Hello, everyone, and welcome to the Mirum Q3 2022 Business Update. My name is Emily, and I'll be coordinating your call today. [Operator Instructions] 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.

Earlier 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 on 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 31, 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, and good morning to everyone joining us on the call today. The last quarter for Mirum was packed with major milestones as we continue 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 and Alagille syndrome 2 months of age and older.

And 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. And 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. And 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, and 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 EU markets, we also expect to see contribution in 2023 from our partner markets with several approvals occurring over the next 12 to 18 months. And 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 to 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 discontinuations 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 6-year outcomes data that has 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 in the magnitude of effects observed across the PFIC types exceeded our expectations.

And we're so excited about what this means for PFIC patients and the [sleep] data set will help answer questions that have until now gone unanswered, and we're looking forward to digging even deeper. And with that said, it is a pleasure to hand over to Professor Thompson.

Professor?.

Thank you very much, indeed. So I -- as a pediatrician, who looks after children with liver disease and conduct 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.

And 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 abnormality is these children have got progressive liver disease. But clinically, the most important thing is that they have is they have this intense atrial pruritus and other consequences thereof in particular, this impact on the quality of life and is that not just for them, but for the whole family.

The most frequent types of PFIC is basalt export pandeficiency and patients with this disorder are the focus of the primary cohort in this particular study but as you will see from the slide there, a number of other subtypes are also described in particular FIC-1 deficiency and 3 deficiency, GJP2 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 will have some benefit mainly on the pruritus rather than the liver disease.

But we have historically used a surgical interruption of the enteropathic circulation of bile acids, which requires the formation of stoma an external bile drainage every day, which we do believe has helped approximately 50% of patients who have been treated in that way, but it is a fairly major surgery, and I believe, as a consequence many patients have not been off of that form of surgery because there's quite a high threshold to offer surgery then you have 50% chance of significant improvement.

As a consequence, of our limited repertoire of treatment. 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 associated considerable risk.

So 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 intrapatic circulation from being synthesized in the liver excreted in bile, they're used in the small intestine, the absorption of fats and vitamins for those that are not used in each cycle are reabsorbed in the terminal volume by the ileal bile acid transporter, which is a sodium coupled transporter.

Bile acids are absorbed from the intestine return through the portal vein straight back to liver from where they're extracted and they go around that cycle in all healthy individuals.

Patients with PFIC, however, reduced transport capacity in the liver, and they have lower levels, therefore, of bile acid, but 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 the maralixibat has been capable of improving the pruritus reducing the bile acid pool size as measured by the peripheral serum bile acids.

And we have in our Phase II study shown that those who do respond are associated with prolonged and native liver survival [Indiscernible] liver transplantation. Slide 6 shows you the schema of this randomized study, and this was in children with PFIC less than -- over 12 months of age, randomized 50-50 to either receive maralixibat or placebo.

And this dose of maralixibat is considerably higher than the dose we used in the initial Phase II studies. And I think that probably is quite important difference in results we've seen in this study.

The patients on entry had to have persistent pruritus, which had to be a moderate or severe system elevated serum bile acid as a further marker of [Indiscernible]. The vast majority of patients went on into the open-label Phase III study -- a Phase II study where they got drug for the Phase III study with a [Indiscernible] drug in the marks on study.

Slide 7 shows the distribution of patients. The full study cohort of an was 93, on the top right-hand corner is the primary cohort, those with BSEP deficiency, which was -- 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 [Indiscernible] box below those is the other PFIC cohorts that I referred to previously FIC1 MDR3, TJP 2 and myosin 5B deficiency. So the data I presented today are on the BSEP primary cohort, the other PFIC cohorts, which then combined to form with all PFIC cohort.

The group on the bottom right are [Indiscernible] on to other then at times, which is clinically important, but more hetrogeneous. And I haven't got endpoint data on those today, but they are included in the safety data, which I'll discuss.

I then showed you the details of the endpoints of the study, and in particular, the left-hand side, the primary end point 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, we'll look for in the all rest of the PFIC cohort that's biologically improvements in serum bile acid as a marker of cholestasis.

We look at in the different groups, along with a responder analysis on a patient by patient basis, which I'll show you [Indiscernible]. Range of biologically and clinically important secondary endpoints into change 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 cohort than the old PFIC cohort and then the full cohort on the right-hand side. You can see these are all children mainly in the first decade of life, or had significant pruritus on the scale which goes from 0 to 4.

They have extremely elevated serum bioacid you see the BSEP cohort 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 hydrophilic bile acid, which is perceived to have some small improvements in this condition.

And approximately 30% were on rifampicin, which is, again, an off-label use of antibiotic, from which some patients appear to have a small benefit. Patients are left on those drugs unmodified [Indiscernible] study.

As you can see, the ALT is a reflection of the fact that they've got liver disease with raised transaminases, suggesting they've got ongoing liver damage and onset. The majority of patients were drawn as measured by with bilirubin particular direct.

although not all patients, approximately 1/3 of the BSEP patients actually were not drawn [Indiscernible]. Bilirubin isn't an intrinsic part of the disease, but it is a marker of how well the liver is functioning as a secondary consequence.

I think you can see at the bottom, measured by the score overall, this cohort were failing to thrive in both height and weight at baseline.

Slide 10 shows you the details on primary endpoints and all these variables were assessed using the mixed model repeated measurement 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 will see the changes observed in the primary cohort and the BSEP patients who achieved a very significant improvement in pruritus as a cohort. And it was with some placebo group, which we expect we always get significant improvements in placebo in patients enrolled in studies such as this.

But 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 be steady state will have about 2 months of treatment, and then persisted for the duration of 26 week study. Slide 11 shows you a very similar data for the other PFIC cohort with these other diseases listed to the top left.

And in fact, if anything else, if anything, the separation of the patients with treatment 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 and in the paler color are the results that I showed you just now for the BSEP cohort. And as you can see, they are really effectively superimposable.

Not surprisingly, therefore, on Slide 12, when we combine the old PFIC cohort, which is the previous 2, that set of data combined we get a significant improvement and a very nice and plots on the right-hand side than clear separation and persistence of the effect between the treated and non-treated patients.

Slide 13 shows some of the biochemical data and the most important [Indiscernible] the changes in serum bile acid [Indiscernible] that over the last 12 weeks of the study.

And there was a -- in the BSEP cohort shown here, there was a marked improvement in serum bile acids a reduction of 176 micromoles per liter compact baseline of approximately 300 as a cohort in the treatment group, but really no change from baseline in the placebo group. And again, those figures are shown on the right-hand side longitudinally.

And here, I think it's very clear that not only was there a significant improvement at 2 weeks, but we've pretty much achieved a steady state in the first month of treatment.

So probably not surprising the changes in serum bile acids predate the changes in pruritus as this is really getting closer to this 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 and in parallel to the previous data, which are shown you for pruritus, these data are reflected in the serum bile acid changes, which were much greater in the really showed no change in the placebo group.

And again, on the right-hand side, you'll see the other PFIC cohort here is like superimposed upon the BSEP cohort, which I showed you on the previous slide.

On Slide 15, again, those cohorts have been combined in the all PFIC cohort, which showed a very clear distinction between previous group and the placebo on the left and the longitudinal on the right, which the duration of action with reduce [Indiscernible] consequence from the increasing impact of the merging 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 improvements of greater than 1 point on the hetro scale and previously, and this is published data 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 and 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 certain bile acids. This is in the all PFIC cohort.

And the cutoff used here are based on the cutoff, which we derive statistically in our surgical retrospective analysis, and a reduction in -- when we use surgical interruption of [Indiscernible] 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.

So we hope that these will be reproducible in the follow-up studies using maralixibat. And we believe that as serum bile acid are intrinsic to the nature of the [Indiscernible] the actual fundamental metrics of disease, we believe that these changes in serum bile acid will be representative of changes in the natural history of the disease.

And as you can see, there was a very small response in this parameter in the placebo group, but 52% of the all PFIC cohort met this change in serum bile acids, which we had previously, as I say, associated with long-term native liver survivors of [Indiscernible] transplantation in retrospective surgical studies.

Slide 17 goes on to look at some of the other biochemical data, and this is the total bilirubin I'd say it's not intrinsic to the disease, but is a good marker of liver health and there was an improvement, which was just significant in the group maralixibat compared to placebo and there's longitudinal data on the right-hand side.

And this, as I said, despite the fact actually further primary cohorts were not outside. The majority of that bilirubin was direct bilirubin, which is what we expect in the disease. And those data are shown on Slide 18.

On Slide 19, you will see the changes in serum transaminases in particular alanine transfer which at baseline were in range of 100 to 200, and there was a very small deterioration increase in the maralixibat group in a very small decrease in the placebo group. And these are very small competitive parameters at baseline.

But clearly, there are something which we are very keen to observe and would potentially be a safety signal. But the changes are small, as you can see on the right hand side, it appears that by the end of the study, actually, the treatment group and appear to converge. And as I said, growth is a very serious complication of liver disease like this.

And here on Slide 20, we can see the changes in the [Indiscernible] left-hand side, which is remarkably better in the treatment group, and there was a trend in the same direction on the right hand side of heights. Improvements in is height always is delayed over improvement 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 [Indiscernible] cohort which was whole 93 patients enrolled in this study. These were sick children.

As you can see, there was a treatment -- treatment-emergent adverse events in those group [Indiscernible] and to placebo group in all those [Indiscernible] patients. There were some significant adverse events that you would expect in treating patients with severe liver disease.

The difference between the 2 groups is probably summarized that's at the bottom of that slide where the gastrointestinal side effects highlighted in particular, increased stool frequency and the diarrhea, which is an expected consequence of diverting bile acid into the colon. None of this was deemed severe, the vast majority was mild.

It did lead to one discontinuation. One teenager who 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. Mainly mild and usually I say resolved after 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 use of maralixibat in PFIC. It was included patients not just with BSEP deficiency but a variety of other PFIC subgroups. And I hope I've demonstrated that the primary and secondary endpoints were met.

And comfortably, and it does look like maralixibat is capable of producing both biologically and clinically significant improvements, particularly in pruritus, serum bile acids across good 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 and the difference between the studies really is that I think we have now optimized the dosing and most of these patients ended up on a significantly greater dose of drug in the previous studies.

And 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 enteropathic circulation of bile acids.

And clearly, in NAPPED academic study, we showed that improvements in serum bile acids through surgical interruption of the enteropathic circulation of bile acids is correlated with native liver survival in the audience of transplantation.

And on the basis of the cutoffs previously identified in that study it looks like [Indiscernible] of producing similar changes across all the different types of PFIC included in the study. As I also shown you, I think we've got significant improvements on bilirubin and weight scores, and the trend is in the right direction in height.

Overall, it looks like maralixibat is well tolerated. There are side effects. They're manageable. Usually transient in early 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 are recruited patients in the study in collective data.

But of course, most grateful to all the families who collected data and put up with the increased monitoring and if necessary to perform a complex study of this nature. So these are the data on so far from this study. And 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 keep patients [Indiscernible]. And probably the most important reflection from my point of view is that I've still got patients who are involved in the Stage II study, we have now got 7 years follow-up.

And certainly, a patient sticks out in my mind because she has an internal control in the sense that her sister was transplanted several years ago for the quality of life and the intense pruritus. And so her sister was transplanted.

I'm pleased to say he's done very well post transplant, but obviously is on the [Indiscernible], et cetera, that you expect after transplant. My patient who is involved in a Phase II study and has now got -- have been on about for 7 years, has normal liver biochemistry. She has normal serum bile acid.

She takes maralixibat and she takes a small amount of vitamin D. All her vitamin levels are normal, normal growth. spleens has gone back to normal. And really, if you were to meet her, if you looked at her biochemistry, you would say there was nothing wrong with her at all.

And of course, that's exactly the sort of end point, which we up here to be able to achieve and clearly the long-term studies are necessary, but all the parameters that we've studied in the safety do point that we're moving in that direction. So I think it's a huge improvement on where we were a few years ago.

So I'm very happy to take any questions, but I will hand over to Chris. Thank you..

Okay. 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 family suffering with pediatric cholestasis.

And with that, we'll open the line for questions for both Professor Thompson and the Mirum team. Operator, please open the line for questions..

[Operator Instructions] Our first question today comes from the line of Jessica Fye with JPMorgan..

Two, one for 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? And then for the physician, can you talk about what you see as clear differences between LIVMARLI and Bylvay? And if we fast forward to a time when LIVMARLI is approved for PFIC, how you would select between those 2 agents for a PFIC patients?.

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..

Yes. Thanks, Jeff. So in terms of the comments, we are seeing an acceleration in the fall, continuing to see that acceleration and new patient starts with LIVMARLI. That's really what gives us confidence in the raising of guidance to $70 million in 20% quarter-over-quarter growth that implies going in from Q3 to Q4.

Looking at the full Q3 picture to your question, we did see some softness in the summer, keep in mind in the U.S. that many of these children are seeing once every 6 or even every 12 months.

So what kind of the phenomenon we observed as families going on vacation, choose not to do their position appointment where new patient starts typically occur in those summer months. So that's what we serving obviously, the summer months for most of Q3, but the acceleration coming in into the fall and continuing now..

So Jessica, obviously, as you know, there are 2 IBAT inhibitors that have been studied in the groups of conditions. And I'm delighted that we've got a positive response from both drugs and disappointing, of course, neither drug treats effectively all the patients that are being studied. So, yes, is there a distinction between the 2 drugs.

I mean the honest truth is that the -- despite the fact that they're similar studies, we haven't done a head-to-head comparison. And I think if you try to do that right at this moment, you would not find this statistically significant difference between the 2 drugs.

They do have a significant response rate and 62% is an excellent response rate, 64% for PFIC, an excellent response rates 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 I'm not sure that statistically significant.

I think from my point of view, on an individual patient basis, we'll have to dig into this picture 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.

So the best way we have of looking at is to kind of look at the individual mutations that these patients carry.

And certainly, that's something I want to do is to dig those down into those [Indiscernible] to see if there's any biochemical predictors of response, any genetic predictors of response, and 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 the 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 is used.

So I think there's that we've got to learn, but there's also other factors which are pharmacological and financial which will impact on it but they're outside my limit..

Our next question comes from Steve Seedhouse with Raymond James..

Just on the acceleration of patient starts, again, I'm wondering if you can comment.

Is there any extent 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 the prescriber base in the U.S. is pretty well defined. I mean there's only a certain number of pediatric hepatologists that take care of these patients. 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. And then in ICP, I wanted to ask you because there's some data coming up for 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 making -- 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 for the question on that. Nothing specific really to call out in terms of the demographics at this point, it'd 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.

So I'll kind of point it in the right direction. Sorry, Steve sounds like you got cut off.

Did you have another follow-up?.

Yes. 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 the nonresponders, any color there?.

I mean the reason for transplant and my understanding is that, that was obviously the family's choice, and they were perceived to be nonresponders. I think the -- I haven't got all the figures to hand, but I'm pretty sure that there was -- the discontinuations were obviously were slightly greater than were 7.

There was 4 of them were in placebo group, 3 of them on drug, and the authority of the ones that went for transplant were nonresponders [Indiscernible] does not responders on drug or deterioration in the function in the placebo group. The majority were in the placebo group.

But the -- obviously, the bile acids and the pruritus storing and everything was not evident of the families that are making decisions and the physicians are making decisions on clinical grounds rather than actual hard data..

Our next question comes from Mani Foroohar with SVB Securities..

I want to 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 [Indiscernible].

And as we start to see more geographies come on next year, can you give us a little bit of detail on exactly how you account for revenue coming in from partnered geographies as opposed to places where you're monetizing yourself? And if there's any nuances we need to be aware of that as we look forward..

I'll comment on the kind of broader international piece and then pass it to Peter for the specifics in the U.S. to date. And when we take a step back, 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.

And what we expect for these distributor markets is that they will have orders that maybe kind of more in monthly for multiple patients at a time for a quarter at a time.

So you could see more of an order based approach to how they come in, and we'll start to -- we could start to see some of that this year even, but expected to come online with early access programs and approvals in some of those smaller markets into next year.

And then when we're -- for 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. And 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 in the clinical program.

So if you refer back to those papers, and that will 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.

Early days saw the patients are perceived to be most severe with their pruritus and other -- and quality of life impact to the disease or the ones that we see the physicians to kind of go for first as they gain more comfort with the product and prescribing experience then we see prescriptions broaden to patients that are maybe perceived to be more moderate.

So we're seeing that phenomenon play out in the recent quarters..

Great. That's really helpful.

On the dynamic around kind of monthly quarterly we have kind of order structure for some of your distribution markets, is it reasonable to assume that, that will introduce a little bit more chunkiness and choppiness into the 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, and that's kind of where our thinking is at this point..

Our next question comes from David Lebowitz with Citi..

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..

Thanks for the question. I mean from a high level, we know our data, how our end points 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 across drug comparisons.

I would say just on the morning versus evening measurements, what we see in our study is that is 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 standpoint..

Got it.

And when you look at the data and compare what you see in PFIC, any thoughts on extrapolating on how they might compare in ALGS?.

Well, 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. And the response rates are much higher here.

When you look at the proportion of days -- a proportion of scores that are at 0 or 1, one of the FDA preferred analysis. 62% of the scores in the treatment arm is a great step forward in terms of what we see for activity. So great response rate and results coming out of the study..

Our next question is from the line of Yasmeen Rahimi with Piper Sandler..

My questions are actually directed to Dr. Thompson, and thank you so much for being with us. The first question for you is when you look at the data from MARCH-PFIC, is there a part of the result that you think are absolutely critical to belong into the label that could drive stronger adoption? That's question one.

And then the question 2 for you is we recently saw Alagille data with bile acid. I would love to hear -- I appreciate your comments about comparing to 2 products in MARCH-PFIC, but if you could share your thoughts on these 2 IBAT inhibitors compare and contrast to one another and Alagille would be really helpful.

And then the third question is, as you know, Mirum is working on dolobaxabat, 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..

So I mean I think the -- the last 2 questions sort of merge in a way because clearly, I do believe that bile acids are causing [Indiscernible] of liver damage and contributing indirectly to the pruritus in both Alagille and the other phenotypes, which you're talking about PBC, PSC, et cetera.

Clearly, there are -- all those conditions are very different from PFIC, where we know that not just an important part of the damage and symptom production but are absolutely the key to the initiation of the disease as well.

So it's much easier to draw a connection between offloading bile acids and the natural nature of the disease and therefore, I think earlier signals that we're changing something in the natural history of the disease as opposed to improving the clinical features.

So I think these studies in a sense are easier to show you the clear distinctions in PFIC, we've been some of these other phenotype. But I do believe that in all those [Indiscernible] phenotypes bile acids are an important driver of the liver damage and retention of bile acid is an important driver of pruritus.

And thinking about the previous maralixibat studies with Alagille that I was involved with, which initially -- initial studies were disappointing. And I think the change came when with the ICONIC study where a much higher dose than maralixibat was used.

And I think that's what we're seeing in the study now is the reflection compared to the early PFIC studies and the ICONIC component of 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 perfect response in terms of bile acids or more importantly, pruritus in all the patients. And clearly, as I said already, that I think we got need to learn to work out if we can and predict which patients are more likely to respond.

And 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, I think that they're coming to us asking about is the pruritus because that is the thing that dominates their life.

And clearly, if we're in PFIC, as we've shown here, we can get 64% of patients getting 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 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 transplant and that's as I say that what we're expecting to happen in our previous experience.

So I think your first question was what's the going to meaningful aspects of the one that most important bits to my point of view. And as I say, I'm less interested in the cohort analysis because that combines responders and nonresponders and is dichotomists.

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. And as I've also said, obviously, we've got patients now in the -- 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.

So I do believe there was quite a significant number of patients in the original studies who failed to respond because they just weren't exposed to a not drug, but am I right in thinking of -- made some sort of attempt to respond to your questions..

Our next question is from Brian Skorney with Baird..

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.

And then for Professor Thompson, we've talked to some other physicians who have noted that maybe 1/3 of patients who get [Indiscernible] have had a partially successful procedure, so one that isn't curative, but also doesn't require an immediate transplant.

Do you think that 1/3 is an accurate estimate? And could you help us characterize the heterogen AD and ITCH and other clinical markers among this subset..

Thanks for the question, I'll comment on the first portion of it. And 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 if the drug can do what we think is possible in the setting of the potential to see real strong impact at that 6-month primary endpoint next year. I'll pass it over to Professor Thompson for the second question..

So in terms of response, I think the original studies, the response analysis was based on largely empirical data. But we do now have these surgical data and the responder analysis I showed you for [Indiscernible] 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 acid to achieve long-term nature of its arrival based on those studies.

And I think that is telling us something about the fact that the liver is protecting itself and although the peripheral serum bile acids are not normal, we appear to have got the levels of down in by the liver low enough, but the -- not only does the pruritus improve, but we don't compare to have progressive liver disease.

So the question is, what sort of level of response do we need? And are the 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 nonresponders.

And I think it's similar to the study, we'll have to go look at those in detail. And what it means is that actually whether you put away exactly you put that cut off, it can be changed quite widely without really making a significant difference to the result.

And so although that cuts off of a 75% reduction or below 102 micromole gave us the best distinction, which are really the responders or nonresponders, actually, a lower level of responses are lesser improvement made little difference to the separation.

So obviously, it remains to be seen whether those sorts of results can be expected with the drug, but we believe that the reaction was the same. And we believe that serum bile acid marker as a reflection of the biological improvement is equally valid. But at the end of the day, we will have to see whether those correlate.

But those are the data we have. And obviously, those are the data that we will be using for the time being to make clinical decisions..

Our next question comes from Ed Arce with H.C. Wainwright..

This is Thomas asking a couple of questions for Ed. Perhaps first one for Dr. Thompson.

Among the [Indiscernible] data that we've seen in the margin 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 these are -- 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.

And so I think the results are, as you've seen them. So I'm going to be telling patients there's a 2/3 chance that they're going to get a clinically meaningful improvement in pruritus.

And I'm going to be said at the moment, it looks like that there's approximately a 50% chance that on these basis, but they will be able to avoid long-term -- delay a 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, but those are the 2 things that I'm going to be discussing with them..

Understood. Dr. Thompson. And 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 [Indiscernible] interim population?.

Sure. Happy to comment on that. And I think -- the -- in terms of the commercialization strategy, the physicians and health care professions that take care patients are largely identical to Alagille. Physicians to take care of Alagille patients.

So it's the same centers that we're already in, now promoting the LIVMARLI for Alagille syndrome, obviously, upon an FDA approval, the promotion would include both Alagille's demand and PFIC products already available.

We've been working with the patient as groups and other stakeholders for years, right, as you've heard today, going back to 7-plus years. So pretty straightforward addition if you're thinking about it from an 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. So a good part of our early effort will be upon approval, converting the patients receiving the clinical drug to commercial drug..

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 steady results possible. And I hope everyone has a great day. Goodbye..

Thank you, everyone, for joining us today. This concludes our call, and you may now disconnect your lines..