Okay, welcome everyone. This is Gavin Clark-Gartner with the Evercore ISI Biotech research team. Really happy to be here with CEO of Mirum Pharmaceuticals, Chris Peetz. Thanks for joining us, Chris.
Thanks for hosting.
Definitely. So been a good year for Mirum and a lot more catalysts coming. So we have the BA data later this year, more data in the first half of next year. But for those who are maybe less familiar, why don't you just give us an overview of the company and where things stand today?
Absolutely. Yeah. So Mirum is a rare disease-focused company now with three, excuse me, three commercial products across different rare bile acid-related diseases. LIVMARLI approved in cholestatic pruritus due to Alagille syndrome, CHOLBAM in bile acid synthesis disorders, and chenodiol, which is in use as standard of care for cerebrotendinous xanthomatosis. All that put together puts us in a really strong financial position. Those are three growing products in different rare disease settings, and looking at the pipeline, actually just had phase III data readout for chenodiol and CTX, which is going to be a label expansion opportunity for chenodiol, ability to get orphan exclusivity as well for that program.
Around the corner, the data events that you're mentioning are what is getting increasing amount of attention, on top of the growing commercial business is biliary atresia, phase II-B study. This is a label expansion opportunity for LIVMARLI, that I'm sure we'll spend a little time talking about. Into the first half of next year, we have a PDUFA date for PFIC, which is a second indication, potential for LIVMARLI in the pediatric liver setting, and then two interim analyses for volixibat in adult settings of cholestasis. So continuing to build out the program, those interim analyses would then lead us into potentially pivotal portions of the study. So, exciting point to be getting to with that program.
Yeah. Awesome. So like you said, near-term focus on biliary atresia. That's where pretty much all my investor conversations have gone, sounds like many of yours, too, so I think we should start there. Just like a high-level question to start: remind us what biliary, biliary atresia is as a disease, why IBAT inhibitors should be applicable, and also what the unmet need is in BA.
From a starting point, just to think about cholestasis in general, and then we can dive in to biliary atresia. I mean, all of these settings that we're advancing the IBAT programs, LIVMARLI and volixibat, are settings of cholestasis, where there's elevated bile acid levels causing high symptomatic burden, as well as progressive liver damage. So the bile acid levels can be extremely elevated in some of these settings, and that damages the liver, leads to a progressive condition and the need for liver transplant in many of these cases. And biliary atresia is a very rapidly progressing example of that. So it's a cholestatic disease that on presentation, is the lack of or occlusion or some kind of impairment of the primary bile duct and the connectivity of the biliary tree to the GI tract.
So there's no bile flow at all. It is really the most extreme cholestasis that you could have, a total absence of bile flow. So these kids need an emergency surgical procedure, known as the Kasai procedure, that helps establish bile flow into the small intestines. That's standard of care, and even with that, it still is an aggressively progressive cholestatic setting. So where we're studying LIVMARLI is in that setting post-surgery, where there's still most of these kids progressing to liver transplant at a, an alarmingly young age. It's actually the leading cause of liver transplant in the pediatric setting, so huge unmet need after that initial standard of care surgery.
Maybe you can give us a little more detail on how exactly the patients are enrolled into the trial and how soon that happens post-Kasai, and how they're managed in the interim when the Kasai happens. Because I also think you noted baseline bilirubin values of 10 before the procedure, seven after the procedure. I'm trying to get a sense of like when exactly those values are.
Yeah, and a little bit on the color of what is happening in the natural history of this setting is, you know, some patients are responsive to Kasai. You know, the rule of thumb that you hear KOLs talk about is 1/3 of them will have a good response and potentially postpone the need for transplant many years. There's some that are kind of in the mid-range that still have elevated bilirubin but are progressing slower than kind of that immediate need for a transplant, and then 1/3 or so of patients that are in more rapid need of transplant. And what we think is one of the driving mechanisms of that liver damage is the accumulation and exposure of bile acids within the liver.
So bile acids at elevated levels are highly toxic, and that by using IBAT, you can potentially knock down that elevated bile pool and prevent the ongoing liver damage. Now, in the natural history setting, one of the current ways that these patients are monitored is really by monitoring bilirubin as a measure of liver function. Are they getting bile flow? Are they able to clear bilirubin? That's one of the key parameters that's used in a transplant decision to decide how urgent the need for transplant is. So when you look at the natural history data, those bilirubin levels are very prognostic of the transplant risk and transplant rate.
And so what we think we can do here is reduce the bile acid exposure, improve liver function, and that will show up as reduced or more patients with that favorable bilirubin response. Ultimately, try and get fewer of these transplants to happen and to postpone it as long as possible.
Yeah, and one point, maybe just give us a little more detail within the trial, how you're capturing some of the bilirubin values for patients who may be kind of rapidly deteriorating and going off to transplant. 'Cause, you know, presumably you want to catch those high values, but at the same time, you don't want them to skew the data too much.
Yeah, yeah. So in the and this is actually a key point in understanding, like, the context of the natural history datasets that are out there, that in general, when you look at the bilirubin values over time, a lot of patients are leaving those datasets and going to transplant. So you're missing some of the values of the escalating bilirubin of patients who progress. When we were designing the EMBARK study, that was, you know, one of the key issues to work around, is how do you deal with the, there's an expectation of some discontinuation for progressive liver disease. That's what's happening in the natural history of the disease. So we're measuring bilirubin as the primary endpoint using an MMRM analysis.
This then uses every bilirubin value available, so every two to four weeks, roughly, is where these lab values are pulled, so that if you do have a patient who's progressing and discontinuing, you're not only relying on that six-month snapshot. You're getting the data from those that are progressing more rapidly.
What should we expect from the placebo arm for bilirubin? I mean, with the context of what you just said about the natural history data probably skewing lower over time, would we expect it to be more or less flat in this trial?
That's our expectation, that you... Looking at the natural history data, it does seem like there's averages maybe trend down, but I think that misses the fact that there are these elevating patients that drop out of the datasets. So anything in the range of, you know, relatively stable to, you know, slightly lower over time, as you see a continued effect of the Kasai. We think we've captured a lot of that Kasai treatment effect in the baseline value, though, with that difference from 10, that is the pre-Kasai bilirubin value, to the seven, that is the baseline for the study. So that's where we're looking at what happens after that first step down in bilirubin.
That makes sense. And just to clarify one point, for the seven, is that roughly three weeks after the Kasai procedure happens?
It's in the kind of 10 days to three weeks, time point. Yeah.
Okay, but it's all beyond a week, where seems like most of the bilirubin reduction happens post-procedure.
Mm. Yes.
At least based on our KOL calls.
Yes, exactly.
Okay. Good, that's helpful. How should we read across the bilirubin reductions from Alagille and PFIC into BA?
Well, I think that's what's most informative about that is that those datasets are looking at very different causes of cholestasis between the two of them, and you see that consistent effect where there's a very near-term reduction in bile acid, and over time, you have a growing impact on bilirubin. Digging into the PFIC data, we saw that just kind of continual gradual improvement in bilirubin levels from baseline to six months, and that's a setting where not all of those patients had abnormal bilirubin at baseline. So you're actually seeing that effect in aggregate is based on a lower starting point than what we have in the EMBARK study, and some patients are already normal, so you're not gonna, you know, really see much change in a patient that's starting normal.
So I look at the kind of consistency and the ability to reproduce that effect over time from different settings of cholestasis as very informative. And then also, I'm, I can't help but to dip into a little bit of the non-clinical data, which is another very supportive piece of evidence, is that one of the most common models of cholestasis is the partial bile duct ligation model. That's actually a post-Kasai model, right? So it's you've got an imperfect primary bile duct that leads to extreme cholestasis, and the IBAT data is very strong in those models, normalizing some of the liver lab values.
Yeah, I think that's well said. And so one theory I've heard, and we'll see what the data looks like, but one theory I've heard is kind of going back to the dogma that you mentioned about 1/3 of patients really don't do well, in terms of transplant, that is. A third of patients really don't do that well. A third do okay, at least for a period of time, and then 1/3 do well for a long period of time.
Is it possible that the bilirubin could kind of follow those trends, meaning in the group who's pretty well off, maybe there's just not that much room to show a bilirubin benefit, and then on the other end of the spectrum, for the more at-risk patients, maybe they're already, you know, the procedure didn't work so well, they're kind of blocked up, so there's less room to show a benefit with the IBAT inhibitor, meaning that maybe only 1/3 of the patients have a bilirubin benefit?
I think there's opportunity to see change in all patient groups. And that, that's one of the questions we're asking in the study, right? Because it's a fair question to think about. But we have examples in the PFIC and Alagille datasets of patients that had very elevated bilirubins, that had really strong responses, as well as those that are more moderate levels have improvements. And even in those with, you know, slightly above normal, you see them normalize. So we're seeing in the other datasets, response across patient profiles. So you know, really interested to see how that looks when you look at the kind of baseline characteristics. That...
That's gonna be one of the key findings also out of this study, is: Are there any, you know, prognostic criteria or something that we can do to help guide treatment decisions right at that post-Kasai period? It's not so well characterized right now.
Mm-hmm. Yeah, that makes sense. Maybe just also level-set expectations. When you kind of give this data release, what should we expect to see? I mean, it'll be the bilirubin data. Will we get any type of data down to the patient level, will be liver transplant data, serum bile acid, anything else we should be looking out for?
Pretty typical for a top-line primary endpoint announcement. We'll expect to have really what we think gives a material picture of the data, primary endpoint, safety, and anything that really stands out from the secondaries that we think is material to understanding what LIVMARLI is doing in the setting.
Yeah, and just level-setting expectations for the liver transplant benefit, because it is a short study at six months. So where should we expect the placebo arm to fall? And do we have any way to kinda gauge the drug benefit at this point?
In the natural history cohorts, in a six-month time frame, you can get towards 30% or even slightly above that in terms of event rate in the setting. So we do expect to have events in this analysis. We're certainly not powered to show a difference, but we'll be looking at it to see if there's a trend or anything numerically different between the groups.
Yeah. Even kind of numerical trends in your direction, given the short time frame, assuming it lines up with the bilirubin, other data, it's probably a great outcome.
Absolutely. Yeah, that would be a real home run to be able to see separation at six months already on those outcomes.
Yeah. Great. All right, so let's shift gears and go over to volixibat. Starting off with PSC, or maybe just starting with PSC and PBC. Studies have taken a little bit longer to enroll, so maybe just give us the quick hits on that rationale or that explanation.
Yeah. So we've, you know, unfortunately had a stretch of more screen fails than we had historically been having. A lot in the works to address it. You know, PSC as an indication, these are working age adults, and so that can be a more challenging setting to enroll clinical studies. But you know, what we're seeing in terms of study conduct, and some of the things that we're doing to address and improve that enrollment rate, do look like they're pointed in a strong direction. The recent screen fails, where we've seen, you know, patients not qualifying because of their baseline labs, we had a probably more stringent than needed bilirubin cutoff that we're working to address.
We've seen compliance with actually filling out the itch tool back to the, you know, working age adults that, you know, if they're not filling out the tool, they're not gonna give us the quality data into the study. So that ends up screening out a decent number of patients. And all of these things that we've incorporated into the study make enrollment take a little bit longer, but we think will result in a better study at the end of the day, making sure we're doing everything we can to address placebo response potential or anything that could, you know, impact study quality, deal with it at the front end, so we don't have an issue to deal with when we get to the unblinding.
Yeah, that makes sense. In PSC, is there the potential to show an underlying disease benefit here? What could that look like?
And again, back to where we started the conversation, right? Multiple settings of cholestatic disease, where over time, if you get the dose right with an IBAT inhibitor, you're having a really profound effect on the bile acid levels, and we see that tying into longer term impact as you look at long-term follow-up, natural history comparisons. So fully believe that's possible in PSC. So we'll be looking at, you know, different fibrosis markers and some of the liver labs to get a sense of what we might see there. All patients are eligible to roll into a single arm open label follow-up after the placebo-controlled period as well.
So an eye towards those longer term data captures and being able to compare this against natural history cohorts, because what the precedent data shows us is that if you can suppress bile acid levels, you should be able to improve, long-term, outcomes.
That makes sense. Speaking of dose, it's obviously gonna be the blinded interim analysis for dose selection in the first half of next year. You have a 20 mg and an 80 mg arm, I believe. I mean, based on the 7aC4 data that we've seen for volixibat and healthy volunteers, kind of bridging that to the LIVMARLI 7aC4 and what it's shown in patients, seems like the 20 mg dose should be workable, but you obviously added 80 mg to go quite a bit higher. So maybe just help us understand why you added that higher dose, and also what it means if you end up selecting the higher dose versus the lower dose.
Yeah, we think it's been a conservative approach to that. To your point, that is exactly how we thought about it, is that the 20 mg dose we thought is very active and we thought is likely to show an effect. And the higher dose was incorporated to make sure we didn't miss, right? And in the history of IBAT studies at lower doses you do see an inverse dose-response at some of the lower levels. So we wanna make sure that we're stepping beyond that part of the dose-response curve. So we see the higher dose as a just in case, the 20 mg is, we're not interpreting the data in the right way, or that you can drive even more response by going higher.
It could be that if, theoretically, again, if you go with the higher dose, there has to be a certain incremental margin of efficacy in order to do that.
Yeah, exactly. And this is. So we're talking about the PSC interim specifically has the pre-specified criteria for the data monitoring committee to take it forward. And in the dose selection criteria, it defaults to the low dose unless there is again a pre-specified further improvement beyond that first threshold. So that means there's a quite striking effect that I would expect if you're going with the high dose.
That makes sense. All right, in the last minute or two, shifting gears to go over to PBC, still with volixibat. Is the main question for this one, it's largely about commercial opportunity and competition at this point. So maybe as a way to frame the question, what data would you need to see for the PBC interim to not advance this, short of just kind of a straight fail overall?
Yeah, I think what we want to see out of this interim is the convincing pruritus data. And in terms of how we interpret that on a go-forward basis, for the commercial opportunity, there is a large segment of this population that is not being addressed by the current development programs and competing products in the first line setting. Those with normal alkaline phosphatase, which is a substantial proportion of the PBC patient population, that still has pruritus, still seeks treatment for their pruritus. So we do see that as a currently, you know, very low competition segment that would be a potential volixibat patient. In that second, third line setting, obviously, it's more of a competitive setting.
For those patients, you know, I'm really interested to see what we get out of the study beyond the pruritus benefit as well. We'll be looking at some of the same things I'd mentioned for PSC on long-term follow-up and some of the liver markers.
Yeah, that sounds great. We're actually just that time. We didn't even get a chance to talk about chenodiol and CHOLBAM, but I think you kind of framed them upfront, so I think we'll leave it there for today, but look forward to hearing more from you guys soon.
Sounds great. Thanks again.