Good morning, and welcome to the Mirum Pharmaceuticals business update call. My name is Kelsey, and I will be your operator today. All lines are currently in a listen-only mode, and there will be an opportunity for Q&A after management's prepared remarks. I would now like to hand the conference over to Andrew McKibben, SVP of Strategic Finance and Investor Relations. Please go ahead.
Thank you, Kelsey, and good morning, everyone. I'd like to welcome you to Mirum's conference call to discuss top-line results from the phase III EXPAND study of LIVMARLI, or maralixibat, in ultra-rare settings of cholestatic pruritus. For prepared remarks, I'm joined today by our Chief Executive Officer, Chris Peetz, and our Chief Medical Officer, Rob Myers. Also joining us for the Q&A portion of the call are Peter Radovich, our President and Chief Operating Officer, and Eric Bjerkholt, our Chief Financial Officer. Earlier today, Mirum issued a press release announcing these results. A copy of that release and our SEC filing, along with a presentation summarizing the data, are available on the investors section of our website.
Before we start, I'd like to remind you that during the course of this conference call, we will be making certain forward-looking statements based on management's current expectations, including statements regarding Mirum's programs and market opportunities for its approved medicines and product candidates and financial guidance. These statements represent our judgment and knowledge as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed. We are under no duty to update these statements. Please refer to the risk factors in our latest Form 10-Q and subsequent SEC filings for more information about these risks and uncertainties. With that, I'd like to turn the call over to Chris and Rob for some brief remarks before we open the call for Q&A. Chris?
Thanks, Andrew, and welcome everyone for another great update from the Mirum pipeline. Today marks another important milestone in our effort to bring LIVMARLI to more patients living with ultra-rare cholestatic liver diseases. We are excited to announce that the phase III EXPAND study demonstrated a statistically significant and clinically meaningful improvement in pruritus. In addition to meeting the primary endpoint, the study met all secondary endpoints, including showing a highly significant reduction in pruritus in biliary atresia patients. Results in biliary atresia are notable, as there are no approved medicines in this setting, and we estimate about 2,000 biliary atresia patients across the U.S. and Europe suffer from pruritus. Our next step is a planned supplemental NDA submission in the first half of next year. Stepping back, EXPAND is a great example of how we think about building Mirum.
We start with patient need, pair it with scientific potential, and then apply efficient execution to bring meaningful medicines to those patients. That approach has now translated into our fourth positive study readout this year, and we see continued opportunity for the Mirum business model ahead. Today, fewer than 5% of rare diseases have an approved treatment. We believe focused companies like Mirum can play an important role in changing that. Finally, before I turn it over to Rob, I'd like to thank the patients, investigators, and study teams around the world who made EXPAND possible. Rob?
Thanks, Chris. My first few weeks at Mirum have been exciting, and I'm thrilled to be here. From the outset, the rationale behind EXPAND was straightforward. Many patients suffer from cholestatic pruritus due to rare liver diseases that are simply too uncommon to support traditional disease-specific development programs. As a result, many of these patients have historically had little or no opportunity to participate in registrational clinical trials. EXPAND was designed in alignment with and at the request of the FDA to address this challenge. Rather than studying a single disease, the trial enrolled patients with different rare cholestatic liver diseases that share a common underlying biology and a symptom that can profoundly impact quality of life, cholestatic pruritus driven by impaired bile flow. This innovative approach allowed us to generate meaningful data in patient populations that might otherwise never be studied individually. Importantly, the results strongly support that strategy.
The primary efficacy population in EXPAND included 46 pediatric patients with moderate to severe pruritus across a range of ultra-rare cholestatic liver diseases. Approximately one-half of enrolled patients had biliary atresia, and patients were randomized to receive maralixibat or placebo during a 20-week placebo-controlled treatment period. Now let me walk you through the results in more detail. Starting with the primary endpoint. EXPAND demonstrated a statistically significant and clinically meaningful improvement in pruritus with maralixibat. Pruritus was assessed using a caregiver-reported scale ranging from zero to four, corresponding to no itch and very severe itch, respectively. Across weeks 13 through 20, patients treated with maralixibat experienced a mean reduction in pruritus of 1.81 points from baseline. Putting the magnitude of this reduction in context of the 2.65 mean baseline value makes it particularly impressive.
This reduction with maralixibat compares to 0.83 points for placebo, representing a placebo-adjusted treatment difference of 0.98 points and a P value of 0.0004. The secondary endpoints further reinforce the primary efficacy findings and the biologic rationale underlying maralixibat's mechanism of action. Serum bile acids were reduced by 70% with maralixibat, compared with 3.5% with placebo, corresponding to a treatment difference of 69% and a P-value of less than 0.0001. Taken together, these findings demonstrate meaningful improvement in a symptom that matters greatly to patients and their caregivers, supported by substantial reductions in the bile acids believed to drive cholestatic pruritus. I want to spend a little more time on biliary atresia, where there are currently no approved treatment options.
This was the largest patient subgroup in EXPAND, and the results closely mirrored the positive results observed in the overall study population. In the pre-specified biliary atresia subgroup, maralixibat achieved a mean reduction in pruritus from baseline of 2.15 points, compared with one point for placebo, corresponding to a placebo-adjusted treatment difference of 1.15 points and a P value of 0.0002. Importantly, the treatment effects observed in patients with biliary atresia were highly consistent with those with other cholestatic liver diseases enrolled in EXPAND. Across both groups, we observed meaningful improvements in pruritus accompanied by substantial reductions in serum bile acids. Now turning to safety. Maralixibat demonstrated a safety profile in EXPAND that was consistent with our prior clinical experience, and no new safety signals were identified. Treatment emergent adverse events were reported in 96% of patients in both the maralixibat and placebo groups.
Serious treatment emergent adverse events occurred in 20% of maralixibat-treated patients and 18.5% of placebo-treated patients. There was one discontinuation from the study in the maralixibat arm and none in the placebo arm. Consistent with the mechanism of IBAT inhibition in our prior clinical experience with maralixibat, the most reported adverse events were diarrhea and abdominal pain, occurring in 64% and 20% of maralixibat-treated patients respectively. Importantly, no patient discontinued treatment due to diarrhea. Overall, we're very encouraged by these results. EXPAND met its primary endpoint and all pre-specified secondary endpoints, while maralixibat demonstrated a safety profile consistent with our prior clinical experience. More broadly, EXPAND adds to a growing and remarkably consistent body of evidence supporting IBAT inhibition as a therapeutic approach for cholestatic pruritus.
Across 5 + clinical studies in multiple cholestatic liver diseases, we continue to see meaningful reductions in pruritus accompanied by improvements in bile acid biology. Taken together, these findings reinforce our belief that targeting bile acid biology can deliver clinically meaningful benefit to patients suffering from cholestatic pruritus, regardless of the underlying disease. Now I'll turn it back to Chris.
Thanks, Rob, and we're very pleased with these results and excited about the potential to bring LIVMARLI to these additional settings. From here, our focus turns to the planned supplemental NDA submission in the first half of next year. This label expansion opportunity comes on top of the continued growth we're seeing in LIVMARLI in patients with Alagille syndrome and PFIC. Today's update adds to an already remarkable year for Mirum's pipeline. The ATEBRIOZ launch in FOP is on track to kick off this month, and we're excited about early feedback on the approval. This is an exciting growth opportunity for Mirum's rare genetic disease business. Brelovitug's recent positive AZURE-1 readout gives us confidence in the upcoming AZURE-4 study readout later this quarter. Those two studies will be the basis of the planned BLA in the first half of next year.
Volixibat provides further opportunity for the rare liver business. VISTAS's results earlier this year in PSC were granted breakthrough designation, and we are moving forward with our strategy to interact with FDA ahead of an NDA submission planned in the first half of next year. Further, the VANTAGE study in PBC is on track for top-line data next quarter. We are closing out the year with a lot of momentum and very excited about what lies ahead for Mirum. With that, operator, please open the call for questions.
We will now begin the question -and -answer session. Please limit yourself to one question and one follow-up. If you would like to ask a question, please press star one to raise your hand. To withdraw your question, press star one again. We ask that you pick up your handset when asking a question to allow for optimum sound quality. If you are muted locally, please remember to unmute your device. Please stand by while we compile the Q&A roster. Your first question comes from the line of Yigal Nochomovitz with Citigroup. Your line is open, Yigal. Please go ahead. We will take another question instead from Ryan Deschner with Raymond James. Your line is open, Ryan. Please go ahead.
Hi, good morning, and congrats on the readout today. On the roughly 70% reduction in serum bile acids, specifically regarding the biliary atresia patients, how clinically meaningful do you interpret this result to be? I have a follow-up. Thanks.
No, thanks for the question. I would interpret that roughly 70% reduction as being very clinically meaningful. We have observed across multiple cholestatic liver diseases now that this degree of reduction is associated with improvements in pruritus that are also clinically meaningful, and we have observed the same thing here, in the overall population and in these biliary atresia patients as well.
Thank you. Appreciate it. Where do you expect pricing on a per-patient basis to shake out relative to LIVMARLI in Alagille and PFIC? Could this be another situation where revenue could grow over time, specifically driven by the actual growth of the patients?
Yeah, thanks for the follow-up, Ryan. First comment is no change in the pricing strategy for LIVMARLI, but pass over to Peter to talk about launch expectations.
Yeah, Ryan, the price for LIVMARLI is already established. The unit pricing is set, therefore the indication pricing is a function of dose and consumption. This would be about a 50% more dose than the Alagille indication, which is about
$400,000-$500,000 net annualized per year. That would be the EXPAND dosing for the protocol. Yeah, you would expect to see weight-based dosing and dose changes over time with weight gain.
Thank you very much.
Thanks for the questions.
Your next question comes from the line of Josh Schimmer with Cantor Fitzgerald. Your line is open, Josh. Please go ahead. We will take a question instead from Kalpit Patel with Wolfe Research. Your line is open, Kalpit. Please go ahead.
Yeah. Hey, good morning, and many congrats on clearing the study. A couple from us. One for the label. What's the minimum and maximum ages that you're planning to seek a label for? Second, have you looked at the percentage of pediatric patients who achieved a sustained one-point or greater reduction from baseline over weeks 13 to 20? If you have done that analysis, can you break that out for the BA and non-BA patients? Thank you.
Thanks for the question, Kalpit. First on label, expect from an age perspective this to be pretty similar to what we see for Alagille and PFIC, where there's a lower end defined in basically infancy to young childhood with no expectation on an upper end as how we expect this to be the case here. Just as a reminder, the inclusion criteria is our best indicator of how that indication statement plays out, which is effectively a definition of exclusion, so cholestatic pruritus excluding some of the larger indications. Then would pass it over to Rob maybe to talk about what we've seen on some of the response rates on itch.
No, thanks, Chris. Yeah, we saw remarkably consistent results in terms of itch response. But in answer to your specific question, in the biliary atresia subgroup, roughly 90% of patients had at least a one-point improvement in pruritus. In the overall population, this was about an 80% response rate. So, quite a clinically meaningful improvement with maralixibat treatment.
Okay, great. Thanks for taking the question.
Yeah. Thanks for the question.
Your next question comes from the line of Jessica Fye with JPMorgan . Your line is open, Jessica. Please go ahead.
Hello, this is Adam on for Jess. Thank you for taking our question. Could you elaborate what are the remaining steps between now and the sNDA submission, please? Thank you.
Thanks for the question. Your pretty typical post-readout where we'll be compiling this data, putting it into a write-up with all the follow-up analyses to a supplemental NDA filing. Really straightforward overall in getting to that in the first half of next year.
Thank you.
Thanks for the question.
Your next question comes from the line of Brian Skorney with Baird. Your line is open, Brian. Please go ahead.
Hey, good morning, team. Thanks for taking the questions. Congrats on the data. I wanted to get your thoughts on the non-biliary atresia opportunity here. You enrolled about 50% of the study in non-BA, and I think BA should be a pretty well-diagnosed population. I guess, was there any stratification in the study to think about? Or do you think that there would be 50/50 in terms of patient flow in the commercial setting of addressable BA patients and non-BA patients? Do you have any thoughts on the penetration of diagnosis of the non-BA orphan cholestatic patients? Do you think it could be greater than the 2,000 BA patients when all is said and done, once more diagnosis is pushed?
Yeah. Thanks for the question, Brian. It is a really good question. The way I would think about it here, this study had 24 sites from U.S. and around the world enrolled for a little over a year. As you note, about half the patients were biliary atresia, half the patients were other. These were pediatric investigators, so I think that is important to know. It is kind of representative of the practice dynamics and setting there. So, in terms of how large that other bucket could be, the non-biliary atresia bucket could be, I think that the actual study enrollment here is probably the best guide. As far as diagnosis, yeah, biliary atresia is very well diagnosed. Substantially all patients are diagnosed as infants. The basket of other, I think it is pretty variable depending on the indication.
But certainly would be hopeful that as you see often in new product introductions, as awareness of a new product grows and there's something to do about pruritus and high bile acids, then hopefully recognition and diagnosis would increase in those settings.
Great. Thank you.
Your next question comes from the line of Joseph Thome with TD Cowen. Your line is open, Joseph. Please go ahead.
Hi there. Good morning. Congrats on the data, and thank you for taking my question. Maybe just now that we have the data out there, and you did mention the updated PFIC patient metrics on the last quarterly call, how are you seeing the breakdown in contribution between Alagille, PFIC, and this sort of other cholestatic disease bucket in your $1 billion plus LIVMARLI expectation from a revenue perspective?
And then second, if you could just talk about your expectations for how quickly this could come to market. Would this be a priority review situation, standard? What's the base expectation given your interactions with the FDA? Thank you.
Thanks for the question, Joe. Yeah, on the latter part of it first, we would see this as a candidate for priority review, just given the unmet need in the setting. I'll pass over to Peter to talk about the breakdown of the $1 billion-plus peak.
Yeah, I think the first message overall, this readout really gives us confidence in the plus part of that $1 billion-plus peak guidance that we have here. We see a lot of different ways to get there from these components. The update we're providing in the materials today, if you look just at the biliary atresia component of the EXPAND study, it's about 1,000 addressable patients in the U.S., 2,000 U.S. plus Europe. That's comparable to Alagille. Actually, when you think about the addressable population of Alagille. Maybe the two differences from Alagille, the dose here is different. It's about 50% higher, so that does play through to the price, and then, of course, no competition in biliary atresia. Although we've had pretty limited effects of competition in Alagille syndrome.
I think as you think about peak sales, the biliary atresia opportunity would be at least as large as the Alagille.
Great. Thank you.
Thanks for the question.
Your next question comes from the line of James Condulis with Stifel. Your line is open, James. Please go ahead.
Hey, thanks for taking my question, and congrats on the data. Maybe one on the epi here. I think historically, you maybe have pointed to more like 1,000 across the U.S. and EU, is that right? Can you talk about what drove that sort of revision upwards to this 2,000? Then a second question here, just sort of on this other non-biliary atresia subgroup. In the real world, do you expect those patients to be adults or pediatrics? Obviously, the study you mentioned enrolled pediatric patients, but just curious, in the real world, is that sort of representative of what that other cholestatic bucket may look like? Thanks so much.
Yeah, thanks for the question. One kind of initial comment and then I'll let Peter speak a little bit more to it. The way we're talking about the epi here really is just a little bit of a shift in framing it because with the results in biliary atresia being so strong, you can look at this from a more traditional kind of epi standpoint on looking at a specific disease just being the biggest component of it versus the others, which is really a long tail of a less common presentation. Peter, maybe speak to the adult versus pediatric and some of the thoughts on the dynamic and the others.
Sure. Yeah. I think in terms of the other patients in this study, and is that representative of pediatric or adult, I think it's well representative of pediatric, right? These were 24 sites. They were all pediatric investigators. So I think if you're looking at the list of diseases on the corporate deck, I think it's a pretty good representation of what you'd expect in the pediatric setting. The adult dynamic's probably a little bit different. We're encountering some of that as we go search for adult PFIC patients. As we've talked about before, there's a pretty good group of other idiopathic cholestatic pruritus patients in adult practices. A decent proportion of them have a PFIC, but probably more don't. But that's a sort of a different population than was enrolled in the study.
Makes sense. Thanks.
Thanks for the question.
Your next question comes from the line of Lisa Walter with RBC. Your line is open, Lisa. Please go ahead.
Oh, great. Thanks for taking our question, and thanks for sharing the presentation this morning. Just a quick question on the open label extension study. I guess, when can we expect to see that data, and do you plan to share the results broken down by other patient subgroups, like the other disease indications or perhaps by adults and pediatric subgroups in the OLE results? Any color here would be helpful. Thanks so much.
Yeah. Thanks, Lisa, for the question. A really pretty rich publication plan opportunity here, and we will let Rob speak on some of the different cuts we can expect to see from the OLE and the primary quickly.
Yeah. No, thanks, Chris. The OLE part of the study is ongoing, and we will have another data cut there after 20 weeks of additional treatment. What I can tell you is that patients who have rolled over into the open label extension are having similar responses to what we observed in the double blind period with maralixibat treatment. In terms of disclosing results for the individual diseases, in general, these are small n's in each group of anywhere from one to two patients for most of these categories. So it will be somewhat difficult to present data for every subgroup. But we feel very confident about the data in the biliary atresia and overall non-biliary atresia subgroups, and they look quite similar.
Thanks for the question.
Our next question will be from the line of Joe Schwartz with Leerink Partners. Your line is open, Joe. Please go ahead.
Thanks. Congrats on the strong data. First, on the patients with biliary atresia, can you talk about them in a little bit more detail? Given liver transplant is pretty common, but the patients here average about six years old with near normal bilis, so they look like successful Kasai patients who still itch. Is that the population behind the label in the 2,000 patient figure? How long do you expect patients to take LIVMARLI before transplant? Outside of BA, I think there were four diseases you said. Has the FDA said whether the label would name those conditions or be a broad label that covers other diseases that weren't in the trial?
Yeah. Thanks for the questions, Joe. On the dynamic in biliary atresia, the way you're thinking about it is what we've seen in the study and how we expect the overall natural history to play out for those patients that have cholestatic pruritus. They're post the successful Kasai. They've gotten through the very young age where you tend to see a lot of transplants happening quite young. Throughout childhood can suffer from that cholestatic pruritus. So expect similar treatment duration and profile to what you see in Alagille syndrome, frankly. On the label, it's premature to really know what the precise label language would be. A lot of back and forth with FDA on the design of the protocol, but we don't really speculate on the label or indication statement at that point. So expect that to be part of the sNDA review.
Thank you.
Thanks for the questions.
Your next question comes from the line of Swayampakula Ramakanth with H.C. Wainwright. Your line is open, Swayampakula. Please go ahead.
Thank you. This is RK from H.C. Wainwright. One quick question in terms of trying to identify patients and how to think about launch economics. How concentrated are potential patients within the existing LIVMARLI prescribers? In terms of expenses, what incremental patient-finding commercial investment do you need to outlay as you get this expanded label over the next year or so?
Thanks for the question, RK. Yeah. Highly concentrated in the same prescribers that currently prescribe LIVMARLI in Alagille syndrome and PFIC. Then your second question, no incremental economics. It's the team we have out there now who can be key patients.
Thanks. Thank you for taking my question.
Thanks for the question.
Your next question comes from the line of Jon Wolleben with Citizens. Your line is open, Jon. Please go ahead.
This is Catherine on for Jon. I just got another follow-up question on the opportunity. You are saying 1,000 pediatric patients with BA. I am wondering, how many of those patients have you actually identified that have itch, or does that number include patients that have itch? Also, when you say the opportunity is similar to Alagille syndrome, do you mean in size or in the opportunity, given the increase in price you are going to see in BA patients?
Thanks for the question, Catherine. I appreciate the opportunity to clarify that. Yes, it is really addressable patients. So the 1,000 patients in the U.S. for biliary atresia, those are biliary atresia patients post Kasai with their native liver and that have pruritus. So those are truly the profile of patients that you saw in this study that we would expect to have on a label versus an overall sort of prevalence number. Likewise for Alagille. That is 1,000 addressable Alagille patients with their native liver who have pruritus that would fit in the current Alagille syndrome label. So that is what we mean. We are really comparing truly addressable patient numbers for both.
Okay. Thank you for the clarification.
Yep. Thanks for the question.
Your next question comes from the line of Yigal Nochomovitz with Citigroup. Your line is open, Yigal. Please go ahead.
Hi. Great. Hopefully, you can all hear me now. Thank you. Maybe you could address one of these. I'm not sure exactly what was already asked, but could you comment on how you're going to handle the six adult patients, if you haven't discussed that already, how that's going to work its way into the sNDA? If that was addressed, if you could comment briefly on the diarrhea. Was there any prophylaxis like loperamide or anything like that done, or was that not necessary? Then, if that was already discussed, then if you could comment briefly on just this expanded population. How much are they concentrated already within the liver centers where LIVMARLI is prescribed, or if it's going to require some additional market diligence to gather those patients. Thank you so much.
Yeah, Yigal, thanks for the question. I'll touch on the last part first, then pass it over to Rob. In terms of identifying the patient population of where they're at, it was actually the interest and demand from investigators and prescribers initially that drove this study design and the interest to do this study. It was from compassionate use and off-label interest that led to the EXPAND design. Just an example to say that these patients are with the same prescribers for Alagille and PFIC, and particularly in the pediatric setting. And so very efficient in terms of being able to get to them and identifying those treatment candidates. But maybe to talk about some of the diarrhea treatment and the adult patient dynamic, pass it over to Rob.
Yeah, no, thanks, Chris. In general, I'd say the diarrhea profile is consistent with what we observed in the past with maralixibat and other IBAT inhibitors. Roughly 60% of patients did have diarrhea. This typically occurred early on in treatment and was short-lived. All of these cases were mild to moderate, and no patients actually discontinued due to diarrhea. In answer to your specific question, we did not use prophylaxis with loperamide for this.
Thanks for the question.
There are no further questions at this time. I will now turn the call back to Chris Peetz, CEO, for closing remarks.
Great. Well, thanks, everyone, for joining today. And again, a big thank you to the Mirum team for making moments like this possible for the company and importantly, for patients living with rare disease.
This concludes today's call. Thank you for attending. You may now disconnect.