Good morning, and thanks for joining us to have a conversation with Chris Peetz, CEO of Mirum Pharmaceuticals. Mirum is a commercial-stage biopharmaceutical company focused on transforming treatment of rare liver and debilitating diseases. The company's commercial base is anchored by LIVMARLI in cholestatic pruritus in Alagille syndrome and PFIC, alongside with bile acid medicines franchise, which together delivered $176.2 million in second quarter revenue and supported raised full year guidance to $680 million-$700 million. Behind the base also sits a dense set of near-term events. We have a PDUFA date for zilurgisertib, the oral ALK-2 inhibitor for FOP, registration enabling AZURE-1 and 4 readouts for brelovitug in hepatitis delta in the second half. Also we are going to see data from the EXPAND basket readout. To talk about the commercial franchise as well as the pipeline, let's get started with Chris.
Chris, glad to see you, and thank you for accepting our invitation and talking to our audience today. To start off, especially for folks who are new to Mirum, what is the long-term strategy for the company? As you grow the commercial base in the cholestatic liver disease, but also you are looking into the potential FOP and the hepatitis delta, how do you put all these pieces together?
Yeah, thanks for hosting. It is a busy year for Mirum, so happy to dive into it and break some of that down. First comment, I will be making forward-looking statements, so refer folks to our SEC filings for full disclosure of risk factors. To dive into first the strategy of Mirum and who we are, what led to the creation of the company about eight years ago, it was really started from a search to look for underappreciated opportunities in rare disease.
Our strategy as a company is to pull together these small to mid-size products that really fly below the radar of most of the larger companies. There are a lot of opportunities out there like this. In fact, across rare disease, probably only about 5% of those rare diseases have approved medicines.
And there's even opportunity to improve on those that have existing medicines. There's really a long list of opportunities that we look at and are excited about across the rare disease settings. Today in Mirum, as you covered some of the highlights, the way I describe it is we have a thriving commercial business based on three approved medicines, LIVMARLI being the real highlight of the growth-
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profile that we can dive into what we're seeing. Really most recently on PFIC has been a real standout in driving that continued growth, and a lot more to come with an estimated 2,000 adult patients that we think are out there that would benefit from genetic testing and a more-
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complete diagnosis. Behind that, across the pipeline, all of these really game-changing potential opportunities for new medicines. The first up is the PDUFA date for zilurgisertib, which would lead to the potential approval of zilurgisertib for FOP.
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We can talk about the launch profile there. Really efficient add for our rare team. Then data readouts also starting later this month for bulevirtide with AZURE-1. AZURE-4 follows next quarter, EXPAND next quarter. VANTAGE for PBC, first quarter next year. It is pretty stacked right now with a lot coming on.
Okay. On the commercial side of things, LIVMARLI and the bile acid medicines and bile acid biology. What is the rationale there, and how do you differentiate Mirum's approach versus other folks who are working in the same cholestatic disease therapies?
Yeah. Looking at LIVMARLI's profile and breaking down what we have seen over time. LIVMARLI's first approval was for cholestatic pruritus and Alagille syndrome, and followed with a label expansion in cholestatic pruritus due to PFIC. The profile for response for patients in both of these indications can be really quite profound in addressing the pruritus that is a hallmark symptom of these diseases. Both Alagille syndrome and PFIC can drive highly elevated circulating bile acid levels, and LIVMARLI interrupts the recirculation of those bile acids to reduce systemic bile acid levels. In the pivotal studies, you saw quite pronounced reductions in itch because of that.
The drug profile, then playing that forward, is one where patients feel better, usually on medication because of that improvement in itch. So you see really good persistence, really strong feedback from patients on how they are responding to drug, and the tolerability of it. The mechanism of the drug actually excretes bile acids in stool, so there is some GI side effects to this, but it is typically seen as a favorable trade-off for the itch benefit that patients see. How it differentiates from others, there is another IBAT inhibitor that is approved in the same indications, and I credit a lot to our clinical profile and our team's performance and the growth profile that LIVMARLI has been able to demonstrate, really quarter over quarter continuing to add both new patient starts, but also supporting strong compliance persistence for patients that are on therapy.
That's led to the commercial performance we've seen for LIVMARLI. We've been spending a lot of time talking about the adult PFIC opportunity
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this year. It's something that's emerged really over the past year and a half, where as we had the PFIC label expansion for LIVMARLI and were more active in some of the adult clinics, really only probably the top 10% is where we've been active historically. We've been seeing that there's historically limited awareness of genetic testing in what's described as the idiopathic cholestatic patients.
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Those don't really have a precise diagnosis of their cholestatic disease, still have symptomatic burden, still have elevated bile acids, but an incomplete diagnosis. When a genetic panel for the cholestatic genetic diseases is run, actually many of them will have PFIC genetics.
That's an effort that we've been building on to help support awareness of genetic testing, of what is once thought of as a pediatric onset disease actually can have an adult onset profile. Getting the genetic testing out into the adult clinics has helped bring a more complete diagnosis for patients. That's turned into also LIVMARLI prescriptions. Where we're taking that going forward, to date, really incomplete coverage on the adult prescribing audience.
We are expanding our commercial team now so that as we get into next year, we will have a more complete call point on the adult liver and GI specialists that treat and diagnose these patients. That actually has two benefits, not only helping support LIVMARLI's continued growth, but also having us ready for the brelovitug and volixibat potential approvals that will be down the road. It is all three products would be with the same
Same team
commercial team.
Talking about LIVMARLI in adult population. How long does it take? You just talked to us about diagnosis. Once diagnosed, how long does it take for a genotypically diagnosed patient to start on therapy?
Once a diagnosis is made, then it comes down to, from what we see, a conversation with the physician and the patient about symptomatic burden and treatment options. With a genetic diagnosis of PFIC, it is on label for LIVMARLI as an option to treat cholestatic pruritus in the PFIC patients. And those that have the symptomatic burden, they are looking for treatment options. And that decision really varies in the amount of time it takes, but those that are seeking more complete diagnosis tend to be doing that because they have symptomatic burden. They are looking for a new treatment option.
Regarding the revenues from LIVMARLI by itself. In the second quarter, it was close to $129 million, which was actually a 13% sequential growth. As we go forward, just to think about what sub-segment patients come into this. Can you break for us between new patient starts and also the patients who are on weight-based dose escalation group?
We have not parsed out and shared each of those different components. They are all at play, though. Across the different components of the total LIVMARLI revenue, Alagille syndrome in the U.S. continues to grow quarter-over-quarter, both through new patient starts, dose adjustments over time for the pediatric patients. PFIC new patient starts, I call out, is the biggest kind of growth driver that we have seen over the past recent quarters. And then international also continues to perform well.
And internationally, that is more predominantly Alagille driven still today, though PFIC has been a bigger contributor of late. Expect continued growth internationally as we roll out both Alagille and PFIC, not only within the current existing markets, but also some additional geographies that we will address through distributors. Latin America is one that has good growth potential going forward. Middle East, still in early days. Each of these on their own is relatively small, but they all add up to be real contributors.
Okay. Talking about the commercial footprint and the expansion that you're putting together. I believe right now you're only detailing about top decile of the adult hepatology and GI prescribers. As you continue to strengthen the commercial team, two questions. How long does it take for these folks to be mature in terms of what they're doing for the business, and when would it actually translate into revenues?
The field expansion is work that we're kicking off now. Efforts underway to build out that expanded call point. For it to be really fully deployed, it's probably not until end of this year or early next. Expect that to continue to support the trends that we've been seeing in adult PFIC as we just reach out to broader into that audience. I would say also beyond just the commercial team, which having this increased presence for adult PFIC, those 2,000 potential adult PFIC patients that we've been talking about in the U.S. There's also broader scientific evidence and recent publications and a lot of the conference material that has been oriented towards genetic cholestasis. It's not just us out there
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building awareness of these genetic panels. It's also being driven from the KOL community as they're further characterizing, identifying more variants that are drivers of PFIC and understanding how to interpret the genetic testing results. All of these are elements of also being driven by research out of the academic community.
Okay. The next big excitement is about the EXPAND study, which is the data coming out in the fourth quarter. What would you consider as a clear win on the primary endpoint itself? Then, what is the accessible population for that once you get the label expansion up?
The EXPAND studies, it's a basket design and was really driven by what we saw for compassionate use requests across a broad profile of different background cholestatic diseases that each on its own was quite rare.
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To have cholestatic pruritus for any of these underlying conditions, and that interest led to a discussion with FDA about how to design a protocol around it. Fast-forward to today, heading into unblinding next quarter, that study is enrolled about half of it in biliary atresia. Patients with pruritus due to biliary atresia. These are post-Kasai patients, different profile than what has been studied in some of the earlier studies that were more looking at infants immediately after Kasai. These will be patients that have had a stable response to their Kasai but develop cholestatic pruritus later in life. The other half, really, I'd describe it as a long tail, like many different causes of cholestasis, each one on its own, being a one-off representation in the study.
Regarding international business, the CHMP has a positive opinion for LIVMARLI, the oral solution, for ages down to three months of age. How should we think about ex-U.S. contribution, let's say, over the next two to three years?
If I look at what we see internationally, Europe is one piece of it, but it's broader than that as well. Our distributors have been really strong performers across different regions outside of our direct markets in Western Europe. Expect that to continue to grow, especially with the same PFIC trends that we've seen in the U.S. See that there's similar opportunities across some of the European markets. Though the mix between new patient starts in existing markets and new distributors, both of those really play in over time.
Okay. Moving on to volixibat. I know you have fielded enough questions on PSC over the last month and a half. But the exciting piece next is the VANTAGE study, which we are expecting soon. When I say soon, in the first quarter of 2027. What do you need to see in that study so that you can take it into a pivotal study as well?
Yeah. Put the volixibat program as a whole into a little bit of context. When we started both the PSC and the PBC study, we, through a written interaction with FDA, designed and asked for feedback to make these both pivotal studies.
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They're both designed as adaptive pivotal studies for cholestatic pruritus in PSC and PBC. The key difference between them is the PSC study was a blinded adaptive design throughout, so operationally seamless. We did not unblind interim data. All of this discussed with FDA, to have this be an adaptive pivotal study. We didn't have interactions with FDA until that data readout. As we've talked about, we're working towards a planned NDA submission for PSC first half of next year. So no changes to what we've shared about the plan for PSC, and that's all underway. For PBC, the interim structure allowed us to have an unblinded-
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announcement and look at the dose comparison for high and low-dose volixibat versus placebo a couple of years ago. Data looked quite strong and was the basis for a breakthrough designation for PBC. That allowed us to then have further interactions with FDA, clarify what they wanted for the safety database size for PBC, and some of the statistical design elements to support VANTAGE being the pivotal study for an NDA. Feel we're in a strong position heading into the VANTAGE readout.
Okay.
What we saw at the interim was a strikingly strong result, and anything close to that I think would be a game changer for PBC patients. It's such a pronounced and rapid reduction in pruritus that we think it would be a really strong product for the PBC market. Thing to point out is we get a lot of questions about how volixibat what role it would play relative to the PPARs that have been recently approved, and that are used in those with elevated alkaline phosphatase on UDCA. A thing to note in the volixibat studies is that it's across the PBC population, so it includes both patients that are well-controlled biochemically on UDCA, as well as those that would be more of a typical second-line patient where the PPARs are used.
We see patients in both settings and consistent pruritus response in that interim data set across both profiles of patient.
Moving on to hepatitis delta, AZURE-1 topline is expected this quarter and AZURE-4 in the fourth quarter. In the phase II, the drug showed 100% virologic response across 46 patients, and also an 82% composite response at the 900 mg every four weeks. Is that the right benchmark for us to look at when the phase III readout?
The key consideration to keep in mind there is that that's a different time point for that specific data point. The phase IIb data that we announced earlier this year, that's the 24-week time point and gives a better sense of where we expect the phase III data points to read out, also 24-week time point. The 300 weekly arm, which actually has slightly higher exposure overall, that's the overall the dose that we would expect to have a stronger response, saw a really strong virologic response. That's 100% of patients having that two log or greater reduction, and also strong ALT normalization. At the 24-week time point, that phase IIb data that we announced earlier this year is the best benchmark to think about. We do expect response to improve over time.
As you get to the week 48 time point and beyond, we're seeing patients that are on therapy longer continue to have improved or lower virologic levels and more patients having ALT normalization.
Then, which is the next catalyst, which is immediate, zilurgisertib, which has a PDUFA date on September 26 for FOP. When you look at Regeneron's drug which just got approved, how do you think the competition is going to look between the two drugs, and what are you watching for from the Regeneron's drug?
For us, heading into the zilurgisertib launch, focused on getting a drug out to patients after this potential approval. Key things that we're excited about that got us excited about doing this deal with Incyte, who did a great job bringing this through regulatory review to date, is that it's an oral once daily, and the pivotal study included patients down to 12 years of age. There's a real desire to start treatment younger to prevent the accumulation of these ossifications. I think that's one of the real strengths in the clinical profile for zilurgisertib is that we expect our label would be for patients 12 years and older for the once-daily oral regimen.
The last question from me is on the financials with the current cash runway that you have, what sort of a runway should we expect?
For this year, it's a bit of an investment year. While we had been cash flow positive in the coming quarters, expect to be roughly breakeven or slightly negative. A lot of that just from the investment for brelovitug scale up as we are adding a second site for manufacturing. Heading into next year, expect to be operational cash flow positive again. Expect that into next year, there's an opportunity to add to that cash balance. Certainly as we get further beyond this CMC investment that we're in now, expect the cash flow to increase.
Thank you. Thank you, Chris, for being here.
Yep. Thanks for asking. Thank you.