All right. Welcome, everyone. I am Josh Schimmer from the Cantor Biotech Equity Research team, and very pleased to be joined by Chris Peetz, Chief Executive Officer of Mirum Pharmaceuticals. A lot going on with Mirum. By design, you have actually created such a diversified portfolio of assets since the beginning of the company, which started around LIVMARLI. Maybe kind of kick things off, frame for us where Mirum is today and where you think Mirum is headed tomorrow.
Yeah. Thanks for hosting and happy to jump in. Mirum, you are talking about by design, a bit about our kind of mission and the business strategy on how we came to be really is based around executing on finding overlooked rare disease assets, bringing them into a platform like Mirum, where we can focus on really high-impact medicines that otherwise get missed by larger companies. The small to midsize products that are overlooked by those that are chasing some of the larger indications like weight loss, for example. I see this as really a high impact and sustainable business model. Put it in the context of all the rare diseases, probably only 5% actually have an approved medicine, and even those with approved medicines have room for improvement. We think there is a long stretch of impact that we can have with that model.
To date, we have now grown the commercial business to we are getting towards $680 million- $700 million for the year this year, across three approved medicines. We have a lot more coming. We have a PDUFA date for a recently acquired program called zilurgisertib for FOP later this month, so that is the next potential launch in front of us. We have potentially pivotal data from a PSC program that we are discussing with FDA, working towards a potential NDA in the first half of next year. It has been a big discussion point for us, so I am sure we will spend some time on it today. Other phase III readouts very near term. Brelovitug for hepatitis delta virus with a phase III readout this quarter and a second study next quarter.
A life cycle indication for LIVMARLI, one of our commercial medicines, has a phase III readout in Q4, and then volixibat in PBC, a data readout in the first quarter of next year. It is a packed window for us right now. A lot going on clinically, commercially, and excited about everything that we have pulled together. One other comment I would make on kind of rolling this forward with all of these launches, we do see a real potential for a financial inflection point as we go through next year and into the years that follow, as the commercial contribution starts to come online from all of these new potential medicines.
We actually had a wonderful breakfast discussion this morning. I actually thought a lot of our time here would be spent on volixibat and PSC and what's going on, but the conversation we had revolved a lot around LIVMARLI and the growth drivers and paths to continue to expand the reach of LIVMARLI. Why don't we spend a bunch of time on that program and what's been driving the very strong growth of the product thus far, and how do you see that evolving over time as you continue to scour the landscape for patients who may benefit from that therapy?
Breaking down LIVMARLI and where it's approved and where we're taking it, current approvals are for cholestatic pruritus and Alagille syndrome and PFIC, and a third leg to the stool with EXPAND being the phase III that reads out later this year in other cholestatic pruritus settings. To date, what we've seen over the time since approval of LIVMARLI is in Alagille syndrome, there's been just a nice steady cadence of patient adds and growth over time as we both see patients grow on drug as well as new patient starts, new geographies coming online. Recent acceleration to that has been in PFIC, and we've been talking about this now for a bit over a year on how we found more PFIC patients out there than was originally understood. We recently put pen to paper on really coming to some numbers of estimating what that could be.
Largely in the adult setting is where it's, we think, pretty dramatically underdiagnosed. When you go to some of the adult hepatology or GI clinics, there's not just as much of adoption of genetic testing to date. That's starting to change, and what we're seeing is as that's changing, those patients that were previously diagnosed as idiopathic cholestasis actually have PFIC genetics. You're seeing that these insufficiently diagnosed patients actually can have a genetic diagnosis. A lot of those patients have the symptomatic burden that is a great fit for LIVMARLI. That's what's been this acceleration of growth that we've seen recently, and we're continuing to deploy against it. Expect to get further into that. We've estimated at about 2,000 adult patients that would be the addressable patient population.
I'm guessing there are a lot more adult hepatologists than there are pediatric to consider. What has your approach been to get into the adult practices? How are you prioritizing, how are you going from engagement with a practitioner to actually diagnosing patients and ultimately getting them onto LIVMARLI? Maybe you can describe that process and then how deep you feel like you are into that process.
The short answer, I don't think we're that deep yet. From the launch of LIVMARLI, which was initially focused on pediatrics, we are probably covering about the top decile of the adult hepatology and GIs who see liver disease, the top decile of those prescribers. Over the past year or so, we've expanded a lot of the medical education around genetic testing as one of the ways to build awareness of the presence of genetic disease in the adult clinics. What we're doing now, starting later this year, is expanding the commercial footprint as well. I think that's going to be a real driver of seeing how much of this 2,000 adult patient estimate we can address with LIVMARLI by actually having Mirum commercial presence in those more community GI clinics outside of what to date has really just been KOL-driven transplant centers.
In terms of that outreach effort to the adult hepatologists, it's probably a little pollyannish to think you knock on the door, you remind them that maybe a patient with pruritic cholestasis may have PFIC, and then expect that they're just going to test every single patient that comes in the door. Maybe tell us a little bit about how do you generate that momentum in a practice? Do you have to keep coming back to them repeatedly and reminding them that this is something they should be looking for? Again, because that'll ultimately help inform the kind of depth of prescribing and patient identification you can reach within a practice, as you're also spreading to adjacent practices with more reps.
I think a lot of the first groundwork comes from what we've been active doing already on the medical education side, and we've seen that start to be echoed with research efforts on understanding genetic cholestasis. That's been showing up at AASLD and EASL, some of the venues where you see a lot of the more research interest in understanding what do these genetic hits mean if they were to find them. I think that's putting a genetic test into the hand of a community prescriber. Interpreting those results is going to be one of the first questions. I think it's important to have a backdrop of research and publications on how to interpret those results, as well as the support system of other prescribers who have familiarity with it that could be referenced or called on.
That's a big part of building the familiarity comfort to test. I think the other piece we also already have, which is you have an approved medicine that can help address a need that some of their patients have. Where you find these patients is those that already have a diagnosis of idiopathic cholestasis. They're in care. There's really not a satisfactory diagnosis, and so there is a desire to refine the diagnosis, and if there's a treatment there for it, we think that is the pull as to why you should consider genetic testing. All those pieces pulled together, knowing what to do with the test, access to the test, which we provide support for, and then a medicine to change an outcome for a patient if you do find a diagnosis.
How should we expect the EXPAND trial results? I guess we are expecting those in the fourth quarter. Many of us are expecting it to be a positive clinical trial, given the mechanism and the unmet need. How do you think about then tapping into the patient populations that EXPAND may help unlock and the extent to which that is primarily a pediatric-only population? Or if we are going to wind up back here talking about leveraging EXPAND in the adult hepatology landscape?
I think there is potential parallels here. When we have designed EXPAND, the primary cohort is in pediatric patients. That is where a lot of the initial interest came from. We have had compassionate use case studies and some of the prescriber interest and demand that has driven the EXPAND study design that we have talked about before. We also have some adult patients enrolled in the study that frankly we focused on pediatric centers for the study, so it is not fully representative of what I think that profile could look like. Just back to how you are framing the question, we have sized this around the pediatric markets, but there is undoubtedly demand in the adult setting. I think it ties into, again, some of the efforts with PFIC on trying to refine diagnosis in the idiopathic cholestatic patients.
If they are presenting with cholestasis and itch, can we help support getting those patients to a more complete diagnosis?
As you think about the types of patients in EXPAND that most likely may have adult contribution, I am guessing like biliary atresia, you are not expecting to find many adults in hepatology practices. Are there other indications that EXPAND will address that may have some more direct read-through into adult practice?
We think so. First, I acknowledge that on the BA patients, absolutely the case. Those patients get diagnosed as infants because there's an urgent need for a surgical procedure, so they're followed throughout childhood. There are a lot of these other genetic disorders, secondary sclerosing cholangitis to other injury. Those types of conditions can present or be diagnosed much later in life, and so that's where I think we'll have a more varied time of onset or diagnosis.
You know I'm super excited to talk about ICP. I get the sense that it's still kind of early, you're not super ready to emphasize the approach that we talked about this morning in terms of finding PFIC amongst ICP patients, but such a fascinating discussion topic. Maybe you can share a little bit of what you're seeing. Well, even backing up and reminding everyone what ICP is and why you may be identifying some PFIC patients amongst the ICP population.
Yeah. The backdrop for ICP, or cholestasis of pregnancy, historically, I think you'd hear people characterize it as an onset of cholestasis that happens during pregnancy and then resolves with childbirth. I think the reality of the situation of those patients as you get closer to it is many of them will have recurrent or persistent cholestasis or itch after childbirth as well. So we've found that it can be a trigger for genetic testing and, again, essentially an idiopathic cholestasis profile that can lead to a PFIC diagnosis. There's some literature showing that of ICP patients, call it in the range of 20%-ish, would have PFIC genetics. So there's certainly some overlap in these conditions. Today, we see that as another potential trigger for genetic testing to find potential PFIC patients if they have persistent symptoms after childbirth.
Also an interest in. We're going to be researching the safety and tolerability of dosing in some of those patients with LIVMARLI, just to understand the clinical profile.
How do you think about finding those patients now? Is the high-risk OB-GYN physician population modest enough in size that you can direct your sales force? It seems like a really important path to find PFIC patients, but maybe not the easiest path to get into all these offices and nooks and cranny of patients and care.
That's right. It is a much bigger touch point. A lot of these patients will have a GI or liver referral, even if it's not the week-to-week managing physician. We think the efforts we're putting in for the upcoming expansion more completely into adult liver GI will have echoes into the awareness for ICP on genetic testing.
I think you've indicated peak sales of LIVMARLI north of $1 billion. You're already annualizing around $500 million. Do you anticipate at some point you may increase the peak sales guidance for LIVMARLI as you explore some of these indications?
Potentially, and we're still learning more. As you know, we've just recently put together that 2,000 addressable estimate for adult PFIC. The EXPAND data around the corner is another piece to that. It's something that having a sense of where we're at on the 2,000 patient on the adult side and EXPAND data, that'd probably be the right time to think about that.
Why don't we turn to volixibat now, and I know you've heard every possible question that could be asked about volixibat and the interaction with the FDA for PSC, and the FDA requesting maybe a phase III trial versus the path to navigate around that. Give us a snapshot summary as best you can to address probably the 50 different plus questions you've heard about this.
Yeah. To try and encapsulate the situation here, a little bit of the backdrop, just for those who aren't as close to it. The VISTAS study in PSC is an adaptive phase II-B study looking at volixibat in PSC patients with pruritus. In the pre-IND format, we had an interaction with FDA where we discussed this as a pivotal study, acknowledged the pivotal intent. FDA described it as a reasonable study and gave some direct feedback on the analysis plan and how we structured the interim. A lot of back and forth that we incorporated all their feedback and so felt good about where we were as having an aligned pivotal study.
Fast-forward to the pre-NDA meeting that we had earlier this year, and I think there was less familiarity with the background of the program, which felt like a preliminary and overly conservative response to recommend a phase III study. The strategy going forward is to build more familiarity with the VISTAS data. We since were granted Breakthrough designation, and so under the Breakthrough designation interactions, we're going to be submitting more of the data that we'd hoped that would be part of the analysis here, clinical study report, safety analyses on some of the areas of interest for PSC, the validation reports, all these things that we can submit along the way and then have another live meeting with FDA to build familiarity and work towards a submission in the first half of next year.
I think the other thing I'd offer up is the thoughts of what would be answered by a phase III, and our view of the data is that the VISTAS results that we have are clear and definitive, and we think that it supports a full NDA and review and can support labeling, and all the analysis you'd need to do is there. We don't see what would be gained by a phase III and haven't gotten clarity on what additional questions would be answered in a phase III. So do feel that we'll be working towards that submission in the first half of next year.
I think for many of us who have been very enthusiastic for the prospects of volixibat in PSC, it comes from one an appreciation of the unmet need. We did the call with the PSC patient advocacy group who really emphasized how problematic pruritus is, and then also recognizing the benefit and the safety profile of IBAT inhibition. Do you have any sense from the FDA's perspective, whether they need to appreciate the impact of the disease more or get comfortable with the safety profile, or is it a little bit of each that you are trying to kind of advance the dialogue around?
I think it is a little bit of everything at this point. In the conversations, there has not been a single issue highlighted, per se, more of kind of a general list of what FDA has questions on. That is why we think getting more of the data in front of them to answer some of those questions they brought up is a productive path forward. The patient voice is absolutely part of that, so we are working on ways to incorporate that. Great advocacy partners that are at the table in support of KOL voices are also part of that, so building support among all of the stakeholders here.
How does communication with the FDA now work at this stage? It seems like there is a lot of educating that you would like to do. Are there kind of scheduled in-person meetings to address this? Do you submit additional information? How do we think about the cadence and the timelines for the dialogue, and when you may feel like you are prepared to move forward with a submission?
It is a mix, especially with Breakthrough designation. There is a mix of formal and informal communication that we are kind of strategizing around. That, in part, is routine submission of some of the datasets and things like that. But then also working towards a multidisciplinary program discussion that is somewhat expected after granting a Breakthrough designation.
I was just going to say, does the BTD designation now make this dialogue much more facile because the communication improves with that designation?
That's what we found with our other Breakthrough designated programs, is you get the ability to ask simple one-off questions in a less formal context, as well as being able to call formal meetings where you bring all the stakeholders together.
We had also talked about pricing of volixibat, and you kind of highlighted the benchmark for PBC drugs, around $150,000, and how the further above that you go, the more class management you may face. As you're kind of honing in on the optimal price for volixibat for PSC and PBC, what are the inputs that you don't feel like you have now that you'll need to have to really finalize that price?
I think probably most of the inputs are there now. You look at linerixibat's launch in PBC. That really was the third approval expected in PBC of the two PPARs and now linerixibat. So that's the reference set that we think is most likely the decision set to consider for PBC. For PSC, we don't see any real medicines on the horizon, so I don't think we'll see any precedent price in PSC. So it really comes down to some of the thinking on the trade-offs of how we think about management on the PBC side versus the overall unmet need and size of indication on the PSC side.
I guess having that final PBC data set may be informative for pricing considerations because it can give you additional confidence in the differentiation versus linerixibat. Do you anticipate if you were to kind of step through linerixibat, it would be hard to get patients onto volixibat because the efficacy delta seems pretty meaningful, which would support actually a fairly straightforward step-through to the best product.
Yeah. Assuming that the interim that we saw is representative of the final VANTAGE dataset, which all signs point towards consistent performance for volixibat across these settings, we do think that will be an advantage. Really having that final dataset confirm it is one element of it, but we kind of assume that in how we look at it, in that there is some level of premium price to a stronger clinical effect that you can have without additional management being put in place.
Yeah.
It is a bit of a sliding scale, so to speak.
Right. Okay. Probably straightforward math once you kind of figure out the success you may have in terms of moving patients past linerixibat to volixibat. That probably is the key dynamic plug that determines your price strategy.
Yep.
Are we likely to hear anything more about price until price is set or no?
No. Do not plan to announce a price until we actually are posting the final price decision.
Moving to brelovitug, which you had highlighted at the outset. A lot of investor debate as to the HDV market, how sizable it is. I know many have done some checks with specialists, and it is just kind of hard to find the HDV patients, but I know you have probably done a lot more work than the small handful of doc checks that any of us have done. How do you address that concern that there are just not a lot of patients and as such, relative to volixibat and LIVMARLI, that brelovitug is not really going to be a major driver of revenue or profitability?
There is a few interesting aspects to touch on there. One is just the context of delta being a rare disease. When you are talking with KOLs that are used to thinking about hep B and hep C, it is by definition going to be far less common. That is expected, that you would not have high numbers of patients managed by any given center or KOL. There is also a dynamic for delta that we expect it is more in the community setting and probably clustered around some of the immigrant communities that tend to be where these patients are found and diagnosed. Think of the major metro areas, some community or clinics that serve the point of care for some of these patients.
The other point to think about here is how many people are actually testing for delta actively, and I think that number is actually probably a lot lower than even the KOLs think. We've started to do some work on looking at some data coming out of some of the lab providers, and it suggests that it could be as low as only 10% of hep B positives being tested for delta in recent years. There's a lot of headroom there to move that, especially if you can automate some of this and incorporate reflex testing at the lab level, more of a policy level. I think there's some opportunities to try to influence that.
What are we looking for next in terms of the AZURE study updates, and when do we get longer-term follow-up from the data that you've already reported? Because it certainly looks like longer exposure and follow-up means deeper and deeper responses.
Yeah. Busy balance of the year for brelovitug. AZURE-1 phase III portion is expected later this quarter, later this month. AZURE-4, the second phase III for the U.S. in Q4. Those are both week 24 time points. For AZURE-1, it is an entirely different patient set than the phase II portion that we presented earlier. That's the phase III readout that'll be the basis for the BLA. In terms of longer-term follow-up, we'll have week 48 time point from the phase II-B portion of AZURE-1 in the fall. We'll look to get that submitted and presented hopefully this fall. We also have from the phase II-A study, the cirrhotic patients in particular had longer-term follow-up that is continuing to be analyzed.
We'll be able to look at some. It's only in the sicker patients, but look at some of that continued improvement of response over time for both data sets.
I don't like the question I'm about to ask because personally, I think biotech needs companies like Mirum that are diversifying and moving to profitability and cash flow generation. But M&A is always an important topic for investors. The question is, as you've added all these incremental programs, very capital efficient and looks like you're generating tremendous returns on your investments, do these make Mirum a more attractive M&A target or a less attractive M&A target?
I'm sure there are bigger companies that could answer that question better. But from the overall profile of Mirum and strategy going forward, as mentioned, I think we're heading into a pretty substantial financial inflection point as we get these other launches through. It's going to have a high-performing financial growth profile. But balance that with that our business model is to find underappreciated medicines and kind of prove people wrong. All of these, they're show me stories, got to get out and build the brands. And I think there's a lot more of them out there that we can go bring in.
Yeah.
I'm more interested in what can we buy rather than the other.
Beautiful. Personally, I like that answer a lot because, as I said, we need this in biotech. As you think about now this upcoming transition to profitability, we see different companies navigate that differently. Some try to make that transition quickly because you kind of know you're on the cusp of now being valued by cash flow, not revenue. And if that transition is too slow, that may have untoward consequences for the stock, right? You'll be a very high multiple PE story. Is there in general, as you kind of reach this point, an urgency to get to meaningful profitability sooner rather than later, or do you look at it different and say, "Oh, we can take our time because we'll still be revenue valued for years from now?
To answer it in a slightly different angle, we look at the new product acquisition lens for value creation, so NPV adds, and less about P&L management. But mixed with that is we want to make sure that we're not creating any kind of financing need or overhang. It's less of managing towards very near-term profitability. I think though, as you go out, not that many years, just the overall launch expectations for these medicines we have coming up, it's going to change that story.
Yeah. Well, can't wait to see how this all evolves. Chris, thank you so much for joining. Thanks everyone for coming out.
Yep. Thanks.