All right, good morning, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the biotech analysts here, and it's my pleasure to introduce Chris Peetz, CEO from Mirum Pharmaceuticals. Just as a reminder, the format for today is a fireside chat, so if anyone in the audience has a question, please feel free to raise your hand and we will address it. But before we get into the discussion, I need to read a quick disclaimer. "For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures.
If you have any questions, please reach out to your Morgan Stanley sales representative." And with that, Chris, thanks for sharing your time with us this morning, and I'll just turn it over to you to make some quick intro comments, before we jump into Q&A.
Great. Thanks, Mike. I appreciate you hosting us here, and I'll make my disclosures first too. You know, we'll be making forward-looking statements, refer you to the risk factors and in our SEC filings. And Mirum is a rare disease-focused commercial biotech company that we're based in the Bay Area. We have three approved commercial medicines, all three growing brands in different rare disease settings, where our products are really taking the place of standard of care in these various settings.
Overall, on track for $310 million-$320 million of product revenue for the year, so a very strong growth year for us this year, and dynamics that, well, we can talk about on across the brands on how Livmarli, Chenodal, and Cholbam are all continuing to grow for the time ahead as well. Busy pipeline behind those products with a new indication rolling out right now for Livmarli, a regulatory filing in for Chenodal for label expansion. Just kicked up a new Phase III study for Livmarli as well, the EXPAND study in broader cholestatic pruritus settings, and a lot of excitement around volixibat in PSC and PBC, which had two positive interim analyses this year.
Now on track into the confirmatory portions, which we think sets are gonna generate pivotal data sets for both of those indications for Volixibat. So, busy stretch here for us at Mirum, and across the board, the company is performing well commercially and in the pipeline.
Yep. Great. Thanks for that introduction, and you know, we agree, a very exciting year for you guys with the Volixibat data. But before we jump into that, maybe we could start with Livmarli. Obviously, it's been your lead program, but maybe for people who aren't familiar with it, maybe just talk about how that, the mechanism of action there and kind of the... Maybe start with ALGS as well, as kind of how it works there.
Absolutely. Livmarli is an oral, minimally absorbed IBAT inhibitor. It's an ileal bile acid transporter inhibitor. Mechanism is really quite simple and relevant for settings of cholestasis. It blocks absorption of bile acids in the GI tract, and then bile acids are expelled in feces. So it's quite simply a way to deplete excess bile circulating bile acids in these settings of cholestasis. Livmarli is approved in for cholestatic pruritus and Alagille syndrome and PFIC in the U.S., for PFIC and cholestatic pruritus and Alagille syndrome in Europe, so slightly different labeling between the two. And for Alagille, in particular, we can start there.
Yep.
This is a genetic disease that has quite severe cholestasis, so very elevated bile acid levels that lead to heavily impacted quality of life. In particular, what you'll see across all these settings is pruritus, the itching that's caused by the persistent cholestasis. It's totally life-changing and really defines the day-to-day for many of these patients. And in the clinical program, Livmarli led to quite substantial and dramatic reductions in pruritus in the Alagille syndrome patients, approved a few years ago now and really continuing its reach and broadening adoption for patients with Alagille syndrome, and also rolling out internationally as well, so launching across a number of different countries this year.
Maybe you can talk about what's driven sort of the growth of ALGS in the past, and kind of looking forward, what are those sort of remaining growth drivers?
So in the launch of Livmarli, we saw a really nice uptake early on. I think of it actually in the most severe patients, right? Those that have the most severe pruritus and how they think of it from a day-to-day standpoint. There's a lot of dynamic here on the conversation between families and physician in getting to a treatment decision. And so early on, it was some of the ones that were, you know, struggling the most with their pruritus from a day-to-day standpoint.
And what we see is, as we've gone further, there are a number of families and physicians that have been broadening their use and, you know, coming to drug over time as they open up a conversation about what the impact of pruritus and the cholestasis is from a day-to-day standpoint. And to, you know, to kind of highlight an aspect behind that, it's not uncommon to have a profile of someone who's living with Alagille syndrome, where they've, you know, for a decade or two, really normalized their day-to-day. And those are the types of patients that we still see coming to drug, as they've just taken longer time to get to a conversation to see if they're a Livmarli patient.
Yeah, and maybe just talk about the entry of a recent competitor and kinda how you're positioned, and then what impact, if any, that's sort of had on your sort of opportunity?
Yeah, we recently saw the approval of Odevixibat in pruritus and Alagille syndrome as well, and you know, from what we see in the Livmarli business, we've not really seen an impact on our adoption, the persistence. Really a highlight of this brand is that, you know, patients feel better on drug. They tend to stay on drug compared to what you might assume for, in general, for a prescribed medicine, and that hasn't changed with their approval.
What we see from Livmarli and kind of our success in the market is continued adoption, driven by, you know, good treatment experience, the really strong clinical data that we have in terms of what we saw for, you know, quite a broad and deep response in the clinical programs. What we've seen for some of the long-term follow-up, showing improvements in transplant-free survival for the patients that are seeing their pruritus improve a ll of that is combined to really, we see Livmarli typically being the, the first choice for Alagille syndrome.
And in Alagille, you know, what percentage of patients are currently being treated today? And, you know, what's the opportunity?
Yeah, we define it. We look at, you know, the approximately two thousand children with Alagille syndrome in the U.S., and you break that down and, you know, it's, you know, probably the majority of those are treatment eligible. So when you're looking at the kind of addressable population, we're probably a third or a bit or so penetrated into that population.
Got it. Maybe we switch gears a little bit to PFIC. You know, it was added to your label earlier this year. Maybe just give us a brief background on that disease and maybe the size of the opportunity relative to ALGS.
So PFIC, also a genetic disorder, quite different in what's causing the cholestasis in PFIC patients, whereas Alagille syndrome, bile duct structure is malformed. In PFIC, it's actually a number of different genetic disorders impacting bile acid-related transporters. So think of the transporters within the liver that process bile, get it into the gallbladder, deal with some of the different transport of bile components as well. So it's actually a number of different genetic diseases that present in a somewhat common way with cholestasis. And that's relevant, the heterogeneity is relevant in terms of the data we've generated and how we're seeing adoption in the very early days.
The Livmarli's approval is based on the MARCH PFIC Phase III study, which covered really all genetic subtypes were allowed into the study, so we have a really broad data set within that Phase III study, also mentioned in the label, and that's very relevant and a real advantage for prescribers that you know the data is there to suggest that you can see a response across all these genetic subtypes. In early days, we're seeing demand that comes across a broad range of genetics for these first patients that have come on drug.
Maybe if you can talk more about just the differentiation. You touched on a little bit with the broader label, you know, versus the existing competitor. Like, are there other sort of points of differentiation in PFIC?
That's a real key one, you know, the broader genetic profile that was in our pivotal study. And the other advantage that we continue to drive with really Mirum's focus on this setting is that you're being a trusted partner for prescribers.
Yeah.
Right? And so they've had good treatment experience. We tend to get really positive feedback on the ease of access and the prescribing process. These are things that matter for these rare diseases, for that small circle of pediatric hepatologists and gastroenterologists that prescribe Livmarli.
Yeah. And you touched on this already, but just early trends you're seeing there, anything else to mention? And, you know, when do you start to see more meaningful impact on the top line from PFIC?
So the PFIC launch is off to a good start. You know, I didn't mention patient numbers. I mean, PFIC is much smaller than Alagille, so we are talking smaller patient numbers. And we're going through a lot of the access conversations now with payers, and, you know, starting to see some policies come together, but really don't expect a full impact until Q4 for reimbursement, and then see that add to the growth as we move into next year.
Got it. And, maybe talk about the recent sort of adjustment to the label. You got any, you know, younger patients and what impact that has or doesn't have?
Yeah. So for the PFIC indication, Livmarli was originally approved for patients five years and older, and it was recently lowered to 12 months and older, and that's where a lot of the treatment decisions are happening. So it's a really important label expansion to get down to those younger patients. And, the, you know, what was behind that was bringing forward another formulation. So we now have a PFIC-specific formulation, because PFIC is at a higher dose, right? So that's what was behind that label expansion. Something that was a pretty straightforward step for us, but really big impact in terms of when physicians and patients are making their first prescribing decisions.
Makes sense. Maybe sticking with Livmarli, and you've—as you've mentioned, you've got two approved indications, but you're working on, you know, further expanding the label. Maybe just talk about that and the path forward there.
Yeah, the EXPAND study. So very excited about this that it's a study that we're initiating now. And EXPAND will look at Livmarli in settings of broader definition of settings of cholestatic pruritus. So you almost think of this as a patient inclusion criteria that is defined a bit by exclusion. So it's cholestatic pruritus that is not Alagille, PFIC, PSC, PBC, or cholestasis of pregnancy. So it's basically excluding the larger indications, because there are a very long list of quite rare other causes of cholestasis that can lead to the same pruritus that is life-changing and debilitating that occurs across all these settings. And what we were seeing since the approval of Livmarli is real demand, right? So we have had, through compassionate use requests, demand that shows up across this...
Describe it as a long tail of different types of cholestasis that have that same severe symptomatic burden. That's what we're going after, is to enable labeling around that, to be able to provide Livmarli to these patients and have it be reimbursed as well. Study's forty-five patients, placebo-controlled, and expect to see a quite broad mix of cholestatic diseases in that study.
Can you talk a little bit more about the trial design, the primary endpoint, and sort of the status? I know you just sort of announced it, so you're probably still working on getting that up and running.
Yeah, working on... The sites are going through opening now. I expect to get the first patient randomized this year, still. 45 patients, placebo-controlled, using pruritus as the primary endpoint. That's something that's very common across all of our iBAT program. And the mix of patients you expect to see in there includes, you know, biliary atresia patients that are further along, older than what we've studied before, developing cholestatic pruritus, so quite different from the ones that we've studied earlier. Secondary sclerosing cholangitis, so, cholestasis that occurs because of, a number of different events that, cause that bile acid build up and a number of other rare genetic types. You know, things like alpha-1 antitrypsin cholestasis, have shown up and other, genetic disorders like that.
You just touched on it, but in the past, you've looked at biliary atresia, but you know, unfortunately, were unsuccessful there. Maybe just talk about what are the key difference this time around and how you become successful.
Yeah, so the... first, as a bit of background, the prior study we conducted in biliary atresia, the EMBARK study, looked at... You think of it as the very acute setting in biliary atresia, right after diagnosis and surgical treatment, to look at if we can prevent the very acute liver disease progression. In biliary atresia, the standard of care is to have a Kasai procedure. This is a surgical procedure to reroute bile for these children. It's life-saving. Without that procedure, biliary atresia is fatal, and what we were trying to do there is to prevent that, within the months afterwards, there are a number of these children that will continue to liver failure despite the surgical procedure.
What we saw was that going after bile acid absorption after a bile acid redirecting surgery is just not going to move the needle. Right? So those that very acute setting, we did not see an improvement in some of the liver parameters because it is such an acute, fast-progressing setting. What we didn't look at in that study was pruritus in the older patients. Another dynamic in biliary atresia is that while they're you know the immediate setting, these children are generally not pruritic when they're younger but over time, they can still have some persistent cholestasis. A small portion of them will over time develop cholestatic pruritus as their cholestasis continues despite that avoidance of a transplant in infancy.
Yeah.
These are patients that we've seen show up for compassionate use. We have some really great response stories from physicians that have treated with Livmarli in those settings, and look forward to having some of that data presented in future conferences. And just like we've seen in Alagille and PFIC, really tremendous ability to impact pruritus in these, these... You know, it's case studies at this point but really great feedback from physicians.
Yeah. Can you maybe talk about the size of the patient population there relative to sort of the Alagille and PFIC?
Yeah, it's a little unlike Alagille and PFIC, which are, you know, genetic disorders that have been studied and have more kind of established epidemiology. This study is a little less clear on how we approach epidemiology. But we think that there's at least 500 patients in the U.S. that would fit this profile, you know, pretty easily just from looking at what we're seeing from experience across different centers. So that's roughly the size of PFIC, is a pretty simple way to think of it in the U.S.
Yep. Okay. Maybe we can switch to just Volixibat. You know, recently shared some very promising interim Phase IIb data in two different indications. But maybe before we dig into some of that, can you just talk about the strategy and just how it fits into to your broader strategy?
Yeah. So volixibat, similar to Livmarli, it's an oral IBAT inhibitor, so it's the same approach here. In settings of cholestasis, look to deplete the excess bile acids. What's different is volixibat has been entirely focused on adult settings of cholestasis. And in the PSC and PBC studies, the VISTAS and VANTAGE studies, we're studying volixibat versus placebo, and using pruritus as the outcome and the primary measure for volixibat in these settings. So these are oriented to support registration using pruritus as the outcome for what would be a full approval, if these studies are successful in their full datasets.
Can you talk about the use of just pruritus and kind of the feedback you've gotten from the FDA, and if there's any risk around that approach?
Yeah, pruritus, you know, quite simply, it's an outcome, you know, and registrational endpoints focus on how a patient feels, functions, survives. Pruritus, it falls into that. It's how a patient feels, and so no surprises here, actually. We're taking what we learned in the pediatric experience and applying it in the adult settings w here in the Alagille syndrome and PFIC approvals, pruritus was the outcome that was the basis for registration for both of those indications, and we're doing the same thing with volixibat in the adult settings. This is particularly relevant and helpful in PSC, where regulatory endpoints are really difficult without using something like pruritus, without using a PRO endpoint. Because the laboratory measures that can be used in PBC are just not as consistent in PSC and are not, just not accepted as registration endpoints. So puts the Volixibat program in a very unique position for PSC patients.
Yeah. Maybe just continuing with PSC, just, you know, VISTAS study and maybe just remind us that trial design and just key takeaways from your recent interim update.
The VISTAS study is a, you know, randomized, placebo-controlled study and broken into two portions. What we just announced was the interim analysis being conducted for the first portion of the study, which had two doses of volixibat. So think of it as a dose-finding lead-in to what will be, you know, a full, potentially pivotal data set. So at that interim analysis, how it was conducted is that a blinded data monitoring committee conducted the analysis and was looking for a pre-specified threshold on efficacy and evaluating safety of the two doses of volixibat. They recommended the study continue with no changes, which means that it has proceeded to go to one dose versus placebo and move into the confirmatory portion.
So those results have remained blinded, and the reason for doing that is that then that first cohort of patients will count in the full data set for the primary analysis.
Okay.
So allows us to be much closer to that pivotal data set. PSC, of the adult indications, PSC is more rare.
Yep.
To be able to conserve the patients for the pivotal data set is really important for timelines.
Yep.
So we now find ourselves, you know, over a third enrolled in our potentially pivotal study for PSC, heading towards completing enrollment second half of next year.
Can you remind us on the pre-specified threshold, just sort of what you've said? Have you? How much detail have you given on that?
So it is a statistical definition, so it's not... Don't think of it as, like, a single value or difference from placebo. So it looks at the statistical effect size of drug versus placebo. What we know is that it exceeded that. We haven't disclosed what the specific number of it is, but the way we approached it is that we wanted that number to be predictive of a positive study outcome. So from our view, it sets us up to be in a really strong position for the second part of the study.
Yep. You mentioned completing enrollment in the study, so second half of 2025. I guess, just remind me the primary endpoint is three months, or is it six months? I can't remember.
So the primary endpoint looks at six months of placebo-controlled data, but evaluating the second half of those six months.
Okay.
So it's an analysis that mirrors what we've done in PFIC, and you'll hear, you know, some consistency here. It's the same thing we're doing in PBC as well.
Yeah. Okay.
And so you look at the analysis looks at the pruritus daily pruritus scores for these patients for months four, five, and six is the simple way to think about it. That provides more data points and also looks at itch over time, right? So you're not looking at a single time point, which could... You could get lucky or unlucky.
Yeah.
And it misses the kind of richness of the data capture that we have from looking at several data points from each patient.
Yeah. Can you maybe talk about the, just the size of the patient population opportunity for PSC?
PSC is looking across the U.S. and EU, about 54,000 patients, about 30,000 in the U.S., is how the epidemiology comes together. When you consider PSC patients with pruritus, 'cause that's the relevant population and labeling that we expect to have, that's about two-thirds of that. So, 20,000 patient treatment opportunity in the U.S. of PSC patients with pruritus.
Yeah. Maybe we can switch to PBC now and just m aybe just describe the disease, current treatment options for patients there, and where the opportunity is.
PBC, another adult setting of cholestasis, and what... Much larger in terms of patient numbers. But also, there are other treatments available. We saw a couple of new additions to available therapies for second line PBC just get approved recently. So in PBC, you know, there's probably a hundred thousand or more patients in the U.S., but we break that down then into different lines of therapy and a bit more, a few more choices for physicians.
Mm-hmm. When you're looking at the unmet need in PBC, most of the advances have been really targeted at second-line therapy, so looking at agents that can reduce alkaline phosphatase in patients that are progressive on UDCA, so have elevated alkaline phosphatase levels, and the recent approvals target alkaline phosphatase of one point six seven times upper limit of normal or higher. That's probably a third of the market. So 2/3 of patients are actually in kind of a what we'd describe as a first-line setting on UDCA, but many of them still having symptomatic burden, pruritus, and really what drives the day-to-day experience for patients is typically that, the symptomatic burden. So that's the target market for volixibat in PBC.
The VANTAGE study enrolled patients across all of these segments, so it included patients with normal and elevated alkaline phosphatase and any baseline alkaline phosphatase status, as long as they had pruritus, they were eligible, they are eligible for the study.
Maybe you can just touch on, like, the key takeaways from the data.
So really thrilled with the findings of the interim analysis. The VANTAGE study interim analysis looked at 30 PBC patients and saw quite pronounced reductions in the Adult ItchRO scale. Think of this as a 0- 10 NRS, you know, so pretty standard measure for pruritus in adult settings. We saw a 3.8 change from baseline, 2.3 placebo-controlled reduction in pruritus, so really strong results across the board.
Between the two doses, so we looked at two doses in the study, the 20 mg and the 80 mg t wice daily were the two doses being studied, saw a very consistent treatment response across both, which based on the dose-ranging work we did heading into the study, tells us that we're maximizing the effect at the 20 mg dose already. So that's the dose that we're taking forward into the confirmatory portion of the study. I think one of the questions we hear is, why are we announcing the actual data results from this interim versus keeping them blinded for PSC? And the answer is, because PBC is a much larger indication, we're looking for a larger safety database in total. There's less need to conserve those patients in the final analysis. We're now moving into the confirmatory portion, targeting, you know, up to another two hundred or so patients in this, the second part, that we will expect to be the pivotal data set for VANTAGE.
You mentioned sort of reductions on pruritus of north of 2% and 3%. You know, can you maybe put that in the context of what's a meaningful reduction?
Yeah, so it's two point three points on the 0-10 scale is the placebo-adjusted change. And when you're framing it for the clinical meaningful effect for patients in a zero to ten NRS, it usually comes out at about two-point reduction, but that's typically looking at it as a change from baseline measure. So the 3.8 change from baseline compared to a two-point change is. That's a really substantial and meaningful reduction for patients.
Yep. And you didn't mention this yet, but just you also saw benefits on fatigue. Why is that important?
So the two most common symptoms talked about by PBC patients are pruritus and fatigue. Right, so this is what is driving a lot of the impact for patients dealing with PBC and PSC, frankly. So there's some commonality in the what the symptomatic burden does for day-to-day life. That fatigue, potentially very related to the pruritus, impacts the ability to go to work, to interact in society, to have, you know, normal relationships. So to improve that fatigue, I've heard it described actually by one of our investigators in a way, it gives these patients their life back because they then are able to go back to work, or go back to work full-time and- o back out and have a normal day-to-day function.
Yep. Maybe we can... We have three minutes left, so maybe we can shift to Chenodal and Cholbam, and maybe just remind us, you know, where the growth comes from in the future and your opportunities to continue to drive that.
Chenodal and Cholbam are bile acid replacement products that are approved and used in a number of different genetic bile acid synthesis disorders. Historically, these products have just kind of grown at a steady, kind of single-digit percentage year-over-year growth from accumulation of new patient starts over time. That's kind of the background of these products. The one really interesting growth opportunity to highlight is for Chenodal, where we are. We read out a positive Phase III study for Chenodal on CTX. Currently, Chenodal is approved for treatment of radiolucent gallstones, but it's really only used in this off-label setting of cerebrotendinous xanthomatosis, so CTX. That has a medical necessity recognition from FDA, so it's really all that's used and available for these patients.
We're going through the work to actually get it labeled, and to be able to promote. So it's currently only passively prescribed, and CTX is likely dramatically underdiagnosed. Most patients get diagnosed late when there has been an accumulation of irreversible damage from the disease. And so, we're optimistic that when we get the approval, expected early next year, we'll be able to go out and help get these patients to treatment and prevent some of the CNS impacts that happen- when you're not treated with CTX.
Okay, great. Looks like we're just about out of time, so why don't we end it there? Chris, thanks so much for spending time with us today.
Yep. Thanks, Mike, for hosting us.