Great. Welcome back everyone to this third day, final day, final morning of the Global Healthcare Conference, here in Miami, Florida. I am Mani Foroohar, senior analyst at Leerink Partners, and for this session, I'm very fortunate to be hosting the one company, I think I have top picked you guys more than any two other companies in my coverage in the history of the time I've been on the sell side. I'm hosting Mirum Pharmaceuticals, Chris Peetz and Peter Radovich. Welcome to Miami. How's your morning?
It's great. Thanks for hosting us. Great conference, and excited about all the conversations we're having.
A pleasure to have you. Could you close that door, please? Thank you. Before we go diving into the busy year catalyst-wise, late stage, let's do a level set on when we're getting what from both the IBAT side of the house, as well as the newly acquired HDV Bluejay assets.
Yeah, busy calendar for us. First comment, we'll be making forward-looking statements, so refer folks to the SEC filings for full risk factors disclosure. You know, this year is set up to be really busy. I mean, first on the commercial side, you know, reiterate the $630-$650 guidance and all the trends durable that we've been seeing on the commercial side, funding some really great R&D programs. Walking through the calendar for the year, starting next quarter, Q2, we have two key data events. First one that's getting the most attention right now is the VISTAS PSC top-line data. This is what was planned to be the pivotal data set for PSC, and sets up a potential NDA filing by the end of the year.
There's also brelovitug phase 2b kind of interim readout from the AZURE-1 study that is next quarter. That sets up then the brelovitug U.S. phase 3 program top-line data second half of the year. Another filing, a BLA filing that will come out of that early in 2027. We'll cap the 2026 calendar with the EXPAND top-line readout in Q4. Moving into next year, volixibat PBC data in the first half of the year. Four pivotals over the next 18 months and a commercial business that continues to grow.
Let's talk about EXPAND and how EXPAND plays into the expansion the acceleration of growth for the existing commercial business, the size of that opportunity, how long it'll take for that to contribute to a further inflection on top-line growth.
Yeah. Maybe I'll give a little bit of history and let Peter speak to how it rolls out commercially. I mean, this program, just kinda to back up a step, the idea came to us really out of demand and interest from prescribing physicians. It's compassionate use requests that fit this kind of, this bucket of other ultra-rare cholestasis. It's a study that's composed of, you know, probably end up being about half biliary atresia, and the other half a very long tail of ones and twos of ultra-rare cholestatic settings. The conversation with the FDA was around how to design a protocol for these indications that can't really be studied on their own. That's how we arrived at this basket study, really from the interest of prescribing physicians.
I think in terms of the commercial opportunity here, really excited about what it could represent. We've talked about, you know, our guidance LIVMARLI peak sales of at least $1 billion, and this EXPAND population can be a third of that, with Alagille and PFIC being the other two-thirds. You know, it's not easy to do epidemiology work 'cause it's just a whole basket of ultra-rare indications. From profiling and interactions, a clear line of sight to at least 500 pediatric patients in the U.S., probably similar numbers in Europe.
You know, in terms of speed of adoption, to your question there, Manny, I mean, this idea was actually kinda brought to us by the KOLs, by the physicians who were really thinking about the physiology here of like, okay, you know, it's great you have indications for Alagille and soon PFIC, but, you know, why not just treat anybody with high serum bile acids and cholestatic pruritus? I think they're kinda already there. Study enrollment probably supports that as well. Super excited about the potential commercialization there.
Let's stay in the core business actually for a moment. Where are we in terms of geographic expansion? Are there any remaining pockets where you think there's still market maturation to be had, internationally? Then separately, where are we in the ramp, initially mostly U.S., of the sort of older PFIC patient population, and that was a contributor to growth last year? Just for those two growth drivers, where are we, and sort of what inning?
Yeah. On the geographic side, you know, into the low to mid-30 countries worldwide with reimbursed sales of LIVMARLI. Would note that, outside of the U.S., Japan, maybe Germany, very little PFIC so far. Almost all the international side of the house has been Alagille. There's kinda indication expansion within geographies we're already in. Then maybe a handful of new geographies that any individual one probably isn't, you know, dramatically large, but collectively, you know, we kinda have opportunities in 2026 in places where we've had limited sales to date, you know, Middle East, Latin America, places like that collectively can be, you know, meaningful for economics and patient impact. In terms of the adult PFIC side, I mean, we still think we're in early innings.
This whole idea of kinda genetic cholestasis in adult liver disease is kind of a newer concept. It really got featured a lot at AASLD last year, where a lot of education on, "Hey, this is something you should be looking at, looking for after you rule out autoimmune cholestasis, like PBC or PSC." We're seeing increased genetic testing among adult providers, but I still think most of it is happening kind of in KOLs and top-tier places. We, I think, still have ground to cover in terms of getting non-academic providers doing genetic testing, looking for adult PFIC.
Yeah, I think the one add-on to that, to torture the baseball analogy, I mean, the dynamic here with continually finding newly diagnosed patients as well, it'll go into extra innings, because this is a consistent kind of growing business between new starts, a really favorable, sticky persistence profile because patients feel better when they're on therapy, and, you know, the weight-based dynamic as well all kind of feeding into this for the years ahead. From there, I do want to pivot to. Well, let's stay in IBAT land, actually. Let's pivot over to PSC. I know the debate around PSC, PBC opportunity, how to price the drug has been one that's. You've had to listen to me talk about this probably for two years. We'll come up on PSC first.
How should we think about what that disclosure of top-line results will look like in terms of what venue, what endpoints you expect to give us, what we should be prepared to get just as we look forward to the release itself?
Yeah, the release itself, you know, we're planning to handle this as we've done prior unblindings, where we'll share top line on the primary, which is the pruritus endpoint. That's the registrational endpoint, looking at ItchRO for volixibat versus placebo, the primary safety findings, and really we wanna make sure we're covering anything material. If there's any material finding out of that, we'll share it at the top line with the primary and the safety data. And then look to get it into, you know, one of the major conferences for presentation as quickly as possible after that for a more complete data presentation of it. Looking to follow our standard playbook for an unblinding.
Great. Now that we're done with that table setting, let's eat. I think a couple of the questions that we've gotten are, as we interpret this data set, like, what size of benefit on a points basis, on a zero to 10 basis, is meaningful for an individual patient in terms of itch improvement? Separately, should we, and if so, how should we interpret sort of a responder rate, the proportion of patients who, over the course of the study, do show some defined two, three, four , whatever point benefit on itch? Like, how does that translate to eventual uptake?
Yeah. On the way we think about the endpoint design and the study conduct, you know, the ItchRO score is a zero to 10 NRS. In a setting like this, two points is considered clinically meaningful. As a two-point change from baseline, from all the validation work suggests that's a clinically meaningful impact for patients. We're looking at that for a change from baseline. All of the precedent data suggests that we should be able to exceed that pretty readily. The placebo-adjusted difference is a little bit of a different concept. That's more about powering and statistical design. We've powered and designed the study assuming a 1.75 difference from placebo.
You know, kind of jumping around a little bit, the PBC interim showed 2.3, so I feel like we're comfortable on how that has been powered as well for the VISTAS study. The one thing I'd say, you know, beyond kind of how you think about endpoint design and the score, that's not something that's used every day by physicians, right? What I think ultimately drives uptake is gonna be treatment experience and kind of evolving how physicians think about managing of symptoms and discussing symptoms with their patients. Some market development work to be done there, similar to what we've done with LIVMARLI, in bringing that more into the conversation.
What drives, like, you know, good treatment experience is all about the patient experience. Initial anecdotes have been, you know, really positive on what this means on an individual basis for patients being able to reengage with normal day-to-day life, the fatigue improvement being a big part of that. That's what we think is gonna ultimately drive uptake and a good launch.
Let's talk about the proportion of patients outside of the trial, because the trial has some characteristics that are a little bit different than commercial reality. Out in the community, presuming approval, stats say clear safety profile as we'd expect from an IBAT. What proportion of PSC patients in the diagnosed pool are actively suffering from meaningful itch now for whom an antipruritic therapy would be meaningful?
Yeah, you know, the number we put out there is about 60%. Just to get some color on that, though, it's kind of interesting and it depends on kinda who you ask, as one part of it. We've done through collaborating with the PSC Partners direct patient work and actually come up with percentages much higher than that if you ask patients directly. One anecdote I like to tell is I've had interactions, separate interactions with physicians and nurse practitioners from the same institution where the physician will say, "Oh, yeah, you know, 10, 20% of my patients have pruritus of PSC," and then the nurse practitioner that this person works with says 80%-90%, and of course, they're seeing the same patients. It does.
This dynamic is in play for LIVMARLI too. It's you have to spend a lot of time in a busy clinic visit. If you just kinda ask one quick question and then move on, you might just get like, "Oh, I'm fine," or, "It's kinda mild," you know. That's as Chris was saying, the market development work we'll have to do to make sure the burden is fully recognized by healthcare professionals and even patients themselves. That's the other dynamic is we see patients and then caregivers on the pediatric side often kinda minimize pruritus. That'll be a lot of the wood we have to chop.
Let's talk a little bit about that dynamic. For these patients who've been living with pruritus, it's almost the water in which they swim. What are the investments have you made to raise that awareness and sort of make this something they think about as a prominent part of the disease as opposed to sort of background white noise of their life?
Yeah. I mean, it's a really good question. I mean, we do a whole range of things. On the sort of direct to patient and caregiver side, we do everything from kinda, you know, video disease state kinda testimonials, where patients kinda describe in their own words, you know, kind of how they came to kinda recognize their burden. Even peer-to-peer programs where, you know, patients can hear from other patients, caregivers can hear from other caregivers. You know, education through collaboration with patient advocacy groups is really helpful. Social media kinda things. They're just different methods. There's not, you know, not really a silver bullet, but it's this very much what we've been doing over the last five years with LIVMARLI too, I'd say. The team is pretty familiar with this kinda work.
Yeah. Let's talk about timeline to launch in the US and then globally. It's the morning after top-line results. Walk us through timeline to launch and how we should think about this launch. This launch velocity, given it's an adult launch, was a little bit different than Alagille, contributing to, flowing through the income statement and contributing how to think about your growth in the next five years.
I mean, on the set up from a timeline standpoint, I mean, that's right after we have those results, we'll be reaching out to FDA to get the pre-submission interaction, and have an NDA filed in the second half of the year. Sets up for 2027 approval, and you know, going from there. From a top-line contribution, really expect that to start showing up in 2028. And from an investment standpoint, there's a significant overlap and synergy with what we're going to be doing for brelovitug and Delta as well. We'll be building out that team really for the launch of both medicines because of this overlap and have one expansion step. From a bottom-line contribution, you know, expect 2027 and 2028 to be really the start of a substantial inflection as you bring these new products into the top line.
Let's go from PSC down the pipeline chart. I do wanna get to brelovitug, but while we're here, let's stay on volixibat. As you are presuming that positive result build out preparation for a launch in 2027 alongside your existing portfolio, to what extent does the result for PBC influence some of those decisions? Are there investments you're making as you're building out this commercial infrastructure ahead of PSC launch to maintain optionality for PBC or is the spend around that totally independent?
I mean, we would see them as really such a high overlap.
Yeah
That whatever we're doing to prep for PSC and volixibat launch is gonna be the same audience as PBC. From, you know, call point expansion and some of the brand awareness and some of the market development that we're talking about, it overlaps with PBC. It's largely the same prescribers for PSC, and it's a lot of it's brand level and how you're thinking about symptom management for your patients.
On that topic, I'm gonna slide over to brelovitug. Let's talk about the development of that market. It is, you know, there's been a lot of debate on how big that market's gonna be, how much uptake you're gonna see. These are obviously patients who are sometimes operating in very poorly resourced environments for the obvious reasons. Walk us through the market building and market maturation investments that you, your competitors collectively will be making.
I think the biggest one to highlight is shifting the paradigm on testing for delta. There's, as we were doing work leading up to the transaction, one of the 'cause we spent plenty of time diligencing aspects like this, and one of the really interesting stories that we've seen evolve over the past few years in Europe is what a shift in testing guidelines can mean for delta. In Europe, Hepcludex has been approved now for a few years, so it's got a little bit of a lead in terms of having a therapy for hepatitis delta.
What we saw is with a medicine available, there was a shift in guidelines to have reflex testing, so every hep B diagnosis would then be tested for delta, and that was a pretty substantial increase in delta diagnosis. We think that's what needs to happen to help find these patients and get them to medication, get them to a treatment once there is one available. Great paradigm shift that's happened in Europe. I imagine, you know, all of the KOLs and the sponsors in the space will be kinda working towards that through AASLD and in a guideline shift for how we manage testing.
Some of the KOLs are already doing that, but it has a lot further to go. That's really one of the key things from bringing more of these patients to market. You know, what we talk about is the 15,000 likely diagnosed and insured based on the claims work we've done. The full prevalent population, we kind of triangulated at 40,000. There's a big gap there to get more of these patients diagnosed.
Let's talk a little bit about quantifying the velocity with which that market grows with a change in testing, recognizing the U.S. is a little less fragmented from a policy perspective than Europe is. What can we extrapolate quantitatively from the European experience as we think about the growth in the diagnosed population in the U.S.? Should we see reflex testing become more broadly adopted?
Yeah, I mean, there's some interesting papers on that from Spain and Italy, and they kind of published the delta positivity rate, you know, among patients with chronic hepatitis B, before, when they were just doing risk-based testing, when the idea was, "Hey, does the patient have risky behaviors? Are they immigrating from an endemic part of the world for delta?" You know, and that number before, when they were just kind of doing smaller numbers of patients, just risk-based, was, you know, depending on the country, 7% , 8%, 9% of patients with B had delta. Then when you actually just screen everybody with B, you know, the question was, "Is this gonna drop?" You know, "Is this gonna drop way down?" The answer is it didn't.
You know, it actually still is that 8%-9%, which kind of proves that risk-based screening just doesn't work. I mean, I think there's kind of every reason to think the same thing would happen in the U.S. once we get physicians to start testing, that if in the U.S. maybe the number is, like, 3% or 4% of B patients have delta, that, you know, that should very likely continue as you just test all B patients.
Let's talk about competitive position and zooming forward, pivotal data, launch approval. Obviously, Hepcludex is not the right competitor to think about. There's yours, there's your competitor, the Vir asset. These two assets have a little bit different profile. Talk about how you think about competitive positioning for convenience, single versus multiple assets, and a little bit of thinking about what endpoints really matter for efficacy in terms of HDV negativity versus ALT AST normalization.
Our program, I think the highlights for brelovitug and its profile is that you're, you know, there's no compromise on activity level. It is a highly active regimen, and it's quite clean, you know. Simple, fully human antibody, that the safety profile has been a real highlight in the clinical data to date. We think that's really compelling from a patient and prescriber standpoint. How that rolls out from an endpoint perspective, we're focusing on the endpoint that's in the FDA guidance.
That's the virologic response with ALT normalization, and that endpoint is the reason why FDA uses that as the surrogate for approval is because it historically has been linked to improved outcomes. B oth reducing viral load and addressing some of the inflammation in the liver, some of the liver damage that's happening, together, is what the objective is, and brelovitug really shines on that endpoint. We saw the 65%-82% out of the early phase 2 data, and I think that's gonna be a real strong point for the brelovitug phase 3 data.
You've laid out a number in terms of the $750 million-ish guidance as sort of a floor guidance number. Talk to us about the assumptions baked into that to the extent that you can disclose them. Recognizing that obviously you're limited by competitive concerns. Just how should we think about the aggressiveness or conservatism baked into that number, what that implies about, you know, breadth of adoption of testing, et cetera?
I mean, the way that we approached that as a kind of estimate of brelovitug floor peak, I guess is the new terminology to put on it here. You know, delta as an indication is new for most people, so we wanted to be able to kind of paint a picture of what a minimum size of what we think this can be, even without some of these dynamics that we're talking about on expanding testing and, you know, really dramatically changing the number of patients that are diagnosed and in care.
The assumption behind that is, you know, let's just say from a starting point, we go into a market, it's split up among three different med regimens, and out of that U.S. population, you get two to three thousand patients on drug. That's what's behind that assumption. We wanted to start out with a pretty conservative look of what brelovitug could be based on those assumptions.
Let's talk a little bit about the geographic variability. I think people are very aware of the geographic variability of HBV, very APAC-driven market in terms of volumes, not necessarily the price. HDV and HBV prevalence are not necessarily one-to-one, despite the biological relationship between the two causal pathogens. Sketch out for us how you think about the opportunity set in terms of patient numbers, patients you could help, and then we'll separately get to pricing by geography. Just sketch it out geographically how you think about accessing the pool of patients by each geography that could be helped by this drug.
Yeah, I mean, I think when you look at the delta endemic kind of hotspots around the world, you know, absent immigration, you kind of immediately go to South Asia as a big hotspot, you know, the area around Mongolia, Pakistan, Eastern Europe, actually, former Soviet Union and then in richer countries, you kind of think about countries where they have a lot of immigrants from those areas. Southern European countries, parts of the U.S. that have people from those that have immigrated from those areas end up being pretty big markets, you know, pretty you know kind of where the opportunity resides. I think the rollout, I mean, initially probably, you know, focus on U.S., Europe. That's where the development plan's focused now with an eye towards the future of how do we broaden access, you know, over time as much as we can.
Now, you guys do not have an established exclusive APAC partner. For example, your competitor does. We've talked about this before, I know. How do you think about which markets should be accessed through a distribution agreement as opposed to something where your counterparty has a little more active control?
I mean, we have a strong presence internationally. We have Mirum teams in Western, Central Europe, as well as Canada, obviously U.S., and then have a great distributor network, that covers Eastern Europe, Middle East, Latin America, for LIVMARLI, as well as licensed partners in East Asia. I mean, that's kind of where we have a team on the ground now that's kind of executed really well with liver docs, and would look to leverage that as much as possible. To the extent there's delta in regions beyond their reach, you know, some of the lower GDP parts of the world, we'll have to look at kind of access strategies, you know, in the future to figure out ways to reach those folks.
We only have a few minutes left. I want to hop over. This is perhaps more of a CFO question.
Okay
I think between the two of you can take care of it. Obviously digesting the Bluejay deal will take some time. You're quite busy with a number of pivotal readouts. Looking forward two, three years out and beyond, how do you think about potentially Mirum remaining active on the hunt for new assets, the role of BD and expansion? Obviously, you're gonna have quite a few indications under your belt, so there's room to grow from the existing pipeline. To what extent is the company staying active on BD, and how should we think about future assets that could be added to what is now a larger portfolio?
We remain active and interested in bringing in more rare disease programs into the company. The criteria remain the same as what it has been before. We have a high bar in terms of, is this, are these medicines that we can add value to? Can we complete a transaction and maintain kind of our financial strength and independence, you know, not have financing overhangs or anything like that? I think we've executed pretty, like, quite well on that over time on meeting those criteria. Bringing in medicines like this, you have to be opportunistic on when there's a right fit to bring something in, you know, a counterparty that sees value in the transaction.
That means you have to stay active to be able to act on those opportunities. It's very much in the DNA of who we are. That's how the company came to be. That's core strategy, is to continue to bring in rare disease products that really don't fit with where they're at or, you know, kind of need the attention of a team like Mirum.
Great. We are running out of time. I'm looking forward to continue following data throughout the year. I'm certain we're gonna revisit these conversations again.
Yeah. Thanks for hosting us. Big year ahead, and look forward to some Q2 updates.
A pleasure to have you guys. Thank you.
All right. Thanks, Mani.