareness of the disease and testing paradigms and hopefully eventually new therapies.

Was there a follow-up, Josh?

It seems that the analyst has dropped. So I will allow them to rejoin the queue in case there's a follow-up. We will move on to the next question, which is from James Condulis from Stifel.

Congrats on all the updates. Just a quick one as it relates to sort of efficacy and what you think matters most to docs in the real world. Just curious, is it the composite, virologic response, certain measures of virologic response? Just like curious what you hear from docs. And then kind of on that point as it relates to the commercial opportunity and sort of the new estimate, can you just kind of expand on what's driving that?

Thanks for the question. Let me ask Nancy and Rob to comment on the first portion and pass it over to Peter for the commercial.

Yes. So to answer your question, so I'm an Infectious disease person, Rob is a hepatologist, so he can opine as well. Both ALT and HDV RNA responses are important. So we think that one of the things that I'll say is that there's been no actual data that shows the predictability of the degree of suppression and how that relates to clinical outcomes. So if you get to, say, 100 unit IUs per ml or you get to LLQ or you get to TND, there has been no data in hepatitis delta suggesting that one predicts better outcomes than the other.

So we know that in hepatitis B, actually ALT normalization predicts endpoints such as liver cancer and progression to decompensation more so than the degree of suppression, particularly TND versus other. So I think both of them are important, especially in therapies that are going to require longer term.

Yes, I agree 100% with Nancy. I think seeing profound viral suppression and ALT normalization in tandem are important. We know that it's liver inflammation and liver cell injury, which drives fibrosis and the complications of hepatitis delta. So the biochemical responses we're seeing are very encouraging. I'll also say we're seeing reductions in liver stiffness, which seem to increase over time, which portend well for prognosis of these patients and looking forward to presenting these data at an upcoming conference.

And then James, on the commercial aspect of the peak revenue update of your question, yes, the primary driver of that is this robust single-agent activity data that Nancy reviewed today. I feel really good about the profile and continued confidence is the primary driver of that. Also I would note that recent entrant in the U.S. of Hepcludex pricing at about 285,000 WACC patient per year came in a bit above the price levels we had kind of assumed in the prior forecast we communicated at the time of the Bluejay transaction.

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

Congrats on 2 positive wins over the weekend. Just 2 quick ones for me. Just in terms of the 300-milligram dose itself, can you throw light what the minimal volume that dose fits into and thoughts on a single auto-injector? And just on sort of competitive labeling ultimately, Brelovitug has a box warning about severe hepatitis flares upon cessation of therapy. Maybe in the current dynamic, it's kind of a good thing to have on label as it emphasizes compliance. But just thinking a competitive landscape, is the assumption that all of these would have on-label warnings about hepatitis flares on stopping therapy? Or is there any data to indicate that you would potentially get around that somehow?

Brian, thanks for the question. I think from a starting point, it's kind of probably too early to speak to label on this and making some of those comparisons. But I'll pass it over to Nancy to talk a little bit about administration of the 300 and the overall profile.

Yes. Thanks, Chris. So the volume of the 300 milligrams is 2 mls, and it doesn't require reconstitution. And then the answer is we are working towards an auto-injector or prefilled syringe, and I can hand it over to Peter.

Sure. Yes, Brian. The presentation at launch, as Nancy mentioned, liquid in vial, no reconstitution required, but we are working on an auto-injector that help to introduce in the life cycle.

And just kind of putting this all together for the profile for Brelovitug, simple once-weekly administration with a single injection really a convenient option for patients, especially when you put in the context of not needing to have a cutoff for baseline ALT or liver stiffness or some of the things that are top of mind for care of these patients.

We can move on to the next one, operator.

Your follow-up question is from Kalpit Patel from Wolfe Research.

So in your Phase II and Phase III studies, you allowed patients with ALT greater than 5x upper limit of normal, whereas it looks like Vir is excluding them. So did those patients respond differently on any of the efficacy endpoints, either things like ALT normalization or TND or any virologic measures? And if you exclude that subgroup, does the efficacy get better on any of those?

That's a great question. So the actual statistical comparisons between those who have a higher ALT at baseline versus those who don't, the subgroups are not large enough to show statistical significance. There's a trend though that if they're higher at baseline, it takes a little longer to get there.

Okay. Got it. And if I can squeeze in a quick follow-up here. Where do you guys see the ultimate differentiation against Vir's combo? And would you consider adding a second mechanism over time to drive perhaps deeper viral suppression and potentially exceed their TND rate?

I think overall, just the profile of Brelovitug is very compelling here. It's very well tolerated, minimal adverse events from the flu-like symptoms and injection site reactions and drives over time a deepening of response with a simple fully human monoclonal antibody. So we think it's going to be a very competitive profile at launch.

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

Congrats on the update. Maybe one on the data. Obviously, seeing good overall responses, but is there anything in a patient's profile maybe in the patients that did not -- maybe had a large of a response that is predictive there, either in terms of disease progression or anything like that, that would predict a nonresponse at this point?

And then second, on the commercial finding patients, when you mentioned the community setting, can you talk a little bit about -- are these patients actively seen by physicians? Or how much of a lift is it going to be to market the drug and kind of get patients to their doctors for a diagnosis?

Thanks for the question, I'll split this one up between Nancy and Peter.

Yes. Thanks for the question. As far as -- so as far as your question on nonresponse, we actually didn't have anybody that didn't have a response. And those who were not responders at week 24 are declining and actually responding and hitting that 2 log threshold at a subsequent time point. So it's hard to do baseline predictors when everybody responds.

Yes. And Joseph, on your question on the patient finding side, it's actually -- it's pretty tractable. These patients are being managed for their hepatitis B. We can see both in medical claims and pharmacy claims they're on NUCs, obviously, where they're being managed and target those physicians. I think the key point we're trying to make is they're just not in academic settings by and large, right? So you think about large hepatology liver transplant settings, that's not where the vast majority of the burden is. But it is a tractable group, largely concentrated in the major urban areas in the United States and something that we don't think will take a substantial investment and that we can largely leverage a lot of what we have here at Mirum already.

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

This is Yesha on for Gavin. We were just wondering how you're thinking about filing in terms of dose. Is the base case both doses? Or are you planning to move forward with one?

Thanks for the question. [indiscernible] is the go-forward dose. But keep in mind that we're still waiting for confirmation of that in the AZURE-4 results in Q4. But all on track for first half submission.

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

I was curious when you talk about the $1 billion peak for Brelovitug. Can that be achieved within the existing diagnosed patient population? And if not, how much patient identification and diagnosis would you see being needed to get there?

Thanks, Jess. Yes, we believe it can be achieved in the existing diagnosed population. I mean that I think you can get a lot of the way there just in the U.S. Of course, there's a substantial international opportunity that we kind of leverage our international team to launch this product as well. I think there'll also be a lot more interest in testing in the future and even now that there's an FDA-approved medicine. So I think the overall -- we'll see the overall number of diagnosed patients increase. But for our revenue guidance, that's really an upside for us.

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

It's Avi Novick on the line for Mike. I guess appreciating that the Phase IIb data on cirrhotic patients, you'll be saving for a medical conference, maybe could you speak to the Phase III population overall and how cirrhotic versus non-cirrhotic patients responded? And then on a related note, I guess, at what point in disease progression are most patients currently being diagnosed today? Are they generally more advanced and have cirrhosis? Or are they perhaps earlier on?

And then I guess, lastly, appreciating a 24-week study is not enough time to collect outcomes data. Are you maybe -- in your longer-term extensions, are you maybe looking at whether cirrhosis can be prevented or reversed potentially in your longer-term studies?

Thanks for the questions. So the first question is there any difference in response between cirrhotics and non-cirrhotics? And the answer to that question is no, there's no very difference between the two. I think the second question was about when are people diagnosed? And in general, patients with HDV because of the speed of progression, they tend to be more advanced upon presentation, at least currently than patients like with hepatitis B. Historically, like in these studies, the rate of cirrhosis usually is between 30% and 50%. So if that gives any idea.

And then the last question about are we studying clinical outcomes? So the answer to that question is yes. So the AZURE studies will look at 96 weeks of treatment. And then subsequently, we have -- we'll have the option to roll over to an open-label extension for an additional 3 years of treatment. And there, we will look at -- so we will look at the rates of disease progression over the course of 5 years and then compare those to a historical control.

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

Maybe from a modeling point of view, should we assume patients will be under treatment with Brelovitug lifelong? Or is there the possibility that some patients could stop treatment after being maintained with the viral load below the lower limit of quantification for some time, similar to what's going on in hepatitis B? Any color here would be helpful.

Yes. Thanks for the question. I mean, pretty [indiscernible] how the protocols are being conducted as well.

Your next question comes from the line of Jon Wolleben from Citizens.

Congrats on the data. Wondering how you're thinking about long-term follow-up in the Phase III population given the similar Phase IIb 48-week response rates you guys said that they seem to be overlapping. And how important is it for docs to see continued benefit over time for chronic use? Or do you think these 24 weeks data is enough to warrant adoption early on?

Jon, thanks for the question. I think the -- what we're seeing here over time, I think is really encouraging for what prescribers hopefully would be able to expect once this gets out in broader use, you see continued improvement across all measures over time. I'll maybe pass it over to Nancy to reiterate what we're seeing at week 48 and even 2-year time point.

Yes. Again, we plan -- we see increasing rates of both ALT normalization and HDV RNA suppression with the deepening of the HDV RNA suppression over time, as I presented in the AZURE-1 IIb. We also remember, presented data on our Phase IIa, and you see the exact same thing there. So 24 weeks is better than 40 -- or 48 weeks, you get better responses than 24 weeks. And again, I'm going to -- not going to say any kind of data, but we hope to present the 2-year data at upcoming conference.

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

This is RK from H.C. Wainwright. Congratulations on the data and the approval. A quick question from me. What evidence do you believe is required before you can call Brelovitug differentiated from entry inhibition or combination regimens, especially on TND and off-treatment durability? And also, will you be reporting the HBV background therapy and also the antigen kinetics when you present the full data?

Thanks, RK, for the question. The last component of it, we will work to get these data presented and kind of a publication strategy to get a lot of that detail out over time. But in terms of the differentiation, we see it all there with a single agent that's well tolerated, simple one injection administration once weekly to drive this kind of response that only deepens over time, we think this treatment objectives for most physicians treating hepatitis delta. So quite excited about what this profile means and how differentiated it will be when we get it out in the market.

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

Congrats on all the recent progress. Can you talk some more about what's specifically needed to close the gap between the 15,000 diagnosed and 40,000 prevalent HDV patients in the U.S. How much of this depends on things like guideline changes, reflex testing, EMR prompts or other factors? And what's the likely time line for certain drivers? And then I heard you acknowledge that HDV testing is currently extremely low, but you're raising your peak sales expectation and you alluded to some initiatives which you've been exploring. So I was wondering what have you learned from these initiatives, which points to a higher TAM?

Yes. Thanks for the question, Joe. I think the points you make, EMR prompts, reflex testing, guideline changes, those are all important. I'll say, though, I think one of the things that strikes me the most from all the conversations we've been having, Mirum with HBV clinicians over the last year in the U.S. as to the reason why the testing is extremely low is that there's just been no available therapies. The conversation is frequently -- yes, we could talk about EMR prompts, we could talk about reflex testing, but why, right? Why do I want to give someone a diagnosis for the most deadly form of viral hepatitis if I don't have a therapy to offer them.

So I -- my editorial view is, I think, certainly, with the FDA approval of Hepcludex, we're going to see that change. And hopefully, with more approvals coming in the future, we'll see a lot more interest from clinicians for that baseline interest to actually do the testing. And in terms of how, I think that the how is exactly what you described, getting on guidelines, EMR prompts, et cetera.

And then you asked about our peak sales guidance. That really was around -- our change there was primarily around the confidence in the product profile that from the data that Nancy presented, the robust single-agent activity that you see improve over time. That's really the primary driver for us increasing that. Also mentioned in response to a previous question that our assumed price has kind of gone up a little bit from what we communicated at the time of the Bluejay transaction based on how Hepcludex price landed with the Gilead launch. And then any increase in the number of diagnosed patients under management, which is currently about 15,000 in the U.S., that would really -- that would be kind of upside. That's not baked into our base case thinking.

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

A quick follow-up. What can you tell us about your updated expectations on Atebrioz's pricing, in particular, given where Regeneron has priced their drug?

Yes. Thanks, Ryan. We communicated with the press release on Friday, we'll launch in October and plan to make a final decision on price with launch. But yes, I would -- just for general guidance, I would expect it to be in the corridor of where [indiscernible] priced.

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

Okay. Well, thanks, everyone, for joining the call today. Obviously, a very exciting moment for Mirum and more to come in the fourth quarter. Have a great day.

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

All right. Hello, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the biotech analysts here. It's my pleasure to introduce Chris Peetz, CEO from Mirum Pharmaceuticals. Just as a quick reminder, the format for today is a fireside chat. But if anyone in the audience has a question, you can raise your hand, and we'll try and address it in our discussion here. But before we get started, I just need to read a quick disclosure. 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, Chris, thanks for sharing your time with us today, and maybe I'll just hand it over to you to make some introductory comments.

Yes. Thanks for hosting. It's great to be here. And I'll make a quick disclaimer on my end as well. I will be making forward-looking statements. So, I refer you to the SEC filings for Mirum for a more complete risk factor disclosure. And a bit about Mirum, we are a company that's established just under 8 years ago and focused on pulling together high-impact medicines for rare disease that are often overlooked, missed by some of the bigger companies, but really compelling opportunities, not only from patient impact, but also as a business model and pulling these together in an efficient way.

This year, we're on track for $680 million to $700 million of revenue across 3 approved medicines, really had a, kind of, emerging growth trend in one of our indications, in particular, with PFIC that I'm sure we'll spend some time talking about, and a pipeline that is very busy right now. So, later this quarter -- later this month, actually expecting to announce the top line data of the AZURE-1 Phase 3 study of brelovitug in hepatitis delta. We have a PDUFA date from one of our newly added programs in FOP -- more readouts, 2 more Phase 3s reading out next quarter and another study in PBC first quarter next year.

All this on the back of entering into a regulatory conversation for PSC for volixibat as well. So, it's a busy stretch for Mirum and, kind of, on the other side of this, see a real inflection on business performance from all of these data readouts and launches that we expect in the near term. So, exciting time across the board.

Yes. Great. Thanks for that introduction. Yes, lots to get through here. So, maybe we just start with the commercial business and LIVMARLI, and you touched on this in your prepared remarks, but you're seeing some nice sort of growth in PFIC. So, maybe talk about what you're seeing there and how you think about that going forward?

LIVMARLI is approved in 2 different indications, cholestatic pruritus due to Alagille syndrome and cholestatic pruritus due to PFIC. And first approval in Alagille syndrome continues to be a growth driver. So, we, across the board, continue to see new patient starts. The response profile for most patients is quite meaningful and see strong compliance and persistence as well. So, that plays well for the brand over time, both this is U.S. as well as international performance.

The PFIC indication was added subsequent to the Alagille syndrome launch. And it's been an interesting story over time. Initially, we saw this as a pediatric opportunity. That's what our field team is primarily targeting and finding the pediatric profile of the PFIC patient. As we've been in market with LIVMARLI in pruritus due to PFIC, we've found that there is also a substantial underdiagnosed population in adults that actually have PFIC and have to date been labeled as idiopathic cholestasis. So, really just an incomplete diagnosis in many of these adult cholestatic patients with pruritus.

And that's something that we've seen start to contribute to the top line over the past year, a very durable trend in everything we're seeing. In fact, we're now in the process of expanding the field commercial team to help support some of that patient finding and diagnosis, help build awareness of genetic testing and availability of it for adult patients. We estimate there is probably about 2,000 adult PFIC patients in the addressable market that are out there in the U.S. So, that's, kind of, one of the near-term drivers for the continued growth on the commercial business.

Yes. As we look next year and beyond, you also have a Phase 3 EXPAND study ongoing that could even further expand the opportunity there. So, maybe just talk a little bit about that, maybe give a little bit of background how you ended up sort of targeting that indication and what to expect when we see data, I think, in the fourth quarter.

Yes. LIVMARLI as a whole, we see it as a $1 billion-plus brand opportunity, driven by all these different components, EXPAND being a substantial contributor to it as well. It is a basket study. So, it's a collection of ultra-rare causes of cholestatic pruritus that by definition in our discussion with FDA are too small to run a stand-alone study in. So, a good number of them in the study are biliary atresia. That's probably the only one that's a little bit more common of the mix and then very small numbers of other genetic and nongenetic causes of cholestasis that end up with a pruritus presentation.

Study looked at both pediatric and adult patients. The readout -- the primary endpoint that we're expecting next quarter is in a pediatric cohort. That's what the study was primarily powered and designed around. So, expect to see that as the top line next quarter, the pediatric patients with an identified subset looking at biliary atresia as well as a secondary because it is about half of the patient population. There is probably 500 pediatric patients in the U.S. that make up the addressable market that we've identified in size. That's an early estimate. It's hard to tell how big of an indication this could be in adult settings as well. There are some adult patients out there, certainly. We just don't know quite how many. So, it's a nice add-on to what we're already seeing in Alagille syndrome and PFIC.

Can you talk about what drives your confidence in being successful there? Any prior data you can point to?

Yes. There's -- really the genesis of the study design came from physician interest and compassionate use case studies. So, we do have -- not in the clinical trial format, but we do have anecdotal case study evidence seeing response in a number of these types of settings. Biliary atresia, in particular, we presented some of the case studies of a series of biliary atresia patients with cholestatic pruritus being treated. And it's what you'd expect for an IBAT treatment. In a patient with cholestasis, elevated bile acids and itch, you can expect to see a nice response in the clinical data that comes out from those studies.

Great. And if we just sort of stick with the commercial portfolio and specifically the bile acid portfolio, you added that a couple of years ago, and it seems to be performing well. So, maybe just talk a little bit about that, what's driving that and the outlook there?

The bile acids, CTEXLI and CHOLBAM, have grown nicely with a dedicated team behind it. One of the things to note when we brought those products in, a realization we had is that the prescriber universe is not entirely hepatology and GI. Many of these patients, in particular for CTEXLI and for some of the CHOLBAM indications, are in medical genetics or neurology. It's more of a patient finding and diagnosis effort that doesn't exclusively happen in hepatology. So, we built a separate team that focuses on those other settings and the patient finding. And they've done a fantastic job over time with these products.

It's about having a dedicated effort that is -- it's a different strategy than what the liver team is doing. So, it makes sense to have a different team staffed against it. And actually, it fits really well with one of the things to come on FOP. That's the team that's going to be launching zilurgisertib in FOP. And it's a really similar effort, overlapping call points in terms of the institutions that these people are visiting and in contact with, a similar effort in terms of following data on diagnosis and leveraging some of the referral patterns that happen for these ultra-rare conditions like FOP, like CTX.

Yes. Maybe talk a little bit more about FOP and, kind of, what attracted you to that asset and kind of what drove that decision?

Somewhat from, kind of, what I was just talking about with our expansion into medical genetics and, kind of, thinking of rare disease as a therapeutic area, we've been looking for other programs that could fit with that, kind of, team and call point to put more in the hands of this team that's been executing so well. As we started looking into FOP and the programs being run there, the biology and the data are striking. So, this program that Incyte did all the work on the Phase 2 study that supported the NDA submission, really compelling data that's come out of that showing that you can really -- versus placebo have a striking difference in the volume of ossifications that build up over time for these patients.

We see this as groundbreaking data for FOP patients to be able to halt that formation of new ossifications and dramatically change the course compared to placebo in those data sets. So, both that clinical data and how clear it is as well as the fit with our team and the business model comes together in a great story. And the conversation with Incyte, it's a story of focus between 2 companies, right? This is something that didn't fit with their business model. It's clearly aligned with what we're trying to do. So, it was a natural transition that we set up.

Yes. Makes sense. With the PDUFA date coming up here, can you just talk about launch preparations? Can you hit the ground running? It sounds like you probably can, but maybe just talk a little bit about that.

Yes. And for launch preparations, field team is the same team that's already out there for the bile acid medicines. So, in terms of the staffing, largely, that's all in place. And so, we're ready for the PDUFA date decision in a couple of weeks here, looking to -- that's the point that triggers a transition of sponsorship from Incyte. So, a couple of steps there to get this launched in Q4.

Okay. Great. Since we've been sort of on the topic of BD, you've obviously been pretty active over the past few years. So, maybe just talk more broadly about your BD strategy, your thoughts currently? Are you looking to add more programs? Or do you have enough catalysts over the next 6 months?

I'm a little -- we're a little busy for the next 6 months. But it takes time for these deals to come together. But I think is -- I mean, that's behind the overall strategy for Mirum, how we got to where we are today. And the vision for the path forward is to always be active to find the opportunity that is compelling both from the biology data and patient impact, but then also that fits with the Mirum business model that you can have an intersection where the deal economics work for both sides. It takes time and being a little bit opportunistic. So, we never rest on the BD front. We're always active looking at things. The range of things that could be of interest remains the same. Phase 2 opportunities through to early commercial are all of interest and could fit well. But granted, the next 6 months are a little packed. So, adding a Phase 2 sounds like a pretty good idea to me instead of another launch next year.

Yes. Understood. And I guess what areas of focus? Is it, like, rare genetic, liver? Could you go outside that at all? Or that doesn't make sense for you or...

Yes. We look outside of liver and outside of the broader current therapeutic areas where we're active because we see rare disease as the therapeutic area, as the expertise that we bring. So, the ability to commercialize medicines where they are maybe harder to diagnose, harder to get to a point of care, where there is maybe a first product in class or in the indication and, kind of, setting and changing the standard of care. These are the types of opportunities that our team has shown that they can execute on.

And so, it's not so much tied to the specialists, but more the model around a rare disease product launch. And we're seeing, as we saw with the bile acid products, how we're approaching the zilurgisertib launch, you can leverage this into new therapeutic areas pretty easily. So, adding on the endocrine call point and some of these tertiary centers for the -- what we call the GEM team is pretty straightforward, actually.

Great. Maybe we can keep it rolling moving to volixibat and maybe just start with PSC and just maybe talk a little bit about the market opportunity there and the unmet need and how you see it.

So, backdrop of PSC as an indication. This is autoimmune-driven cholestatic condition presents most commonly in adults, but there is a pediatric onset form of it as well. And the hallmark of it being the fibrotic structures forming around the bile ducts, leading to progressive liver complications. It's also associated with frequent episodes of cholangitis, highly variable liver labs and just really a very difficult setting to treat clinically. And it's been very tough for drug developers historically. So, we've seen a number of programs early on exploring different endpoints using histology, using different biomarkers. None of those have really panned out.

When we approached it with volixibat, we were coming at it with -- from a different angle. So, leveraging some of what we learned on the pediatric side, using the symptomatic burden as the endpoint for our registration program and clear that pruritus is a substantial clinical burden for these patients. That aligned well to be an endpoint in PSC, similar to how we've used that in Alagille syndrome, PFIC and PBC. So, a good precedent for how it's used in other settings.

And with the VISTAS program in PSC for volixibat, which I'm sure we'll talk about, kind of, diving into it here, had that conversation with FDA, good clear written correspondence discussing the study design, the registrational intent, pruritus as a substantial patient need endpoint and indication and had good alignment on the study design and announced earlier this year, really strong top line data. So, clear we presented at EASL this year, a really compelling impact on pruritus in the VISTAS study for volixibat in PSC.

Yes. You also shared that positive data with the FDA and the FDA sort of requested Phase 3. So, maybe just walk us through what happened there? And what are your thoughts on that going forward from here?

So, working through the situation on the regulatory front now, it was a bit of a surprise for us. So, after the positive readout, we went for a pre-NDA meeting with FDA and had the surprise recommendation from them to conduct a Phase 3 study. A surprise for us in many ways because we had alignment on the study from the start as a pivotal study. In the conversation, a lot of the different aspects of the program were discussed. All of them were present at the start of the program and were considered with the original study design.

So, we're a bit surprised by the reaction. Subsequent to that meeting, we were granted breakthrough designation. So, we're using that as an ability to have a bit more access. So, over the balance of the year, planning to have interactions with the FDA through written submissions, sharing more of the VISTAS data with them. Admittedly, that we have not submitted full data sets to them yet. So, I think there is a lot to be gained from getting them closer to some of the data sets that answer a lot of the questions on treatment in this patient population specifically and even get to a live meeting potentially.

And all this with the goal of submitting our NDA in the first half of next year. So, absolutely still the plan to submit an NDA for volixibat in cholestatic pruritus due to PSC based on VISTAS first half of next year. The strategy between now and then is to build familiarity with the robustness of the data set and, kind of, bring the review team closer to, kind of, how we're seeing things before we get to that submission.

Yes. Can you walk us through some of the potential scenarios there? Are you pretty confident that you'll be able to file on existing data? Or are there other data you could use? Maybe what are some of those potential outcomes, I guess?

Well, in the interaction with FDA, it's already -- it was made clear that we can submit at our election, right? So, there's not been something put on the table to prevent us from submitting an NDA. So, there was a recommendation from them to run a Phase 3 study. We think the points brought up in the meeting really can be addressed by the current study. So -- and frankly, we don't know what new would be answered by an additional study. So, scientifically, we haven't heard something that needs to be answered that can't be answered in the VISTAS data set. And that's what's behind our strategy to take steps forward to bring the current data set to an NDA next year.

Got you. Maybe we can switch to PBC and maybe talk a little bit about the market opportunity there relative to PSC.

So, in PBC, we're also conducting a Phase 2b study, adaptive design with volixibat in cholestatic pruritus due to PBC. We already presented interim data a couple of years ago from that study that showed a really striking improvement in pruritus versus placebo in 2 doses of volixibat. The adaptive design then took 1 dose forward for the confirmatory portion. That's the data we expect in the first quarter of next year, granted breakthrough designation, have some more clarity on the regulatory front on that one from those interactions last year as well and, kind of, tying this to the clinical setting.

In PBC, it's a much larger indication in terms of just overall prevalence -- probably 80,000 or more patients in the U.S. with PBC. And there are other medicines approved in PBC for different settings. So, UDCA is standard of care. That's generally where patients start. There's a second-line setting for those that are not controlled biochemically on UDCA. So, in other words, if they have elevated alkaline phosphatase levels, they'd be considered for a PPAR, which were recently approved. And then in the backdrop, symptomatic management is emerging with new tools available and becoming available.

So, there was recently an IBAT inhibitor approved for cholestatic pruritus in PBC. That's relevant across both first and second-line PBC just like we are developing volixibat. So, volixibat is being studied in both first and second-line PBC. In the interim analysis, we saw both settings were represented in those patients, and we see a nice improvement in pruritus across both profiles. So, I feel that we're on track to have a potential medicine that can address symptomatic burden across all lines of therapy.

And you're going to share, I think, the Phase 2b registrational study in 1Q. I guess you shared some prior data. Is that, like, a good estimate of what the outcome might be? Are there a reason to think the outcome might be a little bit different on the pruritus endpoint?

The best evidence we have is from that interim analysis of the VANTAGE study, where we saw a 2.4 point placebo-adjusted difference that -- that's a really strong result. Compared to some of the other data sets out there, anything around a 2-point difference from placebo in PBC is a really impressive result. So, getting close to that in the full data set would be a real home run.

Yes. Makes sense. And I guess, your level of FDA interaction on PBC and the risk that they may also want you to run a Phase 3 study here? Or what's the thinking there?

We've had the opportunity for more recent interaction with PBC. And one of the things that we've looked at is the division leadership has changed over the course of this program. So, more recent interaction, I think, is quite relevant and helpful. We've gotten, kind of, feedback from the current contemporary team that's in the division. And after the breakthrough designation, we were thinking about the ultimate study size for VANTAGE, and we had some flexibility to potentially keep it smaller or upsize it. That was one of the decisions we wanted feedback on in the context of a pivotal study.

So, in written correspondence with FDA, we confirmed some questions on study design and on the analysis plan. So, I feel like we have more recent input from them. And that's why the study has now ended up over 300 patients in total to align with, kind of, what other PBC programs have had for their submission data sets. And even in these correspondence, we even have direct direction on if these studies are considered pivotal, these are the analysis steps that you should take, and we're able to accommodate all of them. I feel like we're aligned on PBC.

Okay. Great. And then we'll just keep moving here. So, for brelovitug, HDV, you have some Phase 3 data coming up soon, but maybe just to start, paint the picture for us, why HDV, what was attractive for this program?

Yes. So, hepatitis delta is a co-infection with hep B. It's rare, so it's far less common than hep B, but it is far more dangerous and progressive. So, it is a highly progressive condition where these patients tend to progress to cirrhosis, liver failure, liver cancer, cholangiocarcinoma, like, all these complications at a much faster rate than hep B alone. So, the goal of treatment here is to suppress the viral levels. So, we're looking at HDV RNA response and improve long-term liver outcomes. And one of the ways that's measured in the studies is ALT normalization, looking at that as part of the composite response.

In the U.S., we think there's -- we estimate there is 15,000 patients with hepatitis delta diagnosed in care. That's from insurance claims data. So, also, kind of, in the insured population, estimate 15,000 patients. But that -- it's likely very underdiagnosed. The practice and guidelines for testing for hepatitis delta in hep B patients has been more of a risk-based paradigm, and it's likely not even sufficiently doing it at that level.

So, a very low percentage of hep B patients get tested for hepatitis delta. And so, we think there is probably 40,000 patients that are in total in the prevalent population in the U.S. So, a lot that can be done if we can help support changing some of the reflex testing that really should happen now that there are therapies emerging for hepatitis delta. Interesting parallel in Europe, actually, where we've seen this play out with approval of Hepcludex about 5 years ago in Europe, you saw a shift in guidelines.

And that did result in a meaningful change in the testing patterns from 10% to 20% of hep B patients being tested for Delta now towards maybe as high as 90%. And the positivity rate on those tests hasn't changed. So, they're capturing far more of these patients that would otherwise be undiagnosed and have a more progressive background disease.

And in terms of the data, maybe just walk us through a little bit of what we've seen so far and, kind of -- is that a good proxy again for the data coming up here?

The brelovitug program has had some just really impressive response profile in the Phase 2a and Phase 2b data sets. There is 2 different studies that have read out. Phase 2a was, kind of, sequential dose exploration study looking at different doses and regimens, and that, kind of, gave the signal for what became the AZURE program. The AZURE-1 study that has its Phase 3 readout in the next couple of weeks here. The Phase 2b portion of that, I think, is the most instructive data to look at. It's a randomized controlled evaluation of 2 regimens of brelovitug versus delayed treatment, looking at 300 weekly and 900 monthly and nice response across both regimens, in particular, the 300 weekly dosing looking quite strong.

We're seeing 100% virologic response -- at only 24 weeks, you're already getting a substantial proportion of these patients with ALT normalization. And our program has no baseline ALT requirements. So, some of these patients are coming in with very high ALTs. And so, to get them to normal in that time frame is quite impressive from a response profile. And so, that's, kind of, what we look to as the best guide for what to look for in the Phase 3 readout. A lot of overlapping sites from those first patients in AZURE-1 to, kind of, look at what's possible for the Phase 3 portion.

Makes sense. Can I also ask just about competitor also is going to have Phase 3 data coming up later this year as well? So, maybe just talk about key points of differentiation or how you position your product?

Yes. The real -- part of what got us so excited about brelovitug really, I think, will stand out as we get into a competitive launch. Yet another one. We've done -- we tend to like these situations. Brelovitug is a fully human antibody. I think that has some real advantages on the safety tolerability profile. In terms of what we see is very low injection site reactions or flu-like symptoms. I think that's going to shine commercially when we get out there. And the response profile at 24 weeks is good and appears like it's only going to improve over time. So, that's another thing that we'll be looking to share data on as we go is some of the data updates as these Phase 2b and eventually Phase 3 patients get towards 48 weeks or 98 weeks, where with a single agent fully human antibody, you can really control the HDV RNA levels and get more and more patients to ALT normalization.

Great. Maybe in the last few minutes here, we just switched to just Fragile X syndrome. Maybe give us, kind of, the background there and, kind of, your latest thinking.

So, the MRM-3379 program for Fragile X is a PDE4D inhibitor. And we're looking at trying to impact some of the cognitive scores and measures in Fragile X patients in the dose-ranging Phase 2 study that we're running. Important to note, this study was based on a signal from a different Phase 2 program of a PDE4D inhibitor that had an interesting signal on cognitive scores. We've not seen that replicate in the Phase 3 study. So, it does, kind of, call into question some of the strategy here.

I will say that we're asking all the right questions. So, in our Phase 2 program, we're doing a more complete dose ranging than was done in this competing program from what we've seen. And one of the things that excited us about 3379 as a program is that it has a high CNS penetrant. So, it was designed for CNS exposure. I think that's the right profile for this setting, but we'll have to wait and see what comes out of the data next year. Study is enrolling well. It's a really engaged patient community and setting. So, we'll have an update when we get to data next year.

Yes. Great. I think we covered it.

I really appreciate the time. And I think just to, kind of, come back on a closing thought, where Mirum is at a real inflection point here. Commercial business on its own is already performing well with that $680 million to $700 million top line for the year. We're seeing that and expect it to really in the next couple of years, start to play through in an impressive way on a margin basis as we start to launch these additional products and build on the efficiency on what we've built here with the liver team eventually having 3 products, LIVMARLI, brelovitug, volixibat, a lot of reasons to be, kind of, a leading thought partner for hepatology and GI. And then on the Genetics and Endocrine metabolic team, having an exciting launch to work with there with a team that knows how to get out there and have an impact and help bring patients to therapy.

Yes. A lot to look forward to. So, thanks so much, Chris. Really appreciate your time today.

Yes. Thanks for the time. Thanks for the interest.

So welcome, everyone, to Citi's Biopharma Back to School Summit in New York City. I'm Yigal Nochomovitz, Senior Biotech Analyst at Citi. Our next company, we launched on, I guess, it was a couple of quarters ago, Mirum Pharmaceuticals, a super interesting story, and I have with me the CEO and Founder, Chris Peetz as well as Andrew McKibben, who is SVP of Finance and IR.

So welcome, both of you. Thank you very much for joining. Obviously, there's a lot of news flow coming. So maybe we could just start with the cadence of data because you are getting a lot of Phase III data and some Phase II data. So maybe just kind of walk us through what investors should expect from the catalyst perspective over the next several quarters.

Yes. Great. Thanks for having us. First, point out that we'll be making some forward-looking statements. So I refer people to the SEC filings for more complete risk factor disclosure. And a couple of kind of intro words on the cadence of events over the year for Mirum.

We're a commercial stage rare disease-focused company. That just kind of how these programs and readouts that we have tied together is pursuing opportunities in rare disease to bring forward medicines that are generally overlooked. So kind of the overall strategy is finding the small to midsized medicines that fall off the radar for big pharma and address real rare disease problems, recognizing that there's only 5% of rare diseases actually have approved medicines for them.

There's just a lot of runway for us to find medicines like that and bring them together in Mirum. And a lot of great ones that are making progress this year. So on top of revenue of $680 million to $700 million expected this year, several really important readouts ahead of us. And later this month, actually, a Phase III readout expected for the brelovitug HDV program. That's 1 of 2 Phase III readouts. The second one reads out next quarter, AZURE 1 & 4 are those 2 studies.

Together, they will constitute an expected BLA filing in the first half of next year. So exciting moment for brelovitug and a new therapy for HDV patients as we get to that data readout. We also have later this month, a PDUFA date for zilurgisertib in FOP.

Zilurgisertib is an ALK2 inhibitor for FOP. And based on -- that submission is based on some really impressive Phase II data that formed the submission, a program that we acquired from Incyte earlier this year, and we take over at the approval expected later this month.

Into Q4, in addition to the brelovitug second Phase III readout, we also have a Phase III readout for LIVMARLI. So the EXPAND study looking at a basket of cholestatic pruritus indications, kind of the third leg to LIVMARLI's growth profile with that study reading out in the fourth quarter. And then into Q1 next year, we also have a second indication for volixibat reading out in PBC. I'm sure we're going to spend time talking about the PSC data and FDA conversation, but another data readout for that program in Q1.

Well, we'll get to that later, but let's focus on some of the near term. So let's start with HDV, and we can move our way through. So I guess a really basic question. What gives you confidence that you're going to show strong data for those 2 AZURE-1, AZURE-4? Of course, you had the Phase IIb data, which looked really nice.

So just help us understand what gives you confidence? And then the 2 studies are similar, but there's a little bit of a difference between them, if I'm not mistaken.

Right. Yes. So the brelovitug program, brelovitug is HB surface antigen antibody. So really straightforward approach in this co-infection setting to knock down the surface antigen that Hep Delta relies on for replication and infection. And the Phase II data, as you point out, are really clear and strong.

So not only the Phase IIb data from AZURE-1, which read out earlier this year, there's also a Phase IIa study conducted previously by Bluejay Therapeutics, where this program originated, the clinical program originated. And consistent effect overall across the doses evaluated and from one study to the next, where you're seeing very high viral response rates.

So most patients -- most cohorts reaching 100% virologic response of 2 log or greater reduction and impressive rates of ALT normalization over time. There's a mix of different time points that have been looked at Week 24 and 48, but it's clear that by Week 24, which is the Phase III time point, you can get 100% or near 100% virologic response and the majority of patients achieving or being near ALT normalization.

And you've done a lot of -- in the diligence leading up to the Bluejay acquisition, obviously, you've done a lot of diligence on the HDV market. So maybe just kind of help us understand how you see that opportunity. You see it in obviously a very positive way and perhaps understand it in a way that others maybe didn't. So can you kind of go into that a little bit in terms of what the opportunity is in the United States and of course, ex-U.S. as well?

And this is one of the key things that we were looking at when we were kind of thinking about entering into Hep Delta. And it is still, I think, one of the debates that we hear brought to us as a question pretty commonly is on patient finding. It's something that the Mirum team, I think, has done really well in other settings.

So really strong conviction in what we've seen to date and how we're approaching it. A couple of the observations and estimates we have. We think there's about 15,000 diagnosed insured patients in the U.S. So it's based on some claims data work. And where these patients are, I think, is important to spend a moment thinking about because when -- in interactions with KOLs, you might actually extrapolate to a lower number because these patients are often more dispersed in the community.

In particular, in some of the major metro areas, there'll be nontraditional for liver care points of care that are more primary care oriented or community clinics that would see most of these patients. So a lot of the launch prep work we're doing is profiling who are the physicians that are seeing these patients that are already diagnosed because that's going to be the first opportunity at launch. And the second leg to this is thinking about diagnosis rates. So Hepatitis Delta, we think, is very much underdiagnosed. And there's a story here on incorporating reflex testing for Hepatitis Delta based on Hep B diagnoses.

And we've seen this play out in Europe over the past 4 or 5 years, where they've shifted from what's kind of thought of as at-risk Hepatitis Delta testing, which ends up being very limited testing for Hepatitis Delta in Hep B patients. And as Europe converted to their guidelines and their practices to be more automated test for delta if you have a positive Hep B result, the number diagnosed climbed rapidly.

And so we're hoping that can be deployed against here in the U.S. as we have now already one approved and more coming new medicines for Hepatitis Delta, expect to see a change in some of the practices on how it's tested for. Ultimately, we think there's probably at least 40,000 total patients in the U.S. So the majority of them being undiagnosed.

Meaning if you sort of did the math and you know how many HBV there are and you just do the 5% or low single-digit percent of co-infection, you get that 40,000.

Exactly, yes. So in the estimates you see are in the 2% to 5% range of Hep B would be Hep D infected as well.

So of course, there are some competitors in the marketplace in HDV, Gilead and Vir. Any comments you want to offer there in terms of how you are differentiated relative to those other options?

I think a lot of it comes down to what we're excited about in brelovitug's profile being a single-agent regimen with a fully human antibody, I think is a very favorable tolerability profile. We see that come through consistently in clinic and gets to a really impressive virologic response, 100% of patients having a 2 log or greater reduction.

And over time, as we look at some of these maturing data points, we expect to see those numbers continue to improve. So the TND rates, the ALT normalization rates at Week 24 is just the starting point, and we do see patients continue to improve their response over time.

What are the hepatologists feel as most important when they look at endpoints, what are they focused on? Is it the liver enzyme normalization and the rate, the virologic response? What -- just how do they assess efficacy when they're looking at different options?

With these new medicines coming to market, I think this is going to set the tone on treatment objectives as they have some tools to work with. When you're looking at some of the longitudinal data from natural history cohorts and in different settings as well, the outcomes are tied to both virologic response and ALT normalization.

So I think the profile where you can meet both of those objectives logically links to the improved risk for long-term outcomes in this setting.

Okay. So assuming you're successful with these 2 readouts, just very quickly, what's the time line to file your -- with the FDA and get approved?

Yes. Plan is to submit with FDA in the first half of the year. So BLA submitted first half based on the AZURE-1 and 4 data sets. In Europe, we have 2 other studies, AZURE-2 and 3 that include HEPCLUDEX comparisons, bulevirtide comparisons. So the European submission would be a bit later. But in the U.S., we'll be planning to file first half of the year.

And in those European studies, what's the comparison? Are you showing like a non-inferiority? Or is it a superiority? What's the test that you're doing versus HEPCLUDEX?

We're looking at superiority versus 2 different approaches. One is treatment-naive head-to-head Hepatitis Delta patients. And the other is those that have been on HEPCLUDEX and doing a switch versus continued HEPCLUDEX treatment, kind of both relevant for how you think about the rollout, more relevant in Europe where HEPCLUDEX is more established, also reads into the U.S. where HEPCLUDEX is recently approved and being launched.

Right. Okay. All right. Well, let's move on. So you mentioned as well this EXPAND data set, which is sort of a an expanded bucket of additional options for LIVMARLI. So talk about what that could imply in terms of expanding the market opportunity. And then also, you're getting good traction in PFIC in the adult population. So those 2 factors hopefully will inflect the trajectory for LIVMARLI even more.

Yes, absolutely. Yes. The LIVMARLI growth profile has been one that -- I mean, our understanding and expectation in these settings has evolved over time, just as we've been in there and finding where are the patients, how are they diagnosed. PFIC, in particular, has been an interesting story where in a recent earnings call, we talked about some of the patient finding efforts, in particular, in adult settings, where genetic testing is just not as well adopted.

So there is a lot of opportunity in these adult clinics to change how genetic testing is thought of and incorporated, in particular, in patients that are today diagnosed as idiopathic cholestasis, which really is an incomplete diagnosis, right? It's -- and getting standard of care to have genetic testing for those patients will bring a more accurate diagnosis and start to find more PFIC patients.

And we've seen that start to play out in a relatively limited set of centers already for adult hepatology. So we see a lot of growth from more expansion into adult liver for PFIC. EXPAND is kind of that last piece of the LIVMARLI profile where the idea for the study actually came from the hepatology community. And what we saw was demand and interest for treating a range of patient types that had cholestatic pruritus, but from a variety of different reasons.

Biliary atresia is the most common for what we saw. So we have some presented case studies that inform kind of our confidence in the upcoming readout where you see a nice response profile and compassionate use examples of biliary atresia treatment. But given the amount of interest in these kind of these other cholestatic settings with FDA, we designed a protocol to put them together in a basket protocol that is the EXPAND study.

Now fully enrolled and on track for data next quarter. What we see in that patient population in the study, it's about half biliary atresia. So that's prospectively written in as a secondary endpoint to look at the biliary atresia cohort independently after the full study is analyzed.

And then the other half of the study really is kind of a mix of many different types of cholestatic disease. So post procedural secondary sclerosing cholangitis, a number of other genetic causes of cholestasis. So it's quite a broad mix.

And would this study be sufficient to support an sNDA for this broader set of opportunities? Or do you have to do some further clinical work?

That's the plan and the discussion with FDA was to have this be label enabling and really came from FDA reaching out about the volume of single patient IND and compassionate use requests that they want -- they want us to put a protocol together around it. And so in that interaction, we discussed how to make that label enabling. So this is pointed towards an sNDA in the first half of next year.

And our kind of estimates are that in the pediatric setting alone, there's probably at least 500 patients in the U.S. that fit this profile. There's an adult opportunity here as well that's a little harder to characterize and haven't gotten our hands fully around what the size of that could be. But it's a nice addition to the addressable patient population for LIVMARLI.

And just remind everyone, if adding Alagille and PFIC, what's the addressable just so people can get a sense of the scale when you would include the 500 from EXPAND would just roughly.

Well, the -- how these have evolved over time, and we have to kind of undo some of the prior statements we've made about how the relative sizing of these indications are. We originally thought Alagille was the bigger opportunity. What we've seen in PFIC has kind of proven that wrong. So for Alagille, the original estimate was that for addressable patients, we're probably 1,000 or just over 1,000 Alagille patients. In PFIC, when you combine the pediatric and adult, you're probably towards 2,500.

And for EXPAND, when we're looking at the pediatric that 500 or more, it's a sizable addition to what's already there. But I don't think we really have our head around how many are out in the adult settings either. So we'll have to get out there with the label that we end up with before we have a firm estimate of that.

Yes. I think in our model, it's -- we preserve that as an upside for the EXPAND population. So we'll have to model that once we see the data.

Yes. I think that's fair. I mean this is -- each rare disease, if you know one rare disease, you know one rare disease. And so as we get into each setting, understanding where the patients are and being able to go out and promote against it is how you find the actual size of the patient population.

Start with an estimate, and we tend to -- we like to be conservative on how we're thinking about these early benchmarks and product sizing estimates and see if we can find more impact once we get out there.

Okay. Let's spend a few minutes on what I guess is the most proximal catalyst, which is at the end of the month, the PDUFA date for FOP. So I guess you're in the very final stretches now. I gather you're maybe in the labeling conversations. What can you say there? And there are some -- I believe there are a few other products that are in the market. So how do you differentiate with your drug?

Yes. The FOP landscape is kind of recently evolving. Historically, only one medication was approved, SOHONOS, that from community feedback and treatment experience was kind of overall a difficult drug to take, and many patients actually opted for clinical study instead, which helped bring these recent 2 programs along.

Regeneron has recently launched a new medication for FOP. So looking at that as kind of a new entrant and provides some direction on, frankly, price points to consider as well. And then our program, zilurgisertib in the review with FDA has gone well. So nothing really to comment on late cycle comments, didn't raise any issues, and I think we're tracking towards approval at the PDUFA date.

So we're ready for launch in Q4. Zilurgisertib is an oral daily ALK2 inhibitor. So targets what is the overactive receptor that's a driver of disease in FOP. So excited about the mechanism. The clinical data that was the basis of the NDA, really strong, showing stopping the -- compared to placebo, a dramatic difference in volume of new ossifications. So great data to have out there supporting the launch next quarter.

And how are you positioning zilurgisertib as a frontline option instead of Regeneron or the other one you mentioned? Or would it be used after? Like how does that shake out?

Overall, I think it's to be seen how physicians kind of look at the 2 medications. What we're doing is leading with our profile and our data, which I think is quite attractive. One kind of important thing to note from the clinical program for zilurgisertib is that the Phase II program that's the basis of the submission started at age 12, so we can treat some of the younger patients. We fully enrolled the second cohort of patients that brings that age potentially lower.

So looking to move towards generating the data for potential sNDA already to even improve on that 12 and older patient population and trying to get at where the desire to treat these patients as early as possible to prevent some of the accumulation of these ossifications over time.

So just to clarify, the other 2 drugs, their label is only for 18 or older adults? Or is it -- how do they structure there?

That's correct.

Right. Okay. That's what I thought. Okay. So that's coming up. And then there's this -- there's the PBC top line data in the first quarter of 2027. So that's a Phase II study. So just walk us through the data that supports a positive outcome there for volixibat.

Yes. So the VANTAGE study for volixibat is an adaptive Phase II study with pivotal intent. So similar to the VISTAS study, we discussed this program at length with FDA when we were designing it and had the opportunity to actually have further discussion with them in written correspondence last year.

As a reminder, the VANTAGE study had an interim analysis a couple of years ago with really strong data coming out of that. So seeing quite pronounced improvements in pruritus versus placebo. That was the basis of breakthrough therapy designation in PBC for volixibat for treatment of cholestatic pruritus in PBC.

And with the breakthrough designation, we had some back and forth with FDA confirming some of the NDA components. So we had clear direction on what FDA wanted if we were to consider VANTAGE a pivotal study. We've incorporated that all into the upcoming readout in Q1. So we do see this as a pivotal program for volixibat in PBC.

And worth commenting a little bit on the treatment landscape because there's been a lot of progress in PBC over the past few years, where we've seen 2 PPAR agents approved and think of it as a second-line PBC setting. So those patients not controlled by UDCA. And those PPARs now been on the market for getting on a couple of years.

The most recent evolution is another IBAT inhibitor that was approved for treatment of cholestatic pruritus in PBC. So see some precedent out there on the regulatory approach. I know that comes up as a question, very clear that cholestatic pruritus is an approval path for PBC. And overall, I think our dosing for volixibat in this setting is going to lead to some impressive headline data.

So excited about getting to that data readout and what it means for treating cholestatic pruritus across all lines of therapy in PBC. So we're addressing both those first-line patients controlled on UDCA and also the second-line patients where you see PPAR use as well. It doesn't really address pruritus for all patients.

Okay. There's one more, which we can spend 30 seconds on the Fragile X, if you want to comment. I know that's more of like a high-risk, high-reward opportunity, but any brief comments there, and then we can spend a little bit of time on the topic you mentioned at the beginning in terms of the FDA feedback on PSC.

Yes. In Fragile X, we're running a dose-ranging Phase II study of a PDE4D inhibitor for trying to improve cognitive scores and some of the behavioral scores in Fragile X patients. A lot of what informed and got us excited about this program was data that came out of a PDE4D inhibitor at Shionogi that from what they've announced, did not replicate some of their Phase II data.

So it does -- there's a little bit of a question on what informed the study design. I think one of the things to keep in mind is that the dose-ranging work we're doing is different and more fully explores the -- what we expect to be the target therapeutic dose. And MRM-3379, our program, has a much higher CNS penetrance compared to the Shionogi program.

So it is differentiated and we're asking some different questions here. So while unfortunately, the signal we were following didn't play through, it is going to be an interesting data set to look at next year.

Okay. So then obviously, there was a lot of debate around the FDA feedback on PSC and their surprising request for Phase III when you had alignment. So just kind of can you update us in terms of what the state of play is there with regard to the FDA interactions and what we may expect now and into next year in terms of a resolution or clarity on filing the NDA for PSC?

Yes. So overall, I mean, no update or change to the status of things. And just to kind of recap where we sit today, had our pre-NDA conversation with FDA. Subsequently, we were granted breakthrough designation. And now our strategy is to bring FDA closer to the data, right? So the original feedback was based on a pretty standard briefing book, which doesn't have the full data sets, doesn't have a full safety analysis, clinical study report, all the validation work that would be part of an NDA package.

So we see an opportunity to get some of that in front of the review team and work towards a multidisciplinary conversation with them. That's part of being granted breakthrough designation is the expectation to have a conversation like that. And this data set is very convincing, right? So it's a highly persuasive data set showing a clear improvement of pruritus versus placebo in PSC patients.

The study has confirmatory evidence built into it. There's a second cohort of patients with mild itch that were also significant in their improvements versus placebo. And the profile from a safety standpoint looks like an IBAT.

So we think this is a data set that's absolutely sufficient for review and labeling, and we're -- our strategy is to work with FDA towards an NDA submission. In terms of guidance and what we can share publicly, our guidance is that we do plan to submit in the first half of next year.

Don't expect there'll be much to update along the way. So while we will be having interactions with FDA, I don't plan to provide kind of updates on those conversations unless something materially changes in terms of the feedback that they give us or our plans for that first half submission.

So team is hard at work in prepping some of these data sets, analyses and follow-ups for FDA and working with them towards the submission.

Okay. So based on what you're saying and also what you mentioned earlier in the year at the earnings call, it sounds like you have a solid degree of confidence that you'll be able to work collaboratively with the FDA to get them to understand what you've achieved in the VISTAS trial and not -- obviously not have to run a Phase III, which would by all indications seem totally superfluous.

Yes. That's our thinking as we've considered the recommendation for a Phase III and looking at what you would try to answer. We -- based on what's VISTAS, we don't know what other question would be asked. And so I think this data set is definitive for cholestatic pruritus treatment. And while we can't control FDA's ultimate thinking on it, what we can do is work through making the case on how clear this data set is.

And by the way, you mentioned VANTAGE and PBC.

So just can you clarify that was obviously with pivotal intent and you have breakthrough -- you have breakthrough for that one as well. Is there a clarity there from the FDA that they understand that, that is a pivotal trial? Or is there still something to work out with the FDA, so they're on board considering it as a new group that's taking a look?

We think there's better alignment there based on some of the written correspondence last year at the current -- under the same leadership of the division last year as this year. So there's, I think, good consistency of the people that we're interacting with and did have clear feedback in those written correspondence on what they recommended we do for this to be considered pivotal.

And there was some thought, or there was an idea that perhaps you could include some of the PBC data in supporting PSC, but what's the latest on that? It seems like that may not be necessarily the way it's going to go.

We think -- I mean, the readout in Q1, we think is not necessary. The interim analysis already from VANTAGE is supportive evidence, supportive data. We're pairing that with kind of a scientific explanation and write-up of how cholestatic pruritus between these 2 indications is similar.

While the underlying disease is different, the cause of cholestasis is different, the cholestatic pruritus driven by circulating bile acids is common. And so that's the indication statement that interim data from VANTAGE already is supportive data. The supplemental cohort within VISTAS already is supportive data. So we really see there's already enough here.

As the time line plays forward, there is a scenario where we consider if VANTAGE should be included, but that's not currently the plan.

But the original interim from VANTAGE, did that get put in the NDA for PSC in some respect or not?

It was brought into the discussion with FDA in the pre-NDA meeting.

Okay.

Yes. And I think to be clear on that, the initial conversation was debating how related the indications are. And the -- looking at PBC versus PSC being different underlying diseases and distinct. So kind of downplaying the role of that as supportive evidence. We think that is not really supported actually.

The cholestatic pruritus indication that these are addressing is quite related. So we're building that case as one of the pieces of what we're taking back to FDA. So it's another one of the arguments that we're working on for the PSC conversation.

Okay. I guess final question, which is change of topic here, and we're asking everyone, so forgive me, but the AI question, how are you leveraging AI at your organization, either just to make things faster to get to answers quickly, analyze data, operational efficiencies drawing conclusions, helping with submission of filings?

Yes. We've rolled it out company-wide. So at Mirum, employees have access to it in a kind of integrated AI system. And I think it's being adopted for many different use cases. It's actually kind of exciting to hear how people are using it in different ways. So we kind of have different programs to help people use it to improve the speed and quality of drafting analytical documents.

Our corporate development team uses it extensively for BD analysis, for diligence analysis, for understanding even down to molecule design as we're looking at other programs. So we've rolled it out in a lot of different ways. And I'd describe it as letting the company organically find the places where individuals can use it best to kind of streamline their day-to-day work or improve their...

Is there a certain flavor that you're focused on like Claude versus Gemini versus something else? Or is it you just have to kind of use all of them?

We have a couple of options all through Copilot actually and have loved how Copilot integrates across the other file sources and structures in the company. Personally, I find it helps me find files so much faster. And now I don't need to bug other people. I can actually just ask my Copilot and say, where is that attachment that somebody sent me 3 months ago? I think it was about this or that and it pops right up.

I need to learn how to do that. Okay. All right. Great. Well, thank you very much. Great to be obviously formally covering you guys. So I'm looking forward to a lot of important updates starting in basically 2 weeks, I guess, PDUFA date. So...

Yes, exciting stretch, and thanks for making time to talk about it.

Great. Thank you.

Good afternoon, and welcome to Mirum Pharmaceuticals Second Quarter 2026 Earnings Conference Call. My name is Alexandra, 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, Alexandra, and good afternoon, everyone. I'd like to welcome you to Mirum Pharmaceuticals Second Quarter 2026 Conference Call. 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. Lara Longpre, our Chief Development Officer, will be joining us for the Q&A portion of the call. Joanne Quan, our Chief Medical Officer, could not be with us today due to a family matter.

Earlier today, Mirum issued a press release announcing the company's results for the second quarter of 2026. 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. At Mirum, we're growing a rare disease leader focused on delivering high-impact medicines for often overlooked diseases. This quarter demonstrates continued progress with strong commercial execution on our approved medicines as we head into the potential launch of our fourth commercial medicine later this year. We have a busy pipeline with multiple pivotal readouts in the quarters ahead, all delivered with a strengthened capital structure and overall financial performance, giving us greater capacity to invest throughout the business.

In the second quarter, our commercial business generated $176 million in net product sales, reflecting strong demand across the portfolio and excellent execution by our team. Based on this performance, we are increasing our full year 2026 net product sales guidance to $680 million to $700 million. Fueled by the strong commercial performance, we're driving towards the next phase of Mirum's growth with multiple milestones over the coming months. Our next commercial milestone will be the potential launch of zilurgisertib for FOP with a PDUFA date next month. This is fast progress for a program added to our rare genetic business only in the second quarter. Peter will cover more of the launch profile in his remarks.

Moving to the pipeline for our rare liver business. It's important to spend some time today on volixibat in PSC, which just had some key U.S. regulatory interactions. First, as a reminder of the background of the VISTAS study of volixibat in cholestatic pruritus and PSC, we designed this adaptive study with input from the FDA as a pivotal trial for this difficult clinical setting, including alignment on study duration, endpoints and analysis plan. As we've announced previously and presented at EASL this year, VISTAS met its primary endpoint, showing highly significant improvements in pruritus in the primary cohort with consistent significant results also observed in a second cohort of patients with milder baseline pruritus.

We are excited to share that the FDA has now granted breakthrough therapy designation for volixibat in cholestatic pruritus due to PSC based on these strong results. We see this as recognition of the potential for volixibat to address a serious unmet need in PSC.

As planned, we recently held a pre-NDA discussion with the agency about the submission of an NDA based on the VISTAS study. In the meeting, the FDA recommended conducting a Phase 3 study. We believe the VISTAS study provides a robust and clear data set to characterize the use of volixibat in patients with pruritus due to PSC and is a clinically and statistically highly persuasive study. VISTAS is the largest randomized clinical study conducted in patients with pruritus due to PSC with an extensive overall data package that includes more than 180 PSC patients randomized, one year safety exposure data for over 100 PSC patients and growing results from an independent committee evaluating liver safety, all totaling over 600 subjects across the clinical program to date.

So while we are not currently aligned on the NDA submission package, we will be engaging in discussions with the FDA on how to further supplement our planned submission based on the VISTAS study. This engagement will delay the planned timing of our NDA submission, which we are now targeting for the first half of next year. We're positioned to move quickly once we have further clarity from the agency. We'll provide updates as we work towards our goal of bringing a much-needed therapy to this unaddressed clinical setting.

In parallel, the VANTAGE study in PBC is progressing well and has completed enrollment, reaching over 330 patients randomized. In PBC, our earlier breakthrough therapy designation has enabled more dialogue with the agency during the conduct of the study. We have recent feedback from FDA for VANTAGE to serve as a pivotal study of volixibat in pruritus due to PBC if the study is successful at its first quarter top line readout next year.

Our next clinical readout for the rare liver business is expected to be the brelovitug AZURE-1 top line results later this quarter. This is the readout of the Phase 3 portion following strong results of the Phase 2b portion earlier this year, and we also continue to expect the year four data in the fourth quarter, which keeps us on track for a potential BLA submission for this breakthrough therapy designated program in the first half of next year.

And rounding out the rare liver pipeline highlights, the Phase 3 EXPAND study of LIVMARLI an additional rare cholestatic conditions remain on track for top line data in the fourth quarter.

So putting this all together, we are advancing these clinical programs from a position of financial strength. Our commercial business continues to generate meaningful cash, providing the capacity to invest in potential launches, clinical development and opportunistic business development where we see a compelling strategic fit and the potential to create value.

I'm proud of the team's progress and the promise of our current medicines and pipeline, and I'm excited about what lies ahead for Mirum. And with that, I'll turn the call over to Peter to discuss our commercial performance and launch readiness in more detail. Peter?

Thanks, Chris. The second quarter was another strong quarter for Mirum's commercial business with total net product sales of $176 million. LIVMARLI and the bile acid medicines both continue to perform well. And based on the demand we see, we are increasing our full year 2026 net product sales guidance to $680 million to $700 million.

Second quarter net product sales for LIVMARLI were $129 million, with the U.S. contributing $92 million. Alagille growth remains durable, supported by continued new patient starts, sustained persistence on therapy and weight-based dose increases.

PFIC continues to be an important driver of growth, fueled by new diagnosis. We're particularly encouraged by the growing contribution from adult PFIC patients. We're seeing an increase in prescriptions from adult liver providers as awareness of later onset PFIC grows and genetic testing becomes more routine. Based on claims data as well as insights from two years in market, we now estimate an addressable adult PFIC population of at least 2,000 patients in the United States with likely a similar number in Europe. And because genetic testing remains less established in adult practices than in pediatric, we believe the vast majority of the estimated 2,000 addressable patients don't yet have a PFIC diagnosis, and we see a meaningful opportunity to continue expanding diagnosis through education.

Internationally, LIVMARLI continues to grow across our direct and partner markets, contributing $37 million for the quarter. We are seeing contributions from established markets and expanding reimbursement in additional geographies.

On the rare genetic disease side of the business, our bile acid medicines continue to provide a steady contribution, generating $48 million in net product sales for the quarter. Like our rare liver business, our rare genetics business is also poised for growth with the recent addition of zilurgisertib for FOP. Data from the pivotal Phase 2 PROGRESS study of zilurgisertib presented at ENDO showed a compelling clinical profile in FOP patients ages 12 and older. Based on the strong efficacy observed and the convenience of oral dosing, we believe zilurgisertib has the potential to offer an attractive profile to patients with this severely debilitating disease.

If approved by the FDA, the initial launch opportunity is expected to focus on patients ages 12 and older with potential future expansion into younger patients supported by additional cohorts in the PROGRESS study. And following a recent late cycle meeting with the FDA, we believe the NDA is proceeding as expected towards the September PDUFA date, and we are preparing for potential U.S. launch in the fourth quarter.

The U.S. launch will heavily leverage the rare genetics team we have in place now that currently markets our bile acid medicines as the physicians who manage FOP are largely concentrated in the same specialized centers where CetEXI and Clavam are prescribed, building on the efficiency of our rare genetics business.

Also, a marketing application for zilurgisertib has been submitted in Europe, and we will provide updates as this filing progresses. Overall, we are pleased with the continued execution across the commercial organization. We're seeing strong demand throughout the existing portfolio while making the investments necessary to support the next wave of potential launches. We believe that we are well positioned for the remainder of the year and beyond. With that, I'll turn it over to Eric to discuss the financial results. Eric?

Thanks, Peter, and good afternoon, everyone. Today, I'll walk through the financials of another excellent quarter for Mirum. Net product sales for the second quarter were $176 million compared to net product sales of $128 million in the second quarter of last year. Cash, cash equivalents and investments as of June 30 were $561 million compared with $391 million at the beginning of the year.

In the second quarter and first half of 2026, the cash contribution margin from our commercial business was in the high 50s percent approximately a 5 percentage point improvement over the year before.

Total operating expense for the quarter ended June 30 was $219 million, which includes $16 million of in-process R&D expense associated with the upfront payment of licensing zilurgisertib, R&D expense of $76 million, including $29 million related to the development of brelovitug, SG&A expense of $66 million and cost of sales of $23 million, all excluding stock-based compensation expense and intangible amortization.

Stock-based compensation, intangible amortization and other noncash expenses totaled $37 million for the quarter. Operating cash flow was positive in the second quarter despite the expected increase in R&D expense. During the quarter, we significantly improved our capital structure through the issuance of $690 million aggregate principal amount of 0% coupon convertible notes due in June 2032.

Net proceeds from the offering were $672 million. In conjunction with this financing, we settled 75% of the outstanding 2029 notes, added $197 million of cash to the balance sheet and significantly reduced our interest expense. These transactions further strengthen our balance sheet and extend our financial flexibility to execute our strategy. Our commercial business continues to scale, and our pipeline includes multiple near-term value drivers. With that, I'll turn the call back to Chris for closing remarks.

Thanks, Eric. Taking stock of where we are, we are continuing to drive our strategy to bring important medicines to underserved rare disease patients. Commercial business is thriving, now tracking towards $680 million to $700 million in net product sales for the year. LIVMARLI is well on its way to realizing its over $1 billion peak revenue potential. And our rare genetics team is thrilled about the potential launch of zilurgisertib for FOP patients in the coming months.

On the pipeline, we are focused on a collaborative discussion with FDA on the VISTAS study in PSC. Clinical results are clear and breakthrough therapy designation gives us further opportunity to engage with FDA. All said, we have a plan to advance volixibat to PSC patients.

The balance of the pipeline is firing on all cylinders. Recapping our upcoming clinical milestones, we expect clinical readouts from the Phase 3 AZURE-1 and AZURE-4 studies of brelovitug over the balance of the year, which will enable our planned BLA submission in the first half of next year.

Next quarter, we also expect to announce top line results from the EXPAND study of LIVMARLI and additional rare cholestatic diseases, setting up the potential for an sNDA next year as well. And into 2027, we expect top line results from the VANTAGE study of volixibat in PBC first quarter. And finally, we're on track with MRM-3379 for proof-of-concept data in Fragile X syndrome next year. Importantly, we're building an organization capable of reaching many more people living with overlooked rare diseases while delivering strong financial performance.

I want to thank the Mirum team for their continued focus and execution, the patients, families and physicians who continue to partner with us in this work. With that, operator, please open the call for questions.

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

Congrats on the strong results. Curious what your overall take is on the potential read-through from the BOLD study evaluating odevixibat in patients with biliary atresia. And I have a follow-up question.

Thanks, Ryan, for the question. The BOLD study and the study of note in our pipeline that includes biliary atresia patients, the EXPAND study, I mean to put it simply are asking very different questions. I would equate the BOLD study more to what we ran previously with EMBARK, looking at patients in the very acute setting, trying to reduce bilirubin or extend transplant-free survival.

The question we're asking in EXPAND ties much more to where we've seen IBAT perform quite well in other settings, where we're looking at older patients than what was in BOLD and EMBARK and evaluating pruritus changes. It's something that we've seen an impact from IBAT therapy over and over again now in different clinical settings. So we feel there's not really a read-through or connection between BOLD and what we're looking at in the upcoming EXPAND readout.

Appreciate it. And then just on the PSC regulatory discussions, what key topics do you anticipate sort of addressing with these future discussions?

Yes. Thanks for the follow-up on that. I mean just kind of to -- reiterate some of the background here, we did extensively discuss the VISTAS study design with FDA. Back in the pre-IND setting, the FDA acknowledged the pivotal intent, described the design as reasonable, gave direct feedback on duration analysis plan, all these things that designed the study that we read out so successfully earlier this year.

And frankly, the situation now that we've seen is in the meeting, there was a new team from FDA. And so we think there's a lot of work to kind of get them up to speed on the backdrop here. So the history designing and conducting VISTAS and what this study means in a PSC setting. So we think it's going to be an iterative approach to kind of get them up to speed, not only with the current data package, but with the history of the program.

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

First, what was this new FDA's team's rationale to conduct an additional Phase 3? Like was it more of a safety database question? Or was it more around the efficacy side?

For a follow-up, Gavin, the comments about Phase 3 recommendation from them really were not specific. So we don't have great clarity on what specifically they're looking for. There were comments across the board on -- more general on efficacy, which we think VISTAS very clearly addresses and they actually commented on that in the meeting.

On the safety side, the discussion -- the couple of things that were brought up were IBD safety in the backdrop with IBAT GI effects and liver safety. Those were designed into VISTAS as key things to evaluate. So we think it's all there in the VISTAS study, and it's more -- this is more about familiarity with study design and some of the questions that were asked.

Another thing I'd point out is that the breakthrough designation actually was issued after the meeting. So I think that gives us a great opportunity to go back in and build up familiarity with this data set and work us towards an NDA.

Okay. That makes sense. And just a quick follow-up. Is this a team that you have engaged with before on any of your other programs? Do you have any experience working with them? And kind of on a similar point, what other regulatory precedents would support approval based on the similar type of Phase 2b setting?

Thanks for the follow-up. In terms of the team, a lot of times, the correspondence is written. And so you're not -- you don't have perfect clarity on who's behind some of the written correspondence. So it's difficult to answer that question, to be honest.

And in terms of precedent, I mean, we really have looked across all the IBAT settings where you've seen in Alagille, where the first approval was based on four week randomized withdrawal data, all the way to the more recent Lynavoy approval in PBC pruritus with a six month placebo-controlled study that, frankly, looks a lot like VISTAS. It's a little bit larger because PBC is a more prevalent indication. So there's pretty clear precedent for IBAT in cholestatic pruritus settings that line up with VISTAS. [indiscernible] goes back to the whole way that we designed the study and the prior conversations with the agency.

I'm sorry, I may have misheard something. Did you say that this was only happening via written correspondence? Or was this pre-NDA in person with the FDA or virtually?

The pre-NDA was in person. So when you were asking about prior and other interactions, some of those have been written. So we don't know who is behind some of the other written correspondence. This meeting was in person.

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

This is Rohit on for Mike. Just based on your conversation with the FDA, do you see any read-through to the PBC VANTAGE study? Is it possible to request a Phase 3 trial for that one? And also, in terms of commercial prep for FOP, can you talk about where you currently stand and what's outstanding?

Thanks, Rohit. I'll speak to PBC and then pass it over to Peter to talk about FOP. On the VANTAGE study, as you may recall, we were granted breakthrough designation after the interim analysis in 2024. So that actually gave us a great opportunity to have conversations similar to what we expect to go through here with VISTAS.

And so in the correspondence after the breakthrough designation on VANTAGE, we actually received a pretty clear feedback from FDA on what we should do to consider VANTAGE a pivotal study. And we were able to address those. So primarily, the comments related to the overall size, that's part of why we've ended up with over 330 patients in VANTAGE and also the analysis plan and some of the specifics on how the pruritus endpoint is analyzed.

And Rohit, yes, with regards to the commercial prep for the zilurgisertib potential approval and launch in Q4, that's going really well. As I mentioned, we did -- we were able to drop that in the bags of our rare genetics team and had a couple of territories there. Lot of typical prelaunch activity and profiling accounts and understanding where the treaters are. These patients are well identified. There's about 300 or so diagnosed and managed in the U.S. and highly specialized centers, had a good presence at the ENDO meeting earlier this summer as well. So excited about the progress of the NDA review and working towards launch readiness in Q4.

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

I'm going to be annoying and also ask a little bit on FDA's issues with VISTAS just given that it seems like a pretty straightforward data set. Can you just refresh our memories as the review team here is within the division of hepatology. Is Katie Donohue still the Office Director? Was she involved in the meeting? Is Frank Anania still the Division Director and was he in the meeting? And I mean, I hear that they weren't very specific about why they wanted Phase 3, but I mean, did they sort of mention like a need for replication? It just seems like the p-value here is so robust that there's not really another question that could be answered with a Phase 3 other than maybe longer-term follow-up. So any sort of guidance there is helpful.

Thanks, Brian, for the question. On some of the specifics of people kind of in the room, what I would say the office leadership, we think maybe has changed and leadership was not in the room in our review meeting. And kind of getting into some of the -- I mean, specifically on efficacy the -- I think it's -- like you're pointing out, I think it's very easily addressed by the VISTAS data and getting breakthrough afterwards, I think, is a nod in that direction. So given some of the discussion in the room, I think that's something that we can readily address through iterative conversation with FDA. I don't know if that helps.

Yes. Maybe if I could just ask one thing on the PDUFA with zilurgisertib. I think you would have had probably the late cycle review meeting in the last month or so. Just any commentary on how that went and your level of confidence going into labeling discussions?

Yes. Thanks for the question, Brian. Yes, we did have the late cycle meeting. Meeting went very well. So we feel the application is progressing quite well towards the PDUFA date. So full systems go to prepare for a potential launch in Q4.

Your next question comes from the line of Kalpit Patel with Wolfe Research.

One more on the regulatory interaction here. In your communication with the agency, has there been any dialogue so far on potentially running a post-approval confirmatory study instead of running a Phase 3? Or should investors assume that the Phase 3 is what's in the works right now?

Thanks for the question. I think one -- the direct answer is that the conversation with the FDA didn't get to that level of specifics for post-approval requirements. I can comment a little bit on the pathway here that using pruritus is the basis for full approval. So we don't expect to have a post-approval study in the sense of kind of confirmatory accelerated approval type format.

What we would expect and has been added for other IBAT approvals is some level of post-approval registry or kind of long-term monitoring. And so we do think that would be appropriate for this setting as well.

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

Congrats on a great LIVMARLI quarter. Just maybe to be annoying again one more on PSC. I guess like just to clarify, is a Phase 3 on the table? Or are you confident that this can be resolved through like you said, iterations on sort of the data? Just wondering sort of like what your base case is and sort of what informs your confidence of guiding to a first half '27 resubmission?

Yes. Thanks for the question, James. And as we looked at this proposal for a Phase 3 and given the VISTAS results, I think the key question is, what would you learn from another study in this setting? I mean VISTAS is the largest ever conducted in PSC pruritus clear definitive results. It's a big enough safety database for a setting like PSC. So we don't see what would be gained by going down that road and find that just the weight of evidence here is really convincing. So we feel good about where we stand now with breakthrough designation to work through this.

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

Kind of one more on the NDA filing delay here for volixibat. Could this mean that we see more BD in the near term as potentially PSC revenues may now be pushed out? And I just want to ask as well, could you add any clarity on whether the FDA is still accepting pruritus as an approvable endpoint?

Thanks for the questions, Lisa. The first thing on -- to answer your second part first, which is the absolute clarity that pruritus approval endpoint. That's what this discussion is all focused on. So there's no question there. On the BD front, we've always approached BD on being always active and always opportunistic. So don't see this really relating to the overall level of activity we have or our criteria and what we're looking to bring in.

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

Hypothetically, if the FDA doesn't budge, does VANTAGE PBC have any ability to strengthen the volixibat regulatory package for PSC? For instance, if a filing in PBC is an NDA and a filing in PSC is an sNDA, could that order of operations be successful without having to do another Phase 3?

Joe, thanks for the question. What I'd say is potentially, and we're getting into some hypotheticals down the road. The base plan is to get the PSC NDA submitted first. But as we think about the VANTAGE data, another large randomized study playing into a very related pruritus condition, I do see like some weight to that and how we approach that in terms of parallel or sequenced NDAs is something that we'll get to if we end up in that scenario.

Okay. And then a question on brelovitug. Did any baseline characteristics for patients enrolled in the interim analysis cohort of AZURE-1 appear to correlate with better response in the Phase 2b portion of the trial? And how do the baseline characteristics for patients enrolled in the full AZURE-1 population and AZURE-4 compare?

I mean the quick answer to that is no, nothing obvious that really comes out. And we see response for brelovitug across really all patients. So there's a very broad-based response. And that cuts across baseline viral RNA levels, ALT levels, geography, kind of every way we've looked at it, you consistently see patients responding to brelovitug.

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

So more on volixibat. When you, I think, in prepared remarks referred to some options to supplement the VISTAS trial, curious what you could supplement it with?. And second, just based on where we stand right now, what gives you the confidence to outline first half of '27 as the new PSC filing time line?

Yes. Thanks for the question, Jessica. Yes, in terms of supplementing it, the real simple one is actually something I mentioned in the prepared remarks as well as kind of the data cutoff timing where we're able to pretty easily allow more safety data to accrue like to get to 100 patients at the 12-month mark in the open-label follow-up. So that was one of the kind of quick offerings in there. I think some of the other things could be towards things that were mentioned in earlier questions and what could be offered up for post-marketing registry work and things like that.

In terms of the timing, we feel first half is very achievable. It's really based on having enough room to have an iteration or two with FDA. So it's less about time we need to prepare the submission, frankly, because we're -- things are ready to go quite quickly after we kind of have the input we need. It's more about that iteration with FDA.

And really, that's kind of an estimate based on experience. We've done things -- applications like this before back to the original Alagille application, where it took a couple of meetings along the way to kind of build up to that NDA filing for LIVMARLI in Alagille. And so it's a type of situation that we've worked through before.

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

Maybe just setting expectations in terms of when we should hear next steps on sort of the filing progress. I guess, what are you anticipating in terms of relaying kind of your FDA interactions to the Street? And then I think in your prepared remarks, you indicated that this necessarily won't flip over to PBC and that you have some feedback that VANTAGE will be a registrational study. I guess to your knowledge, is that this new group that conveyed that information?

And then one point of clarification just on the updated guidance. Is there anything for FOP in your updated product guidance? Or would that be above and beyond what you've outlined today?

Yes. Thanks for the questions. I'll take the first couple and pass it over for the FOP question. In terms of providing an update, our thinking is that this is likely an iterative process. And so we would plan to give an update when we have kind of a material update. So you don't want to be sharing the blow by blow on what might be e-mail correspondence even with FDA.

And shifting on to the PBC question, those interactions were written correspondence. So we don't know exactly if it's the same exact people behind it, but what gives a lot of comfort there is recency, right? So this has happened over the past year that we've had those PBC written correspondence.

And on guidance, the $680 million to $700 million does not include FOP. So anything we see in Q4 would be above and beyond, although we really expect the revenue to start more in 2027.

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

Chris, I'm wondering if you could just talk us through what this iterative dialogue looks like in terms of using breakthrough therapy or formal meeting status and scheduling of these just for a little bit more expectations on that flow of information between you and the agency?

Yes. Thanks for the follow-up, Jon. I mean one of the benefits of breakthrough designation is it does allow for more frequent advice from FDA, more frequent interactions. And so quite simply, that just means we'll be able to reach out more informally and also have more advice meetings.

How those sequence out really depends on basically how the dialogue with FDA progresses. So we can't really give too much more specific at this point. But we will keep you guys updated as we make progress through it.

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

This is RK from H.C. Wainwright. A couple of really quick questions. Based on the interactions that you have had so far for the PSC indication, are you planning to make any changes at all in your approach for the -- with the PBC indication once the VANTAGE data comes out? And also, if you do go ahead and submit in the first half of '27, notwithstanding the recommendation, do you run into a risk of refuse to file kind of a situation? And let's say, everything goes fine and you still continue to apply, would you expect an AdCom at the end of this?

Thanks, RK, for the question. In terms of the PBC approach, given the recent interactions, I think we have direct input for that indication for VANTAGE. So we feel like that is on a good course. So I wouldn't make changes at this point to what we're doing in PBC. We've kind of already made recent adjustments to accommodate what FDA asked for having VANTAGE being confirmed as a pivotal study.

And then on some of these questions about submission risks, I think it's how I would describe the question. That's the reason for this -- iterative interaction with FDA is to try to work through things that might be an RTF risk and try to get those off the table. And frankly, an AdCom, it might be something that could be helpful given the huge impact that volixibat has shown in a really terrible setting for patients. The relief -- pruritus relief improvement in sleep and fatigue that patients experience with volixibat treatment is really life-changing. So I think that could be one way that this gets highlighted.

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

Great. Well, thank you all for joining us today, and hope you have a great afternoon.

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

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.