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

Great. Good afternoon, everyone. My name is Jess Fye. I'm a biotech analyst at JPMorgan, and we are delighted to be continuing the conference today with Mirum. Format is a little different this year. We don't have to all shuffle over to another room for Q&A. The Q&A is going to happen right here after the presentation concludes. [Operator Instructions] So with that out of the way, let me turn it over to Mirum's CEO, Chris Peetz.

Thanks, Jess, and thanks, everyone, for the interest in Mirum. Excited to walk through the story here today. I'm going to just make some kind of overview comments, dive a little bit deeper into our commercial program in Alagille syndrome, talk about some of the pipeline across pediatric and adult cholestasis and then kind of wrap up the story and why we're so excited about 2023. I'd be making forward-looking statements. So I'll refer you to our SEC filings for a more complete disclosure of risk factors. And Mirum is a high-growth rare disease company, commercializing life-changing medicines across a number of rare cholestatic settings. We just completed our first year in market with LIVMARLI and Alagille syndrome with tremendous success throughout the year with growing revenue. We'll dig into some of that story. We have a pipeline of additional label expansion and a second product opportunities driving further growth behind the Alagille syndrome launch and the team and the financial resources to really deliver on all the value creation that we've set up here with Mirum. Just yesterday, we announced preliminary results from the top line for 2022 and a tremendously successful first year in market with LIVMARLI. Total revenue for the year of $76 million and finishing with a very strong fourth quarter with $27 million of net product revenue in the fourth quarter for LIVMARLI and Alagille syndrome. That $27 million included a really strong start for our distributor markets as well. Most of the year was focused on U.S. commercialization to drive that $76 million of top line. But we had $5 million of international distributor market sales as access began across a number of additional markets. And looking forward, we're positioned for another strong year in 2023. The U.S. business, we see a clear line of sight to 50% year-on-year growth for the U.S. Alagille syndrome business in the U.S. and additional incremental growth from international markets beyond that. Behind that, a number of label expansion opportunities. So we're on the cusp of submitting our sNDA for progressive familial intrahepatic cholestasis, a second indication, 3 late-stage clinical studies that will have data events throughout the year. And as mentioned, well resourced to unlock all the value in our programs, $252 million of cash on the balance sheet at the end of 2022. Our commercial business is already cash flow positive so that top line growth driving contribution throughout the year in 2022, and we expect that to continue to grow throughout 2023, and an operating expense profile that's relatively stable. So expect the business performance to continue to improve and drive growth throughout the year of 2023. Now I'll take a step back and just talk a bit about the science behind our 2 programs, LIVMARLI and volixibat. These are both oral, minimally absorbed ileal bile acid transporter inhibitors, if they go target directly at the bile acids that cause all sorts of symptomatic burden and disease progression in cholestatic settings. Cholestatic liver disease is a broad range of different liver diseases that result in a similar concept of disruption of bile flow. In all of these settings, elevated bile acids can cause severe symptomatic burden in particular, pruritus that can be incessant and actually one of the primary drivers of liver transplant in a number of these settings. And it also drives progressive liver damage. So bile acids and elevated bile acid levels throughout the body are really one of the primary disease drivers in cholestatic liver disease. IBAT inhibition targets directly this elevated bile acid level through blocking the reabsorption of bile acids in the terminal ileum with minimally absorbed products, we can deplete that excess bile pool, lowering the serum bile acid levels and thereby improving some of the burden of disease. And we see that quite clearly in clinical studies. We'll walk through some of the highlights of it in a couple of the pediatric settings, where we've had breakthrough data sets. And in the short term, you see bile acid levels reduce. You see the cholestatic pruritus resolve quite rapidly. So a near immediate improvement in quality of life. And in the long term, you see prevention of transplant. So there is long-term improvement of outcomes in the pediatric settings that we've seen improvements in growth on top of that day-to-day symptomatic and quality of life improvement. So tremendous impact across all of these cholestatic settings with IBAT inhibition. We're taking this across a broad range of different settings. LIVMARLI is our approved product in cholestatic pruritus due to Alagille syndrome. We're advancing it in 2 additional high unmet need, devastating pediatric settings. Volixibat, our second program, we're advancing in adult cholestatic indications. Specifically walking through the pipeline, for LIVMARLI and Alagille syndrome, we have just completed our first year in market as mentioned. And just at the end of last year, gained EMA approval for treatment of cholestatic pruritus due to Alagille syndrome. So looking forward to launching across the European markets throughout the year this year. And we presented groundbreaking data in PFIC, our second indication in the fourth quarter last year as well. I'll pull out some of the highlights of this, but a near-term label expansion opportunity for us. We're moving quickly now to submitting the sNDA for treatment of pruritus due to PFIC and expect that label expansion opportunity around the end of this year. Third indication on the pediatric side, biliary atresia, again, another very high unmet need setting of rapidly progressive cholestatic liver disease. We're conducting a Phase IIb study that expects data in the second half of this year. And shifting into adult settings to more common cholestatic conditions with primary sclerosing cholangitis, primary biliary cholangitis, expecting interim data readouts from these adaptive Phase IIb studies in the middle of this year and in the second half. So exciting year full of clinical catalysts and commercial growth ahead for the company. Now I'll dive a little deeper into Alagille syndrome, and I'll start by setting up some of the clinical setting that before the approval of LIVMARLI was a complete unmet need in terms of the clinical setting. Alagille syndrome impacts across the U.S. and Europe about 4,000 to 5,500 children. The disease is caused by a mutation in the jagged notch signaling pathway that causes disruption in vasculature formation and in the liver presentation, which is common across the vast majority of these children, there is severe disruption of the biliary tree and extreme cholestasis. These children have the most severe cholestatic symptomatic burden that you could imagine. In the setting, nearly all of the children have cholestatic pruritus, and that is the leading cause for liver transplant before the availability of IBAT to address the cholestatic pruritus. And this disease is highly progressive. So because of the symptomatic burden and eventual progressive liver disease, most of these children will go to transplant without treatment. Our approval has been met quite well and launch has gone -- has been very strong in the U.S. and excited about what lies ahead for the international markets. You can see the top line performance here on the left side of the page with $74 million of net product revenue in 2022, positioned for 50% growth in the U.S. and additional growth on top of that from international markets and multiple drivers to bring that commercial growth throughout the year. First, just in the U.S., we still feel that we are quite early in penetrating the total opportunity for the Alagille syndrome market in the ballpark of about 20% penetrated into the total prevalent patient population. So we expect to see, throughout the year, continued accumulation of new patient starts as LIVMARLI becomes more widely adopted by the pediatric hepatologists in pediatric gastroenterologists that treat these patients. Europe and distributor markets will also be drivers of growth as we go through the year. In Europe, our commercialization model is to go direct in Western Europe. So we are lined up to launch in Germany in the coming months. That will be the first market to come online for a Mirum-direct international commercialization and expect to continue to add countries across Western Europe throughout the year. And we're accelerating our international launch through distributor partnerships. So using distributors and licensing partners, we've been able to pull forward patient availability and the commercial launch in a number of countries, as shown by that Q4 revenue performance with many of these distributors finding early access avenues to get LIVMARLI to patients with Alagille syndrome in several countries across Central, Eastern Europe and the Middle East. All of this pulled together, making that commercial business cash flow positive across the globe, and we expect the contribution to continue to grow as we go through 2023 and with a strong IP position with patent coverage expected through the year 2040. Now what's behind the commercial success in the U.S. We'll talk about the clinical profile, but a lot of it also comes from a very targeted and all-encompassing rare disease commercialization model. We use a single exclusive specialty pharmacy and an integrated patient hub that allows us to have tremendous visibility and follow-up capability for prescribers and patients as they gain access to LIVMARLI. It has been a real high point from the launch. It drives really strong compliance as well as awareness of the needs of our patient customers and the prescribers and payers that are all part of gaining access to LIVMARLI. As we expand outside the United States, we will have, as mentioned, direct access in Germany, France, Western Europe, and we'll drive a lot of this through, again, a single point of distribution, leveraging very efficient third-party distribution sources to get product to patients across Western Europe and using distributors and partner markets to accelerate and expand availability beyond where we can be on the ground ourselves. The clinical profile is a large driver, obviously, of the uptake of LIVMARLI and the data behind the Alagille syndrome approval are quite remarkable. So on the page here, you see the pivotal data set from the ICONIC study of LIVMARLI in patients with cholestatic pruritus due to Alagille syndrome, a rapid onset of treatment benefit when you look at the pruritus scores over the first 18 weeks of the study, a clear treatment separation from placebo and then long-term sustained effect over years of follow-up treatment with control and reduction of pruritus for these patients. In addition to this data, you see a very similar impact on serum bile acids. So driving that bile acid reduction and a highly significant placebo-controlled separation at the placebo-controlled portion of the study and sustained reductions over time. And the net effect of this is that in the long-term follow up, you see also a tremendous clinical benefit. That's shown here with an analysis we've done to compare LIVMARLI treatment against a matched natural history cohort of patients with Alagille syndrome with similar disease characteristics and severity. And you see over the course of 6 years of follow up, a 70% reduction in the risk of liver event, largely driven by a reduction in liver transplant in the LIVMARLI treated patients for tremendous long-term clinical benefit. And a safety profile that's supportive of a high persistence and compliance across the real-world treatment settings, where with 5 years of follow up and our package insert, we see that there's a very acceptable and well-characterized safety profile. We'll touch on this again as we get into the PFIC data. And in PFIC, we recently announced a pivotal Phase III study, a randomized, placebo-controlled study of LIVMARLI versus placebo in patients with pruritus and PFIC looking at 6 months and then rolling into an open-label extension period. Important to note in the background of this disease, there is a commonality with Alagille syndrome in terms of the severity and course of the cholestasis. It is a very severe disease presentation characterized by highly elevated circulated bile acid levels and severe pruritus, also a major driver of transplant in the setting. The genetic cause of the disease, though, is quite different. PFIC is a disease of several different transporters, disrupting bile flow and formation and secretion within the liver. And important to note that in our Phase III study, we included a very broad genetic profile of patients, including PFIC 1, 2, 3, 4 and 6 as well as additional uncharacterized PFIC genotypes. So to date, one of the broadest and most comprehensive Phase III data sets generated in PFIC. And the results of this study were highly significant and really moving the field forward in terms of driving deeper response and higher response rate. Shown on the page here is the pruritus reductions in drug versus placebo in all PFIC patients, in the all PFIC cohort of patients from the study, a 1.8 point reduction versus 0.6 on placebo. In this setting, a 1-point reduction is clinically meaningful. So we're driving reductions far beyond what is the treatment objective in this setting. Right-hand side of the page is another important analysis to keep in mind as we look at FDA precedent for labeling in the setting, often there an analysis can be looked at for the number of actual pruritus scores that are a 0 or 1 throughout the duration of the study conduct. So basically, how many times is the patient assessed as having effectively no itch. And in the LIVMARLI-treated patients, 62% of scores were 0 or 1. So tremendous benefit showing that you're addressing the cholestatic pruritus. And again, this is one of the benchmarks that we've seen used for regulatory precedent. Now moving beyond the short-term effect and what will be the registrational endpoint, the pruritus effect. We do see similar to the long-term follow-up in Alagille syndrome, the potential for tremendous benefit on the underlying liver health. And that shows up first in just the reduction in bile acids. So this toxic overload of bile acids is rapidly and dramatically decreased with LIVMARLI treatment compared to no change with placebo. And bilirubin, one of the primary markers used to assess the need for liver transplant and track the course of liver health for these patients, you see that continuous decrease in bilirubin on the right side of the page as patients on LIVMARLI see reductions in those liver laboratory values. And from a safety and tolerability side, again, LIVMARLI is a minimally absorbed agent. Primarily, what we see with treatment experience is mild transient diarrhea that's part of the mechanism of the drug, part of the clearing of bile acids that typically does not persist is quite short in duration, and real-world feedback has been quite positive on the safety and tolerability profile of the drug. And all of this points towards really what we hope for the future with patients on LIVMARLI is confirming what we saw in our Phase II study. This data here, looking at the long-term follow-up from the Phase II study of LIVMARLI in PFIC patients that with that bile acid reduction, you can have sustained avoidance of transplant. And that's what we saw from our Phase II study is patients with a serum bile acid response effectively don't go to transplant in a 5-year follow-up compared to you see the general course of treatment in the patients in the red line. So what lies ahead for data generation. Next indication is biliary atresia for LIVMARLI, where we're conducting the EMBARK Phase IIb clinical study. Biliary atresia is another highly severe cholestatic indication that is uniformly fatal without an immediate surgical procedure. The treatment opportunity for LIVMARLI is immediately after that surgery called the Kasai procedure. In these children that receive the Kasai procedure, there is a wide range of response with persistent cholestasis, and the goal of treatment in this setting is to knock down those elevated bile acid levels with LIVMARLI and help these patients avoid transplant. Bilirubin, again, is one of the key markers of transplant risk in this setting. You can see the data on the page here from literature, showing that there's a very clear risk stratification based on bilirubin levels. So our goal is to keep these patients with lower bilirubin levels, suggesting that their liver function is more intact and keeping them from progressing to transplant. Serum bile acid level is also predictive of transplant risk in biliary atresia. The EMBARK study is enrolling patients now, 6-month placebo-controlled study in 72 patients post-Kasai with biliary atresia, sites around the globe enrolling patients and on track for data in the second half of this year. Now shifting to the adult indications with volixibat. Volixibat, similar to LIVMARLI, is an oral, minimally absorbed ileal bile acid transporter inhibitor and from the data we've seen in clinic is highly active on bile acid levels and the bile acid pathway. We're taking this into 2 larger, more prevalent indications in the adult setting, primary sclerosing cholangitis, primary biliary cholangitis, or PSC and PBC, with prevalence levels that are much higher than the pediatric setting that we've been discussing so far. In PSC, probably just short of 30,000 people affected in the U.S. and PBC well over 100,000 being prosecuted in the VISTAS and VANTAGE study. These are diseases of immunoinflammatory disruption of the biliary tree, either through occlusion or inflammation, blocking bile flow and causing disruptions similar to the other settings, elevated bile acid levels cause symptomatic burden and progressive liver disease. So our goal of treatment here is to knock down those bile acid levels, improve the near-term symptomatic burden and improve the long-term outcomes. And there's great clinical data for precedent of IBAT inhibition in these settings. In both PSC and PBC, we've seen data sets where patients with pruritus and elevated bile acid levels see treatment benefit from IBAT therapy. That's what we're looking to confirm and replicate in our studies. The 2 studies we're conducting on the page here, VISTAS study for PSC, VANTAGE for PDC. The VISTAS study is an adaptive placebo-controlled study that will have an interim analysis that we expect to occur midyear this year for dose selection. Worth noting that this is a blinded analysis, and we are leveraging the data monitoring committee to evaluate whether this study crosses a prespecified clinical effect threshold before moving into the confirmatory portion. The reason for this is in discussions with FDA, we have agreement that this would be supportive of an NDA submission that by leveraging a blinded adaptive interim analysis, we can then use these patients in the full confirmatory analysis in the second portion of the study. VANTAGE, also an adaptive Phase IIb study. We expect interim data in the second half of this year, and we'll announce those data when we get to that analysis point. So pulling it all together, Mirum is poised for continued growth throughout the years ahead. We're off -- we're in the middle of a strong launching Alagille syndrome, starting out in our international markets, several indication expansions for LIVMARLI and volixibat ahead of us with larger and larger indications as we get into the adult settings. Catalyst-rich year. So on top of the LIVMARLI launch in Europe and international markets, we have the PFIC label expansion filing expected in the first quarter and then data readouts as we get further into the year. The volixibat PSC data expected interim analysis expected midyear, the biliary atresia primary endpoint expected in the second half of this year and the PBC interim expected in the second half of this year as well. So a catalyst-rich year on top of strong financial performance. And with our 2022 net revenue of $76 million, a strong fourth quarter at $27 million, poised for that 50% year-over-year growth in the U.S. on the back of tremendous accomplishments across the business. So really in stride here at Mirum, a 2022, that was full of accomplishments across the regulatory and commercial standpoint, delivering game-changing data for PFIC patients and excited to get that on the label and extend our launch for LIVMARLI. So with that, I'll wrap there, and so I'm excited about the growth prospects ahead for Mirum, and look forward to hearing your questions.

Great. So as a reminder, if you want to ask a question, just raise your hand and/or submit one electronically, and I'll read it off. I'll start. So with the commentary that we can expect 50% LIVMARLI growth in the U.S. this year, can you talk a little bit more about where that growth is coming from in terms of prescribers, i.e., is this additional prescribers or deeper penetration within the current prescribers and also patients maybe in terms of their severity?

Absolutely. So the dynamic we see in the U.S. is the majority of target accounts have prescribed. So we have the first use of LIVMARLI is pretty widespread across the target pediatric hepatologists and pediatric GIs. So the primary driver of growth we see and actually have seen in the recent quarters is from continued deepening of prescribing across their patient base from those existing prescribers as they move further into their patient population. The dynamic that we're seeing in market is really driven by current standard of care for Alagille syndrome, historical standard of care for Alagille syndrome patients, where the frequency of visit can be 6 to 12 months before patients come in to see their specialists and a growing sense of how to use and where to use LIVMARLI from these specialists. So we do see them continuing to go deeper as they have more of these patient visits and also kind of understand more the role of LIVMARLI in the patients. I mean it's worth noting that in this setting, even with the families and physicians themselves, there is an underestimation of what they're doing to cope with the disease burden. A common profile that we talk about to kind of really highlight the dynamic at play here is that we speak to a specific kind of family and patient that we met, where that really typifies a patient and a family that's been living with the disease for a decade. So someone with a 10-year-old child that has gone through really a terribly burdensome disease course for the first decade of their life, but they've learned to cope with it. And part of their survival mechanism is that they are okay. And they found a way to survive with the off-label medications they've used. And it's really interesting that as we go deeper into launch, having those conversations to help highlight for the family and the physician talking to that family, what they're doing to cope with things that they don't need to cope with and getting them to LIVMARLI start. So there's a lot of patients like that out there. When we look at the epi of 2,000 to 2,500 in the U.S. of the treatment eligible, we expect, we're about 20% penetrated into them already. So plenty of headroom for growth in the U.S. as we continue to get those prescribers deeper into their patient populations.

So in the past, you've talked about a $500 million peak sales opportunity for LIVMARLI in the U.S. in Alagille. How do you plan to get there from where you are today?

It's really digging into that dynamic that I just highlighted in terms of helping to bridge some of the communication gaps and some of the historical coping mechanisms that have built up in care of patients in this setting. And what we've seen is it's very attractable from some of the typical education and promotional efforts to have around the drug. So we have programs that are designed to help highlight for physicians things they may be missing in a clinic visit. So how are they asking about pruritus? Are they just asking, do you itch or are they asking, are you doing anything special to help sleep through the night, are you sleeping through the night? How is your day-to-day life disrupted and getting kind of a layer or 2 deeper into the conversation. And that is and has been yielding additional patient starts and helping to bridge some of those conversations between prescribers and patients.

With the recent approval of LIVMARLI for Alagille in Europe, when should we expect reimbursement to be negotiated in Germany? And how should we think about the cadence of additional countries coming on list?

So we're quite close to the German launch. So we haven't formally set price yet, but that will come first in Germany through their orphan free pricing system. Current regime for that launch in Germany is that there's 6 months of free pricing. And we'll set price soon for that. We expect it to be at a modest discount to the U.S. price. All of this quite transparent once you move into the steps and submit the price. Countries that will follow, we expect France to be next after Germany and other Western European countries to really follow behind that. Our commercialization model is to approach these markets in clusters. So Germany really paired with Austria and Switzerland, France with Belgium and Italy and Spain kind of approach from a common team as well. So we see them continuing to progress as we submit dossiers quite a few of them actually going out in the couple of months ahead.

Okay. And is there any reason why the kind of the cadence of patients coming on to reimburse LIVMARLI in Europe should look similar to or different than it has in the U.S. so far?

We're actually at a little bit of an advantage in Europe in terms of patient starts compared to when we launched in the U.S. really this being an artifact of the clinical program being up and running longer, expanded access being available longer. So just proportionate to the market, we have more patients on expanded access in Europe. Cadence of that starting, though, is really driven more by the reimbursement pathways. So you'll see pockets of these patients come over to commercial drug. We expect them to come over as we get the reimbursement in the markets. So again, Germany being the first, which we think will have some contribution in Q1, it does take time to convert the patients. So most of that will fall in Q2, but the launch happens in the next month or so.

Okay. With the sNDA submission for LIVMARLI in PFIC, how should we think about the label expansion in terms of the kind of tailwind that could represent for LIVMARLI sales?

PFIC, it is a smaller indication than Alagille syndrome. We roughly benchmarked the indication in absolute prevalence to be about 1/3 or so of Alagille syndrome. So smaller but still a meaningful expansion for us. We do have quite a few patients already on drug with PFIC. So across the clinical program, we're at about 100 patients across the various countries, where we've had clinical studies or expanded access open. So those will be eligible for conversion to commercial product as those countries come online. About 1/4 of that's in the U.S., roughly speaking. And so that's kind of the first driver of the PFIC label expansion. And we do expect to pick up new patient starts, and we also see a potential for patients that maybe don't have a complete response or have not responded to Bylvay, the other IBAT inhibitor that's available in the space as we pick up our label expansion for PFIC.

Okay. And how should we think about the price per patient in PFIC averaging out relative to Alagille?