Great. Good afternoon, everyone. Thanks for joining the OpCo Conference. I'm Matthew Biegler. I'm the covering analyst for Fulcrum, so our next presenting company. Joined with Alex and Iain, and we're going to talk a little bit about FSHD and a little bit about sickle cell and the order of those two programs. It's going to be interesting to see, so probably run through a quick presentation then fill it in with some Q&A. So Alex, you can take it away.
Great. Matt, thank you so much, and I appreciate everybody joining. Just as a matter of full disclosure, I will be making some forward-looking statements, so I certainly encourage everybody to review our latest SEC filings for a full listing of all those risk factors. So yeah, I think just as Matt said, just at a high level, Fulcrum's strategy is to really use small molecules to modify gene expression for rare disease. And while there's a lot of companies that are out there that are focused on rare disease where there's a high unmet need, I think the elegance of what Fulcrum is doing is all of the programs in our pipeline are using small molecules to accomplish that goal to modify gene expression. We have two programs. They are wholly owned by Fulcrum. We own the global rights to both of these programs.
Our most advanced asset is a product called losmapimod, having fully enrolled its phase 3 clinical trial for the treatment of FSHD or facioscapulohumeral muscular dystrophy. We'll talk a little bit about what FSHD is in just a little bit. We have been granted Fast Track as well as orphan designation. Our second asset is a program currently in phase 1b. It is a product called pociredir for the treatment of patients with sickle cell. Again, also granted Fast Track as well as orphan designation. We also have a very strong discovery effort really focused both around rare disease muscle as well as non-malignant heme, and we've got a strong cash runway out until 2026.
You can see here is our pipeline, again, having completed our phase 3 trial for FSHD for losmapimod and currently enrolling in our phase 1b study in sickle cell patients with our very potent HbF inducer called pociredir. And then really, most of our discovery efforts are really focused in two key areas, non-malignant heme as well as rare disease muscle. So let me spend a little bit of time and talk about FSHD, and then I'll turn it over to Iain to run through some of the data that we've been able to generate with losmapimod. So FSHD is really characterized by this slow yet very relentless loss of muscle function for these patients year after year after year. And essentially what it impairs is really sort of the upper, the upper shoulders, the upper extremities as well as the face.
That's where you get the name, facioscapulohumeral muscular dystrophy. While you don't see high mortality associated with FSHD, you do have very high rates of morbidity, as I mentioned, of slow but very relentless decline in muscle function in the mid-single digits year after year after year. And about 20%-25% of all FSHD patients essentially become wheelchair-bound. I think what's also really important to mention is that there are currently no drugs to treat FSHD, either approved or drugs that are used in an unapproved use for the treatment of FSHD. So these patients essentially have nothing.
If you compare the prevalence of FSHD to other neuromuscular diseases that you may be more familiar with because of the simple fact that there are drugs to treat some of these other neuromuscular diseases, FSHD is about 30,000 patients in the U.S., and that's about four times the size of Friedreich's ataxia. I think FA is probably the best surrogate across these three examples, these three comparative examples that I'm giving here, because of the simple fact that Friedreich's ataxia or FA doesn't have the morbidity that you doesn't have the mortality that you see with what you may see with DMD or SMA, but has very similar rates of morbidity that we see compared to FSHD. FA is about a prevalent population that's about four times less than the size of the prevalent population in FSHD.
Some of you may be familiar with a drug that was recently approved called SKYCLARYS for the treatment of FSHD, previously marketed by Reata and now marketed by Biogen. That's a little bit about the underlying nature of the disease and the prevalence. I did want to share this one slide because I do think it is important, and that's really trying to answer the question, what are patients looking for? This was research that was commissioned by the FSHD Society, really the patient advocacy group in the FSHD community. This was presented to the FDA several years ago in this Voice of the Patient report.
I think what's striking is that the majority of patients, 62% of patients, when asked what is the most important attribute that you're looking for for the treatment of FSHD, 62% of patients said, I just want something that can essentially sort of slow or stop this slow yet relentless loss of muscle function that I see year after year. So essentially patients aren't necessarily saying, I want to get better from my baseline. I think what patients are looking for is to essentially keep them at baseline. And that's essentially what we've been able to show with losmapimod in our phase 2 study to date. So with that, let me turn it over to Iain to maybe kind of very quickly run through the mechanism of action with losmapimod as well as share with you some of the results of the phase 2 study generated to date.
Then maybe I'll stop Matt and see if there's any questions before we move over to pociredir. Iain, I'll turn it over to you.
Sure. Thanks, Alex. So the underlying etiology of FSHD is an aberrant, inappropriate expression of DUX4, which is a transcription factor normally expressed only in embryogenesis and then silenced. And when it's aberrantly expressed as it is in FSHD, it drives a downstream array of genes that lead to muscle cell death and replacement of muscle by fat in the tissues. Turns out that losmapimod, which is a MAPK p38 alpha beta inhibitor, turns off the expression of DUX4 in a molecular fashion. And so in the presence of an inhibitor like losmapimod, that aberrant DUX4 is significantly down-modulated.
You can see the concentration dependence of that demonstrated in vitro in muscle tube cultures from patients with FSHD, showing a decline in the DUX4 protein along with a decline in one of the transcripts that's regulated by DUX4, as well as a decline in activated caspase-3, which is associated with muscle cell death. So that's the mechanism of action there. Important to emphasize that this mechanism of action does not interfere with the normal myogenic pattern of muscles. So that continues unimpaired at concentrations that inhibit DUX4. The next slide, Alex, is the primary endpoint for the phase 3 clinical trial is called Reachable Workspace, which is an integrated measure of upper extremity function. And it's measurement around the shoulder joint, each one captured in turn, left and right. The patient is instructed through a series of motions around that shoulder joint.
There are four front-facing quadrants, Q1 through Q4, and there's one posterior-facing quadrant, which is Q5 at the back there. You can see, it's functionally associated with hygiene or toileting activities. The camera that's set up as part of this instrument captures the extent to which the arm can reach out into this three-dimensional space. That's captured on the right in that radar plot. You can see these are the front four-facing quadrants there, a healthy individual in red. You can see not entirely reaching out to the 4.25 in each quadrant, but that's the normal pattern for a Reachable Workspace in a healthy individual. Then an example of an FSHD patient in blue with a severe limitation there in quadrants 3 and quadrant 1, and a marked but not complete inhibition of activity in quadrants 2 and relative preservation in quadrant 4.
Each patient will have a slightly different pattern depending on which muscles are impacted at any one time. In FSHD, this has been used in a small natural history study, which is illustrated on the right. That showed that the annual rate of decline in inactivity as measured by the Reachable Workspace was about 3% per year. This conforms with what is known about the clinical progression of the disease, which is a slowly yet inevitably progressive decline in muscle function. Next slide is really just to touch on one of the other endpoints, a secondary endpoint in phase 3, also evaluated in phase 2, which is a whole-body MRI-based procedure to evaluate the muscles across the body and in particular to focus on fat infiltration in the muscles. Since that's the underlying pathology in FSHD, muscle cells die and then are replaced by fat.
By using a specific MRI sequence called Dixon, we can quantitate fat and normal muscle within those. We scan the entire body. We analyze 18 pairs of muscles on either side. So there are 36 muscles altogether. We characterize the muscles as to whether they're essentially normal at baseline with minimal fat infiltration, if they're end-stage with a lot of fat infiltration, or if they're intermediate or Type B . And those are the muscles that we really focus on in terms of the progression of the disease as well as the therapeutic effect, because these are muscles that are showing signs of being impacted by FSHD but haven't yet progressed all the way to being fully fat replaced. So we do that in a quantitative fashion. This is the phase 2 clinical trial design, 80 subjects in this case.
These are all FSHD Type 1 patients, which is 95% of the FSHD population, randomized to either placebo or losmapimod 1:1, and then treated for a 48-week period, at which time they had the option to switch over into an open-label extension in a blinded fashion. We know that about 95% of the patients who enrolled in the study elected to enroll into that open-label extension. We'll move to the endpoints for the phase 3 study. These were secondary or exploratory in phase 2. This is the key finding for the Reachable Workspace, which is now the primary endpoint in the phase 3 study. On the left, what you see is the change from baseline in the average total RSA as measured across all 5 quadrants at the 48-week mark.
If you look at the bottom of the slide, you can see where these patients were coming in at baseline. So 0.54, 0.53 RSA units. The total maximum, theoretical maximum is 1.25. If you just bear that in mind, they're coming in at about 0.5. And then you look at the change, which is the absolute change on the y-axis there. And you can see if you compare the delta between the placebo and losmapimod, it's about 0.05. So about a 10% difference as a treatment effect between losmapimod and placebo over that 48-week period. And that's illustrated by an annualized change on the right there, where you can see that the placebo recipients experience a decline in their Reachable Workspace over that one-year period, whereas those that got losmapimod essentially are stabilized. And then in the open-label extension, that stabilization continues for those that got losmapimod upfront.
The new baseline is established essentially for the placebo recipients. They declined initially on placebo, but then they're stabilized moving forward, which I think is an important concept in the light of what Alex mentioned earlier about what patients are looking for as something that will stabilize their disease. This is the data from the MRI findings in that phase 2 study. Again, on the left is the intermediate muscles, those Type B muscles, the ones that are most susceptible to change. You can see an increase in the fat infiltration among the placebo recipients over the course of the year, whereas for the losmapimod recipients, you see it's essentially flat from baseline over that period. Exact same pattern on the right, which are the Type A muscles, the more normal muscles.
But the magnitude of the placebo effect you can see is somewhat reduced, which is what you'd expect from a more normal-appearing muscle. So this is now a secondary endpoint in the ongoing phase 3 study. In general, the safety profile of losmapimod has been generally very safe and well tolerated. I'll highlight at the bottom right, the last bullet point there, unusual circumstance. This compound was studied in a number of other indications before it was moved into FSHD by Fulcrum. And so as a result, there's a very large clinical safety database exceeding 3,500 patients. And the types of AEs in FSHD are not significantly different from that, which was observed in the other indications, all of which was pretty unremarkable. So a very safe and well-tolerated compound, which we think is an unusual advantage going into phase 3 with a rare disease.
This then is the phase 3 clinical design. The overall design is essentially the same as it was in phase 2, 48-week treatment period, double-blind, randomized study. You can see there we completed enrollment with 260 patients. The study was originally designed to be 230 based on powering assumptions of Reachable Workspace from that phase 2 study. We ended up over-enrolling because of increased demand at the sites and a number of patients in the queue at the time we cut off screening. So 260 was the final number of those. 242 are FSHD Type 1 , 18 of them are FSHD Type 2s . And like phase 2, there's an open-label extension. And the majority of patients that are finishing up the 48-week period and are rolling off at the moment are electing to stay into that open-label extension. So confirming what we saw in phase 2.
What you see below there are the key endpoints. So the primary endpoint, as we discussed, is the Reachable Workspace. There are a number of secondary endpoints, which include MFI, which is that MRI-based fat infiltration endpoint that we mentioned, as well as a number of others that are questionnaires or patient-reported outcomes relating to the upper extremity, or in the case of shoulder dynamometry, a direct measurement of shoulder activity. So that's the phase 3 study fully enrolled and expecting to read out in the fourth quarter. And Alex, I'll hand back to you.
Yeah, that's great. Yeah. So I think just, Matt, sort of where we are at this point is we are fully enrolled. We will be sharing with everyone the results of the primary and the key secondary sometime in the fourth quarter. And if that study is successful, and I think there's many different permutations of that data that could potentially define success, we'll go ahead and file in the U.S. in 2025 with an approval either in late 2025 or early 2026. And our plan right now is to go ahead and stand up our own commercial organization in the U.S. to launch this ourselves, fairly sort of modest commercial investment in order to target these neuromuscular specialists that are focused on these FSHD patients. And then we'll be looking for a potential partner ex-U.S. to commercialize.
Maybe let me stop there, see if you have any questions, Matt, before we spend the last couple of minutes on pociredir.
Yeah, not surprisingly, getting a lot of questions on Reachable Workspace and how valid is it as a tool, the degree of FDA buy-in that you have. But I guess more importantly, how noisy is it? A year, 52 weeks, that's not a lot of time for kind of a chronic degenerative condition, right? So I think in some of the historical studies you've done, it averaged at 3% decline per year. And your own phase 2 is more like 6. So I guess how confident are you in the powering of the trial? I'm assuming based on some of the things that Iain said that you're being more conservative and you're probably more around 6%. But still, it could get pretty noisy. So how should we think of probability of success for this trial?
Yeah, maybe Iain, you want to maybe comment on sort of the powering assumptions that we have built into the phase three?
Yeah, I mean, the powering for phase three included not only the magnitude of that treatment effect, which we showed earlier, but also the standard deviation in that change from baseline. So that was carried over into the phase three. So we're incorporating the variability intrinsic to that assay, at least based on what we learned from the study in phase two. With respect to the difference, natural history study of 3% decline here, either 10% decline if you use the data on the left, or if you're looking annualized, it's more like 6 or 7%. I don't know that there's a lot to make of the absolute magnitude, but it does depend somewhat on the nature of the patients or the severity of the patients going into the study at baseline.
We know in the natural history study, they had some milder patients upfront, and we know that those didn't decline as much as the others. Conversely, in the phase 2 study, we have some restrictions based on clinical severity score. So we're excluding the very mild patients and the more severe patients. In addition to that, which is carried forward into phase 3, we also have a Reachable Workspace cutoff for inclusion into phase 3. So they do a screening Reachable Workspace, and those that are minimally impacted are excluded, and those that are severely impacted are excluded. So we're narrowing the population down, which I think helps to reduce the variability across the study as well.
Yeah, that's fair. Has the FDA been collaborative with you in this endeavor? I mean.
Yeah, yeah, yeah, yeah, very much so. And most recently, we had an interaction with them that included both the review division, which is neurology, as well as the COA division, the Clinical Outcomes Assessment Division, which focuses on these types of novel instruments, and had a very collaborative discussion with them and ended up with them thanking us for the work we're doing because we know that other sponsors are now wanting to use this instrument as well in their study. So we're helping with that education process, I think.
That's right. It's nice to see it. I was just going to say it's nice to see that timeline is still on track for 4Q this year.
Yeah, yep, yeah. And then I think just specifically in answer to your question, with this sort of over-enrollment that we saw of 30 patients, our powering right now in this phase 3 study is around 96%.
Okay, cool. All right. Should we go to the sickle cell program, which now has a name?
Absolutely, yes. And not only do we have a name for the asset, no longer FTX-6058, but pociredir. And we also have a name for the phase 1b study, which is currently ongoing, and that's called the PIONEER Study . But maybe just really quickly on the disease itself, obviously, genetic disorder, the symptoms are really very sort of painful VOCs or these pain crises that patients have throughout the year, as well as anemia, hemolysis. And as Iain always likes to say, the mortality is quite significant in patients with sickle cell. Many times, their life expectancy is cut short by decades, 20 or 30 years. About 100,000 patients in the U.S. have sickle cell. About 4 million patients globally have sickle cell disease.
And I think one of the things that we know about this disease, and I think it's been well sort of documented in some of the more recently approved cell and gene therapies, is the importance of increasing levels of fetal hemoglobin. And two things that we know is that any increase in fetal hemoglobin is going to be beneficial for the patient. But once you get patients to a fetal hemoglobin level in the sort of high 20s to low 30s, that's really when the patient's disease is transformed and the patients become asymptomatic and the VOCs go down to zero.
So that's always been our target to really try to reach a level of fetal hemoglobin that can get you to that sort of high 20s-low 30s and be able to do that with a once-daily oral therapy, which, again, has the potential to really transform how these patients are treated. Maybe just, Iain, in the very, very six minutes that we have, real quick on the mechanism of action, and then let's share some of the data that we've showed that we've been able to demonstrate to date prior to the initiation of the hold, which we are now off clinical hold with the FDA.
Yeah, sure. So very briefly, pociredir was identified as part of a screen by Fulcrum to look for agents that upregulate fetal hemoglobin because we know that that's central to correcting many of the deficits in sickle cell disease. And it turns out pociredir is an inhibitor of the PRC2 complex. It specifically binds to the EED subunit. That complex is responsible for methylation of histones, which regulates gene expression by virtue of that methylation. By inhibiting it, you cause a hypomethylation of those particular loci. And as a result of this, what we see is an induction of the HBG mRNA, which is the mRNA that encodes HbF. And we can measure that both in vitro and in vivo, and we'll show you some of those clinical data. The compound itself is obviously very selective and has a clean off-target profile with composition of matter going out to 2040.
The next.
Maybe, Iain, just in the interest of time, let's go to slide 22.
Yeah, so this is really the punchline from the patient data, if you like. It's the fetal hemoglobin change from baseline on the Y axis, along with the duration of dosing on the right. It's a 3-month study, and you can see the 2 milligram dose and the 6 milligram dose, seeing a nice dose responsiveness in the HbF increase from baseline. And at 6 milligrams, you're seeing around 8 percentage point increase from baseline as the mean. As the drug comes off after that 3-month period, you see a slow decline back to baseline as the drug washes out. So that's what you'd expect. And then with 12 milligrams, which was the last dose we had prior to the clinical hold, we didn't dose all the way out to 3 months.
But you can see that even after 6 weeks of dosing, there's very clearly a dose responsiveness here at the 12 mg dose. And the mean increase there is 10 percentage points from baseline. There was one patient who went from a baseline of 15 all the way to 25, which puts them squarely in the range of that high 20s, low 30s that we believe to be transformative. So we think as you extend the duration out to three months, that line is going to continue to increase. And so we'll map out the full magnitude of that 12 mg dose in the next cohort that we're dosing. And then from our earlier data, we know that 20 mg is going to outperform the 12. And so we have the option to go there as well and see even greater increases in F with a slightly higher dose.
Iain, maybe just in the interest of time, maybe just touch on some of the other biomarkers that we're seeing in terms of total bilirubin, absolute reticulocyte count, total hemoglobin. Let's maybe focus specifically on the 12 milligrams.
Yeah, yeah. And I think the important part, if you maybe start on the right first, is that it's not just the fetal hemoglobin that's going up. It's actually the total hemoglobin that's going up. And you can see here really quite substantial increases at that 12 mg dose, which is the bottom panel, going from 7.5 to 8.5. So 1 gram in just 4 weeks in that particular patient, 2 grams in the patient who went out to 6 weeks. So substantial increases in total hemoglobin in these patients, which I think is reflective of the mechanism of action, which is not myelotoxic, which is the mechanism of HU in particular. And you can see there as we move to the left, then the absolute reticulocyte goes down because we're suppressing hemolysis as the cells with HbF get into the circulation.
The total bilirubin is trending down again, consistent with decreases in hemolysis. The RDW, which is a measure of the red cell variability and size, is also decreasing as a result of the decreased hemolysis. Decreasing the hemolysis, increasing the fetal hemoglobin, and also increasing total hemoglobin.
So maybe just sort of where we are in the interest of time, Matt. So we got off clinical hold at the end of last year. Our focus at this point has really been reengaging and reinitiating the sites that were part of the study, the PIONEER Study, as well as engaging new sites because the new inclusion/exclusion criteria is more narrowly defined. And so in order to achieve our enrollment goals, we need to increase the number of sites that are participating. So we're probably going to triple the number of sites going from about 7 prior to the hold up until probably north of 20 sites. So those site activation, meetings with IRBs, those are ongoing.
I think what we've also shared with everybody is that our internal goal is to make sure that we do have some data that we can share on this study sometime in 2024. Remember, we've got 2 cohorts. As Iain mentioned, we've got a 12 milligram cohort where we're going to enroll 10 patients and a 20 milligram cohort. We do expect the 20 milligram cohort to outperform. We're going to run those 2 cohorts sequentially. So the goal would be to share results of the 12, followed by the results of the 20. I think once we get a little bit more enrollment and we can see what that trajectory looks like, I think we'll be in a much better position to be more specific in terms of when in 2024 we'll be able to share results.
But our goal right now is to be able to share something of meaning for the PIONEER studies with all of you sometime in 2024.
Gotcha. Is that three months of dosing?
Yeah. So that would be yeah, that would be what our plan is. We're going to take all 10 of those patients in cohort 3 all the way through 3 months of dosing, report out that data at that point, as opposed to sort of reporting out in dribs and drabs. Yeah. So we'll have the 3 months of the 10 patients on the 12, and then at some point after that, followed by the results of the 10 patients in the 20 milligram during that 3-month duration as well.
Gotcha. And maybe I'll just ask one question on the program because there's been, I mean, objectively positive news. The data is, I mean, it's like night and day compared to Oxbryta, even if you just look at the hemoglobin increases. I mean, we're starting to get to gene therapy level efficacy here with an oral, which is everything that every sickle cell doctor I've ever talked to has wanted. But then you've kind of got this risk of cancer, which is a well-known risk with gene therapies as well. So I'm just kind of curious, given the positive and, I guess, negative news, how has kind of the reception been from prescribers? Do they want to put their patients on this drug, or are they being a bit more muted now?
Yeah, I would say that so Iain and I were out at ASH, and we probably met with 30 KOLs that are experts in the field of sickle cell across the world, but predominantly in the U.S. And I would say that a small percentage of the physicians that we spoke to said, "This is a small study, only 20 patients. The amount of time and resources that it would take to get this study up and running for maybe only one or two patients in my actual sort of practice, continue to keep me involved in what you're doing because I'm very interested." But for this PIONEER study, given the relatively small number of patients and the fact that we're not an existing site, we're going to take a pass. But I would say that that was the minority.
The overwhelming majority of patients, I think, echoed very much the point that you made, which is this product certainly has the potential with the 12 and potentially the 20 to be able to increase fetal hemoglobin levels that can have the potential to rival that of cell and gene therapy. That's an exciting undertaking, not just for the 100,000 patients in the U.S., but for the 4 million patients ex-U.S. That is something that I would say the majority of physicians in the U.S. specifically definitely wanted to be a part of in this early phase 1b study.
Just a quick clarification. Is it 10 patients in each of those 12- and 20-mg cohorts, or does that include placebo patients?
No. So this is single-arm, open-label, only pociredir, 10 patients in the 12 mg and 10 patients in the 20 mg. So at some point, we will be able to share the results of 20 patients, 10 in the 12 mg and 10 in the 20 mg, having completed three months of dosing.
Gotcha. Alex and Iain, it's always fun. Sounds like it's going to be a really exciting year for you guys.
Absolutely. Thanks so much for the interest. Thanks, everybody, for joining.