Welcome, everyone. Thanks for joining in. I'm Gavin Clark-Gartner with the Evercore ISI Biotech Research Team. Really happy to be joined by Chris Peetz, who is the CEO of Mirum Pharma. Thanks for joining us, Chris.
Thanks for hosting.
Of course. Why don't you just kick us off with an overview of Mirum, where things stand today?
Sure, thanks. And a quick snapshot of Mirum. We're a rare disease-focused, commercial-stage biotech company. Currently, we have three approved medicines used across a number of different rare genetic conditions. Livmarli, our lead program, which is approved in both cholestatic pruritus for Alagille syndrome and PFIC, having a great year this year. And Chenodal and Cholbam, products that we added to the company last year, performing well with a lot of overlap in how we commercialize those products. Coming off a strong third quarter, where we had $90 million of net revenue and updated our guidance to now be $330-$335 million for full-year revenue. So really, things working well across all brands, and nice uptick from the PFIC business and Livmarli International that we saw in the third quarter. Pipeline's working really well, too.
We have, in our pipeline, a label expansion opportunity for Livmarli called the EXPAND study that's just getting kicked off now. Great growth opportunity for Livmarli. Volixibat, another IBAT inhibitor, same mechanism as Livmarli, that had some really strong interim analyses in adult settings of cholestasis, PSC, and PBC earlier this year. Just picked up breakthrough designation for PBC, now moving into confirmatory portions of those studies, so really, really exciting moment for volixibat as well, and then, in the third quarter, we also announced that we added a new pipeline program with MRM-3379, a PDE4D, that we are taking into a Fragile X proof of concept, so nice earlier-stage addition that fits well with Chenodal, one of our products that's often prescribed by neurology, so overall, the company's in a great spot and performing well across all fronts.
I forgot to add that I'll be making forward-looking statements, so refer you to our SEC filings for more complete disclosure. Check that one off the list before handing it back to you for questions.
Yeah, good overview. I wanted to start out with the pipeline and then kind of go to the commercial side of the business. And on the pipeline, maybe it makes sense to start with Fragile X, just because that's the newer program where people have been spending a little bit more time on the diligence side. Maybe just quickly remind us, what's the current treatment paradigm, unmet need, market size for Fragile X?
Yeah, we found the opportunity with MRM-3379 and Fragile X to be really intriguing and particularly really attractive risk-reward undertaking for us. And it came out of a search that we did across genetic neurological indications after we added CTX to the company's list of indications. So we thought it would fit well with what we're already doing in the neurology space. And to your question on Fragile X, what we found in doing some workups on some of these different settings, I mean, there's just a tremendous unmet need there. There's no approved therapies, so a lot of off-label agents used to try to address different components of the disease. And until recently, it has been a pretty tough place to run clinical studies.
What we saw out of some emerging data with this mechanism in clinic, we saw a really strong proof of concept signal that got us excited that this mechanism can have a big impact in a setting that is really desperate for new therapies.
Remind us, too, which approaches have failed in Fragile X? What's still in development?
There's been a number of different kinds of symptomatic and behavioral targeted agents. And one of the issues in how these have been developed in the past has a lot to do with endpoints, is kind of our take on the setting, where many of these endpoints that have been explored before are behavioral checklists and different kinds of caregiver surveys that have real challenging floor-ceiling effects. And so it's hard to distinguish a drug effect. So the endpoint is failing the programs here. And some of these prior programs, like Glutamate, is one that made it pretty far in clinical testing and used one of those behavioral endpoints and was unable to show a distinction on the endpoint, despite having some interesting long-term follow-up data and other kinds of signals from it.
And what's recently emerged in terms of endpoints is the use of the NIH Toolbox endpoint, which is administered to the patient. It's a cognitive battery of different tests that is designed to distinguish in a setting of cognitive impairment, to distinguish and actually be able to show what a treatment effect is without hitting some of those floor-ceiling effects that you get from observer endpoints. So not only are we excited about the kind of advance of the mechanism, but there's just a really simple improvement in endpoints that has had a lot of work put into it for Fragile X.
Yeah. Why don't you just frame, too, what Shionogi's Zatolmilast has shown, how that informed your selection of this program, and then also frame your differentiation?
Yeah, for zatolmilast, what we've seen from a really nice paper that's out on a phase two proof of concept study in Fragile X is an ability to have a very strong effect on the cognitive composite portion of this NIH Toolbox endpoint. That's what we see as the potentially registrational endpoint. So really intriguing proof of concept data for the mechanism. That program, as well as the 3379 program, have a pretty extensive amount of translational work as well, showing how this all ties together to impact neurocognitive function, memory, and even some of the synaptic development for these patients. So we see that as really the evidence for us taking 3379 forward. I would note that the key differentiation that we see in our program is improved plasma to CNS ratio, and that we think we can basically get much higher CNS concentration.
That's where we're trying to drive the activity with less systemic exposure, which for PDE4s as a class can result in some GI-related tolerability effects.
Yeah, and more so tolerability than safety.
Yeah, that's really kind of how it plays out in the clinical data sets. You tend to have emesis and nausea and diarrhea with higher doses of PDE4. And the dose ranging work for 3379, you don't see those effects until you're much higher than the projected active dose that we're going to take into clinic. So we think we're well below any of those tolerability issues that, for long-term administration, would be a factor.
Yeah, and where exactly does the CNS distribution data come from? Is it all preclinical experiments? Was there any signs of this in the phase one data? And then, I guess, also looking forward, are you guys planning to present all of this info at some point in 2025?
The bulk of the CNS penetrance data is from nonclinical models. We are planning to put some publication or a series of them together on what we know from the dose ranging work and some of the translational work, kind of pull the story together to share it, which to date hasn't been out there because this has been in the hands of a private company that was looking for funding and just didn't have the resources to put against that yet.
Yeah. All right, that makes sense. I'll just ask one more since we have to move on for time, too much to fit into 20 minutes. For the upcoming Shionogi phase three data, is there any outcome from that trial that would lead you to not pursue a phase two proof of concept study, for example, if it spectacularly failed?
I would say we're not gating our start of our phase two proof of concept study on any results from that program, and in part just because of the assumption of what a headline release might say is not going to be enough for us to make a call on that. We see it as potentially informative. We don't see it as definitive on what we do with our program. Really looking forward to more data for the mechanism and the disease. We'll figure out how to interpret that against our program and see if there's a way to enhance our program going forward.
All right, great. Shifting gears, going over to volixibat and starting on the PBC side, GSK just recently announced positive top-line results for their study. Obviously, we haven't seen the full data. So what are you looking for in the full data set to discern differentiation?
What we know about the IBAT and PBC really comes from our own interim analysis, where from our dose ranging work, I'd say speaking to our program first, that we've done a lot of work to understand where we're at on how to maximize the drug effect and feel that we are at highly active dose levels for volixibat and PBC. So the 2.4 placebo-adjusted change in pruritus score really is the high watermark from what we've seen across all the other publications. For linarixabat, there's a phase 2b dose ranging work posted. I think we compare quite nicely to those treatment, placebo-adjusted treatment effects there for the dose they took forward. That's in the absence of seeing the phase 3 data, which I'm looking forward to seeing it when they get it presented.
Yeah, that makes sense. What about on the quality of life/fatigue side?
We saw nice signals out of our interim analysis. Unclear what is going to be shared from the linarixabat program. But with volixibat, looked across PBC-40 and some other PRO, patient-administered surveys, and you see a nice signal on fatigue in particular. Saw an early signal in the interim data set. The two things that are most cited by PBC patients for disease burden are pruritus and fatigue. And so to see both of those moving is really exciting for patients and having a medicine that really impacts their day-to-day.
All right, great. Let's shift gears. Let's go over to PSC. Maybe just remind us, too, for those of us who haven't looked in a little while, there was a dose selection. You went forward with the 20 mg, not the 80 mg. What exactly was the criteria to select that higher dose?
Within the PSC study, the interim analysis was designed to remain blinded so long as a minimum efficacy threshold was met. There was an algorithm for dose selection for the independent data monitoring committee. That looked at making sure that, first, the activity threshold was met to continue the study at all. A dose selection is made based on, is there differential activity level to prefer one dose over the other? If they're comparable, you would default to the lower dose. That's kind of the way the treatment algorithm worked. What we saw in the PBC interim was the low dose and the high dose looked almost exactly the same. They're very close to overlapping.
Our dosing strategy here was that we thought the low dose would be near or at the maximally active dose, and the higher dose was to make sure that we didn't miss improving on the activity. It's all played out to our hypothesis. Imagine that's what was happening in the blinded interim data.
Yeah, great. And obviously, you haven't shown the PSC data since it was a blinded interim, as you said. But I think there was a posterior probability calculation that's kind of associated with the program moving forward. Just remind us kind of what the statistics are around that?
Yeah, so the way that we looked at basically the threshold to continue, and keep in mind, this is for the boundary, right? So based on what we see in the PBC data, there's a good chance that we're well above the boundary. It was designed to make sure that we had a high probability of having a fully positive study at the end, given what was seen in the interim. So it's kind of a posterior probability. It's hard to speak to a specific number because it's an effect size that looks at the difference from placebo and the variability. So it's kind of a curve and making sure that the drug is performing beyond that effect size curve.
Yeah, great. Last question for volixibat, just for PSC and PBC together. Just remind us what your guidance is for enrollment and what assumptions are baked into that. And I guess, phrased differently, since you've shown exciting data and since GSK has also shown positive data, could enrollment accelerate in either of these programs?
We actually have seen a nice step up in enrollment since the interim analyses. That is both awareness and excitement in the program and then also site expansion. So by design, at the interim, we had plans to then roll out to more sites and expand the footprint of the study to accelerate enrollment for the confirmatory portions. That's all been underway and showing a nice effect. PSC, which is overall a smaller study, we expect to complete enrollment second half of the coming year of 2025, and PBC, which is a larger study, expect to complete enrollment in 2026.
All right, great. I'm going to squeeze in one question on the EXPAND study. Just remind us, trial design, why the FDA encouraged you to pursue this design, and then specifically for the BA patients, biliary atresia, that are included in this study, how is that different from the prior BARC study that you're in?
Yeah, the EXPAND study, really exciting growth opportunity for Livmarli, and kind of behind your question, what drove us to this was really physician interest, right, so we had a quite sizable number of compassionate use requests that fit what is now how we've designed the EXPAND protocol. So to kind of catch what is, I would describe as a quite long tail of different ultra-rare causes of cholestasis that have an elevated bile acid and pruritic presentation, and through some of these compassionate use requests, we've actually now generated some quite intriguing case studies. At AASLD, we had a poster with five of the biliary atresia case studies that came from the compassionate use requests, where these are patients that are older than the setting that we previously studied.
So they're beyond that post-Kasai acute phase and have more of a chronic cholestatic kind of condition, which means that many of the patients in that kind of condition have elevated bile acids and pruritus. And in the case studies that we presented, you see a quite striking improvement in pruritus with Livmarli. So the EXPAND study puts a protocol around that to look for a label to cover kind of the other, the basket and long tail of other ultra-rare causes of cholestatic pruritus. 45 patients, placebo-controlled. We are looking at sites across North America, Europe, and South America for the program. And see the sizing of it in the US, I think there could easily be 500 patients that would fit within this kind of basket definition that we're pursuing.
Awesome. And I think that takes us into the commercial side of the business, which is certainly, last but not least, just because I figured it made sense to put at the end, given a lot of the earnings calls focus on this more heavily. But before going to Livmarli in more detail, just remind us for Chenodal and Cholbam. I think there's an upcoming PDUFA for Chenodal. What's the latest status there?
Yeah, so with the Chenodal application for CTX, we did receive a three-month shift in the PDUFA date as part of the back and forth with questions, FDA changing the action date to March 28th as the current action date. As a reminder on this quite unique situation for Chenodal, it's still commercially available, and the approval and launch of Chenodal labeled for CTX is an opportunity to more actively promote and find patients. We see this as it's kind of a longer-term gradual growth opportunity and now on track for March.
All right, great. So ending up with Livmarli then, what exactly have you seen in terms of the reweighing dynamic in patients growing as they've been on therapy for extended periods of time?
Yeah, it's a part of the brand. Many patients start in childhood and many of them in infancy, quite shortly after diagnosis, and so you do see physicians kind of monitoring weight and adjusting dose over time. The majority of physicians do keep generally with the labeled weight-based dosing, so as a result, then you see some adjustments for the patients that are on over time, so kind of a natural part of the growth curve that we're seeing.
Yeah, that makes sense. Have you shared any commercial data on kind of frequency of growth and step-up dosing over time?
Not recently. A couple of years ago, we did have a poster at NASPGHAN that spoke to some of the medication possession ratios and compliance and really strong dynamics there, where the rates are generally above what you'd expect for chronic therapies, really in large part because as a medication, it drives symptomatic benefit. So patients feel better when they're responding to medication. And that symptomatic burden returns quite rapidly if you miss doses or if you interrupt treatment.
Yeah. And for the PFIC launch, why exactly did you get off to such a strong start? And how do we read that forward going into 2025? Or extrapolate would be a better word.
Yeah, we've been pleasantly surprised with the uptake in PFIC, in particular finding some de novo IBAT naive patients out there. So we're deploying against that. A lot of that, I think, is awareness and genetic testing for PFIC that is driving some of that. Hard to predict at this point. We're still early in the launch, but really encouraged by the early new patient starts.
Awesome. Well, actually, it puts us right at time. So we'll wrap it up there. Thanks for joining us, Chris, and excited for.