Good morning. My pleasure to host this fireside chat with Fulcrum Therapeutics. I'm Joe Schwartz from the Biopharma Equity Research Team at Leerink Partners, and I'm very pleased to have Alex Sapir, CEO, and Iain Fraser, CMO, with us today to give us an update. Thanks for being here.
Yeah, thanks for having us, and thank you all for joining. Appreciate it.
Great. So maybe we can start, Alex, by having you give us an overview of the company's recent accomplishments and key initiatives and priorities for this year and the updates that you expect to provide going forward.
Yeah, absolutely. So for those of you that may not be as familiar with the Fulcrum story, we are a biotech company that is using small molecule to modify gene expression for a number of rare diseases where there's a very high unmet need. And we think there's a real sort of elegance to what we're doing using small molecule technology. We've got two programs currently in the clinic. Our latest program is losmapimod for the treatment of FSHD. Joe, you had a question about data readouts in 2024. We have completed enrollment in our phase three study and expect to read that out in the fourth quarter of this year. And if that study is successful, then we'll go ahead and file in some time in the first half of 2025 and launch ourselves in the U.S. and look for partners outside of the U.S. market.
Our other program is a product called pociredir for the treatment of sickle cell disease. Just by way of reminding everybody, in early 2023, that program was placed on clinical hold by the agency, but toward the end of last year, we were able to get off clinical hold. So we are back in the clinic now activating sites and getting that study back up and running. And that program is a very interesting program. Pociredir is an HbF inducer. And essentially, what we have been able to show prior to the initiation of the hold is that we were able to get patients to fetal hemoglobin levels, very impressive levels of fetal hemoglobin levels, after only six weeks of 12 mg dosing.
We are back in the clinic now enrolling patients in a 12-milligram cohort, 10 patients in a 12-milligram cohort, followed by 10 patients in a 20-milligram cohort. If what we saw prior to the initiation of the hold is what we see in these next 20 patients, it's a very exciting program, potentially being able to deliver fetal hemoglobin levels that rival that of cell and gene therapy, but be able to do that in a once-daily oral therapy. Two very exciting programs that we have in the clinic currently.
Great. Okay. Thanks for that excellent intro. So maybe we can start and dive into pociredir a little bit more. Can you remind us how you arrive at your or maybe back up a little bit even more than that and give us the overview of who you're able to enroll in the PIONEER study and then what proportion of the overall market does that population represent?
Absolutely. Yeah. Yeah. So one of the required and I'll have Iain dig into a little bit of the details about what the new inclusion exclusion criteria looks like. But one of the things that the FDA was interested in having us do is to more narrowly define the patient population in what is obviously a very sort of early phase 1b study. And maybe I'll turn it over to Iain just to give a little bit more detail as to what the new inclusion exclusion criteria is. And then I'll come back and talk a little bit about what proportion of the overall sort of market in the U.S. meets that inclusion exclusion criteria.
Yeah. Thanks, Alex. So there are two main components to the inclusion exclusion criteria. Previously, when the study initiated, it was an all-comers sickle cell patient population. So as long as you had sickle cell disease, you could be enrolled with no limitation on disease severity. We now moved to one category of disease severity. And there are different ways in which you can achieve that disease severity. One is the more traditional measure that FDA has relied on, which is the frequency of acute events like pain crises or other acute events over the course of a year. It's for pain crises over the previous year, is where we've landed with them on that. But we also have the option for severity in some patients who don't have acute events repeatedly but do have manifestations of chronic disease.
So renal insufficiency, pulmonary hypertension, right-sided heart failure is also another way that you can fulfill those severity criteria. So that's the severity basis. And then there's a second component, which is related to prior therapy. The expectation is that these patients would have tried and failed at least two components. One is for hydroxyurea, which is standard of care, and all patients are expected to have at least tried that and failed that. And in addition, at least one of the more recently approved therapies, voxelotor, crizanlizumab, or L-glutamine. So it's having tried and failed at least one of those. Or we have a special carve-out because we know that there are patients who might otherwise be indicated for those therapies but can't get them because of lack of access. So that is an acceptable criteria around that. So maybe I'll stop there, and Alex can comment on that.
Yeah. So just, Joe, to answer your question, we estimate that about 7.5%-10% of the overall 100,000 patients in the U.S. that have sickle cell meet this inclusion exclusion criteria that Iain spoke about. I think what's also really important to mention is that getting off clinical hold did not in any way change the duration of the study drug during this phase 1b study. So it's still three months, and the FDA had no concerns about the doses that we were using as well, the 12 mg and the 20 mg. So our goal, get these 20 patients in. Hopefully, we'll be able to see very robust increases in HbF.
And then we'll take that information back to the FDA and have a more complete discussion about the risk-benefit with the ultimate goal to potentially relax that inclusion exclusion criteria and thus be able to go to a broader set of the patient population.
Okay. That's very helpful. How is site activation going currently? When do you think we might get another data update?
Yep. Yeah. So I think Iain and I were both at ASH. We had a lot of conversations with many of the sickle cell thought leaders around the world. I think by and large, there was a very sort of strong interest in the idea of having a once-daily oral medication that potentially can get patients to fetal hemoglobin levels that rival that of the cell and gene therapies. Activation is going well. We've reactivated a number of the sites that were in the study prior to the initiation of the hold, as well as activated new sites. Our goal is to enroll, sorry, our goal is to activate a total of 20 sites in the U.S., as well as several sites in the U.K. and South Africa. We've stopped a little bit short of giving specific enrollment numbers.
I think what we really want to do is we want to make sure we've got sort of a good base of patients already enrolled, by which we can then provide a more sort of accurate prediction of when we'll be able to share the results of the 12 and the 20 milligram. I think having that base of patients, I think we'll be able to see what the enrollment trajectory looks like. We'll see what sites those patients are coming from. We'll be able to go back to the PI and find out from them how many additional patients do you have that meet the inclusion exclusion criteria.
I think at that point in time, I think we'll be in a much better position to provide more accurate and more concrete guidance when we'll see the results of the 12 and when we'll be able to share the results of the 20. We have said that one of our goals for 2024, and we're working very, very hard to that, is to be able to share some data in this study sometime in the back half of 2024.
Okay. Makes sense. And then remind us of what you've seen so far in terms of fetal hemoglobin increase and safety.
Yeah. I've been doing a fair amount of talking, so I'll turn it over to Iain to comment on that.
Yeah. The primary efficacy readout is based on fetal hemoglobin. We think that that's a key component of it. I think the work, particularly from the Vertex gene therapy, has reinforced this idea that increasing fetal hemoglobin is beneficial in sickle cell disease. So the data that we have includes both healthy volunteer data initially looking at the mRNA that encodes fetal hemoglobin. What we were able to show is a nice dose response as you went from 2 milligrams to 6 milligrams to 10 and then to 20, in each case seeing an increment in fetal hemoglobin induction. From 20 to 30, it seemed to flatten out over the two-week treatment period in that particular study. If it had gone longer, perhaps there'd been a separation there. But clearly, from 6 to 10 to 20, we saw that dose responsiveness.
In the patients that we've studied, we studied 16 patients prior to the clinical hold. We have at 2 milligrams, there's a sort of minimally observable bump in fetal hemoglobin in those patients, which is what we'd expect. You see a very nice induction as you go to 6. And then from 6 to 12, we see a really pretty sharp jump in the initial slope of that curve. We only had about 3 patients in the 12 milligram dose. With data, the longest that anyone was treated there was 6 weeks, so halfway through the 3-month period. And that particular patient for 6 weeks went from a baseline of 15.15% to 25%. So in just 6 weeks, a 10 percentage point bump.
I think the significance of that is that we think that in that sort of high 20% range is the range where patients become largely asymptomatic from their disease. At least giving an indication, even after just six weeks of therapy, that that 12 mg dose has the potential to get into that range.
Yep. Okay. What do we know about the potential for pociredir to work on top of Hydroxyurea?
Yeah. So the initial part of the study, again, prior to the clinical hold, allowed patients to come in naïve without any background HU or with HU. And if you look at those 16 patients, whether you were on HU or not, didn't seem to impact the initial slope of that induction. So we think that mechanistically, it doesn't really matter if you have HU on board. And that's certainly borne out in some of our preclinical work as well. As we're moving into the post-hold inclusion exclusion criteria, we're not able to dose on top of hydroxyurea at this time point. But there's no reason for there to be any reason why we shouldn't be able to see that in the future.
Okay. You're employing some observed dosing. Can you talk about where that arose?
Yeah. Yeah. It's interesting. In the initial part of the study, there were a couple of patients we're following. It's an open-label study, and we're following the fetal hemoglobin in real time. There were a couple of patients that didn't seem to be shifting their fetal haemoglobins. And so we went back to them. We measured drug in their blood. There was no drug in the blood. We went to the patients and said, "Hey, what's going on? There's no drug here." And it turned out they weren't compliant with the dosing. So we instituted at that time a cell phone-based mechanism by which the sites could call the patients every day and with a camera on their phone, observe them taking the dose. And sure enough, those patients that didn't have fetal hemoglobin induction suddenly started to bump their F, and you could measure drug in the blood.
So we've carried that over into the new version of the protocol. There's been additional refinements in the technology available now. So using an AI-based approach, the site doesn't actually have to physically call the patient every day. They can do it on their phone, and it gets captured on the phone and confirmed, and then a message goes back to the site. So there's a slight refinement in it, but it's essentially the same idea of observing the dosing.
Interesting. Okay. And then if we fast forward a little bit, is this something that you foresee yourselves being able to execute a phase three? And is this something that you would seek to take to market yourselves? How do you think about the development and commercial landscape in sickle cell for an agent like this? Yeah. Yeah. Yeah. I think for us, our goal right now is to all hands on deck in terms of getting these next 20 patients in, take that data back to the FDA. If that data shows what we think it will show, there'll be a more sort of complete discussion with the agency around, can the next study be phase two, three? Can it be a registrational study? And obviously, we'll have those conversations at the right time with the FDA.
In terms of us commercializing it ourselves, I think we're sort of a bit less convicted in terms of our ability to commercialize this ourselves relative to our later stage asset, FSHD, which we have very strong conviction that we can commercialize that ourselves in the U.S. Obviously, sickle cell is a larger market, much bigger players. You've got Pfizer, you've got Novartis, you've got a couple of other sort of emerging players that are coming in. So I think at this point, it sort of remains to be seen whether we'll decide to commercialize that ourselves or look potentially to find a commercial partner to help us, very, very different than, I think, our thinking around FSHD, which we have very strong conviction that we can commercialize that ourselves in the U.S. and do that very successfully.
Anything you would add to the sort of next steps on the clinical front?
Yeah. So I think the approach that we're taking based on our discussions with the FDA around the hold is to generate some data now with these new criteria, but with the understanding that the risk-benefit profile is going to change as we develop data, particularly as we can develop more data on the potential benefit side, and that that will allow us to go back to the agency and potentially be able to relax some of those inclusion exclusion criteria as we move forward to the next steps.
Okay. So one more question on pociredir. How clear is the linkage between fetal hemoglobin induction and clinical improvement, like VOCs? And so how clear is that in the field? And then how clear does the FDA view that relationship? If you're able to demonstrate robust improvements in HbF, do you think that will be sufficient or yeah.
I think it's a great question. I think there are two different answers for what's out there in the field and what FDA necessarily recognizes. I think there's a very strong link between magnitude of fetal hemoglobin induction and severity of disease. We've looked at this in a number of different ways and a number of publications. Clearly, once you get into the 25%+ range, you're starting to see that curve flatten out. If you look at acute episodes of vaso-occlusive crises, for instance, and there's a pretty marked flattening that occurs in that sort of range. I think it's been certainly borne out by the Vertex Gene Therapy data. They obviously were getting much higher levels. They can get into the 40% range. I don't think the data indicate that you need to be that high to see that dramatic reduction in VOCs.
Their presentation around the VOCs prior to and after gene therapy is really dramatic, where there's a high frequency and then there's nothing at all. So I think that that speaks to the mechanism very nicely. But you don't have to get into that high level. So I think there's good precedent there. FDA, in their comments around that gene therapy, said, "Yes, HbF is obviously important, but we know it's the fetal hemoglobin in each red cell. It's not the total HbF that matters." And I think there's emerging data that that is the case, and it's related to the distribution of fetal hemoglobin throughout the cells. So we're looking at that in the clinic. Certainly, in vitro, it looks like we get a pretty pancellular distribution when we look at CD34+ cell maturation in vitro. So that's potentially an advantage.
But I think FDA still has some questions around that linkage, although they've acknowledged that certainly is related.
Okay. Actually, one more question on pociredir. So how long can you treat patients now? Is there any potential to track people in an OLE yet and observe clinical?
Yeah. So right now, coming out of the hold, we're with the same treatment duration that we had going into it, which is a 3-month study. We pressed FDA on what exactly we need to get to the next step. And it was the standard FDA response of, "We'll see the data, and then we'll have a discussion and let you know." So right now, as Alex said, we're very focused on getting those 3-month data, being able to generate some additional HbF and safety data along with that to go back to them and then to move things forward from there.
Excellent. Okay. Let's shift gears to Losmapimod and the REACH study. Congratulations on completing enrollment, over-enrollment. Can you help us understand when we might see that data?
Yeah. So we've been very clear that we remain on track to be able to share that pivotal data. As Joe mentioned, a total of 260 patients. Our target was 230, but we had over-enrolled. And I think that's just simply indicative to the fact that these physicians and these patients that they treat have absolutely nothing for the disease. So very, very strong enrollment. In fact, we beat our timelines even during an era of COVID. So we remain on track to be able to share that data in the fourth quarter of this year. And if that data is successful, then we'll file in the first half of 2025. And then if that drug gets approved, we would expect a priority review.
We could potentially have an approved product on our hands sometime at the end of 2025 or early 2026, depending on when we file in early 2025.
Okay. And then what did you see in phase two, and how did that guide what you decided to evaluate in phase three?
Absolutely. Yeah. Do you want to take that?
Yeah. So the primary endpoint in phase 3, the REACH study, is an endpoint based on a reachable workspace, which is a camera-collected quantitation of the extent to which a patient can move their arm around the shoulder joint in space. That was one of the exploratory endpoints in the ReDUX4 study. But it's something that captures in a fairly integrated fashion the movement in the upper extremity, which is characteristically impacted in FSHD. So that's the primary endpoint in REACH. And we used the data that we observed from the phase 2 study, so the magnitude of the treatment effect as well as the standard deviation coming out of that study to power the REACH study. And using those data from phase 2 and 210 FSHD type 1 patients in the REACH study, phase 3, we had about a 93% power going into it.
With the 260 patients that we've enrolled in REACH, there were 242 FSHD type 1. So we've moved from 210 to 242. The power goes up a little bit to around 96% from there based on the same assumptions and the criteria. And then there are 18 FSHD type 2 patients in REACH as well. They're randomization stratified, so they should be distributed across the groups. And I don't think they'll have an impact on REACH.
Okay. I think maybe the only other relevant data point is the number of patients that are rolling over into OLE. So as of this past Monday of the 260 patients, I'm sorry, 86 patients had completed the Part A 48-week study, and of those 86, 84 had opted to roll over to OLE. So very, very similar to what we saw in ReDUX4. Greater than 95% of those patients are rolling over. Yeah. Interesting. And I think the powering is based on an effect size assumption of 0.05 change?
Yeah. So on the RWS scale, 0.05, the baseline in phase 2 was about 5.2 on that same scale, so almost a 10% magnitude change.
Okay. 10%. So what does that mean for patients? I think you're digging into that as we speak. Can you help us understand those efforts, what's entailed in contextualizing that?
Yeah. And it's exactly that. It's putting it into context. And that's what's emerged from our discussions with FDA, both the review division, which is neurology, and the COA division, the clinical outcomes assessment division. And because reachable workspace has not been used to approve any drugs before, since FSHD has no approved drugs before, they're wanting to understand the context of this. What does it mean for an individual patient? And so what we're doing as part of that, and we have agreements on what that overall package looks like, is gathering the data from individual patients. In parallel with phase 3, we have a couple of observational studies where we're bringing in patients, no loss of treatment, but measuring their reachable workspace, asking them about their activities of daily living, and being able to make some cross-sectional correlations between those two.
And then also doing a more extensive survey of patients about what is most important for you, what are you limited in, what are the things that you'd like to see improvements on. And then the third component is data from the REACH study itself, as it emerges, will be used to inform that clinical meaningfulness, including exit interviews for those patients asking them about their experience in the study. So all of those things will be compiled together into a separate COA dossier that'll be submitted alongside the NDA.
Okay. Interesting. And I know measuring DUX4 is next to impossible, and even DUX4 gene expression is super challenging. I don't think you're taking biopsies and even attempting that, but you did see some improvements in MRI. And were there any correlations with the clinical benefit of RWS?
Yeah. Yeah.
Can you talk about any objective measures?
Absolutely. So in REACH, in phase 3, there are no muscle biopsies. There's no direct measure of that. And I think the learnings from phase 2 is that the technical challenges of doing muscle biopsies in FSHD patients and getting reproducible biopsy content, even from one biopsy to the next, is pretty challenging. But there were a number of other endpoints in phase 2 that have been carried over into phase 3, not just clinical outcomes assessments or quality of life assessments, although those are obviously there. But the secondary endpoints include an MRI-based fat infiltration endpoint, as well as a shoulder abductor muscle dynamometry measurement, which is a measure of muscle strength. And both of those, the MRI in phase 2, as well as the dynamometry, showed favorable results for Losmapimod with placebo.
And particularly for the MFI, which is a measure, so we do a whole-body MRI, and we measure the fat infiltrating within muscle that's not completely normal, and it's also not completely fat replaced. And what we were able to show is that Losmapimod essentially truncated the accumulation of fat that occurred in the placebo recipients. So that's carried over into a secondary endpoint in phase 3.
Okay. Is the work that you're doing to (I'm going to go back to what you were saying before about establishing the clinically meaningful threshold in that initiative) required for the FDA in order to validate the RWS, in order to be able to use it as a surrogate endpoint? Is that why that's being done?
Well, it certainly emerged from those discussions. I would say throughout these discussions, there's never been a suggestion from FDA that we use a different primary endpoint. So that right from the end of phase 2 meeting on has been the primary endpoint of the study. And that's not been questioned by them. But it's more around the novelty of it, the fact that it's not been used before, that they don't have an understanding of it, that we're required to do that. When you press them on exactly what is required, their answer is, "Well, show us the data, and we'll tell you, and we're going to look at the totality of the data." And I think they've made that clear. That's not an unusual response in these circumstances. And it's pretty much what we'd expect.
But I think we look at it, and they acknowledge as well, there's no treatments available for these patients at all. And in addition to that, Losmapimod, because of its prior work in other conditions, has a large safety database that's really supportive of it being generally safe and well tolerated. So combining those two together, I think, is an important aspect of the totality of the evidence.
Yeah. Yeah. And I think in many ways, we are blazing the trail for this market for which these patients have none, right? So if you look at the pipeline of products to treat FSHD, there's a number of compounds that are currently in development. I think the last count was greater than 10. And I think I could make an accurate prediction that for future registrational studies with other therapies for the treatment of FSHD, I believe that they will all be looking at a functional endpoint. And I believe that functional endpoint will be reachable workspace. So I think the FDA, and in particular the clinical outcomes assessment division of the FDA, the COA, has been very sort of complimentary of the work that we've been doing to try to draw some parallels between changes in reachable workspace and what that actually means to patients.
So we're particularly excited that we can kind of be the one that's sort of forging this path forward that many others, I believe, will follow. Yeah. And this is a very motivated patient population who's been visible with the FDA, right? And you've been doing a lot of pre-commercialization work. So can you talk about the work that you've been doing with the payer community as well as payers and patients?
Yeah. Absolutely. So I think on the payer side, we've done a little bit of research with payers in which we shared with them the product profile that emanated from the phase 2 ReDUX4 study that Iain spoke about. I think, again, small number of payers in the U.S. that we spoke to, but I think most payers came back and said we would anticipate that this drug would be priced comparable to other sort of rare diseases in the sort of hundreds of thousands of dollars. I think the comp that they used a lot was Skyclarys for the treatment of Friedreich's ataxia, which I think is about $30,000 a month. And payers have actually been providing really, really good coverage for that recently launched drug.
Then I think on the patient side, what I found really interesting in the FSHD market is that it is highly concentrated from a patient advocacy standpoint. The FSHD Society is essentially the only patient advocacy group that's out there. They're very well funded, very well organized. We've got a very strong relationship with them. One of the initiatives that we've been focused on with them is an initiative called Project Mercury, in which their goal is to try to stand up as many patients as possible with a confirmed genetic testing to show that they have either FSHD1 or FSHD, so that when a drug eventually does come to market, those patients sort of have all the data that would be needed from the perspective of the payer in order to get them on drug as quickly as possible. Yeah, terrific relationship with the FSHD Society.
Great to hear. Thank you so much for the update. I look forward to following the continued progress.
That's great. Thanks so much, Joe. Really appreciate it. Thanks to all of you as well. Appreciate it.
Good job. Yeah. Thank you.