Mirum Pharmaceuticals, Inc. (MIRM) Earnings Call Transcript & Summary

Great. Welcome. Good morning, everyone. My name is Jess Fye. I'm a biotech analyst at JPMorgan, and we're continuing the 43rd Annual Healthcare Conference today with Mirum. First, you're going to hear a presentation from the company, and then we're going to go into some Q&A. So if you're in the room and you want to ask a question, just raise your hand and we'll hand you a microphone or you can also send questions to me via the portal. So with that, let me turn it over to Mirum's CEO, Chris Peetz to present.

Thanks, Jess, and thanks, everyone, for the interest in Mirum very excited to give you an update on the company and what lies ahead for us. First, I'll remind you that I'll be making forward-looking statements. I refer you to our SEC filings for a complete disclosure of risk factors. And it's a very exciting moment for Mirum and for what lies ahead for us. Earlier this week, we announced 2024 net revenue of $336 million showing growth across all 3 of our commercial medicines last year. And all of the drivers of that growth continue into this year where we are guiding towards $420 million to $435 million net revenue for the year showing continued growth across all 3 products. And doing this with a very efficient business model, we also are guiding towards being operating cash flow positive for the year as these products continue to grow in ultra-rare settings. And we've built a pipeline of even bigger indications that follow, and we'll go through all of this, the commercial growth drivers and some of the pipeline dynamics in this presentation today. From a pipeline view, this is what I'll cover as we go through. In green, we have our approved medicines driving that topline growth and the blue some of the upcoming catalysts, a really big year for clinical execution for Mirum as we push our volixibat program towards complete enrollment in our PSC study in the second half of this year. PBC that follows into next year. The PSC opportunity that we'll go through quite exciting in that we're lined up for a potential topline reading in 2026 that would drive an NDA filing for potential approval in PSC. It's an exciting moment for the volixibat program this year as well. And a recent addition to the pipeline with MRM 3379 for Fragile X and we'll go through some of the details of that Phase II program that we expect to start later this year. First, a comment on Mirum's business model, where in a short amount of time, we have created one of the leading rare disease companies with an efficient operating model, we commercialize directly in the U.S., Canada and Western Europe. We've leveraged some really strong partners and distributors around the world to amplify some of the work that we've done in our core geographies and all of that's played through with the results you see on the right-hand side of the page here, we're heading into this year, we're looking to add nearly another $100 million to the top line from our ultrarare platform with LIVMARLI, CHENODAL and CHOLBAM. Behind that, really large opportunities with volixibat and the Fragile X program each being $1 billion-plus opportunities that we can leverage on top of the commercial platform that we've built with LIVMARLI, CHENODAL and CHOLBAM. So that will dive into some of the dynamics for LIVMARLI. And first, a bit of a background on ileal bile acid transport inhibition. LIVMARLI is an IBAT inhibitor that goes right at the absorption of bile acids in the terminal ileum, very relevant across many settings of cholestasis where elevated circulating bile acids drive severe symptomatic burden and progressive components of the disease that IBAT has the ability to reduce those circulating bile acids. In clinic, we've seen, most importantly, rapid and pronounced reduction in pruritus across a number of different settings, resulting from that rapid decrease in circulating bile acid levels. Long-term follow-up in these settings of rare genetic cholestatis, we've seen improvement in transplant, follow-on that pruritus improvement over time and excited about what we can show from the platform in the future studies that we're conducting now. For LIVMARLI, we have been approved in cholestatic pruritus for Alagille syndrome. That was our initial approval. And last year, gains label expansion for pruritus due to PFIC in the U.S. The base business in Allergial continues to be healthy and strong, where we think we're likely in the range of about 40% or so penetrated into the prevalent patient population. So it still remains expansion opportunity in Alagille in the prevalent population as well as addressing new diagnoses, which continue to occur on an annual basis. PFIC was a really strong driver of accelerating our growth in the past year with that label expansion, particularly into the second half of the year, we saw new patient starts with PFIC with LIVMARLI adoption, both in IBAT naive and in patients switching therapies in PFIC. And very excited about what's ahead for the EXPAND study, where I'll go into that in a bit more detail in a further slide, where we're now launching a [ basket ] study to address some of the underserved and understudied settings of cholestatic pruritus. So all of this really lines up with LIVMARLI for continued strong growth. It's a big contributor to our 2025 guidance with the continued PFIC launch and international expansion A big part of last year's growth will continue into this year with key geographies in South America and Japan on the horizon for potential approval and reimbursement as we go through the year this year. Profile for IBAT therapy, really well established at this point. The only -- the most prevalent side effects, I should say, is a treatment-related diarrhea. This is mechanistic. That's what actually drives this results of some of the bile acids being cleared from the body. Now moving on to the bile acid portfolio on the commercial update here. CHOLBAM and CHENODAL are 2 bile acid replacement therapies, that are indicated for -- and used in a number of different bile acid synthesis disorders. This is a list of different point mutations that disrupt the bile acid and cholesterol synthesis pathways and result in various forms and presentations of a disease that can range from kind of liver disease presentation to actually CNS impacts and diseases that are traditionally seen and treated as neurological conditions. So CHENODAL and CHOLBAM continue to be steady performers from a growth perspective as we see uptake across both the hepatology and medical genetics and neurology communities and continue to see steady growth ahead for the brands as well. A key point for CHENODAL, where this year, we are under review for a formal approval for CTX. We see this as a potential driver of incremental growth with the on-label potential for CHENODAL could help us help identify and find and promote to find new patients to get patient starts on therapy for CTX. To date, it is standard of care and the real unmet need that we see in CTX is helping to find and identify these patients earlier and prevent some of the progressive neurocognitive impact that can result from untreated CTX. So continues to be a steady growth driver in performance for CHENODAL and CHOLBAM. Now we'll step into the pipeline, a little bit of what's ahead for Mirum. And first, the label expansion opportunity for LIVMARLI. Cholestasis is the description of the disruption in bile acid processing or flow in the liver. And actually, as you can see from the settings where we have our approvals and have been studying our IBAT inhibitors. There are a long list of different causes of cholestasis. But 1 of the common results of that is elevated bile acid levels and cholestatic pruritus. What we've seen since our launch from LIVMARLI is a strong demand in a number of quite rare causes of that cholestatic pruritus. And -- to date, actually, over 100 patients of compassionate use demand that has come out of what we've seen from physicians in the U.S. from compassionate use and requests for access to drug for patients that cover the spectrum of pruritus in biliary atresia in secondary sclerosing cholangitis and in a number of more rare genetic causes of cholestasis. So to respond to that demand, we've put together the EXPAND study and EXPAND is a placebo-controlled study looking at LIVMARLI in these settings, this basket setting of cholestatic pruritus. We've just launched the study, expect to complete enrollment next year and have designed it as a Phase III label-enabling study, really to capture this long tail of other forms of cholestasis that can result in that cholestatic burden and quality of life impact. And really hard to understate the real need in this setting where many of these patients without treatment will be candidates for transplant to treat that cholestatic pruritus. So excited to get this study up and running and bring LIVMARLI to an even broader set of patients with the EXPAND study. So enrollment completion expected next year for EXPAND. Now shifting to volixibat. We're moving now from the primarily pediatric settings into adult liver and cholestatic diseases with volixibat. And 2 key indications where we're studying volixibat, both of them immuno-inflammatory driven settings of cholestasis, primary sclerosing cholangitis and primary biliary cholangitis. The commonality here, again, back to the mechanism of IBAT is we are looking to reduce the circulating bile acid levels in these patients and improve the pruritus burden that is driven by that circulating bile acid level. The PSC program, in the background of PSC, there are about 30,000 patients with PSC estimated in the U.S. And about 2/3 of them suffer from pruritus, and many of them actively seeking treatment for that pruritus. The challenge in PBC is that there are no approved therapies for these patients. And to date, no real consensus on approval endpoints and how to study drugs for PSC. This has been a setting that's been quite challenging because of the variability and not only liver histology, but also in the serum endpoints that have been studied for PSC patients. By going after the symptomatic burden, we can use that symptomatic improvement as an outcome and an endpoint to use for pursuing an approval in PSC and quite excited about what that means for the PSC patients and the ability to put together a potentially registrational program for the setting. IBAT has seen -- has shown an impact on ITCH in PSC patients. So we started this program with some clinical evidence that the mechanism had the potential to have a tremendous impact on ITCH in PSC patients. And we -- to pursue that, we designed and launched the VISTAS study, VISTAS is an adaptive Phase IIb study looking at volixibat versus placebo in PSC patients with pruritus. Last year, we had an exciting update to the program where we conducted an interim analysis that was a blinded evaluation of 2 doses of volixibat where the data monitoring committee selected a dose to pursue forward into the confirmatory portion of the study. So we are now enrolling in that second part of the study that we'll look to confirm the pruritus benefit that was seen in the first 45 patients that were evaluated in that interim. On track to complete enrollment in the second half of this year. That would put us up for data in PSC next year for volixibat. So exciting moment where we think we're on track to have table to bring the first new therapy forward for PSC patients with the volixibat VISTAS program. Companion indication for PSC for volixibat is evaluating also cholestatic pruritus in PBC. PBC is a more prevalent cholestatic setting. In the U.S., we estimate about 85,000 PBC patients that are diagnosed. And again, the majority of them suffer from pruritus. So this is a tremendous unmet need across the PBC landscape. An important distinction that for how our program is designed compared to some of the recent advances and new therapies that have been approved for PBC is that our program enrolls patients across all settings of alkaline phosphatase. So volixibat is being studied in those first-line patients that are -- have their biochemical markers relatively controlled by UDCA, volixibat being studied on top of UDCA to help improve the symptomatic burden in those patients and is also being studied in the second-line patients that have more elevated and progressive liver biochemistry. So volixibat is positioned to be a potential treatment for pruritus across all settings of PBC. And similar to the VISTAS study, we had a really exciting update with the interim analysis of VANTAGE last year. And we have a snapshot of some of that top line data in the pages ahead here. VANTAGE was similar to VISTAS an adaptive placebo-controlled study. The structure of the interim analysis was different in that we were -- we conducted an open analysis and presented that data at ASLD last year as a late breaker. We also discussed the data with FDA and submitted it for breakthrough designation and were granted breakthrough designation for cholestatic pruritus in PBC, a tremendous acknowledgment of the unmet needs in PBC to address cholestatic pruritus. For the interim analysis, the couple of the pages that were presented at ASLD. As mentioned, the population enrolled in the study included both first and second line. About 2/3 of the patients in the interim analysis were first-line patients with a relatively controlled alkaline phosphatase levels, 1/3 with alkaline phosphatase levels above the 1.67x upper limit of normal cutoff and otherwise, fairly representative population for PBC. The study selected 4 patients with elevated pruritus. So a baseline score of 6.3 to 6.8 in the ItchRO 0 to 10 scale for the VANTAGE study. And the results were quite striking. And you see on the page here, the pruritus scores over time for the 2 doses of volixibat versus placebo where you see in the first few months, there is a relatively rapid onset of the reduction in pruritus levels that is sustained over the 6-month window that is analyzed in the study. So 2.4 point reduction, placebo-controlled reduction for volixibat in the 20-milligram dose that is being taken forward into the second portion of the study. So the confirmatory portion of the study enrolling now continuous enrollment from the time when we did the interim and on track for completion of enrollment next year. Similar to other settings, the -- we also observed reductions in circulating bile acid levels and most common treatment adverse event was the mechanistic related diarrhea that is seen in -- with IBAT treatment. Now moving on to the most recent addition to our pipeline, MRM-3379 is a PDE4D that we are taking into a Phase II study for the treatment of Fragile X. Fragile X is one of the most common inherited causes of intellectual disability, tremendous unmet need with no approved therapies. And we estimate 50,000 male patients across the U.S. and Europe. So quite sizable opportunity. If we can find -- confirm some of the data that's been seen with this mechanism in treating the cognitive impact of Fragile X. The program that we've acquired, the MRM 3379 is a brain-penetrant PDE4D inhibitor that has quite favorable brain-to-plasma ratios. which is 1 of the key differentiators that we see in this program to optimize dosing to get the exposure of drug to where we want to be able to impact the cyclic AMP levels that are depressed in Fragile X patients. PDE4D has been shown to boost cyclic AMP levels in translational models of Fragile X and cognitive impact in memory. So quite excited about what this program can mean for Fragile ex patients. We are planning to discuss our program with FDA in the coming quarters, and we'll launch this Phase II study later this year. So quite excited about the new addition and the potential for bringing a new therapy forward for Fragile X patients. So pulling that all together has been a busy year for Mirum and lots more ahead reiterating kind of where we stand today on track for $420 million to $435 million of top line for the company and guiding towards operating cash flow positive for the year, so continuing to grow and perform with this efficient business model in ultra-rare medicines. And several potential bigger opportunities ahead. Pipeline catalysts, as mentioned, the PSC enrollment later this year with data next year is a real highlight with our next potential registrational program. PVC data that will follow after that and excited about getting the Fragile X and expand opportunities enrolled as we move into next year as well. So a busy year for Mirum. And as in years past, we're excited about what we've built and the potential that we can leverage ahead. I really appreciate the interest and look forward to your questions.

Great. Thanks for the presentation. Maybe starting with LIVMARLI, you gave us guidance for the year. What's driving the growth in 2025.

So for LIVMARLI in particular, there are several growth drivers. And this is actually 1 of the aspects of LIVMARLI's product profile is there are tailwinds in the growth of LIVMARLI that we expect to be persistent for years to come. The treatment response to LIVMARLI is a quite rapid symptomatic improvement. That leads to really strong persistence and compliance because patients feel better when they're on drug. So from the base of patients on therapy, we expect strong compliance persistence and a weight-based dosing dynamic that plays into that kind of continued growth trend from the core business. Adding on top of that, we continue to see opportunity in the prevalent population for Alagille. We've been really pleasantly surprised in the uptake in PFIC since the label expansion there. With PFIC, in particular, it's worth noting a dynamic where we're finding more patients in the adult setting than we had originally anticipated. As we're preparing for volixibat launch, there's a synergistic ability to help educate in the adult setting on the potential for IBAT and the diagnosis and care options for PFIC. So we see PFIC as 1 of the continuing growth drivers. And then lastly, the third component to LIVMARLI's growth is international. And while we have launched in Western Europe, and we have distributors that have been selling product in a number of different countries, the list is expanding. So more country launches ahead and also some of those continued growth drivers in the established markets will continue to grow that current base as well.

When you talked about LIVMARLI being about 40% penetrated in Alagille, was that just LIVMARLI? And then I guess how penetrated is the overall Alagille market?

Yes. That's our estimate for LIVMARLI share. We've also looked at some data pools just looking at IBAT market share in Alagille syndrome. We think we're 90% or higher of Alagille in the U.S. and really attribute a lot of that, not only to our lead in Alagille syndrome, but also just the commercial model where our team has done a great job making LIVMARLI the first choice for physicians for their Alagille syndrome patients.

You talked about PFIC as an opportunity as well. What are the strategies you're using to increase LIVMARLI's market penetration there?

A lot of it comes back to the data sets from the MARCH study. So the MARCH study was the Phase III study that led to the label expansion for LIVMARLI and PFIC and what we see there is just quite striking improvements in pruritus. And beyond that, the data also shows significant reduction in bilirubin compared to placebo and significant growth compared to placebo. So clear that the treatment response to LIVMARLI is multifold. So that you're -- by treating the elevated bile acid levels and ITCH you're seeing follow-on effects that are -- that suggest the patients are doing well across all parameters. That data is quite well known. So the more that we educate on it as well, the more we think that supports the use of LIVMARLI in PFIC. Also I come back to looking at what we've built from a commercial team. The payer team, the market access team has done a great job supporting policy updates for LIVMARLI and PFIC, some of them being quite favorable to brand. And I can't complement the commercial team at Mirum enough on what they've done to make the LIVMARLI PFIC launch go as well as it has.

What are the latest competitive dynamics between LIVMARLI and Bylvay in PFIC? And where does the market share stand there?

So I don't -- less clear on the market share for PFIC. Bylvay certainly has the bigger share in that setting. They've been approved for a number of years before a label expansion. But what I will say is that the LIVMARLI data set does bring something new to the table. I mean our study covered more genetic subtypes of PFIC. And frankly, our team is entirely dedicated to that prescribing base. And so that's helped us pick up, I think, more patients in PFIC than we originally anticipated.

Okay. I think you put on 1 of the slides that volixibat could be $1 billion opportunity. Your FXS asset could be another $1 billion asset. How does LIVMARLI and the CHENODAL and CHOLBAM franchise stack up relative to those?

So we don't have a product-specific peak guidance. What I will say is that the addressable market segments for LIVMARLI are easily over $1 billion in total. And what we're doing is continuing to grow into that. LIVMARLI has IP protection to 2040 and beyond. So Orange Book listed patent protection to 2040. And we expect LIVMARLI will continue to grow throughout that time period.

You also highlighted the EXPAND trial to potentially further broaden the LIVMARLI label. How is enrollment going there? How should we think about enrollment time lines? And -- how does that kind of opportunity factor into the product's peak potential?

Yes. It is -- from a growth potential -- I mean it's a sizable segment. We talk about in the U.S. we estimated about 500 patients that would fit with the profile we're talking about. But that's different from a traditional epidemiology estimate. These are actual patients that we estimate are out there. So we -- 1 way to think of it is -- it's at least the size of PFIC as an indication and certainly could be larger than that. And from how that plays into enrollment is we think it will support robust enrollment. The studies centers have just opened. We've just started screening. So, so far, I can say we're on track for enrollment completion next year. It's a 20-week endpoint, so relatively quick to get to data once we hit full enrollment. And the program was designed based on the demand that was out there. So we are -- we think this is a really great growth accelerator for LIVMARLI once we get to that label expansion.

Maybe switch to volixibat. What can you tell us about enrollment of VISTAS and VANTAGE?

Performing well. So after the interim analysis last year, we saw increased interest from investigators. We've added sites kind of following up on that interest. So several different centers that have reached out and wanted to participate in the study kind of makes us very confident that we're on track for the VISTAS being fully enrolled in the second half of this year and VANTAGE into next year. Worth noting VANTAGE is a larger study. That's the driver of the longer time line as the -- for PBC being a larger indication, we're targeting a bigger safety database for that study. So the energy is quite strong out there based on the interim analysis.

And how are each of those studies powered? And how confident are you in the final result based on the interims?