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

Hello, and welcome -- sorry. Go ahead, Kat.

Yes. I'll do this real quick, and then I'll pass it over to you. So good afternoon, everyone. Thank you for joining us. My name is Kat Lange. I'm a member of the health care investment banking team here at JPMorgan. It's a great pleasure to have Mirum Pharma join us here today for our presentation. So just a real quick reminder, we will be doing a Q&A session at the end of this. [Operator Instructions] And with that, I'd like to hand it over to Chris Peetz, Founder and CEO of Mirum Pharma.

Thanks, Kat, and thanks, everyone, for your interest in Mirum today. Excited to tell you about our programs and an update on the company that we gave this morning. Today, I'll be making some forward-looking statements. We refer you to our SEC filings for a more complete disclosure of them. And at Mirum, we are a company focused on advancing life-changing medicines for rare liver disease. We've gathered a team with extensive experience across multiple commercializations of over 40 products across many settings, including both rare pediatric and liver settings with ongoing regulatory filings for our lead program, maralixibat in the U.S. and in Europe for Alagille syndrome and PFIC type 2, respectively, both of those settings where we have breakthrough designation, rare pediatric disease designation and orphan status. And building a pipeline of additional settings behind that with biliary atresia, intrahepatic cholestasis of pregnancy, PSC and ICP and PBC. All of these, in aggregate, representing a tremendous opportunity across multiple rare liver settings. Page 4 gives a picture of this from a pipeline perspective, where our lead program maralixibat is focused on rare pediatric cholestatic settings. Our lead indication, Alagille syndrome, is in the midst of a rolling submission with the FDA that we expect to complete this quarter. And that's tracking towards a launch in the second half of this year. We've also launched an expanded access program, providing access to patients with Alagille syndrome in the U.S. and in several additional countries. Behind that, we've also completed a submission of an MAA for PFIC type 2 with Europe that is on track for approval around year-end, with a Phase III study enrolling in multiple additional PFIC subtypes as well as a higher dose that we expect to complete enrollment in the second quarter of this year with data around year-end as well. Some exciting developments in the pipeline behind those 2 lead indications, with biliary atresia in the pediatric setting. And our second program, volixibat, is focused at adult cholestatic indications, with 2 interesting studies starting this quarter, expecting to randomize first patient quite soon with primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy and, newly announced today, a program planned in primary biliary cholangitis, that we expect to start in the second half of this year. All of these studies for volixibat with registrational intent. And the commonality across these indications is that they are all rare or orphan cholestatic indications. On Page 5, showing that cholestasis can be driven by a number of different biological factors, both from physical restriction of bile flow as well as transporter defects. But the commonality across all of the settings where we're advancing our programs is elevated circulating bile acids and hepatic bile acids, causing high symptomatic burden, progressive liver damage or other complications. Our programs, maralixibat and volixibat, are both oral, minimally absorbed ASBT inhibitors that block the reabsorption of bile acids in the small intestine, leading to reductions in cholestatic pruritus, reductions in elevated serum bile acid levels as well as other changes in bile acid synthesis and PD markers. Now moving a bit into the specifics of maralixibat. On Page 8, we'll talk a bit about Alagille syndrome. Alagille syndrome is a rare cholestatic disease that's driven by mutations in the Jagged, Notch signaling pathway that has implications in vasculature development, presenting as a multisystem disorder with typically quite predominant cholestasis. That cholestasis is associated with the hallmarks of cholestasis, jaundice, quite debilitating pruritus, stunted growth, xanthomas, and overall prognosis for these children is quite difficult with transplant-free survival at adulthood as low as 24%. Many of the transplants in this setting are actually driven by the severe symptomatic burden that these children experience with the unrelenting itch and no approved medicines available for Alagille syndrome. Page 9 gives an overview of the study, the ICONIC study, which is the pivotal study of maralixibat in Alagille syndrome. The study was a placebo-controlled randomized withdrawal study that looked at children with Alagille syndrome and severe pruritus. In the first 18 weeks of the study, all subjects were on maralixibat. And then there was a 4-week nested randomized placebo-controlled portion, and then all subjects went back on to open-label maralixibat, allowing for both placebo comparisons at week 22 as well as multiple time points to compare back to baseline. Of note, this patient population is quite representative of what we expect to see in Alagille syndrome with a quite high pruritus burden, measured in this study with the ItchRO(Obs) score, a 4-point scale with an average baseline value of 2.9, corresponding to -- a score of 3 corresponding to severe pruritus. Also of note, the serum bile acid level at 283 micromole per liter is extremely elevated against an upper limit of normal of 8.5 micromole per liter. Page 10 gives a highlight of some of the data from the study, showing the pruritus scores over time with the first 18 weeks when all subjects are on maralixibat, quite pronounced clinically and statistically significant reductions in the ItchRO(Obs) score of 1.7 from that 2.9 baseline. And during the placebo-controlled randomized withdrawal period, subjects on placebo go right back to the same average baseline value. And they can recapture that treatment effect with durable effect we see out here to week 193. This study has also been evaluated with -- maralixibat has also been evaluated in Alagille syndrome in the ITCH and IMAGO studies, 2 earlier studies, that also have gone out to 5 years of follow-up, showing durable reductions in pruritus scores. This pruritus data is serving as the primary basis for efficacy in our rolling NDA submission with all of the clinical modules now submitted with the FDA. In addition to the pruritus data, we also see longer-term improvements in some of the markers of cholestasis, some of these is shown on Page 11, where over time, we see reductions in the xanthoma burden for these children as well as increases in height percentile going from the 9th to the 16th percentile on average in this 191-week follow-up from the ICONIC study. The minimally absorbed nature of maralixibat also provides potential safety advantages. On Page 12, we see the safety table from the ICONIC study on the left as well as the ITCH and IMAGO studies that I mentioned earlier. Of note, the profile in the 2 placebo-controlled analysis here, you can see that there's no difference in frequency of diarrhea, one of the monitored side effects for excretion of bile acids, presenting a well-tolerated safety profile over years of follow-up in this study. Taking this forward to our potential launch in the second half of this year. We are -- now have commercial leadership in place in the U.S. and in Europe. Page 13 gives a color of some of the considerations for preparing for the Alagille syndrome launch in the U.S., but this is a very concentrated specialist group of physicians, the pediatric hepatologists and gastroenterologists. They are the primary caretakers for children with Alagille syndrome. So it can be a quite focused commercialization effort with a field force of expected to be 10 reps that we are beginning to staff now. How that plays forward across the globe? On Page 14, we show some of the epidemiology statistics, where we plan to commercialize ourselves in the U.S. and Europe. Some of the patient numbers there for the expected pediatric prevalence for Alagille syndrome and PFIC and then upside potential as we look to engage regional partners and distribution partners and geographies outside of the U.S. and Europe. This takes us now into progressive familial intrahepatic cholestasis or PFIC. On Page 16, some of the considerations for the setting. And similar to Alagille syndrome, this is a genetically driven cholestasis that can be quite severe, with quite elevated serum bile acid levels. Different from Alagille syndrome, it is a familial recessive disorder that is actually a number of different mutations in specific bile acid transporters within the liver. So this is a transporter defect in transit of bile acids and related compounds that results in what can be a very severe cholestatic phenotype with the same unrelenting pruritus and disruptions in quality of life and sleep, also leading to higher rates of liver transplant with the majority of these children having a transplant before adulthood. Similar to Alagille syndrome, there are no approved medicines for PFIC, presenting an extreme high unmet need, where we look to be able to, with successful treatments, have the opportunity to obviate the need for liver transplant in some of these children. Page 17 gives a snapshot of some of the data from our Phase II program with maralixibat in PFIC in the INDIGO Phase II study. This study enrolled both PFIC 1 and 2 children and looked at pruritus and other measures over time. What you can see on the page here, on Page 17, is the pruritus scores by PFIC subtype for PFIC2 and PFIC1. And in our INDIGO Phase II data, we saw in particular a pronounced response within the PFIC2 patients, where you could see a dramatic reduction in serum bile acids of 75% or to below 102 micromole per liter, paired with follow-on effects on pruritus and growth, similar to what we see in Alagille syndrome. And this response is informed somewhat by some of the natural history data that's available within PFIC, some of that highlighted on Page 18, that shows that in response to biliary diversion surgery, children with PFIC2 can have prolonged transplant-free survival if they have a 75% reduction in serum bile acids or reductions to below 102 micromole per liter. So this is the real treatment objective as we look at treatment of children with PFIC2. We've conducted an analysis from the INDIGO study on Page 19 that was presented at EASL last year, looking at that same response profile within PFIC2 on serum bile acids and found that in the children on maralixibat, with a 75% reduction in their serum bile acids, there's that same transplant-free survival advantage versus the nonresponders that was shown by the natural history cohort. In addition to this data, we've also conducted analysis with the natural history effort called the NAPPED Consortium. Both of these data sets have been submitted to Europe as part of our MAA that is currently under review. And in the U.S., we're taking a parallel approach. In addition to discussing these quite striking 5-year data sets with maralixibat, we are also conducting a Phase III study, the MARCH-PFIC study, which is shown on Page 21. MARCH-PFIC is a placebo-controlled randomized study with a cohort of PFIC2 patients as well as the supplemental cohort of all other subtypes of PFIC patients. Both groups randomized, exploring a higher dose of maralixibat that was then used in the Phase II study at 570 micrograms per kilogram twice daily. And this informs by some clear dose-ranging work showing that as we get to higher doses of ASBT inhibition and twice daily dosing, we can see much higher and more pronounced impacts on bile acid clearance from the body. The MARCH-PFIC study is on track to complete enrollment next quarter. The primary endpoint will be the change in pruritus of -- on maralixibat versus placebo. And then all subjects will roll into open-label extension for additional comparisons against the natural history cohorts. Moving into our third pediatric indication in biliary atresia. Biliary atresia is somewhat of a different setting from Alagille syndrome and PFIC, in that it is not specifically genetic driven. It's a more extreme form of cholestasis where there is a lack of connectivity from the liver to the GI system through inflammation, occlusion or absence of the primary bile ducts and potentially intrahepatic obstructions as well that requires an emergency surgical procedure within the first few months of life. And the treatment opportunity for an ASBT inhibitor is in those that have a partial or incomplete response to that surgery as they potentially progress. While that surgery can be effective in some, as many as 50% or more of children will still progress to liver transplant within the first 2 years of life after a Kasai procedure. Page 24 tells us a bit about what we're looking for in terms of response and what are the prognostic factors in the setting of biliary atresia. Two key data sets to consider: one, looking at bilirubin as a marker of prognosis after Kasai procedure. This is what's informing the primary endpoint of our study, the EMBARK study, as well as interesting data showing that serum bile acid also predicts transplant-free survival in an analysis that was presented recently. Page 25 has the summary design of the EMBARK study. This is a 6-month placebo-controlled randomized study looking at maralixibat, again, at 570 micrograms per kilogram twice daily versus placebo with bilirubin primary endpoint. Importantly, all children will roll over to active maralixibat after the 6-month time point for long-term follow-up against natural history cohorts. The EMBARK study as well as the 2 volixibat studies that we'll move into next are all expected to randomize their first patients in this quarter. Shifting now to volixibat. Volixibat is also an oral minimally absorbed ASBT inhibitor that is focused on adult cholestatic settings. Page 27 gives some very informative data on how we think about dosing for volixibat and dose selection that we're taking into our potentially registrational studies. And what we've seen across now multiple settings with ASBT inhibition is that as you move to higher doses and twice daily dosing, you can continually move towards greater excretion of bile acids and impact on the bile synthesis pathways. The data on the page here shows 7 alpha C4 changes over a range of volixibat doses. 7 alpha C4 is one of the key enzymes in bile synthesis that is a marker of dosing in ASBT inhibition. From this data, we selected the 20-milligram and 80-milligram BID doses that we're taking forward into the volixibat program. Page 28, the settings where we're advancing volixibat are intrahepatic cholestasis of pregnancy, primary sclerosing cholangitis and primary biliary cholangitis. All of these adult cholestatic settings, each with quite unique characteristics that we'll touch on as we go through the materials here. A high unmet need across all the settings with ICP and PSC, there are no approved therapies. And with PBC, there's still unsatisfactory treatments to fully address the need and particularly the cholestatic pruritus that's a burden for these patients. First, we'll take a moment and talk about intrahepatic cholestasis of pregnancy on Page 29. ICP is a spontaneous cholestasis that occurs during pregnancy, primarily believed to be related to a shift in hormonal effects on inflammation in the liver. And in this setting, the mother becomes cholestatic with elevated serum bile acid levels. And that on its own is associated with what can be a very severe itch and fatigue that affects the mother. So quite poor quality of life with no adequate treatments, no approved treatments for addressing the pruritus. In addition to impacting the mother, the circulating bile acids that can be a factor in the setting of ICP can also reverse the normal gradients of bile acids across the placental barrier and expose the baby to potentially dangerously high levels of bile acids. So in effect, we see 2 patients to consider in this setting, where we believe a minimally absorbed agent like volixibat that targets circulating bile acids has a quite unique fit for addressing the unmet needs in this setting. And Page 30 gives some color to some of the impacts of the condition. And of note, the serum bile acid levels of the mother are directly correlated to poor outcomes for the child of stillbirth and, of note, that even a doubling of serum bile acids can lead to a doubling of the risk of stillbirth. So tremendous potential impact for an effective therapy in this setting. Page 31 gives the design of the OHANA study, which is the randomized Phase IIb study that we're advancing with volixibat in ICP, expecting first patients in the first quarter, looking at both 20 and 80 milligrams twice daily of volixibat against placebo. This will be an adaptive design where after an interim analysis, it will -- the study is allowed to consolidate down to a single dose to move into the Phase IIb portion of the study. And in addition to the core cohort of the study, there is also a supplemental cohort looking at volixibat in women with serum bile acid levels lower than the primary cutoff. So we will have, also, expecting to see an early interim read from that supplemental cohort for those patients with moderate serum bile acid elevations. For primary endpoint, we're looking at the serum bile acid levels. But 2 key clinical outcomes that we look at for the secondary endpoints, one being the pruritus of the mother; and the second being an outcome -- composite endpoint of outcomes for the pregnancy, including preterm labor, stillbirth and neonatal intensive care unit stay. In addition to starting the ICP study for volixibat this quarter, we're also looking to randomize first patient in the VISTAS PSC study of volixibat in patients with pruritus and primary sclerosing cholangitis. PSC on Page 32 is also an adult cholestatic setting driven by fibrotic strictures in the bile duct structure, leading to elevated serum bile acid levels, what can be a quite progressive liver condition as well as the cholestatic pruritus that can be extremely burdensome for patients with PSC. The VISTAS study, on Page 33, will also be an adaptive design, randomized Phase IIb study, looking at 20 and 80 milligrams twice daily of volixibat, again, being able to consolidate down to a single dose as it moves into the Phase IIb potentially registrational portion of the study, looking at pruritus as the primary endpoint. So a 28-week pruritus assessment being the primary endpoint, and again, looking to randomize our first patient this quarter. So a lot of work going on here at the start of 2021 for volixibat, including the announcement of a third indication with primary biliary cholangitis on Page 34. And the PBC study for volixibat, we've now discussed with FDA in a pre-IND setting and are incorporating feedback into a Phase IIb study design that will also have registrational intent. And looking at PBC from a different angle from the traditional first and second-line therapy construct, where with the volixibat program, we are looking to address the cholestatic pruritus that is such a pervasive burden for the patients with PBC. So eligibility for both first and second-line patients in the volixibat PBC study, looking to randomized first patient in the second half of this year. So taking this all together, with the build-out of Mirum as we approach commercialization, on Page 36, to give a sense of how we see the advancement of our programs and the value of Mirum progressing, starting with potential launch in Alagille syndrome in the U.S. in the second half of this year and adding PFIC in Europe around the end of the year. Seeing these programs have the ability to prevent transplant -- potentially prevent transplant in children with Alagille syndrome and PFIC and really represent life-changing therapies for these settings. So quite excited about the launch in Alagille syndrome and PFIC. And then moving into much larger indications with everything that follows with the biliary atresia and volixibat adult indications. And on Page 37, we're financed to deliver on these programs with what we project as over 3 years of runway. This morning, we announced a year-end cash balance of $231.8 million. And in addition to that cash balance, with the financing facility, with Oberland Capital that we entered at the end of the year last year, we have up to an additional $150 million available from the Oberland Capital facility as well as eligibility for a priority review voucher with the maralixibat approval for Alagille syndrome or PFIC, both of those having rare pediatric disease designation. So quite excited about the financial resources that we've been able to bring into the company to deliver on all of these important programs and bring them to market. Page 38, some of the milestones that we have ahead of us as we work through the -- advancing the pipeline. First quarter, completing the rolling submission of maralixibat for Alagille syndrome with the FDA as well as 3 key randomized study starts with maralixibat in biliary atresia and volixibat in ICP and PSC. Q2, expecting to complete enrollment in the MARCH study, where we look at potential label expansion to additional PFIC subtypes for maralixibat and a higher dose level that we expect to drive broader and deeper response in patients with PFIC. Into the second half of the year, we expect to launch maralixibat for Alagille syndrome and initiate the third potential indication for volixibat heading towards that MARCH-PFIC data around year-end. And then into 2022, where we have our launch in Europe as well as seeing first data from the volixibat program where we expect to see the ICP interim as well as label expansions in both the U.S. and Europe. So exciting couple of years ahead of us and really unlocking a tremendous amount of value in maralixibat for Alagille syndrome and PFIC as well as expanding on what we've learned about ASBT inhibition, potential of this mechanism across all settings of elevated bile acid exposure, where we believe we can drive improvements in the symptomatic burden as well as long-term outcomes with a team that brings a tremendous amount of experience to Mirum. And so with that, I will pause and answer any questions.

Great. Thank you, Chris. That was great. [Operator Instructions] And we'll try to go through those in the next 10 minutes roughly. So Chris, we do have a couple of questions here that we'd just like to run through. Starting with the Phase II trial with volixibat in ICP. As you think about the data there, what would be a win scenario? And what bar has been set by competitive therapies that are in development?

Yes. So the setting of ICP is quite interesting when you pair it with a mechanism and a drug profile like volixibat being a minimally absorbed drug. And so first, speaking to the competitive question, and with a minimally absorbed drug, the safety considerations are quite different. So since we're unlikely to get meaningful drug on board with the mother, we think that also would play into minimal and no drug exposure for the fetus. So important safety advantage for minimally absorbed ASBT inhibitor in this setting. In terms of other competitive agents, the most commonly used agent is off-label UDCA, which has been and continues to be evaluated in a number of different studies. And what we see out of the data on UDCA is somewhat mixed results, which shows some effect in some studies and not in others. But it's generally seen as safe. So typically used as background therapy in this setting. And what we would hope to see for what would be a tremendous outcome in this setting is that, first, hitting that primary endpoint of serum bile acid reduction, we know that across the gradient of serum bile acids, every increase results to an increase in risk of poor outcome. So reducing the serum bile acid load is the first step. And then following on that, to see that translate into our secondary outcomes of improved pruritus for the mother, which can lead to an extended duration of pregnancy, so getting more of these pregnancies to full term. As well as then that having the follow-on effect of improving that composite of outcomes for the pregnancy. So less -- more full-term pregnancies and fewer complications showing up in that composite outcome endpoint.

Great. And then just to follow up on that, on ICP, when is the data readout expected?

So we will have a number of different readouts from the study. As we've put together the study design, the -- as a reminder, there's a first portion looking at 20 and 80 milligrams twice daily of volixibat, so there will be a formal interim analysis conducted on the randomized, placebo-controlled cohort at the placebo versus 20 and 80 milligrams. And eligibility into that cohort has a minimum serum bile acid threshold. However, there are patients with ICP that still have pruritus and still have elevated risk of poor outcomes for the pregnancy that will be below that threshold. And the patients that enroll into that study will be on open-label 80 and 20 milligrams of volixibat. Those patients will be a first interim that we expect to see likely in the first half of next year and the more formal interim would follow after that.

Great. Thank you. And then we did get a very similar question about the Phase II EMBARK trial in biliary atresia. So again, what would be a win scenario for that trial? And what does the competitive landscape look like?

So for the EMBARK study, we're looking at a 6-month bilirubin primary endpoint and then looking at multiple observation points that we can look at long term as all patients go into open-label therapy. We know, I think, a little bit less about the dynamic in a post-Kasai setting with biliary atresia. And that's why we want to be able to look at multiple time points along the way here. That bilirubin has been the most consistent marker of transplant-free survival prognosis. So that's why we're focusing on that endpoint. And that is seen as early as 3 months after Kasai. In terms of the competitive dynamic, we know there's one other ASBT IBAT study that's also being conducted in this setting. And we're looking to get an earlier read on the data with a 6-month primary endpoint playing into the rationale for the study design here with the EMBARK study.

Great. Thank you. So we're going to switch gears to maralixibat in PFIC, and the question relates to the 5-year transplant-free survival data which supported the MAA submission. How has that data inform the Phase III trial design in the U.S.? And I think you also mentioned that there will be discussions with the FDA about a potential earlier submission in the U.S. So just -- can you provide an update on that?

Yes. So first, just to -- there's a couple of data sets available here. One is the INDIGO 5-year transplant-free survival data that we presented at EASL that you're asking about here that's in our materials. There is also an additional analysis that's been conducted by the NAPPED Consortium. So we provided -- we made our data available to that academic consortium. They conducted an analysis that has been included with our MAA filing. So there are 2, 5-year event-free survival analyses that have been submitted to the European authorities. And looking to have the NAPPED Consortium, we'll present that data at a future medical conference. So 2 data sets that inform our positioning for the European filing. And that filing specifically is for an indication of treatment of PFIC2. Because we have this 5-year outcome data, we can look at what is an indication that's treatment of the underlying disease specifically is what we're proposing in that setting. As you mentioned and as we've talked about here, the -- within the U.S., we are discussing that same data set, both of these data sets, with the FDA and how that could be worked into our filing strategy, either for an earlier filing for treatment of PFIC2 or to supplement the ongoing MARCH study. So 2 different ways that this could play out as we discuss it with the regulators. But what we've already discussed is the MARCH study, the key difference here is that the MARCH study is focused on a 6-month pruritus endpoint. So that, across all of these cholestatic settings, is the first clinical outcome that you can get to. So in conversations with regulators, it's commonly been pointed to as being used as -- or suggested as the basis for approval because it is a near-term clinical outcome that you can show in these settings that have been recognized as having high unmet medical need. And so a real collaborative approach from the regulatory side to come to agreement on endpoints that can provide access to new medicines for these patients.

Great. And then I guess switching gears just to the commercial side. I know there was a little bit of an update in your press release this morning on that. But with the potential launches coming up in 2 very significant regions here in 2021 and 2022, can you just kind of walk us through what you're doing as an organization to prepare for those potential launches?

Thanks. So starting in the U.S., where we see the nearest-term potential for approval and, frankly, larger indication, larger potential impact from these first 2 indications, we've onboarded now key leadership across a number of commercial positions. And in addition to having a leadership in position, we've also done some of the typical patient finding efforts and understanding of how maralixibat fits in standard of care for Alagille syndrome, preparing for the launch and understanding the treatment dynamic. There is an urgency among the families and physicians treating these patients to get access to a new medicine. And that's what's been clear across all of the preparatory work. And also, that's paired with a very concentrated group of providers that are active in diagnosing and caring for these patients. That translating to what is really a relatively small footprint that we need to have from a commercial build-out. So we're talking about 10 reps, a handful of individuals on the medical science team being the field force, all lining us up for getting the maralixibat story out to the majority of physicians who care for an Alagille syndrome patient. And then the announcement this morning, excited to bring on commercial leadership for Europe as we work towards launching maralixibat for PFIC2 in Europe starting around year-end.

That's great. And maybe in the last minute here, I think we had one more question just on Alagille, in terms of the market opportunity and again sort of the competition, what's in development or what's being used currently?

Yes. So currently, there are no approved medicines for Alagille syndrome. Typical of some of these other pediatric cholestatic settings, there's a lot of off-label use of UDCA, rifampicin, a number of other agents, antihistamines being quite common. Ultimately, surgery or transplant is really all that's really a powerful tool in -- for treatment of patients in this setting. So coming in as the first -- we expect to come in as the first and only approved medicine for Alagille syndrome. I'm excited about what that can mean for families and physicians. And so we're looking to get as broad of access to maralixibat for those with Alagille syndrome as we launch the product later this year.

Great. All right. So we're at the top of the hour, so we're going to wrap it up here. Thank you very much for joining us. And thank you, Chris, for this very thoughtful presentation.

Thank you, Kat.