Great. Welcome. Good morning, everyone. My name's Jessica Fye. I'm a biotech analyst at J.P. Morgan, and we're continuing the 43rd Annual Healthcare Conference today with Mirum. First, you're going to hear a presentation from the company, and then we're going to go into some Q&A. So if you're in the room and you want to ask a question, just raise your hand and someone will hand you a microphone, or you can also send questions to me via the portal. So with that, let me turn it over to Mirum CEO Chris Peetz to present.
Thanks, Jessica, and thanks, everyone, for the interest in Mirum. Very excited to give you an update on the company and what lies ahead for us. First, remind you that I'll be making forward-looking statements, refer you to our SEC filings for complete disclosure of risk factors. And it's a very exciting moment for Mirum and for what lies ahead for us. Earlier this week, we announced a 2024 net revenue of $336 million, showing growth across all three of our commercial medicines last year. And all of the drivers of that growth continue into this year, where we are guiding towards $420-$435 million net revenue for the year, showing continued growth across all three products. And doing this with a very efficient business model, we also are guiding towards being operating cash flow positive for the year as these products continue to grow in ultra-rare settings.
We've built a pipeline of even bigger indications that follow. We'll go through all of this, the commercial growth drivers, and some of the pipeline dynamics in this presentation today. From a pipeline view, this is what I'll cover as we go through. In green, we have our approved medicines driving that top-line growth, and the blue, some of the upcoming catalysts. A really big year for clinical execution for Mirum as we push our Volixibat program towards complete enrollment in our PSC study in the second half of this year, PBC that follows into next year. The PSC opportunity that we'll go through is quite exciting in that we're lined up for a potential top-line reading in 2026 that would drive an NDA filing for potential approval in PSC. An exciting moment for the Volixibat program this year as well.
And a recent addition to the pipeline with MRM-3379 for Fragile X, and we'll go through some of the details of that phase two program that we expect to start later this year. First, a comment on Mirum's business model, where in a short amount of time, we have created one of the leading rare disease companies with an efficient operating model. We commercialize directly in the U.S., Canada, and Western Europe. We've leveraged some really strong partners and distributors around the world to amplify some of the work that we've done in our core geographies. And all of that's played through with the results you see on the right-hand side of the page here, where heading into this year, we're looking to add nearly another $100 million to the top line from our ultra-rare platform with Livmarli, Chenodal, and Cholbam.
Behind that, really large opportunities with Volixibat and the Fragile X program, each being billion-dollar-plus opportunities that we can leverage on top of the commercial platform that we've built with Livmarli, Chenodal, and Cholbam. So now we'll dive into some of the dynamics for Livmarli. And first, a bit of a background on ileal bile acid transport inhibition. Livmarli is an IBAT inhibitor that goes right at the absorption of bile acids in the terminal ileum, very relevant across many settings of cholestasis, where elevated circulating bile acids drive severe symptomatic burden and progressive components of the disease that the IBAT has the ability to reduce those circulating bile acids. In clinic, we've seen, most importantly, rapid and pronounced reduction in pruritus across a number of different settings, resulting from that rapid decrease in circulating bile acid levels.
Long-term follow-up in these settings of rare genetic cholestasis, we've seen improvement in transplant, follow-on that pruritus improvement over time, and excited about what we can show from the platform in the future studies that we're conducting now. For Livmarli, we have been approved in cholestatic pruritus for Alagille syndrome. That was our initial approval, and this last year gained label expansion for pruritus due to PFIC in the U.S. The base business in Alagille continues to be healthy and strong, where we think we're likely in the range of about 40% or so penetrated into the prevalent patient population. So still remains expansion opportunity in Alagille in the prevalent population, as well as addressing new diagnoses, which continue to occur on an annual basis. PFIC was a really strong driver of accelerating our growth in the past year.
With that label expansion, particularly into the second half of the year, we saw new patient starts with PFIC with Livmarli adoption, both in IBAT naive and in patients switching therapies in PFIC. Very excited about what's ahead for the EXPAND study, where I'll go into that in a bit more detail on a further slide, where we're now launching a basket study to address some of the underserved and understudied settings of cholestatic pruritus. All of this really lines up Livmarli for continued strong growth. It's a big contributor to our 2025 guidance. With the continued PFIC launch and international expansion, a big part of last year's growth will continue into this year with key geographies in South America and Japan on the horizon for potential approval and reimbursement as we go through the year this year. Profile for IBAT therapy really well established at this point.
The most prevalent side effect, I should say, is treatment-related diarrhea. This is mechanistic. That's what actually drives these results in the bile acids being cleared from the body. Now, moving into the bile acid portfolio on the commercial update here, Cholbam and Chenodal are two bile acid replacement therapies that are indicated for and used in a number of different bile acid synthesis disorders. This is a list of different point mutations that disrupt the bile acid and cholesterol synthesis pathways and result in various forms and presentations of disease that can range from kind of liver disease presentation to actually CNS impacts and diseases that are traditionally seen and treated as neurological conditions.
Chenodal and Cholbam continue to be steady performers from a growth perspective as we see uptake across both the hepatology and medical genetics and neurology communities and continue to see steady growth ahead for the brands as well. Key point for Chenodal, where this year we are under review for a formal approval for CTX. We see this as a potential driver of incremental growth with the on-label potential for Chenodal. It could help us help identify and find and promote to find new patients to get patient starts on therapy for CTX. To date, it is standard of care, and the real unmet need that we see in CTX is helping to find and identify these patients earlier and prevent some of the progressive neurocognitive impact that can result from untreated CTX. It continues to be a steady growth driver and performance for Chenodal and Cholbam.
Now we'll step into the pipeline, a little bit of what's ahead for Mirum. First, the label expansion opportunity for Livmarli. Cholestasis is the description of the disruption in bile acid processing or flow in the liver. Actually, as you can see from the settings where we have our approvals and have been studying our IBAT inhibitors, there are a long list of different causes of cholestasis. One of the common results of that is elevated bile acid levels and cholestatic pruritus. What we've seen since our launch from Livmarli is a strong demand in a number of quite rare causes of that cholestatic pruritus. To date, actually, over 100 patients of compassionate use demand that has come out of what we've seen from physicians in the U.S.
From compassionate use and requests for access to drug for patients that cover a spectrum of pruritus in biliary atresia and secondary sclerosing cholangitis and in a number of kind of more rare genetic causes of cholestasis. So to respond to that demand, we've put together the EXPAND study. And EXPAND is a placebo-controlled study looking at Livmarli in these settings, this basket setting of cholestatic pruritus. We've just launched the study, expect to complete enrollment next year, and have designed it as a phase 3 label enabling study, really to capture this long tail of other forms of cholestasis that can result in that cholestatic burden and quality of life impact. And really hard to understate the real need in this setting, where many of these patients without treatment will be candidates for transplant to treat that cholestatic pruritus.
so excited to get this study up and running and bring Livmarli to an even broader set of patients with the EXPAND study. Enrollment completion is expected next year for EXPAND. Now shifting to Volixibat, we are moving now from the primarily pediatric settings into adult liver and cholestatic diseases with Volixibat. Two key indications where we are studying Volixibat, both of them immunoinflammatory-driven settings of cholestasis, primary sclerosing cholangitis, and primary biliary cholangitis. The commonality here, again, back to the mechanism of IBAT, is we are looking to reduce the circulating bile acid levels in these patients and improve the pruritus burden that is driven by that circulating bile acid level. The PSC program, in the background of PSC, there are about 30,000 patients with PSC estimated in the U.S., and about two-thirds of them suffer from pruritus, and many of them actively seeking treatment for that pruritus.
The challenge in PBC is that there are no approved therapies for these patients, and to date, no real consensus on approval endpoints and how to study drugs for PSC. This has been a setting that's been quite challenging because of the variability in not only liver histology, but also in the serum endpoints that have been studied for PSC patients. By going after the symptomatic burden, we can use that symptomatic improvement as an outcome and an endpoint to use for pursuing an approval in PSC, and quite excited about what that means for the PSC patients and the ability to put together a potentially registrational program for the setting. IBAT has shown an impact on itch in PSC patients, so we started this program with some clinical evidence that the mechanism had the potential to have a tremendous impact on itch in PSC patients.
To pursue that, we designed and launched the VISTAS study. VISTAS is an adaptive phase 2b study looking at volixibat versus placebo in PSC patients with pruritus. Last year, we had an exciting update to the program where we conducted an interim analysis that was a blinded evaluation of two doses of volixibat, where the data monitoring committee selected a dose to pursue forward into the confirmatory portion of the study. We are now enrolling in that second part of the study that will look to confirm the pruritus benefit that was seen in the first 45 patients that were evaluated in that interim. On track to complete enrollment in the second half of this year, that would put us up for data in PSC next year for volixibat.
an exciting moment where we think we're on track to have potential to bring the first new therapy forward for PSC patients with the Volixibat VISTAS program. Companion indication for PSC for Volixibat is evaluating also cholestatic pruritus in PBC. PBC is a more prevalent cholestatic setting in the U.S. We estimate about 85,000 PBC patients that are diagnosed. And again, the majority of them suffer from pruritus. So this is a tremendous unmet need across the PBC landscape. An important distinction for how our program is designed compared to some of the recent advances and new therapies that have been approved for PBC is that our program enrolls patients across all settings of alkaline phosphatase. So Volixibat is being studied in those first-line patients that have their biochemical markers relatively controlled by UDCA. Volixibat's being studied on top of UDCA to help improve the symptomatic burden in those patients.
It's also being studied in the second-line patients that have more elevated and progressive liver biochemistry. So Volixibat is positioned to be a potential treatment for pruritus across all settings of PBC. And similar to the VISTAS study, we had a really exciting update with the interim analysis of VANTAGE last year. And we have a snapshot of some of that top-line data in the pages ahead here. VANTAGE was similar to VISTAS, an adaptive placebo-controlled study. The structure of the interim analysis was different in that we conducted an open analysis and presented that data at AASLD last year as a late breaker. We also discussed the data with FDA and submitted it for breakthrough designation and were granted breakthrough designation for cholestatic pruritus in PBC. A tremendous acknowledgement of the unmet need in PBC to address cholestatic pruritus.
For the interim analysis, a couple of the pages that were presented at AASLD, as mentioned, the population enrolled in the study included both first and second line. About two-thirds of the patients in the interim analysis were first-line patients with relatively controlled alkaline phosphatase levels, one-third with alkaline phosphatase levels above the 1.67 times upper limit of normal cutoff, an otherwise fairly representative population for PBC. The study selected four patients with elevated pruritus, so a baseline score of 6.3 to 6.8 in the ItchRO 0 to 10 scale for the VANTAGE study. The results were quite striking.
You see on the page here the pruritus scores over time for the two doses of Volixibat versus placebo, where you see in the first few months, there's a relatively rapid onset of the reduction in pruritus levels that is sustained over the six-month window that is analyzed in the study. So 2.4-point reduction, placebo-controlled reduction for Volixibat in the 20-milligram dose that is being taken forward into the second portion of the study. So the confirmatory portion of the study, enrolling now, continuous enrollment from the time when we did the interim and on track for completion of enrollment next year. Similar to other settings, we also observed reductions in circulating bile acid levels, and most common treatment adverse event was the mechanistic-related diarrhea that is seen with IBAT treatment.
Now, moving on to the most recent addition to our pipeline, MRM-3379, is a PDE4D that we are taking into a phase 2 study for the treatment of Fragile X. Fragile X is one of the most common inherited causes of intellectual disability, tremendous unmet need with no approved therapies, and we estimate 50,000 male patients across the U.S. and Europe. So quite sizable opportunity if we can confirm some of the data that's been seen with this mechanism in treating the cognitive impact of Fragile X. The program that we've acquired, the MRM-3379, is a brain-penetrant PDE4D inhibitor that has quite favorable brain-to-plasma ratios, which is one of the key differentiators that we see in this program to optimize dosing, to get the exposure of drug to where we want to be able to impact the cyclic AMP levels that are depressed in Fragile X patients.
PDE4D has been shown to boost cyclic AMP levels in translational models of Fragile X and cognitive impact and memory. So quite excited about what this program can mean for Fragile X patients. We are planning to discuss our program with FDA in the coming quarters, and we'll launch this phase two study later this year. So quite excited about the new addition and the potential for bringing a new therapy forward for Fragile X patients. So pulling that all together, it's been a busy year for Mirum and lots more ahead. Reiterating kind of where we stand today on track for $420 million-$435 million of top line for the company and guiding towards operating cash flow positive for the year. So continuing to grow and perform with this efficient business model in ultra-rare medicines and several potential bigger opportunities ahead.
Pipeline catalyst, as mentioned, PSC enrollment later this year with data next year is a real highlight with our next potential registrational program, PFIC data that will follow after that. And excited about getting the Fragile X and EXPAND opportunities enrolled as we move into next year as well. So busy year for Mirum, and as in years past, we're excited about what we've built and the potential that we can leverage ahead. So really appreciate the interest and look forward to your questions.
Great. Thanks for the presentation. Maybe starting with Livmarli, you gave us guidance for the year. What's driving the growth in 2025?
So for Livmarli in particular, there's several growth drivers, and this is actually one of the aspects of Livmarli's product profile. There are tailwinds in the growth of Livmarli that we expect to be persistent for years to come. The treatment response to Livmarli is a quite rapid symptomatic improvement. That leads to really strong persistence and compliance because patients feel better when they're on drug. From the base of patients on therapy, we expect strong compliance, persistence, and a weight-based dosing dynamic that plays into that kind of continued growth trend from the core business. Adding on top of that, we continue to see opportunity in the prevalent population for Alagille. We've been really pleasantly surprised in the uptake in PFIC since the label expansion there.
With PFIC in particular, it's worth noting a dynamic where we're finding more patients in the adult setting than we had originally anticipated, and as we're preparing for Volixibat launch, there's a synergistic ability to help educate in the adult setting on the potential for IBAT and the diagnosis and care options for PFIC, so we see PFIC as one of the continuing growth drivers, and then lastly, the third component to Livmarli's growth is international, and while we have launched in Western Europe and we have distributors that have been selling product in a number of different countries, the list is expanding, so more country launches ahead and also some of those continued growth drivers in the established markets will continue to grow that current base as well.
When you talked about Livmarli being about 40% penetrated in Alagille, was that just Livmarli? And then I guess how penetrated is the overall Alagille market?
Yeah, that's our estimate for Livmarli share. We've also looked at some data pulls just looking at IBAT market share in Alagille syndrome. We think we're 90% or higher of Alagille in the U.S. and really attribute a lot of that not only to our lead in Alagille syndrome, but also just the commercial model where our team has done a great job making Livmarli the first choice for physicians for their Alagille syndrome patients.
You talk about PFIC as an opportunity as well. What are the strategies you're using to increase Livmarli's market penetration there?
A lot of it comes back to the data sets from the MARCH study. So the MARCH study was the phase three study that led to the label expansion for Livmarli and PFIC. And what we see there is just quite striking improvements in pruritus. And beyond that, the data also shows significant reduction in bilirubin compared to placebo and significant growth compared to placebo. So clear that the treatment response to Livmarli is multifold. So by treating the elevated bile acid levels and itch, you're seeing follow-on effects that suggest the patients are doing well across all parameters. That data is quite well known. So the more that we educate on it as well, the more we think that supports the use of Livmarli and PFIC. Also, I come back to looking at what we've built from a commercial team.
The payer team, the market access team has done a great job supporting policy updates for Livmarli and PFIC, some of them being quite favorable to brand, and I can't compliment the commercial team at Mirum enough on what they've done to make the Livmarli PFIC launch go as well as it has.
What are the latest competitive dynamics between Livmarli and Bylvay in PFIC, and where does the market share stand there?
So, I'm less clear on the market share for PFIC. Bylvay certainly has the bigger share in that setting. They've been approved for a number of years before our label expansion. But what I will say is that the Livmarli data set does bring something new to the table. I mean, our study covered more genetic subtypes of PFIC. And frankly, our team is entirely dedicated to that prescribing base. And so that's helped us pick up, I think, more patients in PFIC than we originally anticipated.
Okay. I think you put on one of the slides that Volixibat could be a billion-dollar opportunity. Your FXS asset could be another billion-dollar asset. How does Livmarli and the Chenodal Cholbam franchise stack up relative to those?
We don't have product-specific peak guidance. What I will say is that the addressable market segments for Livmarli are easily over a billion in total. And what we're doing is continuing to grow into that. Livmarli has IP protection to 2040 and beyond. Orange Book listed patent protection to 2040. And we expect Livmarli will continue to grow throughout that time period.
You also highlighted the EXPAND trial to potentially further broaden the Livmarli label. How's enrollment going there? How should we think about enrollment timelines? And how does that kind of opportunity factor into the product's peak potential?
Yeah, it is from a growth potential. I mean, it's a sizable segment. We talk about in the U.S., we estimated about 500 patients that would fit with the profile we're talking about. But that's different from a traditional epidemiology estimate. These are actual patients that we estimate are out there. So one way to think of it is it's at least the size of PFIC as an indication and certainly could be larger than that. And from how that plays into enrollment is we think it will support robust enrollment. The study centers have just opened, and we've just started screening. So far, I can say we're on track for enrollment completion next year. It's a 20-week endpoint, so relatively quick to get to data once we hit full enrollment. And the program was designed based on the demand that was out there.
So we think this is a really great growth accelerator for Livmarli once we get to that label expansion.
Maybe switching to Volixibat, what can you tell us about enrollment of VISTAS and VANTAGE?
Performing well. So after the interim analyses last year, we saw increased interest from investigators. We've added sites kind of following up on that interest. So several different centers that had reached out and wanted to participate in the study kind of makes us very confident that we're on track for the VISTAS being fully enrolled in the second half of this year and VANTAGE into next year. Worth noting, VANTAGE is a larger study. That's the driver of the longer timeline for PBC being a larger indication. We're targeting a bigger safety database for that study. So the energy is quite strong out there based on the interim analysis.
How are each of those studies powered, and how confident are you in the final result based on the interims?
We powered the studies originally assuming a 1.75 difference from placebo. In the VANTAGE interim, we saw much larger than that in terms of the treatment effect. So I feel that we're very much overpowered from the original assumptions when you look at that interim data. So I feel great about how we've designed the study. Primarily, the size of these studies actually orient more towards the safety database that we're targeting because that treatment effect is so pronounced at the dose levels that we studied.
Okay. Another question we sometimes get about Volixibat is just how to think about it relative to GSK's Linerixibat. So how do you envision competitive dynamics with that asset in PBC, assuming that you're also on the market there?
Yeah, so IBAT as a class, now we've seen across all these settings, it's very clear and consistent that IBAT can impact cholestatic pruritus. So the Glaxo program announced late last year that they had met their primary endpoint for their phase 3 study. We've not yet seen any actual disclosure of the data. But from what we know from looking at all of the different IBAT data sets across these different cholestatic settings is that the dose response curve is not as straightforward as it is in some other settings where you have serum measures and you can look at PK and have a different way to approach target engagement. And in our dose ranging work, I feel that we have gone to a much higher activity level of dosing for both Volixibat and Livmarli.
That's really what plays back to the differentiation we see in some of the data sets looking at the placebo-adjusted treatment effect and even back to Livmarli, looking at some of these effects that we see from the PFIC study where you're driving some of these other secondary endpoints. We see that all ties back to the work we did in establishing what's the target dose range for IBAT in these settings. So I feel we've reached a point where we've really optimized the efficacy from our dose for Volixibat. And so we haven't seen the data sets. We think that's the real key potential to drive differentiation in the PBC program to have a higher effect size.
Got it. And when you talk about a billion-dollar peak potential for Volixibat in PSC and PBC, how should we split that out between the indications?
To be honest, either one of the indications could drive that. So in total, it's a quite sizable opportunity. A lot of scenarios on how you could allocate and forecast in those indications, either one of them could support a billion-dollar potential.
Got it. You mentioned the upcoming label expansion supporting incremental growth for the Chenodal franchise. Can you put any more kind of color around what we should expect for that business this year?
I mean, our goal there is to kind of build on what has been kind of historical mid-single-digit % growth from kind of passive accumulation of new diagnoses of CTX finding their way to drug. Chenodal currently is not indicated for CTX. It's used off-label with the support of a recognition from FDA of it being a medical necessity, and the work that we've done is to work towards having a label. We think we can support diagnosis and find some of these patients earlier. There's probably only about 10% of the CTX patients that are diagnosed. Most of them actually get diagnosed in their 30s. So if we can help find some of these patients earlier, bring them to brand earlier, that's the growth opportunity. It's a rare disease patient-finding effort, though.
We, from an expectation standpoint, expect it to be kind of a gradual increase in the potential growth versus a traditional launch because patients have access to drug now that are diagnosed.
Okay. Maybe we can talk about your newest asset, MRM-3379. Can you just first maybe talk about the rationale for bringing that product into the company and what drew you to the asset?
Yeah, the answer to that actually bridges right back to CTX, what we were just talking about. And some of the patients with the bile acid synthesis disorders actually present as neurological conditions. So they tend to be some of these indications, which there are several underneath that basket, some of them tend to be seen by neurologists. And so when we acquired those products, we actually kept a separate sales team that calls on medical genetics and neurology. So for a bit over a year, we've had kind of a separate sales team that is calling on some of these specialists that would also potentially treat or diagnose Fragile X. And so we put together a targeted effort to look for other genetic neurological programs that we could bring in to build behind that commercial team.
So this was kind of an intentional strategy to find other products to bring into neurology. And we're quite excited about a phase 2 data set for this mechanism. So there's another data set from PDE4D that was studied in Fragile X and showed a striking significant impact on a cognitive score. The tool they used is called the NIH Toolbox. It's a patient-administered cognitive battery of tests. And it's the first data set in Fragile X that's shown a really clear placebo-controlled impact on cognition. So that got us very excited to see if there were other PDE4Ds out there. And we found one that we think has the ability to be differentiated with this higher CNS penetration. So it's building off of the clinical evidence that we've seen for the mechanism to kind of fit with our genetic neurology franchise that we're building.
And maybe sticking with kind of business development and bringing in new assets, can you talk more about your priorities there, therapeutic areas of interest, maybe size of potential deals?
Yeah, what we've shown since we launched the company. Keep in mind that Mirum was launched six years ago as a search for new high-impact medicines in rare disease. That's who we are. And so that's the genesis and the strategy of the company is to continue to find underappreciated medicines for rare disease. We look at rare disease as a therapeutic area in itself. So the criteria we look for are programs with some level of clinical evidence. And the bookends really are the Fragile X program that we just added all the way to the bile acid programs that are commercial smaller products. Any of those can really bring. We can leverage a lot of what we've built at Mirum to, on the one end, help drive business performance and on the other end, help bring forward new medicines for some of these difficult rare disease settings.
When you say bookends, are you talking about sort of like a degree of de-risking or something else?
I think of it as like the clinical stage, right, so from a phase two ready program to a mature commercial asset. I think those are the types of opportunities that we look to add into Mirum.
Do you want to see what you get from Fragile X before you go on and do the next deal?
No. We're active. We're excited about what our team can deliver on. The thing that I'll say is that we have a pretty high bar. So we say no to most things and really want to continue to be quite diligent that anything we bring in has the right risk-reward profile and is something that Mirum can add value to. And that's certainly the case for the Fragile X program as a good test case of that. The risk-reward profile for this is quite attractive for us. No additional capital needed. It fits right in with the team that we have in place and could build tremendous value for the company and for patients.
Great. Any last questions? Okay. We'll wrap it up. Thank you.
Thanks.