Chris, why don't you kick us off with some opening remarks before we dive into Q and A.
Thanks Rich and thanks for hosting us. We're excited to be here. Yeah, a quick overview of Mirum to kick us off. Mirum is a leading commercial rare disease company focused on bringing rare disease products forward that are really an underappreciated setting with high patient impact. The company started about five years ago around LIVMARLI, our current lead approved product that's approved in Alagille Syndrome and PFIC and that has been a great way to kind of start and inform this company that has huge impact now across a number of rare disease settings. Where LIVMARLI has been approved in the U.S. for a few years, we are rolling out in Europe and internationally as well, primarily in Alagille Syndrome now that have PFIC label expansion around the corner. We just had a CHMP positive opinion that I'm sure we can talk a little bit about.
And then last year took a big step to expand the business by adding two more commercial products, Chenodal and Cholbam to the business and have a label expansion opportunity for one of those products coming up as well that we can talk about. And then finally I think one of our nearest term milestones is this month we are planning to announce interim data for volixibat pipeline agent focused on larger adult settings of cholestasis, evaluating volixibat in primary biliary cholangitis and primary sclerosing cholangitis two exciting adaptive studies that we think can lead to potential approvals in those indications. And I think one other thing just to say it should have led with going to be making forward-looking statements. So refer to our SEC filings for all the risk factor disclosures.
Fantastic. So LIVMARLI, a lot of stuff happening there. Right. So it's approved in Alagille and it's an IBAT inhibitor now facing competition from BYLVAY which was approved in PFIC and recently Alagille. Can you maybe talk about the differentiation between the two and provide some color on the competitive dynamics so far that you see between these two products?
Absolutely. And just to start to give a little background on the setting, Alagille Syndrome and PFIC, these are genetic cholestatic settings where there is an extreme cholestasis in and in the setting of cholestasis there's an accumulation of bile acids. These bile acids can not only result in progressive liver damage, so most of these children are on a course to liver transplant without treatment, but also creates a terrible symptomatic burdens. So these children generally have very severe pruritus, fatigue, lack of sleep, and a huge family impact that's part of the disease. LIVMARLI, as an IBAT inhibitor, goes right at that bile acid accumulation. So LIVMARLI's mechanism of action is to block bile acid reabsorption and deplete those excess bile acids that are causing all of these problems in these cholestatic settings.
And for the differentiation and real impact of LIVMARLI, we found that over the course of the clinical program, that the dosing in these settings is just not obvious in the initial clinical experience. So over time, we've advanced our understanding and have, through the pivotal studies, gotten to higher, far more active doses of LIVMARLI than were originally studied. And that's resulted in really strong clinical impact. So in the Alagille setting, over 80% of children in the clinical program have a pruritus response. That's the registrational endpoint that's used in the setting. And similarly, in the PFIC study, we saw quite substantial improvements versus placebo, not only in itch, but also in bile acids and. And other liver markers like bilirubin having a significant difference from placebo.
I see. Got it. And maybe a little bit about the market dynamic or competitive dynamics between the two. You guys have to defend Alagille as BYLVAY comes to the market, and then you guys have to penetrate the other markets that they've been already operating in a little bit about sort of the strategy there, how you see these two markets playing out.
Yeah. And I'll speak primarily to the U.S. where we have this dynamic now, where both products are approved for both indications. For Alagille Syndrome in that setting, LIVMARLI continues to perform really well. We saw a competitive entrant mid-year last year, and since then we've had a continued steady cadence of new patient starts and a healthy dynamic continuing with Alagille Syndrome and quite favorable reception from payers is one thing I would note where we've seen now an increasing number of policies that actually have LIVMARLI as the first therapy for Alagille Syndrome as a step through, frankly, before you can prescribe another IBAT. That's gone quite well for Alagille Syndrome. PFIC is more recent, so we just had our label expansion in March. Really exciting about being able to bring LIVMARLI to PFIC patients.
The initial opportunity there is really on rolling over clinical study patients and again, you know, moving towards on the reimbursement side. That's where we're busy with now in the next couple quarters to get policies in place and that's gone really well also. Highlighting the advantages that LIVMARLI brings from a clinical impact, the overall budget impact for LIVMARLI is leading to favorable payer determinations as we go through the rollout of PFIC and so all pointed in a quite favorable direction. Maybe bridge to international for a moment as well where the dynamics a little bit different. To date in Europe and particularly Alagille Syndrome, we've been the only product approved there and just had a positive CHMP opinion for PFIC.
And I bring this up to highlight it because something really quite impactful behind getting that positive CHMP opinion in particular paired with a positive orphan opinion, which means to get that part of the review is EMA determining that there was a significant clinical benefit over the available therapy for LIVMARLI. That was a big win for us to get that positive opinion and expect the approval to follow in the next couple months.
I see. Got it. How much of your sales guidance, your $310 million-$320 million sales guidance for 2024, how much is that driven by LIVMARLI and also how much of it's also from the label growth expansion?
For the $310 million-$320 million sales guidance that's driven by growth across all products is the first statement I'd make. The majority of it's LIVMARLI. We haven't broken it out more specifically by product, but LIVMARLI continues to be the larger product of the portfolio and a lot of great growth dynamics in particular as we get later into the year and start to see some PFIC impact.
I see. Okay, so now alongside with the approval in PFIC, you guys submitted an NDA to support a lower age cutoff from five years of age to three months, which is in line with your Alagille indication and BYLVAY PFIC indication as well. So what's driving the confidence that you can make that change and what impact would that have for PFIC?
So the current label for PFIC is for patients five years and older and as part of the review with FDA is FDA requested us to introduce a different formulation for those younger patients and it's one that was used in the clinical study. So this is something that's easy to accommodate. As mentioned, it's already submitted the label expansion for PFIC. We expect it to be two-step for this first submission is to introduce the formulation from the PFIC study to bring us down to 12 months. And that's the same age that was used in the pivotal study. So that's where the confidence comes from that this is largely administrative to bring out the formulation that is a higher concentration for these younger patients. The next step, we're planning to have a subsequent filing take us down to three months of age.
This is the same strategy we followed with Alagille Syndrome where the pivotal study was 12 months and older. And then we had a follow up following to bring down the age for infant patients based on a separate study that's already been conducted for PFIC just has not yet been submitted to FDA.
I see. Got it. So why don't we switch gears to volixibat, your second IBAT inhibitor. So why do you need to develop another IBAT inhibitor? Why can't you just use LIVMARLI and go into other indications?
So from a first statement, I mean, volixibat is from a mechanistic standpoint, has a lot in common with the other IBATs. It's minimally absorbed. It's a very attractive profile to have a minimally absorbed, highly active drug like this. It's also quite potent against the target. The reason for having differentiated development here though is that these settings are very different and the PSC and PBC indications are much larger. They're adult settings. And having the liquid pediatric formulation for that ultra rare pediatric setting and price point, we can have a differentiated product for the adult setting that's more appropriate for that larger indication and the adult.
I see. Got it. And maybe a little bit about the unmet need for PSC and PBC as well.
Yeah, there's some quite significant differences in how we talk about the treatment landscape between the two. And I'll start with PSC because in some ways the competitive landscape and current treatment alternatives are pretty easy to describe because there just are no approved therapies. This is a really challenging setting where the progressive liver damage and symptomatic burden can be quite severe with many of these patients going to a transplant over a 10-year course and along the way having this quite significant symptomatic impact from pruritus and fatigue, both being highlights of that. So the drug development in this setting has been challenging historically because of endpoints to bring any kind of therapy to these patients. That's because some of the biochemical markers are quite variable. Alkaline phosphatase, for example.
ALP has been used a lot in the other adult setting that we're going to talk about in PBC. But it's too variable in PSC to be reliable for a surrogate endpoint. And so what we've done with our program is kind of jumped over all of that and we're going straight to the outcome that matters most for the patients, which is the symptoms. So similar to the pediatric settings, we're using itch as the outcome as the primary endpoint for our program and also an outcome that can lead to potentially to an approval. So the PSC setting for volixibat, really unique in that we've landed on alignment, on a pivotal design, pivotal endpoint for a setting that has no other therapies. And if you can't impact the symptoms, really challenging to find an endpoint for approval. That's always been difficult to be the first one to go into a new setting.
While we're anxiously waiting for the phase II-B interim data in PSC and also for PFIC that's coming out in June. Right. Maybe walk us through the clinical design a little bit more and then the patient population for these two trials.
Yeah. So for PSC starting there and I'll bridge back to give some color on PBC treatment landscape and design. PSC VISTAS study is a randomized phase II-B study with an adaptive dose selecting element to it. That's what's going to be happening at this interim that's coming up is a dose will be selected and the study will continue into the confirmatory portion of it. The study will target in total about 120 patients. But this interim coming up is in the first 45 that have passed the 3-month time point in the study is the way to think about it. The interim for the VISTAS PSC study is somewhat unique. I tried to describe it as kind of the inverse of a futility analysis, actually confirming activity for the study to continue.
So there is an efficacy threshold that the data monitoring committee will review to ensure that the separation from placebo is happening, that they're seeing this treatment effect at a minimum threshold that we think predicts placebo the full study working.
If that's the case, the data monitoring committee has instruction to select the dose and continue with the study remaining blinded. Which gets us to that potentially pivotal data faster I think is the reason for doing that. Those patients in the first portion out in the final analysis. So you're heading into a somewhat de risked pivotal readout because you know the drug's working in some of those patients.
How often do they monitor that?
This is a one-time interim analysis to select the dose and move forward. The measure that's being looked at is the itch in patients in the second half of the study months four, five, and six, you look at itch over time, which helps reduce some of the variability in the endpoints and in a way add power to the final analysis.
I see. Got it. So your VISTAS interim will be blinded. So what should we expect to hear and what should we expect the study to continue as a blinded? On a blinded basis.
That's the great outcome that we're hoping to see. The announcement would be study continues as planned. That means that there's a separation from placebo. We think it's on track for the positive readout and we'll also share some kind of guidance on timelines to complete enrollment so that we have a sense of time to pivotal data.
I see. Okay, got it. And what should we expect from the interim analysis for VANTAGE?
So VANTAGE, you know, quite different setting. Maybe I'll take a step back and talk a little bit about PBC as an indication first at high level summary numbers. To think about it, PBC is probably about 100,000 patients in the U.S. and you divide that further into about 60,000 patients of that likely controlled with ursodiol. That's the standard first line therapy and controlled on their biochemical endpoints, not their symptoms. So many of those patients, while they aren't looking for some of the second line treatment agents, they are having symptomatic burden and potentially progressive disease. In the second line setting. It's about 40% of those patients. That's where the recently approved PPAR and potentially another one coming OCA. That's the treatment setting where you hear a lot of discussion about new competitive entrants.
Also an opportunity to treat pruritus in those patients as well, though they do have more treatment options to consider once the biochemical progression has started.
The VANTAGE study is going after both settings.
We're including first and second line patients. We have no baseline alkaline phosphatase criteria to provide something that physicians can use for any PSC patient that has symptomatic burden. That's the goal. That's the product profile that we're targeting.
The interim analysis will look at the first kind of readout on those symptoms. So we'll share top line data on itch. Not powered for significance, but it's meant to be a dose selection analysis looking at the two doses of volixibat compared to placebo on itch. We'll also look at bile acids and safety, obviously.
I see. Got it. And then going back to the VISTA program, I think you mentioned there's a threshold for stopping the study because you don't see the separation with placebo or futility of the study. Is there a separate threshold where you do stop it? Because you see overwhelming effect as well. And have you defined that?
The threshold is to unblind, not to stop the study.
So if we don't. If we don't. Yeah. If we don't meet that activity threshold, we'll unblind and look at the data.
Look at the data.
Yeah. Because there could be an opportunity to potentially adjust the study and let it roll into the confirmatory portion enriched in some other way.
I see.
Because of our discussion with FDA, because of the safety database that they want, there's no automatic stopping criteria in the other direction.
I see.
Because we know we need to get to that approximately 120 number because of what FDA wants for the full safety data set. So we didn't want to stop the study early for high activity.
I see. Got it. Okay, so why don't we talk about the commercial opportunity in PSC versus PBC. What's the burden of pruritus in these settings and how do you view the market opportunity for both?
It's quite substantial. I mean, it's the lead in comment for it, putting some numbers behind it. In PSC, we think there's about 30,000 patients in the U.S. This is kind of a rough number to put on it. Two thirds of those patients will have pruritus as a part of their disease. So there'll be some level of pruritus and many of them can have quite severe impactful pruritus. But that 2/3 of the market is what we see as the target on label population for PSC. And it's somewhat similar for PBC as well, just the numbers are larger. So 100,000 patients in total and about 2/3 of them have pruritus. And it does seem to be somewhat consistent between the two settings, though there may be a bit of elevation in severity.
As you see, disease progress is present in both first and second line at similar rates.
I see. Okay. So how are you thinking about the regulatory timelines and potential filing? And also have you thought about pricing?
For these two indications from a pricing standpoint? We look to the other PBC agents as kind of benchmarks. We haven't shared anything on our pricing plan specifically, but you see other agents at $100,000 or higher per year per patient is what the benchmarks are that we'll look at. In terms of the regulatory timelines for PSC, it's probably a year or so to complete enrollment and so we'd have pivotal data in 18 months-24 months from now is roughly where we think we're at. We'll give a refined view of that when we announce the interim update.
I see. Going back to pricing a little bit. So you have LIVMARLI, which is also another IBAT inhibitor we talked about. I mean, when you factor in pricing, do you also look at LIVMARLI or you just treat this as completely separate product?
They're totally independent products in their own indications and you have to establish dosing and the clinical effect of that dosing in these different settings, being that they are products that require prior authorization. We see them really largely being used only in the settings where they're approved. As we bring additional the second IBAT to market.
I see. I think we mentioned before that LIVMARLI also does some compassionate use in these two new indications as well.
Do you. Like. How do you factor that in? Is that going to continue? You think you're going to. How would that dynamic change?
When we have an actually an indicated product for PSC, we'd expect that to be the product of choice for physicians. So volixibat as the answer for PSC patients when it comes to market. So I will circle back to the compassionate use dynamic for LIVMARLI. We do see outreach on a growing number of different less common cholestatic presentations, PSC being one of them. And that tends to be a couple examples we have are patients who didn't meet eligibility criteria for the study and the physicians urgently looking for a treatment alternative. And the reports back are that there's quite dramatic responses in terms of pruritus improvement. The quote I've heard recently is they feel like they get their lives back because they can sleep again and can go out and get a job again, things like that. But we see it across other indications as well.
We're looking at ways that we could maybe build a program around some of these other indications just driven by the demand that's out there that we're seeing.
I see. Okay, so a lot of future, I guess, expansion with these products.
Yeah, I think there's an opportunity to continue to develop into other cholestatic settings.
Fantastic. Okay, so why don't we switch gears. I think we only have about 10 minutes left to your other two products that you recently acquired last year, which is Chenodal and Cholbam. Remind us on the history of these two assets and the rationale behind acquiring them.
Yeah. So Chenodal and Cholbam are bile acid replacement products. So these are synthetically made bile acids to replace specific bile acid types in settings where there's been a genetic disruption in the ability to synthesize bile acids. So the settings these are used in are a number of quite rare different disruptions in that signaling cascade to synthesize new bile acids called bile acid synthesis disorders. Zellweger spectrum disorder. Another one that's recently emerged with new data for Cholbam is Smith-Lemli-Opitz syndrome and CTX for Chenodal. So quite a long list of different specific genetically driven disruptions. They all have a commonality where there's something disrupted in that bile acid synthesis cascade. The signaling goes haywire and they tend to have toxic accumulation of intermediaries in that synthesis cascade.
So these products have been generally standard of care for a number of these indications.
Cholbam has been on the market for eight or nine years at this point, used in a number of these indications. So with steady kind of patient accumulation over that time period. So it's a healthy business for an ultra rare setting like this. We do think there's a growth opportunity with this emerging data in Smith-Lemli-Opitz and so we're exploring more investigation around that. Where we talk more about growth opportunity for the bile acid programs is with Chenodal for CTX. And worth talking about that one for a moment because it's a quite unique regulatory background here where Chenodal's approved indication is for treatment of gallstones. But it's really, it's entirely used today off label for CTX.
I see.
We completed a phase III study looking at Chenodal in CTX with an eye towards getting a formal approval largely so we can go do more patient finding and also have exclusivity, orphan exclusivity for the program. The progression of CTX without treatment results in irreversible neurocognitive impact. We think by finding and treating patients earlier you can really have a dramatic impact on the course of that condition. To date it's been all passive because it's not labeled formally for the indication. We think there's an opportunity to go out, find more patients. It's probably only about 10% diagnosed.
Yeah. And so what we're doing now is some work on how can we go out and help support physicians who might be able to catch these patients early on when their symptoms are starting to build.
I see. I think you guys are filing an NDA submission for that.
Correct. We just had a pre-NDA meeting with FDA.
That went well. There were a few non-clinical items to complete for that package. The discussion with the FDA went well and so that submission is imminent.
I see. So if it's already being used in an off-label setting and I think the FDA recognizes it, why do you need to get that as NDA? Why not just you're already, it's already being used in the market. I mean, how, like what would that do for you from a commercial perspective?
Two reasons why there's a lot of value in pursuing an NDA here. The first is inpatient finding. Like, you can help really change the course of disease for these patients that don't get diagnosed until they're in their 30s or 40s and that's the average age of diagnosis today. And while Chenodal is standard of care for patients who are diagnosed, most patients are not diagnosed. So that's where the real opportunity is and to be able to be active, promoting giving. The reason why physicians should be looking for these patients is why we think it's worth getting the formal approval. The second reason to point to is exclusivity. So Chenodal has orphan designation for CTX, so we'd be able to have orphan exclusivity for the indication.
I see. That makes sense. Okay, how has the commercial transition been since you guys acquired them and why do you guys think that you guys are better parents for these two drugs?
Yeah, first of all, I'd say I think Travere did a great job with them. So I wouldn't use the word better, but I do think they're a great fit with us and that has resulted in a very smooth transition to bring them in. There's a lot of overlap in the prescriber base. We actually have an overlap in a lot of the vendors that support distribution. So that's all gone quite smoothly. And we've seen that play out just really in the numbers in terms of what we've seen for patient starts, compliance, the persistence is all remain steady and healthy through the transition.
I see. Got it. We have five minutes left, so if the audience have any questions, please raise your hand and we'll get to you. Okay, so why don't we continue on, talk a little bit about high level strategy and bd, maybe give us a state of the affairs of your financial position and how you thinking about profitability going forward.
So the overall financial position of Mirum is quite strong. You know, we're with that $310 million-$320 million of revenue that we're tracking for this year. That puts us in a position we're on kind of an operating cash flow basis into the back half of the year. We're at break even or better is the direction that it points towards a really strong financial position with over $300 million cash on hand as well. And this kind of self sustaining growing commercial business. So very solid and attractive footing from a financial standpoint. And that speaks to the efficiency of the business. And as we broaden the bile acid programs that synergy and overlap on the commercial platform has played out well in terms of the overall strategy.
Going forward we look to do more of the same in terms of what made Mirum possible from the beginning is finding these overlooked rare disease opportunities where we can add value and help get them across the finish line to patients.
I see. Got it. Maybe speak a little bit about your take on BD in terms of you guys acquired these two assets. How should we think about your strategy from a balance versus organic growth?
For that, we start with looking at, first, where have we been effective at? What are our strengths that we can then apply to future products. And really across the rare pediatric spectrum, there's a lot of places where I think we could add value, particularly with the now expanded business. We have a presence in almost all major pediatrics and have direct interactions across not only hepato medical genetics.
Will further cement that and expand across other pediatric rare settings where the Mirum team could bring a lot. Also on the clinical regulatory side, the regulatory strategies for ultra-rare areas. Or that's a skill set that we've developed inside the company.
I see. I have a blue sky question for you. So what's a long-term aspiration for Mirum and what would the company look like 10 years from now?
When I've answered that question before, just to give the shortcut here, most people say oh, you want to be the next Horizon. Which I think that's a fair way to think about it. We see the ability to leverage commercial commercial expertise and late stage clinical expertise to find programs that we can build value from and have both a dynamic growing healthy commercial business, but also adding clinical programs that can be really value creating.
And about partnerships, commercial partnerships based on some of these interim data we talked about, we're coming up.
Today there's been no need. I mean the Mirum's been able to build out efficiently directly in the U.S., Canada and Western Europe. We'll leverage that as the volixibat comes across the finish line and for other rare pediatric programs would already fit with our team. So we're in a position where we can retain all the value from these programs rather than needing to partner and that's been by design for the type of products that we've pulled together here. They're ones that we wanted to be able to keep all of the value in Mirum.
Fantastic. I think we're running out of time, so I'll leave it to you, Chris, for the final remark.
Well, I just want to say thanks again for hosting, an exciting time at Mirum. Heading towards $310 million-$320 million with three growing commercial products. And look forward to an update soon on the volixibat interims, where we take those into the next. The next leg of their journey.
Fantastic. Thank you so much again and thanks, everyone.
Thanks.