All right. Hello everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the biotech analysts here, and it's my pleasure to introduce Chris Peetz, CEO from Mirum Pharmaceuticals. Just as a quick reminder, the format for today is a fireside chat. If anyone in the audience has a question, you can raise your hand and we'll try and address it in our discussion here. Before we get started, I just need to read a quick disclosure. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, Chris, thanks for sharing your time with us today and maybe I'll just hand it over to you to make some introductory comments.
Yeah. Thanks for hosting. It's great to be here. I'll make a quick disclaimer on my end as well. We'll be making forward-looking statements so refer you to the SEC filings for Mirum for a more complete risk factor disclosure. A bit about Mirum. We are a company that's established just under eight years ago and focused on pulling together high-impact medicines for rare disease that are often overlooked, missed by some of the bigger companies, but really compelling opportunities, not only from patient impact, but also as a business model and pulling these together in an efficient way. This year, we're on track for $680 million-$700 million of revenue across three approved medicines.
Really had a kind of emerging growth trend in one of our indications in particular with PFIC that I'm sure we'll spend some time talking about, and a pipeline that is very busy right now. Later this month actually, expecting to announce top line data of the AZURE-1 phase III study of brelovitug in hepatitis delta. We have a PDUFA date from one of our newly added programs in FOP. More readouts, two more phase IIIs reading out next quarter, and another study in PBC first quarter next year. All this on the back of entering into a regulatory conversation for PSC for volixibat as well. It's a busy stretch for Mirum, and kind of on the other side of this, see a real inflection on business performance from all of these data readouts and launches that we expect in the near term. Exciting time across the board.
Yeah, great. Thanks for that introduction. Lots to get through here. Maybe we just start with the commercial business and LIVMARLI, and you touched on this in your prepared remarks, but you are seeing some nice growth in PFIC. Maybe talk about what you are seeing there and how you think about that going forward.
LIVMARLI is approved in two different indications, cholestatic pruritus due to Alagille syndrome and cholestatic pruritus due to PFIC. First approval in Alagille syndrome continues to be a growth driver. We, across the board, continue to see new patient starts. The response profile for most patients is quite meaningful and see strong compliance and persistence as well. That plays well for the brand over time, both this is U.S. as well as international performance. The PFIC indication was added subsequent to the Alagille syndrome launch, and it has been an interesting story over time. Initially, we saw this as a pediatric opportunity. That is what our field team was primarily targeting and finding the pediatric profile of a PFIC patient.
As we have been in market with LIVMARLI in pruritus due to PFIC, we have found that there is also a substantial underdiagnosed population in adults that actually have PFIC and have to date been labeled as idiopathic cholestasis. Really just an incomplete diagnosis in many of these adult cholestatic patients with pruritus. That is something that we have seen start to contribute to the top line over the past year. A very durable trend in everything we are seeing. In fact, we are now in the process of expanding the field commercial team to help support some of that patient finding and diagnosis, help build awareness of genetic testing and availability of it for adult patients. We estimate there is probably about 2,000 adult PFIC patients in the addressable market that are out there in the U.S. That is kind of one of the near-term drivers for the continued growth on the commercial business.
Yep. As we look next year and beyond, you also have a phase III EXPAND study ongoing that could even further expand the opportunity there. Maybe just talk a little bit about that, maybe give a little bit of background how you ended up targeting that indication and what to expect when we see data, I think in the fourth quarter.
Yeah. LIVMARLI as a whole, we see it as a billion-plus brand opportunity driven by all these different components. EXPAND being a substantial contributor to it as well. It is a basket study, so it is a collection of ultra-rare causes of cholestatic pruritus that by definition in our discussion with the FDA are too small to run a standalone study in. A good number of them in the study are biliary atresia. That is probably the only one that is a little bit more common of the mix, and then very small numbers of other genetic and non-genetic causes of cholestasis that end up with a pruritus presentation. Study looks at both pediatric and adult patients. The primary endpoint that we are expecting next quarter is in a pediatric cohort. That is what the study was primarily powered and designed around.
Expect to see that as the top line next quarter of the pediatric patients with an identified subset looking at biliary atresia as well as a secondary because it is about half of the patient population. There are probably 500 pediatric patients in the U.S. that make up the addressable market that we have identified and sized. It is an early estimate, and it is hard to tell how big of an indication this could be in adult settings as well. There are some adult patients out there certainly, we just do not know quite how many. It is a nice add-on to what we are already seeing in Alagille syndrome and PFIC.
Yeah. Can you talk about what drives your confidence in being successful there? Any prior data you can point to?
Yeah. Really the genesis of the study design came from physician interests and compassionate use case studies. We do have, not in a clinical trial format, but we do have anecdotal case study evidence seeing response in a number of these types of settings. Biliary atresia in particular, we have presented some of the case studies of a series of biliary atresia patients with cholestatic pruritus being treated, and it is what you would expect for an IBAT treatment. In a patient with cholestasis, elevated bile acids, and itch, you can expect to see a nice response in the clinical data that comes out from those studies.
Yep. Great. If we just sort of stick with the commercial portfolio and specifically the bile acid portfolio, you added that a couple of years ago, and it seems to be performing well. Maybe just talk a little bit about that, what's driving that, and the outlook there.
Yeah. The bile acids, CTEXLI and CHOLBAM, have grown nicely with a dedicated team behind it. One of the things to note when we brought those products in, a realization we had is that the prescriber universe is not entirely hepatology and GI. Many of these patients, in particular for CTEXLI and for some of the CHOLBAM indications, are in medical genetics or neurology, and it's more of a patient finding and diagnosis effort that doesn't exclusively happen in hepatology. So we built a separate team that focuses on those other settings and the patient finding, and they've done a fantastic job over time with these products, and it's about having a dedicated effort that is a different strategy than what the liver team is doing, so it makes sense to have a different team staffed against it.
Actually, it fits really well with one of the things to come on FOP. That's the team that's going to be launching the zilurgisertib and FOP, and it's a really similar effort, overlapping call points in terms of the institutions that these people are visiting and in contact with, and a similar effort in terms of following data on a diagnosis and leveraging some of the referral patterns that happen for these ultra-rare conditions like FOP, like CTX.
Yeah. Maybe talk a little bit more about FOP and what attracted you to that asset and what drove that decision.
Somewhat from what I was just talking about with our expansion into medical genetics and thinking of rare disease as a therapeutic area. We've been looking for other programs that could fit with that kind of team and call point to put more in the hands of this team that's been executing so well. As we started looking into FOP and the programs being run there, the biology and the data are striking. This program that Incyte did all the work on the phase II study that supported the NDA submission, really compelling data that's come out of that showing that you can really, versus placebo, have a striking difference in the volume of ossifications that build up over time for these patients.
We see this as groundbreaking data for FOP patients to be able to halt that formation of new ossifications and dramatically change the course compared to placebo in those data sets. Both that clinical data and how clear it is, as well as the fit with our team and business model comes together in a great story. The conversation with Incyte, it's a story of focus between two companies, right? This was something that didn't fit with their business model. It's clearly aligned with what we're trying to do. It was a natural transition that we set up.
Yeah, makes sense. With the PDUFA date coming up here, can you just talk about launch preparations? Can you hit the ground running? It sounds like you probably can, but maybe just talk a little bit about that.
Yeah. For launch preparations, field team, it is the same team that is already out there for the bile acid medicines. So in terms of the staffing, largely that is all in place. We are ready for the PDUFA date and decision in a couple of weeks here. That is the point that triggers a transition of sponsorship from Incyte. So a couple of steps there to get this launched in Q4.
Okay, great. Since we have been sort of on the topic of BD, you have obviously been pretty active over the past few years, so maybe just talk more broadly about your BD strategy, your thoughts currently. Are you looking to add more programs, or do you have enough catalysts over the next six months?
We are a little busy for the next six months. It takes time for these deals to come together.
Yeah.
Which I think is behind the overall strategy for Mirum, how we got to where we are today. The vision for the path forward is to always be active, to find the opportunity that is compelling, both from the biology data and patient impact, but then also that fits with the Mirum business model, that you can have an intersection where the deal economics work for both sides. It takes time and being a little bit opportunistic. We never rest on the BD front. We are always active, looking at things. The range of things that could be of interest remains the same. Phase II opportunities through to early commercial are all of interest and could fit well. But granted, the next six months are a little packed.
Yep.
Adding a phase II sounds like a pretty good idea to me, instead of another launch next year.
Yep. Understood. What areas of focus? Is it rare genetic liver? Could you go outside that at all, or that doesn't make sense for you?
Yeah. We look outside of liver and outside of the broader current therapeutic areas where we're active, because we see rare disease as a therapeutic area, as the expertise that we bring. The ability to commercialize medicines where they are maybe harder to diagnose, harder to get to a point of care, where there's maybe a first product in class or in the indication and kind of setting and changing a standard of care. These are the types of opportunities that our team has shown that they can execute on.
Yeah.
It's not so much tied to the specialists, but more the model around a rare disease product launch. We're seeing, as we saw with the bile acid products, how we're approaching the zilurgisertib launch. You can leverage this into new therapeutic areas pretty easily.
Yeah.
Adding on the endocrine call point and some of these tertiary centers for what we call the GEM team, is pretty straightforward, actually.
Great. Maybe we can keep it rolling, moving to volixibat, and maybe just start with PSC and just maybe talk a little bit about the market opportunity there and the unmet need and how you see it.
Backdrop of PSC as an indication, this is an autoimmune-driven, cholestatic condition. It presents most commonly in adults, but there is a pediatric onset form of it as well, and the hallmark of it being the fibrotic strictures forming around the bile ducts leading to progressive liver complications. It is also associated with frequent episodes of cholangitis, highly variable liver labs, and just really a very difficult setting to treat clinically. And it has been very tough for drug developers historically. We have seen a number of programs early on exploring different endpoints, using histology, using different biomarkers. None of those have really panned out. When we approached it with volixibat, we were coming at it from a different angle.
Leveraging some of what we learned on the pediatric side, using the symptomatic burden as the endpoint for our registration program, and clear that pruritus is a substantial clinical burden for these patients. That aligned well to be an endpoint in PSC, similar to how we have used that in Alagille syndrome, PFIC, and PBC. So good precedent for how it is used in other settings. And with the VISTAS program and PSC for volixibat, which I am sure we will talk about-
Yep
kind of diving into it here.
Yep.
Had that conversation with FDA, good, clear written correspondence discussing the study design, the registrational intent, pruritus as a substantial patient need endpoint and indication, and had good alignment on the study design, and announced earlier this year really strong top-line data. Clear that presented at EASL this year, a really compelling impact on pruritus in the VISTAS study for volixibat and PSC.
Yep. You also shared that positive data with the FDA, and the FDA sort of requested phase III. Maybe just walk us through what happened there and what are your thoughts on that going forward from here.
Yeah. Working through the situation on the regulatory front now, it was a bit of a surprise for us. After the positive readout, we went for a pre-NDA meeting with FDA and had the surprise recommendation from them to conduct a phase III study. A surprise for us in many ways because we had alignment on the study from the start as a pivotal study. In the conversation, a lot of the different aspects of the program were discussed. All of them were present at the start of the program and were considered with the original study design. We're a bit surprised by the reaction. Subsequent to that meeting, we were granted breakthrough designation. We're using that as an ability to have a bit more access.
Over the balance of the year, planning to have interactions with the FDA through written submissions, sharing more of the VISTAS data with them. Admittedly, we have not submitted full data sets to them yet, so I think there's a lot to be gained from getting them closer to some of the data sets that answer a lot of the questions on treatment in this patient population specifically. Even get to a live meeting potentially. All this with the goal of submitting our NDA in the first half of next year. Absolutely still the plan to submit an NDA for volixibat in cholestatic pruritus due to PSC based on VISTAS first half of next year.
The strategy between now and then is to build familiarity with the robustness of the data set and bring the review team closer to how we're seeing things before we get to that submission.
Yeah. Can you walk us through some of the potential scenarios there? Are you pretty confident that you'll be able to file on existing data, or are there other data you could use? Maybe what are some of those potential outcomes, I guess?
Well, in the interaction with FDA, it was made clear that we can submit at our election. There's not been something put on the table to prevent us from submitting an NDA. So there's a recommendation from them to run a phase III study. We think the points brought up in the meeting really can be addressed by the current study.
Frankly, we don't know what new would be answered by an additional study. Scientifically, we haven't heard something that needs to be answered that can't be answered in the VISTAS data set. That's what's behind our strategy to take steps forward to bring the current data set to an NDA next year.
Got you. Maybe we can switch to PBC and maybe talk a little bit about the market opportunity there relative to PSC.
In PBC, we're also conducting a phase II-B study, adaptive design with volixibat in cholestatic pruritus due to PBC. We already presented interim data a couple of years ago from that study that showed a really striking improvement in pruritus versus placebo. In two doses of volixibat, the adaptive design then took one dose forward for the confirmatory portion. That's the data we expect in the first quarter of next year. Granted breakthrough designation, have some more clarity on the regulatory front on that one from those interactions last year as well. Tying this to the clinical setting. In PBC, it's a much larger indication in terms of just overall prevalence. Probably 80,000 or more patients in the U.S. with PBC. There are other medicines approved in PBC for different settings. UDCA is standard of care. That's generally where patients start.
There's a second-line setting for those that are not controlled biochemically on UDCA. In other words, if they have elevated alkaline phosphatase levels, they'd be considered for a PPAR, which were recently approved. In the backdrop, symptomatic management is emerging with new tools available and becoming available. There was recently an IBAT inhibitor approved for cholestatic pruritus in PBC. That's relevant across both first and second-line PBC, just like we are developing volixibat. So volixibat's being studied in both first and second-line PBC. In the interim analysis, both settings were represented in those patients, and you see a nice improvement in pruritus across both profiles. So feel that we're on track to have a potential medicine that can address symptomatic burden across all lines of therapy.
Yeah. You are going to share, I think, the phase II-B registrational study in 1Q, I guess. You shared some prior data. Is that a good estimate of what the outcome might be? Is there reason to think the outcome might be a little bit different on the pruritus endpoint?
It is the best evidence we have is from that interim analysis of the VANTAGE study where we saw a 2.4-point placebo-adjusted difference. Frankly, that is a really strong result. Compared to some of the other data sets out there, anything around a 2-point difference from placebo, in PBC, is a really impressive result. So getting close to that in the full data set would be a real home run.
Yep. Makes sense. I guess your level of FDA interaction on PBC and the risk that they may also want you to run a phase III study here, what is the thinking there?
We've had the opportunity for more recent interaction with PBC. One of the things that we've looked at is the division leadership has changed over the course of this program. So more recent interaction, I think, is quite relevant and helpful. We've gotten feedback from the current contemporary team that's in the division. After the breakthrough designation, we were thinking about the ultimate study size for VANTAGE. We had some flexibility to potentially keep it smaller or upsize it. That was one of the decisions we wanted feedback on in the context of a pivotal study. So in written correspondence with FDA, we confirmed some questions on study design and on the analysis plan. Feel like we have more recent input from them.
That's why the study's now ended up over 300 patients in total to align with what other PBC programs have had for their submission data sets. Even in these correspondences, we even have direct direction on if these studies are considered pivotal, these are the analysis steps that you should take, and we're able to accommodate all of them.
Yeah.
Feel like we're aligned on PBC.
Okay, great. Maybe we'll just keep moving here. Brelovitug HDV, you have some phase III data coming up soon, but maybe just to start, paint the picture for us, why HDV, what was attractive for this program?
Yeah. Hepatitis delta is a co-infection with hep B. It is rare, so it is far less common than hep B, but it is far more dangerous and progressive. So it is a highly progressive condition where these patients tend to progress to cirrhosis, liver failure, liver cancer, cholangiocarcinoma, all of these complications at a much faster rate than hep B alone. The goal of treatment here is to suppress the viral levels, so looking at HDV RNA response, and improve long-term liver outcomes. One of the ways that that is measured in the studies is ALT normalization, looking at that as part of the composite response. In the U.S., we estimate there are 15,000 patients with hepatitis delta diagnosed in care. That is from insurance claims data, so also kind of in the insured population, estimate 15,000 patients. But it is likely very underdiagnosed.
The practice and guidelines for testing for hepatitis delta in hep B patients has been more of a risk-based paradigm, and it is likely not even sufficiently doing it at that level. A very low percentage of hep B patients get tested for hepatitis delta. We think there are probably 40,000 patients that are in total in the prevalent population in the U.S. A lot that can be done if we can help support changing some of the reflex testing that really should happen now that there are therapies emerging for hepatitis delta. Interesting parallel in Europe, actually, where we have seen this play out with approval of HEPCLUDEX about five years ago.
In Europe, you saw a shift in guidelines, and that did result in a meaningful change in the testing patterns from 10% to 20% of hep B patients being tested for delta now towards maybe as high as 90%. The positivity rate on those tests has not changed, so they are capturing far more of these patients that would otherwise be undiagnosed and have a more progressive background disease.
Yeah. In terms of the data, maybe just walk us through a little bit of what we have seen so far and kind of is that a good proxy again for the data coming up here?
The brelovitug program has had some just really impressive response profile in the phase IIa and phase IIb data sets. There are two different studies that have read out. Phase IIa was a kind of sequential dose exploration study, looking at different doses and regimens, and that kind of gave the signal for what became the AZURE program. The AZURE-1 study that has its phase III readout in the next couple of weeks here. The phase IIb portion of that I think is the most instructive data to look at. It is a randomized controlled evaluation of two regimens of brelovitug versus delayed treatment, looking at 300 weekly and 900 monthly. Nice response across both regimens, and particularly the 300 weekly dosing looking quite strong, where you are seeing 100% virologic response. At only 24 weeks, you are already getting a substantial proportion of these patients with ALT normalization.
Our program has no baseline ALT requirements, so some of these patients are coming in with very high ALTs, and so to get them to normal in that timeframe is quite impressive.
From a response profile. That is what we look to as the best guide for what to look for in the phase III readout. A lot of overlapping sites from those first patients in AZURE-1. To kind of look at what is possible for the phase III portion.
Makes sense. Can I also ask just about competitor also is going to have phase III data coming up later this year as well, so maybe just talk about key points of differentiation or how you position your product.
Yeah. Part of what got us so excited about brelovitug really, I think, will stand out as we get into a competitive launch.
Yet another one. We tend to like these situations. Brelovitug is a fully human antibody. I think that has some real advantages on the safety tolerability profile. In terms of what we see is very low injection site reactions or flu-like symptoms. I think that's going to shine commercially when we get out there. The response profile at 24 weeks is good and appears like it's only going to improve over time. That's another thing that we'll be looking to share data on as we go is some of the data updates as these phase IIb and eventually phase III patients get towards 48 weeks or 98 weeks, where with a single agent, fully human antibody, you can really control the HDV RNA levels and get more and more patients to ALT normalization.
Great. Maybe in the last few minutes here, we just switch to Fragile X syndrome. Maybe give us kind of the background there and kind of your latest thinking.
The MRM-3379 program for Fragile X is a PDE4D inhibitor, and we're looking at trying to impact some of the cognitive scores and measures in Fragile X patients in the dose-ranging phase II study that we're running. Important to note, this study was based on a signal from a different phase II program of a PDE4D inhibitor that had an interesting signal on cognitive scores. We've not seen that replicate in the phase III study, so it does kind of call into question some of the strategy here. I will say that we're asking all the right questions.
Yeah.
In our phase II program, we're doing a more complete dose ranging than was done in this competing program from what we've seen. And one of the things that excited us about MRM-3379 as a program is that it has a high CNS penetrance, so it was designed for CNS exposure. We've got the right profile for this setting, but we'll have to wait and see what comes out of the data next year. Study's enrolling well. It's a really engaged patient community and setting, so we'll have an update when we get to data next year.
Yep, great. I think we covered it.
Yeah. I really appreciate the time.
Yeah.
I think just to come back on a closing thought.
Yeah
Mirum's at a real inflection point here. Commercial business on its own is already performing well with that $680 million-$700 million top line for the year. We're seeing that and expect it to really, in the next couple of years, start to play through in an impressive way on a margin basis as we start to launch these additional products and build on the efficiency on what we've built here. With the liver team eventually having three products, LIVMARLI, brelovitug, volixibat, a lot of reasons to be a leading thought partner for hepatology and GI. And on the genetics and endocrine metabolic team, having an exciting launch to work with there, with a team that knows how to get out there and have an impact and help bring patients to therapy.
Yeah, a lot to look forward to. Thanks so much, Chris. Really appreciate your time today.
Yep. Thanks for the time. Thanks for the interest.