All right, I think we're ready to start. I'm Josh Schimmer from the Cantor Fitzgerald Biotech Equity Research Team. Very pleased to introduce from Mirum Pharmaceuticals, Chris Peetz, Chief Executive Officer. Chris, welcome. Maybe let's start with a quick snapshot of Mirum and what we have to look forward to over the next twelve to eighteen months.
Yeah, thanks. Thanks for hosting us. At Mirum, we're a rare disease-focused company, commercial with three approved products: Livmarli in Alagille syndrome and progressive familial intrahepatic cholestasis, Cholbam and Chenodal and different bile acid synthesis disorders, and a pipeline asset, Volixibat, that's in phase IIb, potentially registrational studies in PSC and PBC, with some interim data that read out earlier this summer. Exciting time for those studies as they roll into the confirmatory portions. You know, it's been a busy year for us across all those fronts, with strong commercial growth and it's shaping up to be a year of really strong financial performance as well.
Excellent. Why don't we drill in on Livmarli? You've had a very steady growth trajectory, both US and ex-US, over the past few quarters. How sustainable is that, and where do you see the major growth drivers?
For Livmarli, break down the drivers and trends here by indication. And really starting with Alagille syndrome, which coming up on the three-year anniversary of the approval in Alagille syndrome. And even at this point in the launch, still seeing a healthy, continuous cadence of new patient starts, both in newly diagnosed and in the prevalent pool of patients, and don't see that trend changing, frankly. From what we see from the prescriber interactions and what's going on in the setting, that Alagille syndrome accumulation of patients in the US continues to be strong. Internationally, a point here where we're heading into a period of strong growth internationally, as pricing has kind of been set now in Europe, and that's a big reference point for other markets.
Seeing strong demand growth, and now with price set, expect to see international markets play out well in the quarters ahead. Then the third element for Livmarli is PFIC. You know, with the label expansion in March, we're now seeing reimbursement and policy start to get updated in the U.S. for PFIC. It's smaller numbers than Alagille syndrome, you know, PFIC's maybe a third the size of Alagille syndrome, but we are seeing de novo prescriptions there, so another element to driving growth in the U.S. near term.
Okay, great. Lots of different things to double-click on in there. Maybe we'll start with the U.S. Alagille indication. I think you've estimated you're about one-third penetrated into the patient population. Is that specifically for the U.S., and where do you think you can ultimately get?
That is specific to the U.S., and though it is somewhat mirrored in the European markets where we are direct, you know, where we're commercializing directly in Germany and France. Those started a little later than the U.S., but it has followed a similar shaped curve. Yeah, so we do expect to continue to make progress further into that prevalent pool of patients. Looking at the makeup of de novo prescriptions, probably about half and half between a newly diagnosed, quite young patient and a prevalent patient in what we see in new enrollments. It suggests that there's still quite a bit more to go.
The way to think of it is these, in the prevalent pool of patients, think of them as the more mild to moderate in terms of their perception of their symptomatic burden. Those patients see their specialists less frequently, they're slower to come to brand, but it is happening over time.
Are there any access issues for those more mild to moderate patients?
Not that we've seen, no. I mean, the policies are pretty straightforward and clear, typically require confirmation of Alagille syndrome or PFIC of the diagnosis, and some attestation to pruritus. Severity has not been a component of the reimbursement.
Pricing is weight-based. Maybe you can talk to us a little bit about the trends that you're seeing, both in terms of, you know, patients' growth on drug, as well as that mix of new patients. I might imagine if you're starting to see more mild to moderate patients, you may also be seeing somewhat older patients and, almost paradoxically, somewhat more valuable patients, even though they have less severe disease.
Yeah, well, and, I mean, first, one comment on severity, that it is very much, like, the perception, and what we found is, a patient that sees themselves as mild, a patient that goes to their physician and says, "I'm okay," after they start therapy, their perception of what they were coping with actually has changed. We've had some really interesting feedback that, there's a lot of normalization and coping mechanisms that go on. But in terms of kind of back to where you were starting on the question, this is weight-based dosing. It's a product that, patients feel better when they're on drug, so there's good persistence. They want to stay - they tend to want to stay on long term. So we have seen, you know, patients, especially the younger kids, grow when they're prescribed.
So over time, there's been, on the whole, a slight increase in the average dispense, 'cause it's somewhat balanced out by newly diagnosed patients who are, you know, they're infants and much lower dosed in total.
And what about the, those new prevalent patients coming on therapy? Cause that may be yet another balancing dynamic for bigger patients.
Yeah, so similar, and this has been pretty consistent over the whole stretch here is you do get a mix of some older patients, including adults. And yeah, so they're higher dosed. So included in the average that we've looked at.
Got it. So you highlighted the European pricing dynamic. Just kind of review for us what played out there, where the EU pricing is now relative to the U.S.
Yeah, so we usually are talking about German pricing, because that's what's posted publicly, and is commonly used as a reference price for a lot of other markets. It played out really well, so really pleased with the result there. The German gross price, as posted, it's about 26,000 EUR per bottle. And in terms of what that means for kind of the revenue potential for a rare product like Livmarli, it's really strong. And what we've talked about in terms of how this plays out across the markets from a revenue standpoint, it's effective already in Germany. And some of our indirect markets, so where we use distributors, a lot of those in particular reference to publicly posted pricing, like in Germany.
So we've seen that price now start to be adopted in some of those reference markets that use named patient programs or, you know, direct government programs for access.
Where is that 26,000 EUR per bottle price relative to the U.S.? I'm forgetting the..
We talk about the U.S. really more on the average net revenue per patient per year. Now, it's drifted into the $400,000 plus per patient per year. And so in Europe, you know, you think about that EUR 26,000, and you're just about 12 bottles a year.
Okay, got it. Do you have an estimate for the split between PFIC and Alagille in the U.S.?
I mean, to date, it's really almost entirely Alagille syndrome.
Okay.
And so while we had the label expansion for PFIC in March, in the second quarter, very minimal reimbursed dispenses at that point, 'cause patients were still going through rollover and a lot of payer plans being updated. Overall, from a patient number, it's about one-third the size of Alagille syndrome. In terms of how that shows up in our top line, it's really hard to have something to guide to at this point c ause we're in early days. But I will say that seeing de novo prescriptions of prevalent patients, which we have seen in smaller numbers, it's encouraging, so, we are seeing uptake beyond just the clinical rollovers that we had on study.
I think you've indicated you expect the PFIC to really start contributing more in the fourth quarter. What's kinda happening between then and now for that to occur?
Incremental reimbursement policies coming into play. So we have seen, you know, there are some reimbursed dispenses in Q3. We've seen some nice policy wins, in terms of how Livmarli is making it into formulary for both Alagille and PFIC, and expect to kind of be at full reimbursement, heading into Q4.
How are you, how are you seeing now the competitive dynamics? Ipsen's taken over from Albireo, and since then, the Bylvay revenue line's inflected, you know, quite meaningfully. What are you seeing kind of in the market in terms of how effective Ipsen is in positioning Bylvay, and how do you think about the advantages of Livmarli that, you know, you think patients should prefer?
If we're really hitting on the highlights of what we see and what we're doing, from our team on Livmarli, from the, you know, Alagille syndrome, where we have the longest experience and can look at trends, there's not really an impact that we're seeing in terms of new patient starts, compliance, persistence. And I credit that to what has been a high prescriber satisfaction, a lot of familiarity with Livmarli. Our access team is really strong. They've been able to make sure that we do everything we can to make Livmarli accessible, and that plays out into, just think it's customer satisfaction.
You know, the pediatric hepatologists, they're busy, and if you are gonna go through prior auth paperwork, you wanna make sure that you're gonna get the drug dispensed for your patient. That's been a focus for us, and it's played out well. And on the competitive front, in PFIC, it's early days, but the March PFIC data for Livmarli is very strong. It crosses a much broader set of genetic subtypes, and I think that'll play well.
One of the potentially differentiating factors for Livmarli in PFIC was a higher dose and potential to maybe squeeze out more therapeutic effect compared to the Bylvay dose. It sounds like, for now, the prescriptions coming in are for de novo patients. Do you think you'll be able to convert any of the Bylvay patients, and if so, what might that take?
I think when looking at kind of a second line treatment opportunity like that, there may be some, but we do think it will be, you know, case by case, you know, less common than a de novo prescription. Mostly because in PFIC the numbers are frankly, they're smaller, right? So you're not talking about large enough numbers really to have trends. But if a patient is progressing, is not controlled with either product, you'd expect, before going to transplant, that a physician would, you know, try another drug.
What are the ex-U.S. markets that you've launched in to date, and how should we be thinking about the cadence of new countries coming online?
We are direct in Canada and Western Europe. Speaking to our launch experience there, you know, Germany and France have been commercial for some time now, for a couple of years. More recently, start of the year, we picked up Italy with Alagille launch. Spain is launching now, and from there you move into smaller markets and distributor markets that we'll continue to see. We're already commercial. There's commercial reimbursed dispenses in 20 countries, direct and indirect, for Livmarli. At this point, it's about not only adding new countries, but also, you know, deeper penetration into those 20 that are already commercial.
How has the adoption curve in Germany and France been? They tend to be a little bit more coordinated and efficient in identifying patients and sometimes getting them on the therapy.
You know, in terms of identifying patients, Alagille syndrome and PFIC is really well diagnosed. It's heavily symptomatic, so I think the patients are very well identified in both U.S., North America and Europe. The care is more coordinated in terms of referral centers, so what we saw in Germany and France was maybe a little bit faster uptake with the very first set of kind of think of the more severe patients. But the dynamic of kind of a continuous ramp and steady growth from there, we're seeing similar dynamic to what we've experienced in the U.S.
Do you think you can accelerate the revenue curve as these new countries come online, or are they more likely to maintain the growth that you've been able to show thus far?
In looking at the, you know, the total global number, you know, adding new markets, if you see the same curve dynamics as the U.S., yes, we should be able to kinda incrementally move that curve and add PFIC in there. And sure, we'll talk about the bile acid programs. A lot of different revenue growth drivers heading into next year.
So if I were to... I'm gonna give you three growth drivers and ask if you can try to rank order what you think-
Oh, boy!
is the most important on a dollar basis over the next few years. There's kind of the ongoing U.S. patient identification and adoption effort, right? So penetration in the U.S. market. There's weight, right? And weight and price, you know, the per patient numbers. Then there's the ex-U.S., right? So just kinda three different drivers. Which do you think is gonna be the top or the lowest?
I think it continues to be U.S. new patient starts, right? We are still, you know, not even halfway penetrated in the U.S. prevalent pool, and that's where the bulk of the opportunity remains. And that's where we spend a lot of our time. The things on, you know, the dose evolution and weight evolution, that'll play out on its own. But if we learn how to, you know, drive adoption into that full target population in the U.S., then we can leverage that internationally as well with learnings there. That's where we spend most of our time.
So in the last quarter update, you provided some color and details on the EXPAND trial to drive Livmarli label expansion into some additional cholestatic diseases. Maybe give us a little bit of that, the evolution and history of that program, you know, the trial design and timelines.
EXPAND is a exciting new study that we just started talking about. We're getting close to getting the first patient enrolled, and it is. You know, the I, I'd like to kind of describe it as it kind of presented itself to us as an opportunity. And the study, just first couple of points on the study, targeting 45 patients with cholestatic pruritus, and really defined by exclusion, so not driven by Alagille syndrome, PFIC, PBC, PSC, or cholestasis of pregnancy. So really think of the less common, kind of long tail of ultra-rare cholestatic conditions that can result in pruritus. And we, since approval, have seen a substantial amount of compassionate use requests, off-label demand for these indications.
You know, really through that, the case studies that we've seen of great treatment response, and frankly, FDA saying, "Hey, there's so many of these, you should put a study together around this," we designed the EXPAND study. Intended to be a label expansion opportunity for Livmarli. We think it's probably in the U.S., at least 500 patients. Think of it as at least another PFIC in terms of the size of the indication. You know, I mean, the demand, it's kind of important to stress the demand that we've seen already of over 100 compassionate use requests to date that fit this, the criteria that we're talking about.
How did you come up with the five hundred patient estimate that could unlock?
It's through site outreach and what we know about the centers that we call on, so think of that as it's a little different from how you traditionally look at epidemiology, because this is a collection of several different indications, so it really is from our conversations with sites on identifying treatment-eligible patients, so less of an epidemiology, rather more of what we think the patient demand would be.
Are you gonna be publishing any of the compassionate use experience? And if so, when might we see that?
We're looking to, yeah, so we'll look to have, likely in the form of case studies, some of the physicians that have prescribed write up their treatment experience.
Maybe we can move to Chenodal and Cholbam, and first, just a quick reminder of the difference between those two and how they're used.
Yes. Chenodal and Cholbam are both bile acid replacement products, so exogenous bile acids, cholic acid, and chenodeoxycholic acid, and used in different settings of bile acid synthesis disorder, where in the, the synthesis cascade for bile acids and cholesterol, there are, you know, various number of genetic, defects that disrupt that, that process. And by giving either of these, you kind of replace the next step or a downstream element of the process to restore, some balance. And usually the issue is driven by accumulation of byproducts that are abnormally high in the midst of that, synthesis cascade. And a lot of those overaccumulation of, in CTX, for example, overaccumulation of cholestanol, builds up in the CNS and causes, you know, progressive neurological damage.
So both of these agents are used to kind of restore that balance in the bile acid synthesis cascade. Cholbam is used in a broad range of these different synthesis disorders, and Chenodal is used more exclusively in CTX, or cerebrotendinous xanthomatosis.
Okay, got it. So, and I think you've said a hundred patients on therapy. Is that for both products, or is that CTX patients with Chenodal specifically?
It's about 100 each.
Okay.
Yeah.
I think you've estimated there are potentially one to two thousand CTX patients in the U.S. What is that based on?
That's a literature-based approach to looking at epidemiology. The for CTX, having a real precise patient number is difficult because of the challenge that we're gonna hope to go have an impact on next year, is they are diagnosed late, and they're diagnosed through what is a kind of gradual accumulation of impact of the cholestanol overload over time. So if we can find more patients or find them earlier, I think it'll be a big impact, and you can prevent... With treatment, you can prevent some of the progression of this cholestanol buildup.
How do you think about finding them in any cost-effective way, just given that, you know, they're kind of hiding in different practices?
Yeah, we're piloting some pretty targeted programs to that end, already, in terms of just thinking about, like, finding where some of these patients might be, and looking forward to rolling out really diagnostic support in places like movement disorder clinics, ophthalmology, because in pediatrics, these patients can show up with bilateral cataracts. They'll often get treated without asking why, and without maybe doing some testing. So we're looking at ways where we can help support broader panels for genetic testing in some of the settings where the patients will show up.
Assuming you do get FDA approval for the CTX indication, does that change the market exclusivity dynamics in any way?
Absolutely, yeah. So we have orphan designation for Chenodal and CTX, and with an approval, would have the orphan exclusivity.
Oh, okay. Do you expect an AdC om?
Not expected at this point, and so we're under priority review. PDUFA is now set for end of this year, December twenty-eighth, and so nothing signaling an AdC om at this point.
How do you think about the synergy between Chenodal, Cholbam, and Livmarli? I guess we did see a bit of an SG&A bump by around $40 million a year when the assets came in, but there might have been other things going on at the same time. What is the incremental cost for these programs, and does that change post-approval?
Yeah, that number has, you know, Livmarli international rollout in it, so it's not exclusively bile acids. Really, majority of that is driven by adding the bile acid team, and pretty steady in terms of what the investment will be for U.S. SG&A, maybe a little bit of incremental international into next year, but you know, overall, nothing that's a stepwise increase on the expense side.
So you also recently gave us for Volixibat now, another IBAT inhibitor in the portfolio, interim phase IIb for PBC and PSC. We'll just quickly review the data and the implications for those programs.
Yeah, Volixibat is being studied in two adaptive phase IIb studies in PSC and PBC. Comment on PSC first, where the interim analysis that occurred over the summer looked at two doses of Volixibat, 80 and 20 milligrams, versus placebo, and was conducted by a blinded data monitoring committee. So, we have not reviewed the data. It's been kept blinded, except for that committee, and they were given instructions with a minimum threshold to move the study forward. And what came out of that was a recommended dose of 20 milligrams and no recommended changes to the study, which means we're heading into the confirmatory portion and feel confident in what you know, hopefully we see at the end of the study.
The PBC study, however, is one we were able to unblind, given what we're trying to solve for in terms of patient number, safety database, and all of that, and shared the top-line data for the 80- and 20-milligram doses of Volixibat, which showed a really striking impact on pruritus in PBC patients, so the interim analysis had 30 PBC patients and saw a 3.8 out of 10 reduction from baseline in the pruritus scale, and highly significant versus placebo, exactly what you'd want to see out of an interim like that. Now, that study also has moved into its confirmatory portion, but because we are targeting a larger safety database, that's why we were able to unblind that those patients.
The pivotal study will be just the, you know, the forward, enrolling patients in the VANTAGE PBC study.
I would have thought, and we did kinda see this in Alagille and to some extent, PFIC, that reducing the bile load in the liver would actually be protective of liver health. Now, in PBC, you didn't see the ALP impact. Does that imply that you would not expect to see a benefit on liver health, or there is one, it's just not necessarily captured by ALP?
Yeah, I don't think we know. I think it's the kinda short and simple answer to it. Alkaline phosphatase is a measure of liver progression. It's not, you know, the only measure, and as we've seen recently, some debate on how it plays out over time. So we are gonna continue to look at other measures, you know, given. What I would say is it's not surprising or, you know, discouraging that we didn't see changes in alkaline phosphatase at the interim analysis. We'll look at the rollover patients and long-term follow-up on other measures in addition to ALP.
So we've got a little bit of a matrix set up into PBC and PSC as we think about first price, and as a rare disease, PSC may command a higher price point in theory, and I think you've suggested that the PSC filing would come first, so kind of price for PSC before PBC. PBC now has GSK potentially in the mix. We're gonna get some data next year. GSK is not pursuing PSC, they're doing PBC, so they'll presumably price to PBC, right? The point being, you'll price for PSC, they'll price for PBC. Do you feel like you can make inroads into the PBC market if GSK is there, price lower? And if the end and how does that kind of ultimately inform your eventual commercial strategy here?
Yeah, I think that will play out with the datasets, is what we'll use to guide some of those decisions. I think we've done a very extensive job on how we've looked at dose for Volixibat in PBC and PSC, and we're really pleased with how it played out in the interim analysis, that we thought that the 20 milligram dose would be maximally efficacious, and that's supported by the interim data that we saw. So I think we've got a chance to put a really strong efficacy on the board with the final analysis for the VANTAGE study. So that's a missing piece on how to think about the value proposition overall.
So it feels like in biotech, increasingly, the magic bogey for sales is around a billion. So, you know, you've got Livmarli, you've got the Cholbam products, and you're gonna have volixibat. So I guess two questions. Confidence that that mix gets you to a billion in peak sales, what about the potential that even if you focus on volixibat for PSC, because depending on the lens you look at, those numbers alone could work to get to a billion on a global basis. What do you think about those two paths and your confidence in reaching them?
Well, short of actually putting a peak guidance out there, which we don't have, the—I mean, both of these, the current commercial products and Volixibat, as you're pointing out, hugely impactful medicines, and we think a lot more to come for both.
How do we think about, exclusivity and IP on the IBAT inhibitor portfolio?
That from, in addition to, you know, some of the protections that come with Orphan, there are an extensive number of granted and pending patents. We tend to direct that question to the 2040 family that is Orange Book listed for Livmarli, pending for Volixibat, and really ties back to, frankly, some of the really surprising findings in IBAT dosing that made Mirum possible. And that's part of when we were doing our search to find these programs and start the company, that was really what caught our eye and helped us believe that there was a really high.