I'm Brian Abrahams, one of the senior biotech analysts at RBC Capital Markets. We're really pleased to have our next company here, Mirum Pharmaceuticals, represented by their CFO, Eric Bjerkholt, and their SVP of Finance and IR, Andrew McKibben. Eric and Andrew, thank you guys so much for being here.
Thanks for having us, Brian, and thank you to RBC for inviting us to this conference.
Great. Maybe we can kick things off on the commercial side. You know, you recently reported Livmarli sales. Can you talk a little bit more about the catalysts behind the continued strong commercial performance that you're seeing for this drug, and maybe how far along you are now with market penetration in the ALGS and PFIC indications?
Sure. Let me start out by saying that both Andrew and I will be making forward-looking statements today, so please refer to the Risk Factors in our SEC filings. First quarter was a record quarter for us. Livmarli, we recorded about $73 million in revenues. About two-thirds of that is in the U.S., one-third ex-U.S. In the U.S., we are approved for both Alagille syndrome and PFIC. We expect to see continued growth for many, many years for both Alagille and PFIC in the U.S., and also continued geographic expansion internationally. Specifically, to answer your question on the Alagille syndrome, we think there is about 1,000-1,200 prevalent population of Alagille patients that are addressable with Livmarli in the U.S. We are approaching 50% penetration of that population.
In addition, the annual incidence is about 100 patients, maybe 120, and we're capturing really a major share of those newly diagnosed patients with pruritus. And so, you know, given that we're only less than 50% penetrated, we see significant growth opportunities continuing throughout the patent life, which reaches out to 2040. For PFIC, we're just scratching the surface, just starting. We're capturing newly diagnosed patients. We're capturing, finding actually already diagnosed patients that have not yet seen an IBAT inhibitor. But, you know, we're clearly behind Bylvay, who was launched first in PFIC and still has the majority share, but we're very pleased with our launch so far and expect to see significant growth in PFIC as well. And then internationally, we're now in over 25 countries. We're commercializing ourselves in the major Western European countries and now starting also in the mid-sized Western European countries.
We use distributors and partners in other geographies. We expect continued geographic expansion this year. Our partner Takeda in Japan just recently was approved for both Alagille and PFIC, and we expect them to launch in Japan very soon and have high hopes for that market where we have really good economics.
Great. I know you guys are looking in this EXPAND study, the basket study for additional indications, cholestatic pruritus indications. Can you talk a little bit more about that study? How many additional patients do you think you can bring onto Livmarli? How enrollment's going? Maybe remind us of the process for those data to translate to the potential commercial expansion to some of these smaller subcategories.
It's important to take a step back and understand how that trial came about, the EXPAND study. We had a number of compassionate use requests, in fact, so many that the FDA complained and said, "Too many requests, please run a study." In collaboration with the FDA, we designed this basket study, which consists of a number of, you know, much smaller cholestasis indications. Primarily, the biggest one of those is probably biliary atresia. We think in the aggregate, it's at least 500 addressable patients, which means, you know, put it in context, it's probably at least a PFIC indication. We're planning to enroll that study and complete enrollment next year. It's about a six-month study. We'll get data, you know, sometime after full enrollment.
Got it. Good. You have talked recently about the new tablet formulation of the drug. Can you tell us a little bit more about sort of how important, how different that is from the prior formulation, and how important that can be both to driving additional market uptake and sort of capturing the space that's still kind of remaining that you talked about earlier, and then also how it impacts your competitive positioning overall?
Yes, thank you. Yeah. The tablet formulation was approved very recently by the FDA. The prior formulation is a solution, which is appropriate for small children. But as kids get older and thrive on Livmarli, there was some demand for a solid formulation, which is more convenient as you're a teenager or an adult. Think about, you know, you're not taking a liquid kids' Tylenol anymore. You probably prefer the tablet. It's similar with kids as they transition to adulthood. We now have approval for four different solid doses in addition to the liquid. For each patient, they would only take one pill per dose, which puts us in a very good competitive position versus Bylvay, which requires multiple large pills per dose.
It could be as many as 18, could be as low as six, depending on what weight you are and what dose you're on. Previously, you know, we were at a competitive disadvantage with older patients because we didn't have a solid formulation. Now we think we're at a competitive advantage because of the lower pill burden.
What proportion of the sales or the market are these older patients?
It's a little hard to tease out, but we're and it's going to be an increasing share, I think, as the kids that are on Livmarli age into the teenage years and adulthood. But, you know, I don't know if you want to mention again.
Generally, the average age is around, you know, six to seven. It is skewed lower.
Okay. Over, like you said, over time.
These patients grow.
Yeah, they'll become more prominent. Okay. Let's talk about CTX. I guess I'm curious on, you know, recently approved Cetexly, what you guys are seeing on the ground in terms of new patient starts, just how broadly this disease is diagnosed and how patient-finding efforts are going. Like, what's the ultimate opportunity you see there?
Yeah. Let me broaden my answer a little bit. The bile acid portfolio, which consists of Cetexly and Cholbam, generated about $37 million in revenues in the first quarter. It is important to know that we acquired this asset from Travere a couple of years ago. That is a 50% increase over the last quarter in Travere's hands. We have been able to move the curve a little bit. They had previously been growing at low single digits annually, and we think we are able to move that. For Cholbam, much of the growth is coming from Smith-Lemli-Opitz syndrome. For Cetexly, it is all CTX, and it is standard of care for CTX. Right now, you know, it is only a little over 100 patients diagnosed and on Cetexly or on Cetexly.
We think that's only 10% diagnosed, 10% of the potential, which doesn't mean it's going to be easy to increase the diagnosis. Now that we have approval, we have the ability to, one, promote and try to actively find those patients, whereas previously we couldn't. Secondly, we can do co-pay reimbursement now, which we previously could not either. For both of those reasons, we are hopeful that we will be able to find new patients and put them on Cetexly for the long term.
Great. Let's shift gears to PSC. I know you guys are looking at what looks about there. Maybe talk about the overall market opportunity for PSC, just, you know, how big of an issue pruritus is for those patients. What are we continuing to learn about the impact IBAT inhibitors can have on pruritus in PSC?
Yeah, I mean, overall, you know, we see about 30,000, maybe more patients in the U.S. And, I mean, net-net, see it as a very substantial opportunity. These are much larger PSC, PBC, much larger indications than the ultra-rare Alagille and PFIC settings, where pruritus is a major issue for these patients. If you kind of look at the patient community and, you know, what they talk about, it's pruritus and fatigue. You know, and generally in the range of 60% of patients from the work that we've done and kind of triangulating with some of the patient advocacy groups, about 60% of patients have active scratching. And, you know, frankly, this is these kind of the patients who would be on label for volixibat directed treatment. They have nothing approved, nothing approved to treat the disease or to treat pruritus. They currently cycle through off-label therapies.
There's some experimentation that physicians do, but lots of debate and controversy over the therapies that are currently used for the disease. For pruritus, it's the same types of things that we see in the pediatric community. Cholestyramine, which is not well tolerated from a taste perspective, so rarely do patients stay on that. Rifampin in some cases, antihistamines, which kind of just knock you out. None of that stuff is that effective. You know, what we see with IBAT inhibition in, you know, all of these cholestatic settings where you have something that's impairing the bile flow, driving symptomatic pruritus and really a toxic level of bile acids in the liver and body, IBAT inhibition flushes that out. You see a very rapid and dramatic reduction in pruritus. Importantly, if you optimize your dosing, at low doses, you see it kind of work.
At maximal doses, you see a much different effect. We've seen that across our development program. I think we're there with the right dose for volixibat. I would say as it relates to PSC specifically, we have two data sets with Livmarli in PSC, one run by the previous sponsor several years ago, and then recently at DDW, a set of patients on compassionate use of Livmarli for PSC. What you see is over half resolved their itching. Very consistent effects, you know, to us, not a surprise, but, you know, very excited about the VISTAS study past its interim, on track for data in Q2 of next year.
Yeah. And speaking of the interim, can you talk a little bit more about that? I guess how the overall study is progressing, you know, what this interim read told you, and what you're viewing as what could be a clinically meaningful ItchRO score reduction at 28 weeks.
Yeah. Study's progressing very well. You know, very excited about that. We kind of clarified or narrowed our enrollment completion timing to Q3 of this year. So very happy with the progress and momentum of that study. Typically, you know, what you want to see from a clinically meaningful change from baseline is about a two-point change. So two-point improvement on a 0-10 numerical rating scale of worst itch. A very simple scale, two-point improvement from baseline is what your target is. And then, you know, generally at least a one-point improvement over placebo. So the placebo-adjusted score. The PSC interim was a blinded interim, so we did not see the data. It's a smaller population than PBC. And we really wanted the study to keep going if we were seeing a positive effect that was predictive of a final positive data set.
We did not want to slow it down. In conjunction, we also unblinded the PBC interim analysis since that requires a larger safety database that gave us some room to take a look at the data. Just to put that in context, we saw almost a four-point improvement from baseline and a 2.5 placebo-adjusted improvement. Very clear signal, which is why we had confidence in taking this approach in PSC, that if the study is on track, keep it going. Now we have those patients from that interim count as part of the final data set, and we know we are seeing something positive there.
Okay. Great. As we sort of get closer to that data set, can you talk a little more about the regulatory path in PSC? I know for disease modification, there's been challenges, but for pruritus, there seems to be a tried-and-true path that you guys can follow from your other indications. Talk a little bit more about that. You know, what's your latest expectation? Has that changed at all with some of the changes to the FDA and how you're thinking about what potential labeling might look like ultimately in PSC?
Yeah. We haven't seen any changes. I think that this kind of touches on one of the really unique aspects of our program is that pruritus in and of itself is an outcome. Feel, function, survive, that's what the FDA looks at. Outcomes are what they want in PSC. Given that pruritus is an outcome, you know, this is an endpoint that confers full approval. Not surrogate approval, but full approval, which, you know, we are very excited about. That's something you can study in a short period of time. That's how we've designed this study, you know, in conjunction with the FDA reviewing the endpoint and approval pathway and statistical analysis plan. Unlike the disease modification endpoints, which, you know, as it stands, there's no surrogate that's approved.
You are looking at some aspect of an outcome study, which is, you know, long and expensive and, you know, carries some degree of risk. Really unique. It positions us to be the first approved therapy for PSC, which is very exciting.
Excellent. You touched a little bit on the interim on PBC. Can you talk a little bit more? I know you recently had kind of some longer-term data at EASL. Just maybe what that longer-term follow-up tells you about the durability of effects with volixibat.
Yeah. I mean, the durability was very clear. So effectively at Easel, a few weeks ago, we presented the full 28-week worth of data for all the interim patients. So about 31 patients out to week 28. And what you see is a very consistent durable response that, if anything, you know, improves a bit at the margin. You also see improvements in fatigue, which is very important. I mean, something we'll be looking at closely in PSC as well. Pruritus and fatigue are two of the main symptoms and, you know, not necessarily linked to just improvement in pruritus if you're seeing improvements in fatigue, as well as some changes in markers of inflammation. So IL-31, for example, and some interesting signals with Pro-C3.
Excellent. Can you also help us contextualize the benefits that you guys are seeing versus some of the emerging competitive data from others? I guess I'm curious how similar the designs or different the designs in populations are to really enable a true comparison.
Yeah. I mean, we see these data sets as very comparable. We're using the same scale for itch measurement, the 0-10 NRS scale. Ours is branded ItchRO, but it's effectively the same thing. The duration of about six months of treatment is also a very fair comparison to look at from a timing perspective. You know, ultimately, I think this comes back to dosing. You know, we put a lot of work into making sure we were optimizing the level of IBAT inhibition with the doses selected. We know that, you know, GSK, because I think this is the main data set to reference, phase three in PBC presented at EASL a couple of weeks ago. They went with a lower dose than had been evaluated in their dose ranging in phase two. You know, conversely, you see an effect.
The study was stat-sig, but the placebo-adjusted benefit was not particularly strong. It was about 0.7 improvement over placebo versus a 2.5 point improvement in the Volixibat study. I think the dosing piece matters. We've seen that very clearly in PFIC with Livmarli, where early studies, you see an effect, but when you and we effectively doubled the dose and did twice daily, there you saw a much more pronounced benefit.
Got it. What's your sense as the payer landscape in PBC and PSC?
Fairly receptive. You know, I think there's some on the payer side, some hesitancy to pay for biomarker improvements. You know, it's harder to correlate that with an outcome. That takes some time to play out in PBC, particularly. Pruritus is, you know, very material to a patient's daily life. If you're improving that, that's a very tangible benefit. Payers like tangible benefits. We've done quite well from a pricing and reimbursement perspective with Livmarli and would expect to do well here too.
Great. Maybe just in the last few minutes, can you tell us a little bit more, give us the latest on the Fragile X program, what you see as the potential advantages of your agent and what you'd be looking for to learn out of Zynerba's upcoming phase three?
Yeah. I'm, you know, very excited about this program. This is with MRM-3379. It's a PDE4D inhibitor. We are planning to start a phase two study later this year, you know, actively, very active engagement with the FDA, which has been great. I haven't seen no disruptions on that front. That program's on track. Why we're excited about it is this is the, you know, one mechanism that has actually been shown to work in Fragile X, particularly on the cognitive aspect of the disease. We reference the Zynerba program as, you know, part of our rationale for moving forward with this deal to bring this asset in. They have a PDE4D inhibitor that had a positive phase two, showed clear benefit on an endpoint called the NIH Toolbox and Assessments of Cognitive Impairment. At a three-month endpoint, they're taking that into phase three.
That's in phase three now and should read out actually towards the end of the year. Our compound is a bit different from theirs in that it's got higher brain penetration. The one advantage of that is that you may be able to deliver more PDE4D where you need it. Improve on the efficacy profile potentially while also improving on the tolerability profile. Systemic exposure of PDE4D at some point leads to dose-limiting tolerability. Emesis is particularly what this can trigger at some levels. You see that with the pan PDE4s out there. Higher brain penetration can basically enable more effective dosing. That is what we'll be exploring in the phase two.
Good. Makes sense. Maybe just in the last two minutes, can you remind us your IP position across your portfolio and then maybe also work in how the tablet formulation might impact Livmarli?
Yeah. And, you know, as Eric mentioned, for Livmarli, we have IP to 2040. And this is Orange Book listed dosing patents, which, you know, we're very excited about. The tablet formulation that was just approved, that also had IP grants, I believe last week, to 2043. And that was not a trivial exercise to turn it from a liquid into a tablet. You know, quite happy with the portfolio that we're building and will continue to build. Volixibat will likely fall under that same 2040 dosing family. This kind of goes back to the comments I made earlier about the dosing finding that higher is better. That's actually a novel finding and quite important to establish effective dosing ranges for IBAT. And then for Cetexly, there with this approval, we've been granted seven years of orphan exclusivity.
Kind of think about that as seven years from February.
Great. We're out of time. Eric, Andrew, thank you guys so much. Really appreciate it.
Thank you very much.
Thanks again.
All right. Thank you.
Thank you guys for being here.
Thanks very much.