All right. So let's go ahead and get started with the next fireside chat. My name is Dae-Gon Ha, one of the biotech analysts here at Stifel. For the next half hour, we'll be chatting with Mirum Pharmaceuticals. And from Mirum, we've got Andrew McKibben on the far left, VP of IR and Finance, as well as Eric Bjerkholt, Chief Financial Officer, right next to me. So, gentlemen, thanks very much for the time. As I always do with these fireside chats, I thought we would start off with leveling the playing field in terms of giving an overview of Mirum, the high-level story, or the pitch, if you will, and then we'll dive right into Q&A.
Great. Thanks, Dae-Gon. And thanks for having us. And we will be making forward-looking statements during the next 30 minutes. So please refer to our risk factors in our SEC filings. So at Mirum, we have three commercially available medicines. And we just reported a record quarter with over $90 million in revenues, with strong growth for all three medicines, which are Livmarli for Alagille syndrome and PFIC, as well as what we call our bile acid portfolio with Chenodal and Cholbam, with a number of approved indications, but primarily CTX for Chenodal and Smith-Lemli-Opitz syndrome for Cholbam. We expect continued growth from all three medicines headed into the fourth quarter and into 2025 and beyond, with strong growth both in the US and internationally.
Behind that, we have Volixibat, which is another IBAT inhibitor, which we're developing for PSC and PBC, two very significant indications with significant unmet needs. And we just in-licensed a new product candidate, which is ready to start phase II next year for Fragile X Syndrome, which we've renamed MRM3379. We're very well financed with nearly $300 million in cash. And in the third quarter was our first quarter where we were operating cash flow positive. So that's a happy new development for the company. So we like to call ourselves financially independent.
Okay. Great place to start. Let's start on the commercial front. You mentioned record quarter, but you also raised guidance for the full year to the tune of $330-$335 million. Just walk us back in terms of what you have seen this year so far, or any kind of a blip or pull forward that you saw in Q3 that led you to revising the guidance higher to that $330-$335 million.
Yeah. So for Alagille syndrome, we're continuing to execute according to plan. We've been pretty steadily in the U.S. We've been seeing roughly $2 million quarter-over-quarter growth. What's new in the third quarter was the beginning to see revenues from the PFIC indication, where we had expected the reimbursement discussions to take a little bit longer and not really see revenues until closer to the end of the year. But we're very happy to see that those discussions have gone well, both in terms of converting patients that had been on clinical trial to paid patients, but also starting to see de novo prescriptions. And so that generated some revenue in the third quarter, and we're expecting that to accelerate in the fourth quarter. And then internationally, we also had a strong quarter. And that's all for Livmarli.
And then for the bile acid portfolio, I think especially for Smith-Lemli-Opitz syndrome, I've seen a nice uptick that has led to strong growth for that franchise.
So within that PFIC side of the story, a positive surprise, as you characterized it. How would you maybe, going into a level deeper, break out between patients who have converted from the clinical trial on the PFIC side versus de novo? I mean, any thoughts you can provide in terms of how many patients have converted versus how many are de novo?
At this point, it's primarily conversions with a few de novo patients. But going forward, obviously, we think that the de novo patients will dominate the growth.
Okay. And let's think a little bit about the Alagille side of the story, because that's ultimately what you have more experience with in terms of Livmarli. Remind us what the label language says, specifically on the age cutoff, and what's been sort of the physician feedback as it pertains to uptake, patient compliance, patient satisfaction, and so forth.
For Alagille syndrome, both in the U.S. and Europe, it's two-to-three months is the cutoff. For PFIC in Europe, it's three months. And the exception is PFIC in the U.S., which is 12 months. But we haven't seen the 12 months as really being an impediment so far. And the earlier for Alagille syndrome, the two or three months is definitely an advantage, because those patients tend to get diagnosed quite early in life. And so getting them on treatment early is an advantage relative to our main competitor, Bylvay, which has a one-year cutoff for Alagille syndrome.
So some early doc checks we had done, the physicians were of the mindset that both Bylvay and Livmarli are pursuing the same mechanism, IBAT inhibition, for the same indication. So the age cutoff they consider to be a pretty meaningful driver, given that Livmarli has a younger age cutoff. And once you start, they don't really see the need to switch. But I guess you have a more firm understanding of boots on the ground. So what can you speak to in terms of compliance once patients start? Do you see kind of consistent inbounds, a consistent influx of patients, or how should we think about the growth trajectory over the medium to long term?
Yeah. So the persistence is good. We're seeing in the first year some drop-off, because some of them go to transplant in the first year. But after the first year, the drop-off, based on our experience to date, has been much lower. And that's why we're seeing continued growth. And the compliance is very, very high, because it's an indication where if you miss just a few doses, you can feel it. It comes back pretty quickly. And so we tend to see very high compliance. So happy with both the persistence and the compliance to date.
Then when you say discontinue within the first couple of months, I mean, do those patients ultimately come back? Because, as you pointed out, pruritus comes back fairly aggressively, fairly soon.
Not necessarily after transplant. Some of them will continue to have, or each might come back for some of them. But generally, if they go to transplant, I don't think we have good data on how many of them would come back.
So at this point, what's your general sense of market share as you guys see it on the Alagille side, given you have more experience in that segment?
We think our market share in the US is very, very high, probably in excess of 90%, I think, in Alagille syndrome. We do have that age advantage. We also have a formulation advantage for the little kids. There are some teenagers who would prefer a more solid formulation, which Bylvay has. We are planning to come out with a solid formulation as well to level that playing field. But those are more one-offs than anything else to date.
Okay. What about in terms of Chenodal? I mean, Chenodal was formerly under Travere. You guys got that bile acid portfolio, Chenodal and Cholbam. And you have an upcoming PDUFA date for Chenodal. What's been sort of the commercial progress you've seen so far? And as you anticipate that the decision could go your way, how should we think about that growth opportunity once sort of full-force promotional activity can commence?
Chenodal is standard of care for a very rare neurological condition called CTX. And we think there's about 1,000 patients, and it's about 10% diagnosed. So the question is, with approval, which gives us the ability to promote, can we improve the diagnosis rate? And we don't know, but we're going to try. And so we'll invest some resources after approval to see if we can move the diagnosis rate. And if we can, then that would justify additional investments. But we're not sort of beating the drum on that, because we're not saying it's going to be easy, but it's a potential upside.
So when you say it's a standard of care but not approved, can you talk about sort of the call points that you would need to employ once you do get the approval? And how does that differ from your Livmarli/Volixibat approaches?
Yeah, so it's geneticists as well as pediatric neurologists are the primary call points, and we have been calling on those already, but we don't have the ability to promote actively.
Okay. And just maybe finally on the bile acid portfolio, what should we make of the Cholbam progress? I mean, the way we think about it, Chenodal has that catalyst of an approval. But is Cholbam just going to continue being sort of a modest year-over-year growth, or is there an inflection that we should be thinking about on that?
With Cholbam, we do see some potential growth drivers. I wouldn't overstate the inflection. But there's one indication that is on label. So it's for bile acid synthesis disorders. And Smith-Lemli-Opitz syndrome falls within its approved label. To date, there had been really no data in this setting. And last year, some data was presented that showed a nice benefit in a portion of these patients. So we have been seeing use increase in Smith-Lemli-Opitz syndrome, and that may help the growth trajectory going forward.
Okay, so presumably linear kind of year-over-year growth, but not so much of an inflection every so often.
Generally, that's what I would expect. I mean, maybe the curve starts to bend up a little bit. But these have been growing steadily for the last 10 years and expect that to continue.
Right. Right. And presumably, we would get some kind of a full-year 2025 guidance in sort of a couple of months' time. So we can expect some additional commentary there. Switching over to Volixibat, which as of summer of this year started getting a lot more traction. Remind us of the difference between Maralixibat, which is now Livmarli, and Volixibat, sort of the strategy as to pursuing why Volixibat and Maralixibat separately, and why PSC and PBC?
Yeah. So in terms of differentiation, I mean, some of this just comes down to population size, right? Livmarli is targeting Alagille and PFIC. These are ultra-orphan settings. Livmarli is priced and formulated accordingly for pediatrics. Volixibat is targeting much larger settings. So there are about 80,000 PBC patients, around 30,000 patients in PSC in the US. So your pricing strategy is going to be different there. But effectively, they're both IBAT inhibitors doing the same thing. And what you do want to make sure of is you're just optimizing the dose for the disease, which is the whole purpose of our interims in June.
And so you guys are currently in two different phase II-B studies, one for PBC called VANTAGE, one for PSC for VISTAS. One thing that I think a lot of people are still trying to come up to speed on is the aspect of pruritus as an endpoint and how that might determine sort of your go-to-market strategy. So PBC, people are familiar with Seladelpar as well as Elafibranor. PSC, there's nothing approved. Can you sort of walk us back? What was sort of the evolution of pruritus as an endpoint in these two indications? And in particular, what's your sort of differentiation when you do get to the market?
Yeah. I mean, what's important about pruritus is that, one, it is one of the main symptomatic burdens in both of these settings. It's what patients are dealing with on a daily basis, and it's quite severe. It's also a clinical outcome. So that means it's an endpoint that confers full approval. So it's not a surrogate full approval, which is particularly important in PSC, where the approval pathway based on surrogates has been quite challenging. And there's still not clear guidance from the FDA on what a surrogate could be in that setting. Pruritus, as an outcome, would confer full approval for PSC, which is why we think we're positioned to be the first approved drug in this setting. And for PBC, it also carries the benefit of being applicable to the entire PBC population. So pruritus in PBC is common regardless of where your alkaline phosphatase levels are.
It's differentiated from the recent approvals that we've seen in that we're targeting the entire population, where pruritus affects 60% of patients. We see that pretty consistently in our data sets. Not just that last third that fails UDCA, essentially.
What do you make of the Intercept recent decision from the FDA? The FDA, basically, after the adcom, it was unanimously against full approval. And so FDA followed suit, not approving on a full approval basis. But yet they still maintain accelerated approval. So it's not fully retracted. So does that put the pruritus kind of strategy more strong or advantageous position?
I think with the pruritus strategy, it's more about the population you're looking at. There was a lot of drama around this decision, and I think for the patient community, a bit unfortunate, since it sounds like people know how to use OCA in that second-line setting. But from a pruritus perspective, there are roughly two-thirds of the population that don't have anything. If you're in the second-line setting, PPARs look like they may have some benefit, but the two-thirds that are not there have no treatment options, and that's really the attractive aspect for us about pruritus as an endpoint for these patients.
Okay. Let's go into your two trials, specifically the interim data update. If you wouldn't mind just reminding us what you saw from VANTAGE, and then we can chat a little bit more about VISTAS separately.
Yeah. So really excited with the interim data we saw from VANTAGE. We looked at two doses of Volixibat, 20 milligrams and 80 milligrams twice daily versus placebo. Both showed about 2.3 placebo-adjusted improvement in pruritus. So an absolute change of 3.8 points on a 0 to 10 scale, which was fantastic, statistically significant with p-values of less than 0.0001. So we were extremely happy with that result. Decreases in serum bile acid. So the IBAT inhibition was kind of doing everything you'd expect and had a very pronounced effect on pruritus, which has allowed us to select the dose for the confirmatory portion, and that's currently ongoing.
Right, and that's the 20 milligram BID.
Correct. Yeah.
So I guess another quick question on that is, why not just at this point cut it, given the statistical significance that you're seeing on the functional outcome, and approach the FDA? Is there something required from the FDA that says you need to go through a full study?
Yeah, exactly. And that's part of it. I mean, very happy to see stat-sig on such a small population, which I think kind of speaks to the pronounced effect of IBAT inhibition and cholestasis. And we've seen that kind of across the settings where we've studied it. But it ultimately comes down just to kind of regulatory expectations. Typically, they like to see around 200 patients in a registrational data set. Some of that is safety database, which is why we have this confirmatory portion that we're enrolling right now.
The enrollment guidance is 2026.
Correct.
It is a fairly large population. Are you guys making a conservative estimate here? I mean, I would imagine with good interim data, the word will spread, and people might be more interested and therefore expediting enrollment. So how should we think about that enrollment cadence?
I mean, it's going really well. I mean, we've had a lot of engagement with investigators coming off that data and the patient community. Engagement with the patient community is a really important part of commercialization and development on the rare disease side. Really happy with their responses and their support, so I'd say enrollment in both studies is going very well, and I think as we continue, we will likely narrow that guidance, but for now, it's 2026.
What was sort of your latest interactions at AASLD? Because that's obviously a big liver meeting, and I'm sure you get to expose yourself to a lot of the hepatologists on the field.
Yeah. It's still going, and the interactions there were all very positive. We had data on Volixibat, obviously, and data from Livmarli, too, in Alagille and PFIC, which all very supportive of the benefits this mechanism can have in cholestasis, both on serum bile acids and how that translates into long-term outcomes and on pruritus.
One of the competing molecules also in the IBAT inhibitor space is Linarixibat from Glaxo, and we can't be 100% confident in the specificity of clinicaltrials.gov, but I think the primary completion date was October 28.
Yeah.
So kind of curious, given the similar mechanism, what should we be thinking about from a read-through standpoint? Is there something that makes the GLIMMER trial data relevant for you guys or somewhat less relevant? And in what respects?
Interestingly, our view on the GLIMMER trial was we expected it to be positive. They actually press released today that it was positive. No data in the press release. Not terribly surprising. I mean, their phase II data looked pretty good to us, and we know IBAT works in these settings. It's really a question of how much benefit are they driving. I think that question remains. The improvements that we saw in our interim data, and caveat that it's an interim, were some of the largest improvements in pruritus that we've seen in the PBC space. We think we may have an advantage there. Now it kind of depends on when they share that data, and we'll confirm it.
Got it. Let's quickly pivot to VISTAS. I mean, there is not a lot disclosed from that interim update, recognizing it's a blended update. But how should we think about from an optimism standpoint? Like, why does this keep you guys optimistic or enthusiastic as we head into the full enrollment completion in the second half 2025 and the top-line data thereafter?
Yeah. I mean, across cholestatic settings, we see a profound impact on pruritus with IBAT inhibition. We saw that in the PBC study. And with VISTAS and PSC, it's a smaller population. And so we structured a blinded interim analysis to help, or at least provide a path to keep the study efficient, if we saw an effect at the interim that was predictive of a positive final data set. We clearly saw that. We passed a threshold that was predictive of positive final data for efficacy and safety. And so that allows us to continue the study as is, which effectively just shortens the study because you need fewer patients to get to that final data. So we feel confident. I mean, we've seen IBATs work in PSC. There was a proof of concept with Livmarli, but it feels like it's moving in the right direction.
Would you say biologically or physiologically PBC or PSC are more prone to clinical benefit on the IBAT inhibition, or is that less well-defined?
It's less well-defined. I mean, you typically see or hear more about pruritus in PBC, in part because it's a larger population, so I think you're more likely to hear about it, but it's really the commonality of cholestasis. When you have cholestasis, impaired bile flow, and the resulting pruritus, addressing that bile accumulation has a profound impact on pruritus, and we see that across various settings, regardless of what the cause of cholestasis is.
At this point, are we pretty confident that these are both going to serve as registrational trials for full approval?
That's how we've designed them. We have feedback from the FDA on endpoint, the statistical analysis plan, study size. So we've positioned them as best we can.
So maybe we can make the final pivot to MRM-3379, which is the newly introduced Fragile X syndrome. Walk us back to sort of what was the origins behind this molecule, and how does it fit into your overall strategy for the Mirum story?
Yeah. So this molecule, it's a PDE4D inhibitor. It was developed, I think, out of Dart NeuroScience. And I think their initial mission was looking at various treatments for Alzheimer's, among other things. PDE4D has been a candidate for some of these neurological disorders. We think it applies extremely well to Fragile X syndrome because effectively, in this setting, you have a mutation of the FMR1 gene that ultimately results in depressed levels of cyclic AMP in the brain. PDE4D specifically converts cyclic AMP. So inhibiting it helps restore those levels pretty clearly. And you see that in preclinical models. That plays a very important role for proper synaptic function, which affects learning and memory, and also just balance of excitatory signaling in neurons, which is why in FXS patients, you see impaired learning and memory and also behavioral disorders, so high anxiety, hypersensitivity.
What got us very excited about this was in both preclinical and clinical settings, inhibition of PDE4D showed really nice and, in the clinical side, statistically significant impacts on learning and memory. So really good rationale for the compound, attractive economics. So we really like the risk-reward profile of it. And it fits nicely with the capabilities that we're building on the rare neurology side.
Right. It leverages sort of the CTX build-out that you're anticipating by December.
Exactly.
Can we maybe just quickly, are you planning on presenting any of that data? Because obviously, PDE4D, there is a precedent out there. And to try and figure out the differentiation, the data would obviously help.
Yeah, yeah, well, I think we'll get something out. Coming from a much smaller company, they hadn't published very much, so we're kind of going through some of those materials, and I think it would be helpful to put some of that out there.
How should we think about, I have a very difficult time pronouncing this drug, Zatolmilast from Shionogi? That obviously has some clinical precedent. Same mechanism. What's your angle there? And how should we think about your probability of success or differentiation vis-à-vis what they might be presenting along the way?
Yeah. I mean, it clearly had nice phase II data. And they're running a phase III currently, which we actually expect data later next year. So a lot of good learnings from that program that we'll work into our phase II. From a differentiation perspective, they're both PDE4Ds. We have a higher brain-to-plasma ratio, which we think could be an advantage.
Yours is 5 to 1, right?
Right.
Brain-to-plasma.
Yeah. It's 5x.
Yeah.
Theirs is quite a bit lower.
Okay.
So it's brain preferential, but not nearly as high as ours. And I don't have the exact ratio, but we're a couple of fold higher. And effectively, that means you're getting more PDE4D where you need it. So that could help with your dosing. But we'll see. I mean, that's something we'll be exploring in the phase II.
Okay. So similar to Glycin and its read-through to Volixibat, are we basically making the supposition that whatever they present from Shionogi's side, the brain penetrance is going to be the differentiation that could lead to better efficacy?
Yeah, that is our hypothesis around this compound.
Okay. Okay.
So for both of them, we think there's an opportunity to be best in class.
Do you see the PDE4D inhibition as sort of Fragile X only or as a beachhead project to something much larger in the neuro space?
Right now, it's Fragile X. I think as we get to know the program, we'll think about other expansion opportunities if it makes sense and is a fit. It's certainly a compelling mechanism. And I know it's been explored in other areas. But for us, Fragile X is squarely in focus and on strategy. So I think we'll continue to evaluate other opportunities, but we don't want to distract ourselves by going too big, too fast.
Got it. Eric, you're probably memorizing responses to this follow-up question, which is BD. Obviously, you've done this BD. You get the question a lot. At this point, operating cash flow positive being a milestone, do you want to kind of lean onto that?
Raise the commercial operating margin, if you want, and we do expect that we're going to see significant improvement in those margins next year, and that would generate cash flow that we can think about how best to invest to continue to grow the company.
Any loose guidance on when profitability might become more of a story for you guys versus cash flow?
No. I mean, we have some very significant non-cash charges. So it would take a while to be GAAP profitable. And that's not really a goal. The goal is to continue to grow the company.
Okay. Well, with that, we're a minute over. But thanks very much, gentlemen, for spending the half hour.
Thanks for having us.