I'm Ellie Merle, one of the biotech analysts here at UBS. Very happy to have Mirum Pharma here with us at the UBS Biopharma Conference in Miami. Joining us from Mirum is Eric Bjerkholt, Chief Financial Officer, and Andrew McKibben, VP, Investor Relations and Finance. Guys, thanks so much for joining us. Maybe just to kick it off, you guys have a pretty wide portfolio in both commercial and clinical programs. Can you give us an overview of your pipeline and what you see as the key milestones over the next year?
Absolutely, and, Ellie, thanks for having us. It's really fun to be here. And, before I start answering the questions, let me say both Andrew and I will be making forward-looking statements, so please refer to our SEC filings. So, we are building a leading company in rare diseases. Currently, we have three approved products for liver disease: LIVMARLI for Alagille syndrome, we have Chenodal for CTX, and Cholbam for bile acid synthesis disorders as well as SLOS. And if you take our Q3 revenues and annualize, we have a $260 million run rate, and we see significant growth potential across all three programs.
We ended the quarter with $306 million in cash, so very well-financed, and yeah, look forward to continuing to grow the company with a lot of milestones coming up that we look forward to talking about in the next 20 minutes.
Okay. And on that note, I mean, you've guided to cash flow break- even in the fourth quarter. How are you thinking about balancing R&D investments as well as potential profitability going forward?
So as I said, we're very well funded, and our goal is to continue to grow the company. So we don't have a specific goal to be cash flow positive. We hope that our clinical trial results coming up will justify further investment in R&D. But I think given the growing revenue base and good margins in our commercial portfolio, that will help fund a lot of our growth going forward.
Absolutely. So what are the main contributors to LIVMARLI growth you've been seeing, and what do you expect to see from the growth trajectory going forward?
So the growth to date has come from Alagille syndrome, where we think the addressable market is 25%-33% penetrated. So there's additional growth potential in Alagille. And as you might recall, we have a PDUFA date for PFIC in early March, and assuming that gets approved, there's additional growth opportunities there. And then internationally, we're also seeing good growth, and we're in the middle of reimbursement negotiations in a number of European countries and hoping that those will, you know, have a satisfactory outcome and will continue their growth internationally. For Chenodal, we are filing an NDA for CTX in the first half of the year. CTX is a rare disease that we believe is only about 10% or so diagnosed.
If we get approval for CTX, we see significant growth potential there. With Cholbam, there's new data in a rare disease called SLOS that has caught people's attention, and we're seeing increased interest from that patient population in using the medicine for that indication.
Maybe just on Alagille and PFIC, can you talk to the competitive landscape and how you see that impacting your trajectory, if at all?
Yeah, sure. So in Alagille, we've been approved since September 2001. Recently, BYLVAY was also approved in June. Ultimately, we've had very strong successive quarters in the US and haven't seen much impact. It's not to say that they won't do something there, but we've got a very strong profile compared to BYLVAY, a broader label, formulation that is very well suited to pediatric dosing. U ltimately, while we do expect there to be competition, we haven't seen much to date.
Maybe turning to biliary atresia, can you tell us sort of the rationale here and what we should be looking for in the upcoming data?
It's the most common pediatric, cholestatic diseases. Over 400 in U.S. and Europe are diagnosed every year. And ultimately, there are no effective treatments in this setting. It's a highly progressive disease. The vast majority of children progress to liver transplant at a very early age. So, there's a real, we see a real opportunity. And our approach in this study is really focused on bilirubin. Bilirubin is the most important marker in this setting. It is highly prognostic of a patient's trajectory and frequently used the key decision criteria in transplant timing. So our study is a six-month placebo-controlled study looking at bilirubin as the primary endpoint. We have confidence that, you know, we've shown improvements in bilirubin in PFIC.
So in this setting, we'll be looking at change versus baseline, compared to placebo at 6 months. We'll be looking at other elements as well, including outcomes, where we expect to see some, but those will really be tracked over the extension portion of the study. But you know, ultimately, showing an improvement on bilirubin is really meaningful in this space, just given how important this measure is, you know, for you know, prognosis and progression in these children.
Absolutely. And in thinking about the development strategy, what would be the theoretical next steps after data? Is there a potential for accelerated approval and opening those conversations? And you mentioned bilirubin, how should we think about what would be clinically meaningful there in terms of the change?
So there certainly is a potential for accelerated approval, and, you know, that is a case that we have positioned ourselves to make. That's a combination of our study data and also natural history data that demonstrates in kind of a paired fashion, how bilirubin is a key prognostic indicator of time to transplant. So that's gonna be our approach. We're doing this natural history work in parallel. That's been successfully done in the setting of PBC and working with the same statisticians who established Alk Phos in that setting, so a very similar approach there. So it really kind of comes down to the data and the argument that we'll be able to make with the FDA around bilirubin as an approvable surrogate in this setting.
Great. And since you mentioned PBC, what should we be looking for and the timing of getting sort of the interim data in both PBC and PSC?
So really excited about the interim reads in both of these studies. Those will be in the first half of 2024. And I'll start actually with PSC and then move to PBC. So PSC is. There's a significant unmet need here. There are no approved therapies, and you know, really it's traditionally been a challenging development path going after fibrosis. We're very uniquely positioned in that our study is based on pruritus, and pruritus is an endpoint that is an outcome, so it confers full approval versus surrogate approval. So really excited that this study is, you know, potentially the first positioned as registrational and potentially could be the first approved therapy in PSC. So when we look to the interims, for us, this is really about a dose selection.
The PSC interim will be blinded, and we've set a very high bar for success here in terms of dose selection. Obviously, we want, we don't want to continue a study that hampers its ability to meet a registration-enabling outcome, and so we've oriented our decision criteria around that. So what we would share is a dose is selected, and the study continues. That way, in that sense, you would know that we've had a positive effect. We're confident in that effect supporting the registration-enabling ability of this study, and the study would continue. PBC is a little bit different. PBC, same study design, but that interim analysis will be an open analysis, so we will share top line, which would consist of pruritus, serum bioassays, and safety, for example.
Great. And since I guess we'll be getting the data in, or at least the more detailed data from PBC, how are you thinking about what's clinically meaningful and commercially relevant in the context of the landscape and what you're hoping to see there?
Across all the cholestatic type diseases, pediatric and adult, IBAT inhibition has shown really significant impacts on pruritus. And from our perspective, you know, we've seen 3 points + is what we'd be targeting. And so, you know, ultimately, clinically meaningfulness is generally a 2-point improvement, 1 to 2-point improvement, so we think we can do better. And importantly, as we went into these programs, we really paid attention to dosing. You see a dose-dependent response in terms of efficacy on pruritus across the development program or our development history. And we've really done a lot of work to make sure that we have optimized the two doses that we're going into in these studies.
We think that we're positioned to have a very compelling profile in both PSC and PBC.
Great. And I guess maybe in the context of PPARs, how do you think the IBAT inhibitors will compare in terms of the magnitude of impact on itch?
they clearly have an impact, and, it's not surprising. But in terms of, you know, relative comparisons, I think that, you know, with our dosing approach, our profile would be quite compelling compared to a PPAR. And I think just worth pointing out, too, that often in the context of PBC, you think about lines of therapy, and PPARs are really positioned for kind of the non-responders to urso in terms of Alk Phos , which leaves a significant portion of the population that would be eligible for IBAT inhibition in the first-line setting. In the second-line setting, also meaningful opportunity .
The data that we've seen to date, and look forward to seeing more, hopefully, in the coming days at AASLD, suggests that PPARs do have an effect, but only in a portion of patients, where you kind of see an optimal pruritus improvement. So if you see 40% of patients on a PPAR achieving a 3-point + or better, that's great. That still leaves a significant portion of patients who may not be optimizing their pruritus benefit, which would be eligible for IBAT inhibition.
And how should we think about the timelines for potential data from the confirmatory portions of each of these studies?
G enerally speaking, we think it'll take us about 12-18 months to fully enroll both of these studies, and then another 6 months from there to final data. Both of these studies are 6-month studies.
Got it. I guess from a regulatory perspective, help us understand what might be required in order to get a label for pruritus?
Well, frankly, we've been successful in that with Alagille. So the study designs that you know we're pursuing in both PSC and PBC, a lot of conversation with the FDA around pruritus as an approval endpoint, and a lot of discussions around the staff, too, to make sure that we are positioned to support a registration. Generally speaking, there's you know dynamics in how they want you to analyze pruritus and over what time period you want to analyze pruritus. We've done that in our PFIC study, and it's a very similar approach that we're taking in both PSC and PBC.
Absolutely. Maybe turning back to the commercial strategy, can you talk a little bit more about the rationale behind the deal with Travere and the value proposition of Chenodal and Cholbam?
Yeah, I mean, they fit really well with our strategy of rare liver diseases. It's the same call point. In fact, we talked to them when we were setting up our commercial infrastructure for LIVMARLI to learn how they were doing things, and so we ended up setting things up very similarly, and that made for a really smooth integration. Same call points, our sales people are to the extent they can, are now selling both of those programs. And then, we've also taken over a few of the salespeople who have joined us and increased the footprint into other settings, where we think there are patients that can be found and diagnosed.
So really smooth transition, very high synergies, and we're thrilled to have the programs. And as I said, we see opportunities to continue to grow those programs going forward.
And you recently reported data in CTX. Can you tell us a little bit more about the commercial opportunity there? And I know it's, it's available now, but medical necessity and just how filing will, you know, shape the opportunity.
Yeah. So, you know, very excited about that data. Very rapid and very significant impacts across, you know, the core biomarkers and markers of disease progression in this setting. So really well- positioned, kind of going into this NDA filing, in the first half of next year. From a commercial opportunity perspective, CTX is underdiagnosed. It often presents in specialties outside of pediatric hepatology. It may show up early as juvenile bilateral cataracts, for example. And it can be a difficult process for patients to get diagnosed because awareness of CTX is fairly low outside the hepatology setting. So from a opportunity potential, you know, we've positioned a portion of our sales force to target those specialists and help with that disease awareness. A label really helps you do that because it allows you to promote.
To date, CTX use has been, use in CTX has been driven by this, medical necessity status, which has that limitation of not being able to promote. So being able to take more active steps, to, shorten that diagnosis journey is really important, and so we're putting programming in place and then efforts in place to potentially impact that.
Maybe taking a step back, strategically, how are you thinking about potential for further business development or collaborations from here?
We'll be opportunistic. We do see a lot of growth potential in what we already have in-house, so we don't have to do anything. But it is our goal, as I said in the outset, to be a leading company in rare diseases. And if we can find opportunities that fit with that strategy and where we believe in what the value proposition is for those potential medicines and see how we can add value to them and they're appropriately priced, then we would absolutely be interested in growing the pipeline.
Really, makes sense. Maybe just going back to biliary atresia with two minutes left. Can you tell us a little bit more about the rationale for IBAT in biliary atresia and your confidence that this could work?
Well, yeah. So this is a cholestatic disease, and, you know, ultimately, cholestasis is defined as impaired bile flow. And IBAT inhibition directly addresses that, and we've seen that play out across pediatric and adult diseases very clearly, by effectively reducing that accumulation, systemically and importantly, in the liver, where that accumulation and prolonged exposure in bile acid, at these levels are hepatotoxic, does confer liver damage. So we know that we're directly targeting it. We have great data in other similar disease settings where we see serum bile acids come down, and we see bilirubin come down, which gives us confidence going into this study. You know, ultimately, this is a very severe form.
So that's why we're taking the approach that we're taking, is doing a six-month study to see if we can impact these key measures in a short timeframe. The timeframe matters here for these patients.
Absolutely. I guess, how should we think about the timeline for when you might engage with the FDA and when we could learn more about the strategy there?
It really depends on the data. And so, you know, data will be by the end of this year, we fully enrolled the study in May. Coming out of our data readout, where we will share top line, you know, obviously, we will be working towards that FDA dialogue as quickly as we can. We have our study component, we also have our natural history component that we're working on currently in parallel. So it'll be kind of a combination of those two efforts. But, you know, obviously, you know, everybody wants these to go quickly, and we just wanna make sure that we have a quality package going into that conversation.
Absolutely. Well, seeing as how it's November now, any more granularity you can give us on when before the end of the year o r no?
No.
It's okay.
Like we said, we said Q4 by the end of the year, and, you know, there's only so much time left.
Sometime in the next four weeks.
Oh, thank you. Maybe just to close things out, can you remind us of your key milestones over the next twelve months?
For the biliary atresia data by year-end.
Thanks.
March 13 is the PDUFA date for the PFIC indication. As we hope to file an NDA for TCGX in the first half of this year, and the INTRIGUE data, most of this data.
And then, of course, we hope to be able to report continued revenue growth over the next several quarters.
Great. Well, with that, thank you guys both for joining us, and thanks everyone in the room for being here and joining us in Miami.
Thank you. Thanks, Sarah.