Hello, everyone, and welcome to the Mirum Q3 2022 business update. My name is Emily, and I'll be coordinating your call today. At the end of today's presentation, you will have the opportunity to ask a question by pressing star followed by the number one on your telephone keypads. I'll now turn the call over to our host, Ian Clements, CFO of Mirum. Please go ahead, Ian.
Thanks, Emily, and good morning, everyone. I'd like to welcome you to Mirum Pharmaceuticals' Third Quarter 2022 Conference Call. I'm joined today by our President and CEO, Chris Peetz, our Chief Operating Officer, Peter Radovich, our Head of R&D, Pam Vig, and Professor Richard Thompson from King's College London. Early this morning, Mirum issued a news release announcing the company's results for the third quarter of 2022. Copies of this news release and SEC filings can be found in the investors section of our website. Given that we have Professor Thompson on the call today to discuss the exciting full results from our Phase III MARCH- PFIC study, as presented earlier this week at AASLD, we intend to keep the rest of our updates brief. Full details on updates from the quarter can be found in our news release and the 10-Q issued this morning.
Before we begin, I'd like to remind you that during the course of this conference call, we'll be making certain forward-looking statements about Mirum and our programs based on management's current expectations, including statements regarding Mirum's business plans, development programs, strategies, prospects, market opportunities, and financial forecasts and guidance. Mirum is under no duty to update these statements, and they are subject to numerous risks and uncertainties, and actual results could differ materially from the results anticipated by these statements. Investors should read the risk factors set forth in Mirum's 10-K for the year ended December 31st, 2021, and any subsequent reports filed with the SEC. With that said, I'd like to turn the call over to Chris. Chris.
Thank you, Ian. Good morning to everyone joining us on the call today. The last quarter for Mirum was packed with major milestones as we continued to realize our vision of bringing life-changing medicines to patients suffering from rare diseases around the world. The Livmarli launch in the U.S. continues to track well, with $47.2 million in net sales year to date, on track for an estimated $70 million in net product sales in 2022 for a strong first full year of approval. Setting the stage for growth outside the U.S., we recently received a positive CHMP opinion for Livmarli in Europe for treatment of cholestatic pruritus in Alagille syndrome, 2 months of age and older. Our launches in key European countries next year will also be supplemented by further approvals and demand from partner markets like the recently announced approval in Israel.
We're excited about the potential for label expansion based on the positive results of the MARCH-PFIC phase III study. These data build on the years of treatment experience we have in Alagille syndrome and PFIC with a broader genetic type and higher response rate than earlier studies, showing the potential for improved outcomes for patients. It is a moment where the Mirum team is hitting its stride on both commercial performance and realizing the value of our pipeline. The great advances we've made at Mirum are only possible with the participation of patients and dedicated researchers. On that note, we're delighted to have Professor Thompson join us today to share the recently presented details from the MARCH-PFIC Phase III study. With that, I'll pass the call over to Peter for a couple of brief remarks on the commercial business before diving into the new clinical data.
Peter?
Thanks, Chris. Today, I'll share additional color around Livmarli's third quarter net product sales and upcoming plans for the commercial business. We are happy with the continued quarterly growth with $18.8 million in Livmarli net sales in the third quarter. We are raising full year net product sales guidance estimate for Livmarli to $70 million. We continue to observe high levels of compliance and persistence to Livmarli and maintain strong reimbursements. Coming into the fall, we've seen an acceleration in new patient starts on Livmarli and continue to believe we're early in reaching the full addressable Alagille syndrome patient population in the United States. Our commercial business is strong and profitable, which positions us well as we turn to launches in international markets.
Germany will be the first European country to come online in Q1 of 2023, with others following over the course of 2023 and into 2024. Beyond our core U.S. and E.U. markets, we also expect to see contribution in 2023 from our partner markets, with several approvals occurring over the next 12-18 months. Outside the United States, over 130 Alagille patients are currently receiving Livmarli from clinical and expanded access programs. These patients will be eligible to transition to commercial Livmarli upon local approvals. On that note, I will turn the call over to Pam. Pam?
Thanks, Peter. Over the last few months, our team has continued to take major strides in advancing Livmarli for pediatric cholestatic diseases. We've just returned from the AASLD Liver Meeting where we presented exciting late-breaking data. First, we reported on PK safety and tolerability in infants with Alagille from 2 months of age to 1 year of age. These results observed in infants were similar to those observed in children greater than 1 year of age. We also showed real-world safety and tolerability data, which demonstrated a profile that was well-tolerated with only 8% GI-related disorders, including diarrhea and no GI-related discontinuation from this analysis. Now this aligns with feedback from the commercial use of the product where the tolerability profile has been very well received.
This profile, along with the efficacy observed in Alagille, including the six-year outcomes data that have been previously presented, really highlights the ability of Livmarli to make a meaningful impact in these patients' lives. Now, we are most thrilled by the late-breaking presentation of our MARCH- PFIC Phase III study by Professor Thompson. The MARCH study enrolled 93 PFIC patients, which is the largest PFIC study conducted. The study met its primary endpoint and secondary endpoints and included PFIC types that have not previously been studied. The postulation that higher doses would translate to a greater magnitude of response and higher response rates has played through, and the magnitude of effects observed across the PFIC types exceeded our expectations.
We're so excited about what this means for PFIC patients, and this deep data set will help answer questions that have until now gone unanswered, and we're looking forward to digging even deeper. With that said, it is a pleasure to hand over to Professor Thompson. Professor.
Pam, thank you very much indeed. So I, as a pediatrician who looks after children with liver disease and conducts research into the underlying causes of these diseases, I'm really pleased to be able to present these data because I think they are important. Following Pam's introduction, I think we can jump straight through to slide 4, which talks about what PFIC is, which is progressive familial intrahepatic cholestasis, which is actually a group of genetic disorders characterized by abnormalities of bile composition and flow. The consequence of those genetic abnormalities is these children have got progressive liver disease. Clinically, the most important thing is they have this intense itch or pruritus and other consequences thereof.
In particular, this impacts on their quality of life, and in fact not just of them, but of their whole family. The most frequent of the types of PFIC is Bile Salt Export Pump deficiency. Patients with this disorder are the focus of the primary cohort in this particular study. As you will see from the slide, there's a number of other subtypes are also described. In particular, FIC1 deficiency, MDR3 deficiency, TJP2, and Myosin 5B deficiencies, all of which are in the other PFIC cohort which I'll go through today. Previously, we've treated all these patients with a variety of off-label drugs which have had some benefit, mainly on the pruritus rather than the liver disease.
We have historically used a surgical interruption of the enterohepatic circulation of bile acids, which requires the formation of a stoma and external bile drainage every day. Which we do believe has helped approximately 50% of patients who have been treated in that way. It is a fairly major surgery, and I believe as a consequence, many patients have not been offered that form of surgery because there's quite a high threshold to offer a form of surgery with only a 50% chance of a significant improvement. As a consequence of our limited repertoire of treatments, historically, the majority of patients have ended up with liver transplants in childhood, which is an effective form of treatment, but obviously is a major undertaking and with associated considerable risk.
I'm delighted that IBAT inhibitors are now becoming available and as an alternative pharmacological treatment for the conditions. If you move to slide 5, you'll see the concept, which is the bile acids undergo this enterohepatic circulation from being synthesized in the liver, excreted in bile. They're used in the small intestine for the absorption of fats and fat-soluble vitamins. But those that are not used in each cycle are reabsorbed in the terminal ileum by the ileal bile acid transporter, which is a sodium-coupled transporter. Bile acids that are absorbed from the intestine return through the portal vein straight back to the liver from where they're extracted, and they go round that cycle in normal healthy individuals. Patients with PFIC have a reduced transport capacity in the liver, and they have lower levels, therefore, of bile acids in the intestine.
Most importantly, they have accumulation of bile acids in the liver where it is strongly associated with the pruritus, but also with progression of liver disease. As you will see on the right-hand side from previous studies, we have certainly seen that maralixibat has been capable of improving the pruritus, reducing the bile acid pool size as measured by the peripheral serum bile acids. We have in our phase II study shown that those who do respond are associated with prolonged native liver survival and the avoidance of transplantation. Slide 6 shows you the schema of this randomized study. This was in children with PFIC over 12 months of age, randomized 50/50 to either receive maralixibat or placebo. This dose of maralixibat is considerably higher than the dose we used in the initial phase II studies.
I think that probably is quite important in the difference in results we've seen in this study. The patients on entry had to have persistent pruritus, which had to be moderate or severe, persistent elevated serum bile acids as a further marker of cholestasis. The vast majority of patients went on into the open-label phase II study where they got drug for the phase III study where they got drug in the MARCH study. Page, slide 7 shows you the distribution of patients. The full study cohort, as Pam said, was 93. On the top right-hand corner is the primary cohort, those with BSEP deficiency, which had to be non-truncating. So that's the vast majority, 90% of patients with BSEP deficiency fall into this category, but they have the potential for some residual BSEP function.
Combined with the other pale box below those is the other PFIC cohort that I referred to previously, the FIC1, MDR3, TJP2 and Myosin 5B deficiency. The data are presented, they are on the BSEP primary cohorts, the other PFIC cohorts, which then combine to form the all PFIC cohorts. The group on the bottom right are assortment of other phenotypes, which are clinically important but more heterogeneous, and I haven't got endpoint data on those today, but they are included in the safety data which I'll discuss. Slide 8 shows you the details of the endpoints of this study. In particular, the left-hand side, the primary endpoint was an improvement in pruritus measured by the ItchRO tool, which has been previously published, and that is an improvement in the BSEP cohort.
A number of clinically and biologically important secondary endpoints are shown on the right-hand side. In particular, similar changes in pruritus were looked for in all the rest of the PFIC cohort. That's biologically improvements in serum bile acids as a marker of cholestasis, looked at in the different groups, along with a responder analysis on a patient-by-patient basis, which I'll show you some odds as well. There's a whole range of biologically and clinically important secondary endpoints, including changes in bilirubin and changes such as growth, which I'll show you some preliminary data on those as well. Slide 9 shows the distribution of the patients at the time of enrollment, in terms of the BSEP cohorts, then the all PFIC cohorts, and then the full cohort on the right-hand side.
As you can see, these are all children mainly in the first decade of life. All had significant pruritus on the scale which goes from 0-4. They had extremely elevated serum bile acids. You can see the BSEP cohorts were around 300 compared to a normal range in the general population of less than 14 micromoles per liter. The vast majority of patients were being treated with ursodeoxycholic acid, which is widely available and very happily used chenodeoxycholic acid, which is perceived to have some small improvements in this condition. Approximately 50% were on rifampicin, which is again, an off-label use of an antibiotic from which some patients appear to derive a small benefit. Patients were left on those drugs unmodified through the rest of this study.
As you can see, the ALT is a reflection of the fact that they got liver disease. They got raised transaminases suggesting they've got ongoing liver damage at onset. The majority of patients were jaundiced as measured by the bilirubin, and in particular, direct bilirubin. Although not all patients, you know, approximately a third of the BSEP patients actually were not jaundiced at onset. Bilirubin isn't an intrinsic part of the disease, but is a marker of how well the liver is functioning as a secondary consequence. As you can see at the bottom, measured by the Z-score, overall this cohort were failing to thrive in both height and weight at baseline.
Slide 10 shows you the details of the primary endpoints, and all these variables were assessed using the mixed-model repeated measurements technique of analysis, which interrogates all the data from 15 weeks to 26 as compared to baseline. On the left-hand side of the slide, you'll see the changes observed in the primary cohort in the BSEP patients who achieved a very significant improvement in pruritus as a cohort. It was with some placebo change in the placebo group, which we expect will always get significant improvements in placebo in patients enrolled in studies such as this. The difference between the treatment group and the placebo group was marked and highly statistically significant.
On the right-hand side, you can see the same data represented longitudinally with clear separation of the treatment group and placebo group very early on from approximately 2 weeks of exposure. The pruritus response continued to improve over the first few months and appears to have reached steady state for about 2 months of treatment, and then persisted for the duration of the 26-week study. Slide 11 shows you very similar data for the other PFIC cohort with these other diseases listed at the top there. In fact, if anything, the separation of the patients with treatments of maralixibat and placebo was even greater, and again, obviously highly significant in these other additional patients.
On the right-hand side, those patients are shown in the darker red and blue plots, and superimposed in the paler color are the results that I showed you just now for the BSEP cohort. As you can see, they are really effectively superimposable. Not surprisingly, therefore, on slide 12, when we combine the all PFIC cohort, which is the previous two sets of data combined, we get a significant improvement and a very nice and plots on the right-hand side showing clear separation and persistence of the effect between the treated and untreated patients. Slide 13 shows some of the biochemical data, and the most important being the changes in serum bile acids, again, over the last 12 weeks of the study.
In the BSEP cohort shown here, there was a marked improvement in serum bile acids, with a reduction of 176 micromoles per liter compared to the baseline of approximately 300 as a cohort in the treatment group, but really no change from baseline in the placebo group. Again, those figures are shown on the right-hand side longitudinally. Here, I think it's very clear that not only was there a significant improvement at 2 weeks, but we'd pretty much achieved a steady state in the first month of treatment. Probably not surprising that the changes in serum bile acids predate the changes in pruritus, as this is really getting closer to the actual biological change which we're hoping to achieve with the drug. Slide 14 shows you the same data now for the other PFIC cohort.
In parallel to the previous data which I showed you for pruritus, these data are reflected in the serum bile acid changes, which were much greater in the treatment group and really showed no change in the placebo group. Again, on the right-hand side, you'll see the other PFIC cohorts here is largely superimposable upon the BSEP cohort, which I showed you in the previous slide. On slide 15, again, those cohorts have been combined in the all PFIC cohorts, which showed a very clear distinction between the treatment group and the placebo on the left and the longitudinal on the right, which shows the duration of action with reduced error bars as a consequence of the increased enrollment of the data.
Slide 16 shows a responder analysis, which obviously is clinically extremely important because I want to be able to tell patients what how likely they are to be able to respond to treatment. On the left-hand side is the pruritus responses, and that is measuring an improvement of greater than 1 point on the ItchRO scale. Previously, and this is published data, a change of greater than 1 point has been associated with a clinically meaningful improvement in pruritus. As you can see, 26% of the placebo group responded, but 64% of the treatment group responded, which is a very highly significant difference. On the right-hand side, we looked at the response in terms of serum bile acids. This is in the all PFIC cohort.
The cutoffs used here are based on the cutoffs which we derived statistically in our surgical retrospective analysis. When we use surgical interruption of enterohepatic circulation, a reduction of 75% from baseline or a reduction to below 102 micromoles per liter was strongly associated with the avoidance of transplantation in an 18-year follow-up. We hope that these will be reproducible in the follow-up studies using maralixibat, and we believe that as serum bile acids are intrinsic to the nature of the bile acids are part of the actual fundamental nature of the disease. We believe that these changes in serum bile acids will be representative of changes in the natural history of the disease.
As you can see, there was a very small response at this parameter in the placebo group, but 52% of the all PFIC cohorts met this change in serum bile acids, which we had previously, as I say, associated with long-term native liver survival and the avoidance of transplantation in the retrospective surgical studies. Slide 17 goes on to look at some of the other biochemical data, and this is the total bilirubin. As I say, it's not intrinsic to the disease, but it's a good marker of liver health. There was an improvement which was just significant in the maralixibat group compared to placebo. There's longitudinal data on the right-hand side. This, as I say, is despite the fact that actually a third of the primary cohorts were not children with the disease, and those data are shown on slide 18.
On slide 19, you will see the changes in serum transaminase, in particular alanine transaminase, aminotransferase, which at baseline were in the range of 100 - 200. There was a very small deterioration, increase in the maralixibat group and a very small decrease in the placebo group. These are very small compared to the parameters at baseline. Clearly, they are something which we are very keen to observe and would potentially be a safety signal. The changes are small, and as you can see on the right-hand side, it appears that by the end of the study, actually the treatment group and placebo group appear to have converged again. As I said, growth is a very serious complication of liver disease like this.
Here on slide 20, we can see the changes in the weight Z-score on the left-hand side, which was markedly better in the treatment group. There was a trend in the same direction on the right-hand side for height. Improvements in height always is delayed over improvements in growth. Slide 21 just summarizes some of the safety data, which is now looked at for the whole cohort, the PFIC cohort and the exploratory cohort. There's a whole 93 patients involved in this study. These were sick children. As you can see, there was treatment-emergent adverse events in both the treatment group and the placebo group in almost all patients. There were some significant adverse events as you would expect in treating patients with severe liver disease.
The difference between the two groups is probably summarized best at the bottom of that slide where the gastrointestinal side effects are highlighted, in particular increased stool frequency and diarrhea, which is an expected consequence of diverting bile acids into the colon. None of this was deemed severe. The vast majority was mild. It did lead to one discontinuation. One teenager who was deemed to have mild diarrhea was unhappy with this, and that was the only discontinuation as a result of side effects observed in the study. There are side effects. They are manageable. They're mainly mild and usually, I would say, they resolve fairly early in the studies. Slide 22 summarizes really most of what I've just told you. This study, a phase III study, which is the first using maralixibat in PFIC.
It was including patients not just with BSEP deficiency, but a variety of other PFIC subgroups. As I hope I've demonstrated, the primary and secondary endpoints were met very comfortably. It does look like maralixibat is capable of producing both biologically and clinically significant improvements, particularly in pruritus serum bile acids across the types tested. I do think that we've seen much greater improvements in this study compared to the phase II study that was undertaken some years ago with maralixibat, where the responder rate was less. The difference between the studies really is that I think we've now optimized the dosing, and most of these patients ended up on a significantly greater dose of drug than the previous studies. I think we've learned very much from those.
As I also said, as an academic community, we pulled together a study called the NAPPED study, which was looking at the surgical interruption of enterohepatic circulation of bile acids. Clearly, in that academic study, we showed that improvements in serum bile acids through surgical interruption of the enterohepatic circulation of bile acids is correlated with native liver survival in the avoidance of transplantation. On the basis of the cutoffs previously identified in that study, it looks like maralixibat is capable of producing similar changes across all the different types of PFIC, including this study. As I've also shown you, I think we've got significant improvements in bilirubin and weight scores and a trend in the right direction in height. Overall, it looks like maralixibat is well-tolerated. There are side effects.
They're manageable. They're usually transient and early in the disease, and there's no new safety signals using this large cohort of patients on a higher dose. I am extremely grateful to all my colleagues who recruited patients into this study and collected data, but of course, most grateful to all the families who collected data and put up with the increased monitoring and things which were necessary to perform a complex study of this nature. Those are the data we analyzed so far from this study. Clearly, as I said at the beginning, as a pediatrician who looks after these patients, we are delighted that we've now got tools which will help us treat the patients.
Probably the most important reflection from my point of view is that I've still got patients who are involved in the phase II study. We've now got 7 years follow-up. Certainly the patient that sticks out in my mind because she has an internal control in the sense that her sister was transplanted some years ago for the quality of life and the intense pruritus. Her sister was transplanted and I'm pleased to say has done very well post-transplant, but obviously is on immunosuppression, et cetera that you would expect after transplant. My patient who was involved in the phase II study and has now got been on maralixibat for 7 years, has normal liver biochemistry. She has normal serum bile acids. She takes maralixibat and she takes a small amount of vitamin D.
All her vitamin levels are normal. She has normal growth. Her spleen size has gone back to normal. Really, if you were to meet her, if you were to look at her biochemistry, you would say there was nothing wrong with her at all. Of course, that's exactly the sort of endpoint which we appear to be able to achieve. Clearly, the long-term studies are necessary, but all the parameters that we've studied in this six-month study do point that we're moving in that direction. I think it's huge improvements on where we were a few years ago. I'm very happy to take any questions. I will hand over to Chris. Thank you.
Great. Thank you, Professor Thompson. As you can tell, the results from the MARCH- PFIC Phase III study show convincing promise for Livmarli. We plan to begin regulatory submissions early next year to get Livmarli to PFIC patients as quickly as possible. It was a great quarter for Mirum and for families suffering with pediatric cholestasis. With that, we'll open the line for questions for both Professor Thompson and the Mirum team. Operator, please open the line for questions.
Thank you. If you would like to ask a question, please do so now by pressing star followed by one on your telephone keypad. If you change your mind and would like to be removed from the queue, please press star followed by two.
We ask that when preparing to ask your question, please ensure that your device or your microphone are unmuted locally. Our first question today comes from the line of Jessica Fye with J.P. Morgan. Please go ahead, Jessica. Your line is open.
Hey there. Good morning. Thanks for taking my questions. Two. One for the management team and one for the physician investigator. First, for management, I think in prepared remarks, I think you mentioned an acceleration of new starts on Livmarli, and I may have missed the time frame of when you saw the acceleration, but just wondering how to reconcile that with what looks like a deceleration in revenue growth that was reported. For the physician, can you talk about what you see as clear differences between Livmarli and Bylvay? If we fast-forward to a time when Livmarli is approved for PFIC, how you would select between those two agents for a PFIC patient? Thank you.
Thanks, Jess, for the question. I'll go ahead and hand it straight to Peter to comment on the top line and then to Professor Thompson for your second part.
Yeah. Thanks, Jess. So in terms of the comments, yeah, we are seeing an acceleration in the fall, continuing to see that acceleration in new patient starts with Livmarli. That's really what gives us confidence in the raising of guidance to $70 million and the 20% quarter-over-quarter growth that that implies going in from Q3 to Q4. You know, looking at the full Q3 picture to your question, you know, we did see some softness in the summer. You know, keep in mind in the U.S. that many of these children are seen once every 6 or even every 12 months.
What kind of the phenomena we observed is families going on vacation choose not to do their physician appointment where new patient starts typically occur in those summer months. That's what we observed in, obviously, the summer months for most of Q3, but the acceleration coming in into the fall and continuing now.
Jessica, I'm obviously, as you know, that there are two IBAT inhibitors that have been studied in these groups of conditions. I'm delighted that we've got a, you know, a positive response from both drugs. Disappointingly, of course, neither drug treats effectively all the patients that have been studied. Yes, is there a distinction between the two drugs? I mean, the honest truth is that they, despite the fact that they're similar studies, we haven't done a head-to-head comparison. I think if you tried to do that right at this moment, you would not find a statistically significant difference between the two drugs.
They do have a significant response rate, and you know, 52% is an excellent bile acid response rate, 64% for PFIC is an excellent response rate in terms of pruritus. I think the people sitting around the table will tell me that that is greater than that shown in odevixibat, but as I say, I'm not sure that's statistically significant. I think from my point of view, on an individual patient basis, we'll have to dig into these data and see if we can see any differences between the response rates. I believe the major determinants of whether a patient responds or not in these conditions is the amount of residual bile acid transport. The best way we have of looking at is to go and look at the individual mutations that these patients carry.
Certainly that's something I want to do is to dig those down into those patients, see if there's any biochemical predictors of response, any genetic predictors of response. Only when we've done that can we really see whether there really is any clinically meaningful difference between these drugs. Obviously, there's other factors that come into it, availability of the drug, the formulation of the drug, and I'm sure in some territories, certainly the price of the drug will be an important factor, but in deciding which drug to use. I think there's a stuff that we've got to learn, but there's also other factors which are pharmacological and nutritional which will impact on it, but they're outside my remit.
All right. Thanks, Jess, for the question.
Great. Thank you.
Our next question comes from Steven Seedhouse with Raymond James. Please go ahead, Steve.
Hey, good morning. Thanks so much. Just on the acceleration of patient starts, again, I'm wondering if you can comment. Is there any sense that that's being driven by repeat prescribers at this point, or are you still mostly gaining patients through new prescribers?
I think we see both. You know, the prescriber base in the U.S. is pretty well-defined. I mean, there's only, you know, a certain number of pediatric hepatologists that take care of these patients. You know, quarter-over-quarter, we do see more come on board, particularly from the medium or smaller centers that might not have as much volume. But in terms of the acceleration, I think it kind of comes from across the board.
Okay. Then in ICP, I wanted to ask here because there's some data coming up or an interim analysis at least, first half of next year. It seems like enrollment in that study has picked up after some of the protocol changes you had talked about implementing earlier this year. I was hoping you could just comment on anything you're learning about just the number of patients seeking treatment with ICP unmet need and also the demographic that you're enrolling in that study just with respect to, like, is it mostly third trimester patients, first or second pregnancies, just anything trending in that study that would be noteworthy to mention. Thanks.
Yeah. Thanks for the question on that. You know, nothing.
Specific really to call out in terms of the demographics at this point, it can be premature to comment on what that looks like until we get to the analysis cohort. We are on track for the first half of next year, and have seen patients come in with this updated protocol. All kind of pointed in the right direction.
Okay.
Sorry, Steve, sounds like you got cut off. Did you have another follow-up? Okay, great. Thanks for the question.
I was just asking about MARCH-PFIC and the patient with the liver transplant, if you could share details of why they ultimately elected for that, were they a non-responder? Just any color there. Thanks.
I mean, the reason for transplant, in my understanding, is that that was obviously the family's choice, and they were perceived to be non-responders. I think they haven't got all the figures to hand, but I'm pretty sure that there was the discontinuations were obviously slightly greater. There was 7. There were 4 of them in placebo group, 3 of them on drug. And the majority of the ones that went for transplant were non-responders, perceived as non-responders on drug or a deterioration in liver function in the placebo group. The majority were in the placebo group. But they obviously, the bile acids and the pruritus scoring and everything was not evident to the families.
They were making decisions, and the physicians were making decisions on clinical grounds rather than actual hard data.
No, thank you.
Great. Thanks for the question.
Our next question comes from Mani Foroohar with SVB Securities. Please go ahead, Mani.
Yes. Thanks for taking the question. I wanna drill down a little bit on patient dynamics and growth going forward. Have you seen any mix shift in age, mean body weight, et cetera, for patients in this recent sort of additional fall patients coming on versus the initial slug? As we start to see more geographies come on next year, can you give us a little bit of detail on exactly how you might account for revenue coming in from partnered geographies as opposed to places where you're monetizing yourself? If there's any nuances we need to be aware of that as we look forward.
Thanks, Mani, for the question. I'll comment on the kind of broader international piece and then pass it to Peter for the specifics on in the U.S. to date. When you take a step back to think about the international markets, we are building and launching ourselves in Western Europe and using distributors in some of the other geographies around the world, licensing partners in Asia. What we expect for these distributor markets is that they will have orders that may be kind of more in, you know, monthly for multiple patients at a time or for a quarter at a time. You could see more of an order-based approach to how they come in, and we could start to see some of that this year, even.
Expect it to come online with early access programs and approvals in some of the smaller markets into next year. When we're in the countries where we're in market doing it ourselves, pretty standard for rare disease where we'll recognize revenue as we sell it through to the pharmacy when orders come in for patients. With that, I'll pass it to Peter to dive in a little deeper.
Sure. On the patient mix in terms of age and body weight, no changes there in recent months, really consistent with the types of patients that were put on early after the FDA approval, which is also consistent with the ICONIC pivotal study and the clinical program. If you need, you can always refer back to those papers, and that'll get you in the ballpark of the average age and weight that we see. Maybe the only other comment is similar to what we've talked about before, kind of the perception of the phenotype.
You know, early days saw the patients who are perceived to be most severe with their pruritus and other quality of life impact of the disease are the ones that we see the physicians kind of, you know, go for first as they gain more comfort with the product and prescribing experience. You know, then we see prescriptions broaden to, you know, patients that are maybe perceived to be more moderate. We're seeing that phenomenon play out in the recent quarters.
Great. That's really helpful. On the dynamic around kind of monthly, quarterly kind of, order structure for some of these distribution markets, is it reasonable to assume that that'll introduce a little bit more chunkiness and choppiness into the quarterly, quarter-over-quarter numbers, or am I overreading that?
I'd say at this point, we don't know, and we have to just kind of see the cadence of how the orders come in. The one thing I'd note is that there are several different distributors, several different countries, so we do expect it to be coming from a lot of different sources, which I think would smooth out anything that could be chunky. That's kind of where our thinking is at this point.
Okay. That's really helpful. Thanks, guys.
Yep. Thanks for the question.
Our next question comes from David Lebowitz with Citi. Please go ahead, David, your line is open.
Thank you very much for taking my question. Would you be able to comment on comparability with Bylvay given differences in the trials, such as measuring in the morning versus measuring in the morning and night, and just overall how efficacy was calculated in one study versus another?
Yeah. Thanks for the question. I mean, from a high level, we know our data, how our endpoints were calculated. That's really what we can speak to in detail. So not in a position that we can really make any kind of definitive cross-study comparisons, cross-drug comparisons. I would say just on the, you know, morning versus evening measurements, what we see in our study is that is, you know, effectively the same results. So it's something we've looked at across all of the readouts we've had, and it's highly consistent, whether you look at morning, evening, average, worst, et cetera. So that holds up. We wouldn't expect that to be a difference for the measurement time point.
Got it. When you look at the data and compare from what you see in PFIC, any thoughts on extrapolating on how they might compare in ALGS?
What I can say is what we see from these PFIC results and kind of what we've walked through here on the call, if you step back and look at the maralixibat program over history, is we have taken a huge step forward in the impact for patients. The response rates are much higher here. When you look at the proportion of scores that are a zero or a one of the FDA-preferred analyses, 62% of the scores in the treatment arm is a great step forward in terms of what we see for activity. Great response rate and results coming out of the study.
Got it. Thanks for taking my question.
Thank you.
Our next question is from the line of Yasmeen Rahimi with Piper Sandler. Please go ahead.
Good morning, team. My questions are actually directed to Dr. Thompson. Thank you so much for being with us. The first question for you is, when you look at the data for MARCH-PFIC, is there a part of the results that you think are absolutely critical to belong into the label that could drive stronger adoption? That's question one. Then the question two for you is we recently saw Alagille data with Bylvay and would love to hear. You know, I appreciate your comments about comparing the two products in MARCH-PFIC, but if you could share your thoughts how these two IBAT inhibitors compare and contrast to one another in Alagille, that would be really helpful.
The third question is, you know, as you know, Mirum is working on volixibat, a number of other indications from ICP to PSC and PBC. Any comments there where you think the mechanistic rationale is stronger, may have a higher probability of success? Sorry for asking you so many questions, but really want to take advantage of having you on this call this morning. Thank you, Dr. Thompson.
Right. I mean, I think the last two questions sort of merge in a way because clearly I do believe that bile acids are causing a significant part of liver damage and contributing indirectly to the pruritus in both Alagille and these other phenotypes, which you're talking about, PBC, PSC, et cetera. Clearly, they are, you know, all those conditions are very different from PFIC, where we know that bile acids are not just an important part of the damage and symptom production, but are absolutely the key to the initiation of the disease as well.
It's much easier to draw a connection between offloading bile acids and the actual nature of the disease and therefore, you know, I think earlier signals that we're changing something in the natural history of the disease as opposed to improving the clinical features. I think, you know, these studies, in a sense, are easier to sort of show you clear distinctions in PFIC than in some of these other phenotypes. I do believe that in all those cholestatic phenotypes, bile acids are an important driver of the liver damage, and the retention of bile acids is an important driver of pruritus. As I think, you know, thinking about the previous maralixibat studies with Alagille that I was involved with, which initial studies were disappointing.
I think the change came when with the ICONIC study, where a much higher dose of maralixibat was used. I think that's what we're seeing in this study now is the reflection compared to the early PFIC studies and the ICONIC compared to the original randomized studies in which I was involved, where the higher dose has clearly achieved a much greater response. Obviously, from a patient point of view, I mean, it's still disappointing that we're not giving, you know, a perfect response in terms of bile acids or more importantly, pruritus in all the patients.
Clearly, as I said already, that I think we're gonna need to learn to work out if we can predict which patients are likely to respond. You know, in the next few years, once we start using these drugs in real life, whether we can actually find any way of improving on the responses that we're getting. Clearly, from the patient's point of view, the thing that they're coming to us asking about is the pruritus because that is the thing that dominates their life. Clearly, you know, if we in PFIC, as we've shown here, if we can get 64% of patients giving a pruritus response, that's something that's extremely meaningful to them, and that's what they want to know.
From my point of view, I'm equally interested in the bile acids because, as I've shown you that I do believe because it is absolutely the heart of these diseases, it, logically, should transition into a reduction in the damage to the liver and the, avoidance of long-term interventions such as transplants. That's as I say, what we're expecting to happen based on our previous experience. I think your first question was what's the clinically meaningful aspects of the one of the most important bits from my point of view.
As I say, I'm less interested in the cohort analysis because that combines responders and non-responders, and seeing that it is dichotomous, what is important is how good that response is in the responders and whether we can then maintain those in long-term response and avoid transplantation. As I've also said, you know, obviously we've got patients now who did respond, particularly when the dose was increased in the original PFIC study, who now are long-term responders 7 years out. Actually, the dose, even with the increased dose, they're still on a lower dose than the dose we're using in the current study. I do believe there was quite a significant number of patients in those original studies who failed to respond because they just weren't exposed to enough drug.
Am I right in thinking I've made some sort of attempt to respond to your question? Please tell me if I've not.
No, no, that's very helpful. Thank you, Dr. Thompson, for your thoughtful remarks.
Great. Thanks, Yasmeen, for the question.
Our next question is from Brian Skorney with Baird. Please go ahead.
Hi, this is Luke on for Brian. I just have a couple on biliary atresia. For management, have you had any recent discussions with the FDA around EMBARK and the path to approval in this indication? For Professor Thompson, we've talked to some other physicians who have noted that maybe a third of patients who get the Kasai have had a partially successful procedure, so one that isn't curative but also doesn't require an immediate transplant. Do you think that one-third is an accurate estimate? Could you help characterize the heterogeneity in itch and other clinical markers among this subset? Thanks.
Thanks, Luke, for the question and comments on the first portion of it. We discussed the biliary atresia program with FDA prior to initiating the study and are excited about what the potential for patients are in the study. When we have those results, we'll go back to the agency and talk about the registration plans. I'm quite excited about what you know if the drug can do what we think is possible in this setting, the potential to see real strong impact at that six-month primary endpoint next year. I'll pass it over to Professor Thompson for the second portion.
In terms of response, I think the you know the original studies, the responder analysis was based on largely empirical data. We do now have these surgical data, and the responder analysis I showed you for bile acids was based on the observations we made in those studies. I mean, it's interesting that obviously we don't appear to have to achieve normal serum bile acids to achieve long-term native liver survival based on those studies. I think that is telling us something about the fact that the liver is protecting itself. Although the peripheral serum bile acids are not normal, we appear to have got the levels down inside the liver low enough that not only does the pruritus improve, but we don't appear to have progressive liver disease.
The question is, what sort of level of response do we need? Are these partial responders actually going to avoid transplantation, for instance? Actually, if you go back and look at the surgical data, there was quite a wide separation between responders and non-responders, and I think it's similar for this study, which we'll have to go and look at those in detail. What it means is that actually where exactly you put that cutoff can be changed quite widely without really making a significant difference to the results. Although that cutoff of a 75% reduction or below 102 micromoles per liter gave us the best distinction between responders and non-responders, actually a lower level of responses, a lesser improvement, made little difference to the separation.
Obviously it remains to be seen whether those sorts of results can be expected with the drug. We believe the mechanism of action is the same, and we believe the serum bile acid marker as a reflection of the biological improvement is equally valid. You know, at the end of the day, we will have to see whether those correlate. Those are the data we have, and obviously, those are the data that we'll be using for the time being to make clinical decisions.
Great. Thank you.
Thanks for the question.
Our next question comes from Ed Arce with H.C. Wainwright. Please go ahead, Ed.
Hi. Good morning, everyone. This is Thomas here asking a couple questions for Ed. Thank you for taking our questions. Perhaps first one for Dr. Thompson. Among the positive data that we're seeing in the MARCH study in PFIC, which attributes of Livmarli do you consider to be unique and most important to patients?
The attributes that are most important from patients. I mean, as I say, I think it's about endpoints, and I want to be able to say to a patient what are the chances that they're going to get a clinically meaningful improvement, and also linked to that, what are the chances that we're going to avoid transplantation. I think the results are as you've seen them. I'm gonna be telling patients there's a two-thirds chance that they're going to get a clinically meaningful improvement in pruritus.
I'm going to say that at the moment, it looks like there's approximately a 50% chance that on this basis that they will be able to avoid long-term liver transplantation in the long term, based on the results we have so far and our extrapolation from the data which I've described from previous clinical studies. No doubt that those are the two things that I'm gonna be discussing with families.
Understood. Thank you, Dr. Thompson. Perhaps one question for the team. Can you outline the key components of Livmarli's potential U.S. PFIC launch? What are some overlaps and differences between your strategy between PFIC and Alagille syndrome population?
Sure. Happy to comment on that. I mean, I think in terms of the commercialization strategy, you know, physicians and healthcare professionals that take care of PFIC patients are largely identical to ALGS. The physicians take care of ALGS patients. It's the same centers that we're already in now promoting Livmarli for Alagille syndrome. Obviously upon an FDA approval, the promotion would include both ALGS syndrome and PFIC products already available. You know, we've been working with the patient advocacy groups and other stakeholders in PFIC for years, right? As you've heard today, going back 7 + years. You know, pretty straightforward addition if you're thinking about it from a SG&A perspective.
Maybe the only other comment to make is, we have about 100 patients from our clinical and expanded access programs with PFIC who are currently receiving Livmarli around the world. A good part of our early effort will be upon approval converting the patients receiving the clinical drug to commercial drug.
Got it. Thank you again for taking our questions, and looking forward to European approval by year-end.
Thanks, Thomas, for the question.
Those are all the questions we have for today. I'll now turn the call back to Chris for concluding remarks.
Thank you, operator, and thanks everyone for joining today's call. I'd like to thank again Professor Thompson for joining us today, all of the investigators and families that made these study results possible, and hope everyone has a great day. Bye.
Thank you everyone for joining us today. This concludes our call, and you may now disconnect your lines.