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

Great. Good morning, everyone. Welcome. I'm Jess Fye, senior biotech analyst at JPMorgan, and we're continuing the 42nd Annual Healthcare Conference today with Mirum. I'm joined on stage by the company's CEO, Chris Peetz. He's going to give a presentation on the business, and then we're going to go into Q&A. If you want to ask a question in the room, you can raise your hands. Someone will bring you a microphone or you can submit them via the portal. So with that, let me pass it over to Chris.

Thanks, Jess, and thanks for hosting us here today. I'm really excited to give you an update on Mirum, and introduction for those not familiar, and a quick note that we'll be making forward-looking statements in the presentation. So I refer you to our SEC filings for a more complete disclosure of risk factors. And Mirum is a commercial rare disease company with a leading position in pediatric hepatology. Took dramatic steps forward in building out both the operating scale and commercial presence of the company over the past year. Now having 3 commercialized products in rare disease settings. A pipeline of 4 late-stage label expansion and new product opportunities. And really strong breadth of operations now having dispensed commercial reimbursed product in 18 countries and growing. So a very exciting time as we are on a strong growth trajectory off of 2023 and into 2024. At the start of the week, we gave a preview of our 2023 performance, and had $178 million to $180 million of net product revenue for the year and guided to continued growth across all 3 of our commercialized medicines, and a lot of drivers behind that to reinforce the trends that we've seen recently for LIVMARLI, CHENODAL and CHOLBAM that have driven the strong growth to date. LIVMARLI of note, we are still early days in our penetration into the Alagille syndrome market, which we see in the U.S. is a $500 million opportunity, and internationally, having strong demand growth that is now going through establishing reimbursement and breadth of country engagement as we go further into that international launch, so strong trends on that as we head into the year, and an upcoming label expansion opportunity. For CHOLBAM and CHENODAL, these are newer to the Mirum story and have historically had steady commercial growth that we expect to continue into the years ahead, and an exciting label expansion opportunity for CHENODAL that we'll speak to in a moment, and to late-stage clinical data events with interim dose-selecting analyses for volixibat in adult cholestasis. Take a view of that from a pipeline snapshot here. Approved in both the U.S. and Europe for cholestatic pruritus for Alagille syndrome with LIVMARLI. I mentioned the PFIC PDUFA date, that's March 13, so coming up for label expansion opportunity for LIVMARLI. CHENODAL, we are on track to submit our NDA for label expansion to CTX in the first half of this year. We'll speak a bit to the dynamic in that indication where there's a real need to help diagnose and treat patients earlier that we think can reinforce the growth of the bile acid franchise as we get towards that potential approval. And then volixibat, reinforcing our guidance that these interim analyses for the first half of this year are dose selection opportunities that will move these into the confirmatory potentially pivotal portion of these studies. And we'll highlight a couple of the dynamics in PSC and PBC and the real high-impact role that volixibat can play for patients in those settings. And a bit about the direction ahead. Mirum is on the back of a really strong fourth quarter last year. And ambitions for 2024 that match all that we did last year in growing the company and the top line, where we'll look to continue our commercial penetration, look at label expansion opportunities across all of our programs. An exciting ability to advance late-stage indications in the adult cholestatic settings, leveraging all of the knowledge that we have from administering IBAT in the pediatric setting into adult settings of cholestasis. And then the fourth point, looking at new pipeline additions to continue to grow the company. And make the note that we are both financially and have the team resources to continue to execute on this plan. So we ended the third quarter with $306 million on the balance sheet, and a team that's experienced in a number of different rare disease settings, advancing, developing and commercializing life-changing medications. Now I'll dive a little bit deeper into the commercial update. And we announced on Monday morning our 2023 commercial performance. Diving a little bit further into the fourth quarter, which is where you see the full impact of the additions to the company last year. We had about $70 million of net revenue in the fourth quarter, $42 million of that driven by LIVMARLI and Alagille syndrome, $28 million of that from the bile acid program. This is the largest quarter for both of those to date and strong growth dynamics that continue across all 3 products as we move into 2024. Our commercialization model is to be direct in the U.S., Canada and Western Europe, allows for a very efficient and patient-driven approach in the U.S. now having 3 products, offering an industry-leading hub service with Mirum Access Plus that helps support prescribers and physicians and then also helping to support diagnosis of patients with rare pediatric cholestatic diseases with the cholestasis panel that identify 77 different genetic mutations that are linked to various cholestatic diseases. Internationally, we have a team and direct presence in Western Europe that has had great success to date in its launch of LIVMARLI, and leveraging distributors and efficient ways to tap into broader international markets that have had a very impressive contribution in the early days. Expect more from that in the year to come. A bit about LIVMARLI and Alagille syndrome. So LIVMARLI is an oral, minimally absorbed ileal bile acid transport inhibitor. Very direct and relevant mechanism for settings of cholestasis. In cholestasis, disruptions in bile flow cause elevated bile acid accumulation. This can lead to progressive liver damage and severe symptomatic burden. So in the settings of cholestasis, commonly pruritus fatigue is one of the day-to-day burdens of the disease on top of a progressive liver disease setting. Using IBAT to target bile acid accumulation. Quite simply, we help prevent the reabsorption of excess bile acids in the terminal ileum. This results in pronounced reductions in circulating bile acid levels. In clinical studies, we've seen quite rapid reductions in pruritus and symptomatic burden. And over time in the data sets showing improvements in markers of liver health and transplant rates in the pediatric settings where we have 6 years of follow-up on these patients. So tremendous impact in the near term on patient symptomology and the promise of long-term impact on the disease course itself. In Alagille syndrome, the majority of these children that are diagnosed with this genetic disorder have a severe and persistent cholestatic pruritus that's part of the disease. Nearly 90% of them report having this as part of their disease course. And most of these children untreated will go to transplant by adulthood. In the LIVMARLI clinical program, we've seen dramatic reductions in serum bile acids, 84% response rate on pruritus in the near term. And for those that have that pruritus response, a really impressive reduction in the transplant rate, which the pruritus can be so severe in these patients that it is a leading indication for transplant. So by reducing the bile acids, we're having a pronounced short term as well as extensive long-term effect for the course for these patients. And from -- sorry, my slides aren't matching here at the moment. The -- in terms of the commercial performance in 2023, we saw 89% growth for LIVMARLI off of 2022. So just a real banner year in terms of increasing the impact for LIVMARLI in patients with Alagille syndrome. And a lot of the trends that created that growth continue as we look into the year ahead, with, in the U.S., the opportunity for increased penetration. As we look at the market, we still have the majority of patients being untreated and eligible for treatment with LIVMARLI as we go further into the prevalent pool. Still see newly incident patients across the U.S. and Europe, about 200 new cases identified each year. And a profile for LIVMARLI, that is really favorable. So we see -- because of the near-term symptomatic benefit for patients, we see really strong persistence and compliance for LIVMARLI that is now playing out in addition to the U.S. across our international markets. So a lot of drivers of growth that we see continuing for LIVMARLI into 2024. And a safety profile that's well characterized. And frankly, for a minimally absorbed drug is a very attractive profile for LIVMARLI in these patients. Now a bit on the commercial progress for the bile acid programs, CHENODAL and CHOLBAM. These are exogenous bile acid replacement agents that in settings of bile acid synthesis disorders. So mutations in the enzymes that are part of the synthesis cascade for bile acids. There are a number of different rare genetic mutations that can cause disruption. In these diseases, typically the byproducts of this disrupted synthesis cascade over-accumulate and cause symptomatic and organ damage to patients over time. And by -- in the various indications using CHOLBAM and CHENODAL to replace what is not being synthesized, you can help restore the homeostasis of the bile acid pathway and help improve long-term outcomes as those toxic intermediates are reduced. So a number of different indications where CHOLBAM and CHENODAL are standard of care across these different indications. And the -- these products have continued to grow steadily through the accumulation of patients receiving benefit from CHENODAL and CHOLBAM. An exciting update that we announced late last year for the CHENODAL program, a Phase III study in CTX, somewhat of a unique opportunity for CHENODAL, and that is currently used as standard of care off-label for CTX patients through what is a recognized medical necessity through the work that we've done as well as with the prior sponsor Travere to conduct a Phase III study. We're submitting an NDA to then get CHENODAL on label for CTX. And this, we expect will allow us to go help identify patients and help move the diagnosis of CTX earlier. Currently in CTX, the course to diagnosis can be quite lengthy. And by the time of the average age of diagnosis and often when someone's in their 30s, irreversible organ damage has accumulated. So we can have a high impact for patients by being able to actively promote and support earlier identification of CTX patients and prevent that long-term accumulation of organ damage that occurs in this disease. So exciting NDA submission coming up in the first half of this year, an important growth driver as we look out into 2025 and beyond. So now a bit about the pipeline and taking a look at the label -- a quick mention of the label expansion opportunity for LIVMARLI and PFIC. We have conducted a Phase III study of LIVMARLI in progressive familial intrahepatic cholestasis, a lot of parallels with PFIC to Alagille syndrome in terms of the genetic cause of bile acid disruption, but more disease of transporters than biliary tree formation. The symptomatic burden and high unmet need and high transplant rate is common in the setting of PFIC. In our Phase III study, we saw a pronounced reduction in pruritus from LIVMARLI versus placebo. And we are in review with FDA, PDUFA date of March 13, and excited about the potential to bring LIVMARLI to PFIC patients, also in review in Europe with EMA, decision expected in the first half of this year. Again, safety profile for LIVMARLI well-established and consistent in the PFIC patient population. Stepping forward to volixibat. Another minimally absorbed ileal bile acid transport inhibitor. Volixibat is being evaluated in 2 settings of adult cholestasis. And in this stage of the pipeline, we're moving in -- volixibat is moving into much larger, more prevalent indications of cholestasis in the adult setting. Primary sclerosing cholangitis and primary biliary cholangitis are 2 immuno-inflammatory driven settings of cholestasis where the commonality, similar to the pediatric setting, is that bile flow is disrupted and excess bile acids accumulate, contribute to liver damage and importantly, contribute to severe symptomatic burden. And so in this setting, there's a high unmet need for agents that can address that bile acid overload, and help improve the symptomatic burden for the patients as well as the potential to impact the long-term liver progression that is a factor in both of these settings. In primary sclerosing cholangitis, the unmet need is quite extreme. There are no approved therapies. And in this setting, where in the U.S. and Europe, there are approximately 54,000 prevalent patients by our estimates. About 2/3 suffer from active pruritus. And most of these patients are seeking active treatment for their pruritus in the setting of PSC. So we see a tremendous immediate unmet need to address the symptomatic burden of the disease. On the right side of the page, you can see what the patient-reported severity is here with a median score of 8 out of 10. In discussion with the patient groups, this is, by far, the most common and most prevalent factor of the disease that is dealt with by the patient community. So we're very excited about what volixibat can mean as a potential therapy for these patients. In terms of the precedent data for ileal bile acid transporters in cholestatic -- in primary sclerosing cholangitis, there's an important proof-of-concept study to point out that was conducted with maralixibat. And in this 27-patient pilot study, we saw what we've seen in the pediatric settings with IBAT inhibition in cholestasis, which is a very clear reduction in pruritus for those that had elevated pruritus at baseline, so 70% reduction for the patients in this study and a 40% reduction in bile acid levels, showing that the modulation and prevention of that accumulation of bile acids can lead to the same near-term symptomatic benefit in PSC patients. We're pursuing that with the VISTAS study. VISTAS is a placebo-controlled adaptive Phase IIb study. The interim analysis that we're expecting in the first half of this year will be dose selection. And then that study will seamlessly move on to the potentially pivotal portion of the study with a dose selected after the interim. The interim will be conducted by a blinded group that looks at, can the program hit a prespecified minimum effect size for efficacy. So really looking for validation that the pruritus benefit is sufficient to have both clinically and statistically meaningful impact for these patients, which then rolls into the confirmatory portion. So this interim analysis that we're expecting in the first half of this year is a key point and moving this into the pivotal stage, which is already seamlessly enrolling patients towards the pivotal data set now. I think a bit of context to put on the PSC program is that the search for valid endpoints for approval of new therapies in primary sclerosing cholangitis has been extremely challenging. And what we've done with this program is oriented the program towards an outcome that can be used for approval. So the pruritus in this setting is both very meaningful for the patients, addressing what is sometimes known as the suicide itch in PSC patients, and also is a valid outcome that can be used for regulatory purposes. So we do see the pruritus endpoint here as a potential breakthrough for PSC patients to have an endpoint that can be used for registration studies. We're mirroring this with a study in primary biliary cholangitis as well. Some commonalities in PBC, pruritus also a predominant issue in these patients, and both in the first and second line setting. And in PBC, we segment the market for PBC patients looking at levels of alkaline phosphatase, where the current standard of care is to treat with UDCA and those who are responsive on alkaline phosphatase will stay in that first-line setting. And some patients will not be controlled with alkaline phosphatase and will move on to second-line agents for treatment. Our program looks across both of these segments. So there's no baseline alkaline phosphatase criteria in the VANTAGE study. So allowing us to be positioned as both a first or second line agent, again, using pruritus as the outcome for approval here. So the VANTAGE PBC study, similar to VISTAS is heading towards a dose selecting interim in the first half of this year and excited about sharing that update with everyone when we get to that data readout. So I'll wrap here just with a quick recap of where we're at as Mirum. We've created a very dynamic rare disease company with a leading pediatric hepatology franchise; a growing, efficient commercial business coming off of fourth quarter with $70 million of net revenue; and growth drivers in place across all of our products that we expect to continue to drive growth into 2024; multiple regulatory and clinical milestones with the PFIC PDUFA date in March this year; CTX NDA filing in the first half of this year; and really key volixibat interim analyses to take that program into the pivotal stage in the first half of this year. So a very exciting moment for Mirum, and I appreciate all the interest in the company. And now I'll turn to Jess for questions.

Great. Thanks for the presentation. So you talked about the business growing in 2024, and then I think there was a stack bar chart that had like a bar for '24. Should we be using a ruler on the bar chart to kind of estimate the growth you're anticipating? Or is there any more kind of bookends you can put around expected growth this year?

So I wouldn't use a ruler on that. But what I can do is I can give some more color on kind of component by component, some of the drivers that we see in the business. And really, which is behind our guidance of growth across all products and growth across all of the segments that are consistent with what we saw in the close of 2023. So with LIVMARLI in the U.S. as a starting point, in Alagille syndrome, we've seen consistent quarterly accumulation of new patient starts, strong persistence and a steady growth quarter-over-quarter. We expect that trend to continue. So we're still early on in penetration. So what you've seen in 2023 in terms of the Alagille syndrome growth, that's a consistent trend that we see going into the year ahead. PFIC as a potential label addition. You can look at as an opportunity that in 2024 from a revenue standpoint because of label expansion needing to establish payer policies for reimbursement is more back-end loaded this year, but is an ability to potentially increase that growth trend that we see for Alagille syndrome. And then on the international business, it's very strong demand growth around the globe for LIVMARLI, and we'll see a continued progression of gaining reimbursement market by market as we go through the year. So -- and what we've seen in the previous quarters for LIVMARLI internationally is that strong demand growth and increased reimbursement over time. So all of those trends are healthy and strong and continue into the year. Bile acid programs, similar, we've seen those historically grow at low to mid-single-digit percent. And as you saw in the fourth quarter, having that over -- in Mirum, that continues. So the fourth quarter being largest quarter to date and all of the trends in terms of patient identification, new patient starts continue as they have historically.

Great. Maybe you can talk a little bit about how the competitive dynamics are playing out in the U.S. with Bylvay in Alagille. And I guess -- maybe talk about what the right way to think about the proportion of market share you expect LIVMARLI to keep is?

So there's a difference by geography here to speak to. In the U.S., where we saw Bylvay's label expansion to Alagille syndrome in June. We now have 2 quarters with both agents approved in the setting. We've not really seen any impact to our trajectory. So I feel we're in a really strong position and continue to see that strong -- further penetration as well as continued persistence. So the dynamic has been quite favorable. And some of that driven by familiarity with LIVMARLI, being first in the larger indication, there's a pretty broad familiarity with pediatric hepatologists with the product. You have to credit our commercial team for the services that they set up in terms of the Mirum Access Plus Hub, that's led to some of that persistence in the profile. So in the U.S., we see a really strong dynamic and continued leadership position. In Europe, the regulatory situation has really put Mirum in a very clear leadership position for Alagille syndrome, where Bylvay was not able to maintain orphan designation for their application. And so they have withdrawn their application. They may be pursuing country-by-country specific approaches. But for now, LIVMARLI is the only agent approved in Alagille syndrome in Europe.

Okay. What about in PFIC, can you just talk a little bit about how you're thinking about the overall market opportunity for LIVMARLI in that setting? I don't know if you -- it's like relative to Alagille or kind of from a market share perspective, what can you tell us there?

So PFIC relative to Alagille in total addressable market is roughly 1/3 based on what our work has shown in terms of prevalent patients and incidence rates. And Bylvay has been indicated for PFIC for a couple of years now. So what we don't expect to see is a high number of switches. And we see this from our experience in Alagille syndrome where we're not seeing that on the Alagille side. Where we see potential for growth with the PFIC patients is that our Phase III study not only showed unprecedented effect size compared to prior data on pruritus and serum bile acids, potentially allowing us to improve response for patients that aren't fully controlled. But our study also included a broader genetic data set than prior studies have. So we have randomized data across all PFIC subtypes. And while this isn't necessarily a labeling differentiation, we could see this play out to be a reimbursement differentiation, where payers that go kind of beyond just the label in prior authorizations having that broader genetic profile of PFIC proven out in our Phase III study will be great support for reimbursement and allowing access to some of these less common subtypes that are different genetic disorders to be reimbursed that might have difficulty getting reimbursed today.

Great. And maybe last one on LIVMARLI. Can you just share what the kind of learnings were from that Phase IIb EMBARK study that didn't hit the primary endpoint? And the extent to which you think those results do or do not have read through to IBAT inhibitors in other indications, particularly in the adult indications with volixibat?

The biliary atresia setting for EMBARK was very different from every other setting and scientific question that we've looked at. And the key thing to point out here is that, that study was on top of surgery. So is LIVMARLI adjuvant to the Kasai procedure, which is a surgical procedure directed at establishing bile flow. So a very direct and relevant procedure on the bile pathways where LIVMARLI is active. What we saw in that study was a much higher-than-expected response to the surgery, which is great news for patients and so that the Kasai procedure led to in both arms quite pronounced response on bilirubin. So there's patients that did well on the surgery over the course of the study continued to do well. Those that did not tended to progress to events relatively quickly. So the surgery really was the defining element of that study and that it drove a really strong response for patients. Now all of the other settings, what we've seen in Alagille syndrome, PFIC, what we're looking at in PSC, PBC, those are not adjuvant to surgery. Those are -- so there's more in common between those agents -- those studies compared to EMBARK, which is just a very ambitious setting, I think, is probably the best way to describe it.

Got it. So maybe switching over to volixibat. Can you just recap what some of those factors were that impacted the enrollment in the PSC and PBC trials? And can you talk about what gives you confidence heading into those updates in the first half?

Yes. So we, in particular, last year, had a period of time where we updated our time lines due to a batch of screen fails is really what happened there. The reasons for screen failures that we've seen across the program typically have to do with laboratory values, so minimum safety laboratory levels for entry into the study, pretty standard for liver disease studies and also compliance with completing the patient-reported outcome tool. And then a smaller number just to have -- make sure that they have pruritus when they come into the study given its a pruritus study. We've implemented quite a bit to improve enrollment rates, and we've seen increased activity. And for the interim analysis, we do have the patients in the study now. So clear line of sight that the interims will be conducted in the first half of this year.

Great. In the slides, I think you flashed up some PSC data for maralixibat. How reliable do you think that data is? Or maybe put differently, how much is the placebo response typically in PSC if we kind of think about like mentally adjusting for the open-label aspect of that data?