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

Hello, and a warm welcome to the Mirum Phase III Top Line Results Conference Call. My name is Candice, and I'll be your moderator for today's call. [Operator Instructions] I would now like to pass you over to our host for today's call, Ian Clements, CFO. Please go ahead.

Thanks, Candice, and good morning, everyone. I'd like to welcome you to Mirum's MARCH-PFIC Phase III top line results conference call. I'm joined today by President and CEO, Chris Peetz; Head of R&D, Pam Vig, Chief Development Officer, Lara Longpre; and Chief Operating Officer, Peter Radovich. Earlier this morning, Mirum issued a news release announcing positive results from our Phase III MARCH study. Copies of the news release can be found in the IR section of our website. Also in the IR section of our website, you can find a slide deck outlining results in this study. We will refer to this deck as we go through the results this morning. Before we begin, I'd like to remind you that during the course of this conference call, we will be making certain forward-looking statements about Mirum based on management's current expectations, including statements regarding Mirum's business plans, development programs, regulatory strategies, prospects, market opportunities and financial forecasts environments. These statements are subject to numerous risks and uncertainties, and actual results could vary materially from the results anticipated by these statements. Investors should read the risk factors set forth in Mirum's Form 10-Q for the period ended June 30, 2022, and any subsequent reports filed with the SEC. With that said, I would like to turn the call over to Chris. Chris?

Thanks, Ian. Good morning, everyone, and thanks for joining us. This is an outstanding day for both Mirum and children and families suffering from severe cholestatic liver disease. Before we get started, I want to first extend my gratitude and appreciation to patients and investigators around the globe who participated in this important Phase III trial and help make these results possible. I also want to again express my sincere thanks to the Mirum employees for their dedication to the LIVMARLI program and to our company. This impressive group of people, once again, delivered remarkable results. The MARCH study was positive on both pruritus and serum bile acids end points across all PFIC subtypes. These results are a substantial advance for the earlier breakthrough results in the INDIGO study and show that even greater promise of higher dosing tested in the MARCH study. Over the course of LIVMARLI development, the potential for IBAT inhibition to treat severe cholestatic liver disease has been evident, and the results that we will present today further validate our efforts to maximize efficacy across the highly burdensome cholestatic diseases we're studying. The positive evidence for this model in PFIC is now clear, with years of transplant-free survival in the INDIGO Phase II study and now increased and deepened response rates in the MARCH study. I'll pass it over to Pam to walk through the top line highlights, but we'll note that we plan to present further details of the results at an upcoming medical conference. Now without further delay, over to Pam. Pam?

Thanks, Chris, and good morning, everyone. I'm delighted to share the results today from our MARCH-PFIC Phase III study, the data that I'm sharing can also be found on our website. First, a reminder on the background of PFIC, which can be found on Slide 3. PFIC is a group of conditions, which are genetically inherited that share a similar phenotypic presentation. There are a number of different genetic mutations, which all affect bile acid transport from the liver into the intestine. This transport deficiency becomes very problematic as bile acids build up in the liver and spill over into the bloodstream. The elevation of toxic bile acids drives cholestasis significant symptoms affecting quality of life, poor growth and progressive liver disease, all of which results in the majority of children being transplanted by adulthood. Now if you could please turn to Slide 4 for the study design. The MARCH study is the largest global Phase III placebo-controlled study in PFIC designed to assess the efficacy and safety of LIVMARLI. The study was an international effort conducted in 30 cities in 17 -- sorry, in 30 sites in 17 countries and enrolled an impressive 93 patients across multiple PFIC subtypes. There was a one-to-one randomization of all patients to receive LIVMARLI or placebo for 6 months. The study is analyzed in 3 groups: the PFIC2 cohort of 31 patients; the all PFIC cohort of 64, which is PFIC2; plus an additional 33 patients with other PFIC subtypes, PFIC1, 3, 4 and 6. Finally, the full study of 93 includes a supplemental group of 29 patients with previous surgery, truncating mutations and variants that are unidentified. As a reminder, the dose studied in MARCH is 570 micrograms per kilogram twice a day, and this dose was tested on the potential for improved efficacy informed from our deep experience with IBAT inhibitors. The primary objective of the 6-month MARCH study was to evaluate the efficacy of LIVMARLI versus placebo on the severity of pruritus in patients with PFIC2. Secondary objectives included serum bile acids in patients with PFIC2, severity of pruritus and total sBA in the all PFIC cohorts and safety in the full study population. Turning to Slide 5 on baseline characteristics. Key inclusion criteria were patients aged 12 months to less than 18 years with genetically confirmed diagnosis of PFIC, a history of significant pruritus and elevated serum bile acid levels. Looking across all cohorts, baseline characteristics were very well balanced. Here, you see that baseline pruritus, serum bile acid and age were all comparable between LIVMARLI and placebo groups with no notable differences observed. On the next slide, Slide 6, I will share the primary results. Here, we show changes in pruritus as measured by the ItchRO observer-reported instruments, which is 0 to 4 point pruritus scale. The chart on the left is our primary end point in the PFIC2 cohort. And on the right, you will see the same measure for the all PFIC cohort, a key secondary end point. In the primary cohort on the left, the PFIC2 subjects treated with LIVMARLI show a dramatic 1.7-point mean reduction in pruritus versus 0.6 for placebo with a statistically significant p-value of 0.0098. In the all PFIC cohort of 64 patients, on the right-hand side, we see a consistent improvement with a mean decrease of 1.8 points for patients treated with LIVMARLI versus 0.6 for placebo with a p-value of less than 0.0001. Now there are some other pruritus results, which we'd also like to share with you today. The first is that a consistent pruritus effects was also observed in a full study population of 93 subjects. Now this is a remarkable result given the heterogeneity of the population. Another analysis which was conducted looked at the proportion of pruritus scores of 0 to 1, meaning little to no itch, over the duration of the study. In the all PFIC cohort, this was 62% for LIVMARLI versus 28% for placebo and was statistically significant. Now turning to Slide 7. Our other secondary end points measured the change from baseline in total serum bile acids. Again, on the website is the PFIC2 cohort with a placebo-adjusted difference in serum bile acids of 187 micromoles per liter and a p-value of 0.0013. On the right, the all PFIC cohort had a placebo-adjusted difference of 160 micromoles per liter and a p-value of less than 0.0001. The overall magnitude of the serum bile acid and pruritus response observed across all cohorts is unprecedented. In addition, the proportion of patients that achieve the serum bile acid threshold that is predictive of transplant-free survival has gone from 1/3 to over 1/2 at these higher doses, and we're so pleased to see that this holds across all subtypes given this highly cholestatic phenotype. Now moving on to safety on Slide 8. We do not see any new safety signals. Consistent with IBAT inhibition, the most common treatment-emergent adverse events regardless of relatedness for GI disorders. Among these, diarrhea was the most common and observed in 57% of LIVMARLI versus 20% of placebo over the course of the study. In line with previous studies, diarrhea was predominantly mild and transient with a median duration of only 5.5 days. There were no severe diarrhea events. The rate of severe treatment-emergent adverse events and serious treatment-emergent adverse events was low and comparable across groups, and no deaths were reported. Overall, we are very happy to see that LIVMARLI's safety and tolerability profile is consistent with previously published data and with IBAT inhibition in general, even at the higher dose evaluated in this study. Now on the next slide before I turn it back to Chris, I would just like to share a few other exciting observations looking across all PFIC subtypes. The response in serum bile acid and pruritus were rapid and observed at the first post-baseline time point, and these effects have been sustained into the extension study. We also observed improvements in growth as well as statistically significant improvement in bilirubin, all within the short duration of the study. And I'd just like to say that this is an incredibly rich data set with a lot to begin to, and we are really excited to continue our analysis and look forward to sharing more with you soon. And on that happy note, I will hand it back over to Chris. Chris?

Thanks, Pam. It is gratifying to see the unprecedented impact on pruritus and serum bile acid in the MARCH study. The implications for children and families suffering from severe cholestatic liver disease are profound, and we will move rapidly towards regulatory filings for PFIC. Overall, this is another great milestone on our journey to being a leader in rare disease, building on the recent CHMP opinion and approval in Israel for pruritus and Alagille syndrome. Thanks for your interest and support. And with that, I will now open the call up for questions. Operator?

[Operator Instructions] So our first question comes from the line of Jessica Fye of JPMorgan.

Nice results. Curious if you could talk a little bit about how you expect the launch trajectory to go in PFIC maybe relative to how [ bil-based ] PFIC1 has done given the respective product profiles?

That's an excellent question. Actually, I'll turn it over to Peter for a couple of comments but just know now that it's really early days for mapping that out.

Thanks for the question, Jess. I think we expect that a gradual steady build. We're really excited about the results today when we're announcing what we were able to see that the higher dose, capturing more responses and a higher proportion of days or the pruritus assessment of 0 and 1. So we think that's an exciting profile, but we're doing -- we see the [ market ]. We see it as a gradual steady build.

Our next question comes from the line of David Lebowitz of Citi.

First, would you be able to dig into the competitive dynamic, how you think the therapy data stands up as compared to other therapies currently on the market, how that might mean for ALGS when competitor data actually is presented as well? And if you could offer additional granularity on liver enzymes and whatnot, is it a liver-targeted drug?

Thanks for the question. We get a couple of comments here, but it's really probably not appropriate to make cross-study comparisons. But what we can do is a lot of what we've done over the weekend, beginning with this data, is looking at what the MARCH results mean in comparison to the INDIGO study. So just looking at how we've been able to improve the efficacy, top line results here with increased dose over the history of the LIVMARLI program. And these results are a substantial increase in effect size from what we saw from the earlier studies. So just showing that we've been able to really move the needle here in terms of increasing not only a proportion of response on the ItchRO scores, also, the FDA responders based on the NAPPED criteria, that 50% -- up about 50% response rate is a big step-up from what we saw in earlier studies. And looking at the first glance into the extension data, these responses are maintained. So it is a very compelling data set and excited about what this means for patients and also just duration and the long-term impact that LIVMARLI can have in this setting. In terms of liver enzymes and some of the lab values, we'll dig into some of that and share at an upcoming conference, but we did see significant reductions in bilirubin already at 6 months. That was – [ I think that was ] surprising for us to see an effect already at that early time point, so really compelling data coming out of the top line.

Our question comes from the line of Mani Foroohar of SVB Securities.

Congrats on the data as well. I guess, I'm talking about the experience thus far in Alagille versus a little bit of a different dynamic in PFIC. Can you give us a sense of how important first-mover advantage is in these markets? Are there -- would you expect to see any difference in terms of openness to switching between these 2 patient populations? How that plays into how you think about competitive dynamic in your own launch strategy?

Thanks for the question. Just from a starting point in PFIC, recall that in our last update, we shared that we have nearly 100 patients already on drug with PFIC across the clinical program. So we already have a good starting point and expect to see those patients convert to commercial drugs once we get to those regulatory eventual approvals and reimbursement. So from kind of as we think about first-mover, we're already out there with LIVMARLI based on the clinical program and expanded access program that's open. There is some first-mover advantage. We see that very clearly in the Alagille syndrome indication where the launch has been really strong in the U.S. excited about expanding into Europe with the CHMP opinion expected full approval later this year to build on that being -- having LIVMARLI out there first for Alagille syndrome, and PFIC will build on top of that.

Our next question comes from the line of Yasmeen Rahimi of Piper Sandler.

Congrats on the data. Two quick questions for you. One is I know that you clustered all the PFIC subtypes together outside PFIC2, any commentary on how the shape of the curves look like when you look at the PFIC1 population solely? And then question number two is, how should we be thinking about given that this is a higher dose of 570 micrograms per k BID is the dose is used currently an Alagille, whether obviously the cost of it would be identical, just some commentary around that could be helpful for us?

Thanks for the question. I'll have Pam pass this one, have PAM speak to the clinical data and then Peter comments on second part of the question.

Yes. So thanks for the question, yes. So with regards to specific question on PFIC1, you're right in the INDIGO Phase II study, the PFIC1 patients at the lower dose, we did see much of a response. We still have half of the patients still on study after 7 years interestingly. So similarly having some response. But once those patients have the higher dose in the MARCH study, the effect is really incredible. And when you look at the subtypes altogether in the all PFIC cohort, which includes PFIC1, PFIC2 PFIC3, PFIC4, PFIC6, you see this enormous response that, frankly, is almost -- I guess we were almost fully surprised at what we saw at this higher dose really showing the breadth and the depth of that efficacy response from both serum bile acid and pruritus and frankly also on bilirubin.

The second question, yes. I think as we've been [ counting ] so far, I mean we're both really excited with what we saw in our original Phase II data [indiscernible] patients at the lower dose is to get really meaningful clinical benefit on the modeling lasting for years. And also really excited about our results today that we can actually optimize the dose and capture even more clinical benefit for patients on the higher dose. So I guess what we're saying is we see the story that's emerging here as a dose optimization story at a patient level in PFIC. And I think it's probably too early to hear specifics on pricing. As we mentioned, our next step is to submit regulatory applications and as we progress through those and move towards potential approvals and labeling, I think we'll be in a better position to comment.

Our next question comes from the line of Steven Seedhouse of Raymond James.

I'm curious, first of all, bilirubin, just how robust the effect was? And as you think about your trial in biliary atresia where change in bilirubin at 6 months is the primary end point. Does this increase your confidence in that endpoint using essentially this dose? Or maybe you can comment on other aspects of those diseases that make that read-through challenging?