Great, good, good morning, everyone. My name is Ted Tenthoff, and before I begin, I'm required to point out certain disclosures regarding the relationship between Piper Sandler and our next presenting company, Fulcrum, which are posted at the back of the room and also at the registration desk. So Fulcrum is conducting the phase III REACH trial of losmapimod in FSHD and also has recently gotten a clinical hold lifted to recommence a study for pociredir in sickle cell disease patients. Here with us from Fulcrum today is President and CEO, Alex Sapir, and also Iain Fraser, Chief Medical Officer. Thanks for being with us.
Thanks for having us.
Thanks, Ted.
So I'm going to start off with your most advanced program, losmapimod. Perhaps you can start off by describing facioscapulohumeral dystrophy, or FSHD-
Yep.
and really the therapeutic role of p38 inhibition.
Absolutely. Yep, and, thanks for, thanks for having us, and thank you all for joining. So as Ted mentioned, the disease is FSHD, stands for facioscapulohumeral muscular dystrophy. The disease mainly affects muscles in the shoulder and the humeral muscles, although patients can have... All of their muscles can be impacted, including some of the leg muscles.
Mm-hmm.
What these patients essentially experience is a slow, progressive decline year-over-year in their muscle function, to the tune of about 5%-7%. About 25% of all FSH, FSHD patients become wheelchair-bound, and really, the cause of the disease is an overexpression of DUX4. So because of this overexpression of the DUX4 gene, that's really essentially what causes this this muscle breakdown and this loss of muscle function in the single digits year-over-year. You mentioned p38, so losmapimod, which is our phase III study that is currently has completed enrollment in our phase III study.
It is a p38 alpha/beta MAP kinase inhibitor, and essentially what losmapimod is able to do is to inhibit that overexpression of DUX4, and therefore, by doing that, losmapimod has been able to show that we can preserve muscle function.
That's really helpful. Now, this is going back a little bit, but you guys did report the phase IIb ReDUX4 data-
Yep
on losmapimod in FSHD. Remind us of what that data told you, and then we'll get into the phase III trial.
Absolutely. Absolutely. Yeah. So just as a quick reminder, the phase II study was an 80-patient study, 1-to-1 randomization, placebo and active. The patients in the active arm received, 15 milligrams of losmapimod BID, so it's a twice-a-day oral, daily, oral dose. And essentially, what we were able to show is that, in patients that were enrolled in the active arm over that 48-week period of time, essentially, we were able to preserve their muscle function. When you compare that to what was seen in the placebo arm, those patients in the placebo arm, as I mentioned earlier, experienced about a 7% decline in their muscle function over that 48-week period of time.
I think what's also really interesting is what we observed in the open label portion of that study after the 48 weeks, and for those patients that were in the placebo arm, for the initial 48 weeks, and that switched over to losmapimod in the open label extension. Essentially, what we saw was that preservation of muscle function-
Mm-hmm.
But they were never able to regain that 7% of muscle function that they lost during the first 48 weeks.
Right. So, you know, how big of a deal is that? Like, what is the lifestyle of these people? You know, what could maintenance of that muscle function to that degree, how could that impact their lives?
Yes. Iain, you want to take that?
Yeah, yeah, absolutely. So as Alex said, the disease is relentlessly progressive year on year, and the patients, often because most of the cases are familial, have some acknowledgment that they've seen folks go through this before, and they know that for a significant proportion of them, they end up wheelchair-bound. And so I think that's top of mind for many patients, is that that's what lies ahead of me, even though my lifespan may not be impacted. There's significant mobility associated with that decrease-
Sure
... in mobility that occurs, inability to conduct activities of daily living, general weakness, being able to use their upper extremities. And then one aspect that's not that well acknowledged is because they lose some of their facial muscle expressions, their social interactions are significantly inhibited as well, because they don't appear to be laughing at a joke or, you know, providing the usual facial cues that people do during interactions. And so people kind of regard them as they're odd, or they're socially awkward or inadequate, and that's a big, big component for some of the patients. So there are multiple ways in which this relentlessly progressive disease impacts their lives, and they kind of have a sense of what lies ahead at all stages.
Yeah. So you mentioned that you've completed enrollment, excuse me, of the phase III REACH trial. Walk us through the trial design here. What are the primary endpoints? When do you anticipate reporting data?
Absolutely. So again, similar to the phase II study, it is a two-arm study, one-to-one randomization, placebo to losmapimod, again, 15 milligrams BID. Initially, the planned enrollment was 230 patients. That puts us at about a 95% powering to detect a statistically significant difference. The primary endpoint that we're looking at is can we essentially, through this measure called relative surface area or RSA, which is a score of sort of how well those muscles are being preserved. Essentially, what we're The primary endpoint is designed to show can we sort of preserve that muscle function in the patients that are on losmapimod compared to the patients that are on placebo, and we would expect to see that sort of slow, steady decline during that 48 weeks of the trial that I mentioned earlier.
We have completed enrollment. We actually over-enrolled, not intentionally, so we enrolled about 260 patients. I think that that's really just a testament to, the unmet need in the marketplace. There are no treatment options for these patients currently. So we did over-enroll. That took our powering up slightly to about 96%. And then we would expect to, because it is a 48-week study, we have, shared publicly that we'll be sharing the top-line results in the fourth quarter of 2024.
Great. And walk us through this market opportunity. It's actually one of the larger-
It is.
-muscular dystrophies.
Yeah.
Again, as you mentioned, there's really no approved therapies-
That's right.
So you could be, you know, launching with a first disease-modifying agent in a large orphan condition. Tell us about some of that initial thinking.
Absolutely, and I'm glad you brought that up. So this market is about the same size as DMD, so there's about 30,000 patients in the U.S. that have FSHD. The majority of those patients are treated at a handful of neuromuscular centers and MDA centers by neuromuscular specialists. I think for us, the goal is to get this drug read out the top-line results, file the NDA in early 2025, get this drug approved in late 2025, early 2026, launch this ourselves in the U.S. I think we can do that with a fairly sort of modest amount of commercial investment, given the fact that the majority of these patients are treated at a handful of neuromuscular centers here in the U.S.
We would be looking to find a commercial partner, ex-US, so we don't have plans to launch beyond the US. But it's something that I think that we can do and do quite successfully as a small company. And I think the other two interesting elements that I'd like to bring up is there's a lot of development dollars in FSHD right now. In fact, the last time I checked, I think there was over 19 compounds that were-
Ooh!
being studied for the treatment of FSHD. The closest competitor that we have is Roche's product. It's an anti-myostatin, and they're not planning to read out their phase II study until the second half of 2024. So that gives us about, we believe, somewhere between a 2-3-year head start in this marketplace before the next competitor comes to market. So it gives us a really, really nice runway to essentially sort of-
Mm-hmm.
Own this market. The other thing that we've also done is we've done some initial work with payers, and payers expect that, given the fact that this is a rare disease, they would expect sort of rare disease pricing of losmapimod in the sort of hundreds of thousands of dollars range.
Yeah.
So, yeah. So it's an exciting time-
Yeah, it's a great position to be.
Yeah.
You know, I'm so glad you mentioned that, market leadership, because you really could become standard of care, and then future therapies would be add-on or-
Exactly.
We'd see how all of that plays out, where the data comes in, but that's really interesting.
Hundred percent.
So I'm just going to pause there for a moment and see if there's any questions, moving on from losmapimod to pociredir. So switching gears here, it's been quite a rollercoaster ride, with your sickle cell disease program. Maybe you can start off by describing the target and how it impacts fetal hemoglobin.
Sure, sure. I've been talking a lot, so I'll turn this portion over to Iain.
Absolutely. Happy to do that. Yeah, so, so, pociredir targets one of the subunits of the PRC2 complex, polycomb repressor complex, that is responsible for methylation of histones, so it regulates gene expression. And by inhibiting that complex, you decrease the histone methylation and alter gene expression. As it turns out, when you do that, one of the most abundantly upregulated genes following that inhibition is the HBG gene, which encodes the globin component that contributes to fetal hemoglobin. So inhibiting the PRC2 complex results in an expression or increased expression of fetal hemoglobin. And we know that in sickle cell disease, levels of fetal hemoglobin correlate very closely inversely with the severity of sickle cell disease.
We know that from genetic conditions like hereditary persistence of fetal hemoglobin, but also pharmacologically with hydroxyurea that's been in the market, that if you upregulate fetal hemoglobin in patients who have sickle globin mutations, that their clinical course can be significantly altered. And so we're essentially mimicking that in a pharmacological sense and increasing fetal hemoglobin as the underlying mechanism of action.
We could get next week approval of a gene-edited therapy, which even further kind of cements that mechanism.
Yes.
Although I think there's probably some limitations to how broadly a gene-editing therapy would be used, this could really be an oral therapy that kind of replicates that mechanism. Congratulations on getting the FDA hold lifted. I know that was a big overhang and consumed a lot of, of all of your time. You know, walk us through the data you've reported to date. What were some of the trial modifications that you're making, and when could you resume dosing?
Sure. Yeah, so I think the key clinical data that we have to date, which is data in patients with sickle cell disease from the early parts of this phase Ib study, where we have data from a 2 milligram once daily dose, a 6 milligram once daily, and then a few patients, 3 patients, at the 12 milligram once daily dose. And what those data showed was this dose-related increase in fetal hemoglobin, which is what I was alluding to earlier. And in that 12 milligram cohort, even though there were only 3 patients at the time of the clinical hold, and even though we only dosed for 6 weeks at the time the hold was instituted, so we weren't even fully through the dosing period.
We saw about a 10 percentage point increase in their fetal hemoglobin over that short period of time. And that gives us a lot of encouragement that we're going to see even greater increases as we increase the dosing duration out to three months and potentially later on, even beyond that. So that's the first part in the patients, and then that's very much in line with what we'd seen previously in healthy volunteers in our initial dose escalation study. Where instead of looking at the fetal hemoglobin at the protein level, looked at the mRNA from the gene level, and showed a very clear dose responsiveness as we went again from 2 milligrams once daily to 6, from 6 to 10 in that study, and then from 10 to 20.
At each step, we're seeing incremental increases in that, in the gene induction in that study. So we expect that the 12 is really going to continue to deliver what we've already seen in a few patients. We think it's going to be even more as we increase the duration of the dosing, and then our intent is to go to the next step, which would be from 12 to 20, where we'd expect to see yet further incremental increases in the fetal hemoglobin. So that's the immediate next steps. It consists of two cohorts in the study. So we're going back, we're reinitiating the 12 milligram cohort. Expect to enroll 10 patients there. The cohorts are designed sequentially. That was always the study design, so that has not changed.
There's a data monitoring committee that'll review the data after the first eight patients have gone through four weeks. That'll then trigger the 20 milligram cohort, so we expect that to roll off. And once we've enrolled the ten patients at that 12 milligram cohort is when we expect to be able to provide some data readout on that. So that's, you know, kind of where we are at the moment. In terms of your question of what are the modifications of the trial-
Yeah.
So, as I alluded to, the overall structure of the trial, these sequential panels of 10 patients, has not changed at all. The dose escalation scheme has not changed at all. What we were working with FDA around the time of the hold was really redefining the patient population.
Yeah.
It's a more severely impacted patient population, and it's really a question of balancing out, you know, what are the potential benefits of the therapy? What are the potential risks, and how do we balance them out? Since we're really early in development, it's a phase I study. Obviously, the benefit side is still early days, as encouraging as it is, and so we're needing to generate more of those data to better balance out the risk-benefit ratio, and that's really the immediate goal of as we're reinitiating the study.
I believe, too, when you're not allowed to combine with hydroxyurea, right?
Yes, that, that's correct.
Yeah.
I should have mentioned that. That was one of the requests.
Sure
... from the agency. Important to emphasize that that was not based on any specific preclinical combination data or anything else along those lines. It was more a question of hydroxyurea for sickle cell, carries a black box warning for myelosuppression and for malignancy. And FDA said, "Well, there's some concerns around the PRC2 mechanism of action-
Right
for malignancy, so we, FDA, don't think you should be combining of, you know-
Yeah
... a black box malignancy warning and a potential investigational compound.
Yeah.
So it's a kind of theoretical concern.
So let's just pick up on that for one moment, because hydroxyurea is not a great drug by any means. You mentioned the black box warnings, but it is still pretty widely used in a big, for a big reason, because it's one of the only real options patients have, and there's a couple new therapies that are coming along.
Mm-hmm.
You know, how would you be able to develop pociredir, you know, kind of in the intermediate term, if you're not able to combine with hydroxyurea? You know, what could that ultimately mean for the market opportunity?
Yeah, I, I think that's a great question, and I think the way I would sort of frame it at a high level is that the patient population, as it's defined for the clinical trial now coming out on the hold, is not where we envision the patient-
Right
population is going to be at the end. I think it's very much a means to an end. I think it's really important that we generate and demonstrate the potential efficacy for this agent, and I think, again, based on what we've seen already, we're very optimistic that that'll be the case. That the levels of HbF, fetal hemoglobin induction that we can see will start to move into the range which is likely to be transformative, so in the high 20% absolute level. And the other piece of it is that, you know, the... One of the
... One of the concerns about the hydroxyurea mechanism is that it's essentially myelosuppressive. And you talk to physicians, they dose hydroxyurea to the point at which they see evidence of myelosuppression.
Right.
The white counts are going down, the platelets are going down. That gives them an indication that they're at a dose that's a good dose-
Mm-hmm.
to be given, but it has, carries with it the baggage of that myelosuppression. The mechanism for pociredir being completely distinct from that of HU isn't associated with that, and the data that we've seen to date in the patients doesn't provide any indication that we're seeing myelosuppression.
Yeah.
I think there's a clear differentiation at that level as well.
Yeah, Ian, I really appreciate you explaining that, because again, as you said, this is we're kind of stepping out of the basement here, where we're going to establish some data, really see what it shows you, and then likely, hopefully, with the opportunity to treat broader swaths-
Right
-of patients. One last question on this, if I may, just before we move on a little bit. You know, these are severe patients. What percentage of that population kind of meets this new higher risk criteria? And an additional question, I mentioned, the, you know, I guess it's CASGEVY, maybe is the new marketed name for exa-cel, the gene editing agent. We're also have a PDUFA date coming up for a gene therapy. How do you see those therapies kind of changing the landscape in these-
Sure.
More severe patients?
Yeah, so when we first had agreed on this new inclusion/exclusion criteria with the FDA, I think our first question was: Are there enough patients-
Yeah
-out there? And we did a fairly sort of extensive deep dive, looking at a lot of various different sources of data. And essentially, what we were able to conclude is that there's somewhere between 7,500 and 10,000 patients in the U.S. that meet this more narrowly defined inclusion/exclusion criteria that was agreed upon by the FDA. So somewhere between 7.5% to 10% of the patients meet that. And the fact that we need 20 patients, we felt really good that there's enough patients out there that we'll be able to effectively recruit from. I think as Iain mentioned, we see this as sort of a starting point and not an ending point.
The reason that I say that is, and it really gets to the second half of your question, I think what cell and gene therapy, what lovo-cel and exa-cel have been able to show is fantastic. They've been able to get patients up to the sort of 35% fetal hemoglobin, and what it's essentially been able to show is that these patients become cured. However, in order to participate in cell and gene therapy, it's a $2-3 million price tag. It's 2-3 months in the hospital.
Right.
It's myeloablation, which carries a set of risks associated with it as well. And so we do believe that there is a place for cell and gene therapy for sickle cell patients, but that's probably going to be a relatively small percentage of patients. When you then contrast that with what we've been able to show with 12 milligrams, with only six weeks of dosing, you know, there's a potential that we may be able to get with this oral once a day therapy, levels of fetal hemoglobin that rival that of the cell and gene therapies. And that to, that to us, is a really, really exciting place to be because we believe that pociredir has the potential to really transform the way that these sickle cell patients are being treated in the future.
That's a great point. So Alex, I just, with the time that we have, remaining, you guys ended the third quarter with a very healthy cash position.
Yep.
$257 million. How long does this fund the company? What's it enable you to fundamentally accomplish?
Absolutely. No, it's a great, great question. I think that's one of the advantages of Fulcrum, and one of the reasons that I decided to join when I did, is that we had a very, very robust balance sheet, and one of the first tasks was not having to go out and raise money in this environment. So, specifically, the answer to your question is it takes us out until early 2026. And it allows us, obviously, to be able to flip over the very important phase III losmapimod data card in the fourth quarter of 2024, but still have on the back end of that, greater than 12 months' worth of cash. And we think that that's a really, really strong position to be in.
Well, great. Awesome. Well, thank you.
Great. Thanks, Ted. Great-