Okay. Great. Let's get going with the next Fireside Chat session. My name is Dae Gon Ha, one of the biotech analysts here at Stifel, so joining me for the next half hour, we've got the team from Fulcrum Therapeutics, Alex Sapir, CEO and President, and we also have Iain Fraser up here on stage as well.
So we get to discuss both high level as well as some of the nitty-gritty science stuff. So Alex, I'll turn it over to you for a brief overview of Fulcrum. I know things have evolved, and so now the story is something different, and so maybe we'll level set there and then dive into Q&A.
Absolutely. Yeah, a nd thanks for having us, Dae Gon. Always love the Stifel conference. It's a great conference. So, yeah. So Fulcrum, even though we have evolved over the past several months, our mission obviously remains the same, which is really to develop oral therapies to modify gene expression in rare diseases where there continues to be a high unmet need.
Our focus right now is very much on benign hematology. We have a Phase Ib program, a product called pociredir, which is looking at developing a treatment option for the patients with sickle cell disease. Very interesting market. Has seen a lot of changes over the last couple of months with the withdrawal of Oxbrita.
But we also have some earlier- stage assets that are also targeting benign hematology, in particular some of those small, rare, inherited aplastic anemias such as Diamond-Blackfan anemia, Shwachman-Diamond syndrome , Fanconi anemia, for which there are currently no treatment options.
So our mission has become sort of more focused in the treatment of benign hematology, our overall mission in terms of using small molecules to develop, to modify gene expression in some of these rare diseases where there is a high unmet need remains intact.
Okay. So pociredir being your main focus going forward now, let's just level set where things stand now. It's been a while and I know things have changed ever since the clinical hold. So what are the implications on the clinical trial design and where do things stand today?
Yeah. So, prior to the initiation of the hold, we had initiated three cohorts, a 2 mg , a 6 mg, and a 12 mg. We saw very nice increases in fetal hemoglobin in a very dose-dependent manner. So we saw very impressive increases in fetal hemoglobin in the small number of patients in the 12 mg cohort.
In particular, several of those patients were able to achieve fetal hemoglobin levels that could potentially result in these patients becoming asymptomatic. So that got us very, very excited. So where we are today is we are off clinical hold. We are enrolling patients. We have activated a number of sites both in the U.S. as well as outside of the U.S a nd we are in the process of enrolling an additional 10 patients in the 12 mg cohort.
T hen after that, we will also be enrolling an additional 10 patients in a 20 mg cohort. U ltimately, the goal is to be able to replicate some of the data that we saw in that initial handful of patients that was in the 12 mg cohort, in terms of being able to increase their levels of fetal hemoglobin to the point to which these patients essentially could become asymptomatic from a symptomatology standpoint.
Okay. On that point, what is the latest understanding of the fetal hemoglobin level that translates to asymptomatic state?
Yeah. Maybe, Iain, you wanna take that one?
Yeah. So there, there's abundant evidence across a number of streams, including genetic evidence. So patients who co-inherit sickle cell disease along with hereditary persistence of fetal hemoglobin. There's pharmacological evidence, mostly from hydroxyurea. There's now gene therapy evidence, particularly the Vertex CRISPR therapy that specifically induces fetal hemoglobin. A ll of those data point towards any increase in fetal hemoglobin from baseline as being beneficial to the patient, to the individual patient.
In the early hydroxyurea data set, there was a cut at around 8% fetal hemoglobin showing an improvement in mortality, using that particular cut point. T hen if you look at VOCs, it's somewhere around the mid-20% range, 25% and up, where VOCs are essentially abolished. S o at that level across the patient population, you're looking at abolition of most of the symptoms and manifestations of sickle cell disease.
Okay. So, thinking about that, the drug ever since the clinical hold was lifted had to undergo a sort of modified protocol as it pertains to inclusion exclusion. So Iain, maybe you can just remind us what is that refined inclusion- exclusion criteria a nd then we'll keep the conversation going.
Yeah. So importantly, the overall study design was not changed from prior to the hold to afterwards. It was all around redefining the patient population, into a patient population, that is one that's more severely impacted by their sickle cell disease and which has few therapeutic options to treat their disease.
So it's really focused around that. T he specifics include prior experience with hydroxyurea, but not responded to that or had intolerance to it. You know, some of the patients can't tolerate it. T hen there was also a requirement that patients had at least tried one of the more recently approved therapies, which at the time included L-glutamine, crizanlizumab, and voxelotor. Of course, now voxelotor is not available.
T he criterion for those three more recently approved therapies at the time was that patients either had tried them and not succeeded, been intolerant to them, or lacked access to them. S o now, almost by definition, nobody has access to voxelotor. So they kind of meet that inclusion criterion anyway. So that's on the prior experience, drug experience point of view.
T hen there's also disease severity criteria, which involves a number of VOCs per year a nd the threshold there is four VOCs per year. So relatively high frequencies of VOCs required to go into the study and some variance on that, depending on whether it's a pain crisis or an acute chest or sequestration event. T hen at the other end of the spectrum on severity are patients who might not be having acute events, but do have manifestations of chronic disease.
T hat includes renal insufficiency, right-sided heart failure, pulmonary hypertension in particular. So those patients may not be having acute VOCs, but those criteria will get them into the study.
Okay, the trial itself, ever since coming off clinical hold, I understand there's a lot of progress been made, but not necessarily shared with the public, b ut one of the questions I have is the fundamental shift from having this second option, right, voxelotor, criz, and/or Endari. Now, two of those three, or at least one of those three is unavailable. In EU, it's unavailable in two of those.
Have you enrolled any patients into cohort three that may have sufficiently addressed that criteria, but going forward is probably not going to meet that necessarily? What I'm trying to get at is, does the prior medical history or medication history impact how we should think about what pociredir does?
Yeah. So patients who were sort of previously on Oxbrita or voxelotor and who now are having to come off it would not have been eligible to participate if they were still continuing to take it. Once they come off it, they are potentially eligible. There's a 60-day washout period. So there are some patients who might not have been eligible before, but who now are eligible because they have to wash out of the voxelotor 'cause it's no longer available.
So those potentially become more available. The withdrawal was only two months or so ago. So we're not even at that 60-day pool. We are right around that 60-day time point. So too early to tell if that's directly gonna impact the enrollment, but the sense is most likely it will.
Then for the other overall criteria, I think as the protocol is written, the very fact that voxelotor is not available means that pretty much everyone with sickle cell meets that second criterion. So that should make it easier for enrollment, not more challenging.
When you speak to the investigators on trial sites that are already activated and onboarded, right, recognizing that is an ongoing process for you guys, what's the general sense that the sites that are already active have more than sufficient patients given the washout period will just fill up all the requirements that you need for the twenty or so patients you need?
Yeah, I can. Yeah, I'm happy to jump in there. So, yeah, and just to sort of level set with everybody right now, as of today, we have 14 active sites both across the U.S. as well as a site in South Africa. Our goal is to have 20 sites by the end of this year. So doing the math, it would be one site per patient, in order to be able to hit the 20 that we need to complete this study.
We had a chance to have an investigator meeting in Dallas about a week and a half ago. 15 of those 20 sites were represented. What I heard across the board from many of these physicians is that they definitely have patients who meet the inclusion exclusion criteria.
They gave me specific times of when those patients are supposed to come in for their next follow-up visit so that they can talk to them about the study. T hen I think just more in general, they were also saying that given the withdrawal of Oxbrita, they believe that they would have more patients that would be eligible.
I think what I heard from those investigators when speaking with them is one of the things that the patients like about this Phase Ib study is the fact that, there's a 100% chance that you will, receive drug during that three-month period of time a nd most, most, most patients, even though many will enroll in trials, they don't think they like the fact that they know there's a 50% chance that they may be, enrolled into the placebo arm.
So I think they like the fact that single arm, they know they're going to get drug. I think the one concern that patients have raised with the physicians is that if this drug is as promising as you're saying it is, and I do go on the study, what happens at the end of that three months? A s of right now, the patients would have to discontinue and go off of drug because it is only a Phase Ib study.
But obviously there's a number of discussions ongoing now about the possibility of writing a new protocol, presenting that to the FDA at the appropriate time to potentially for future patients that enroll in this study and others being able to go on to some type of extension, extension study after this initial three months.
So if I may press on this, in a different way, I mean, are you able to talk at least about the visibility you have on the cadence of patient enrollment now that we have this withdrawal? I mean, 'cause this program has been ongoing for quite some time.
Yeah.
Recognizing FSHD took the lion's share of your efforts for quite some time-
Right.
-but it has been kind of in the backdrop for a while. So anything you can provide there?
Absolutely, and I think it's an excellent question. I'm glad you raised this. I think in fact, in some of the discussions that we've had throughout the day and some of the one-on-ones, I think some of the investors have said, "You've been enrolling this study for, you know, the better part of fifteen, sixteen, months, w hy is it taking so long?"
I'm not sure that's entirely accurate. When we got off hold in August of last year, I think what we quickly realized is that while there were enough patients in the U.S. that met the inclusion- exclusion criteria, many of those patients did not reside at some of the existing sites that were part of the study. Some of those sites tended to treat younger patients.
Many of them were pediatric sites that, you know, were treating patients in their sort of late teens, early twenties, and most of the patients that we have tended to be farther along in their disease and tended to be older patients, so essentially what we had to do at the end of last year is start from scratch, enroll these, or I'm sorry, activate these new sites.
Unfortunately, as hard as you try and as hard as you push on the sponsor side, it always takes an average of nine months to activate one of these new sites at one of these large academic institutions, so that takes us up until September, when we now feel like we're in a place where we have the right sites in place.
We're pleased with the enrollment that we're seeing in terms of guidance of when we will be able to have data that we can share with everybody. I feel that we're at the point now where in early 2025, I believe we'll be able to provide more specificity in terms of when in 2025, i.e., what quarter of 2025 we'll have the results of the 12 mg to share, and then subsequent to that, when in 2025 or early 2026, when we'll have the results of that second cohort, the 20 mg cohort to share with everyone.
Okay. T hinking about the data readouts, you mentioned that these would be separate readouts, cohort three and cohort four. Just curious, what led you to that decision rather than kind of bundling it all up in, in terms of saying we've now looked at cohort one, two, three, four? It looks like out of the totality of the data, this might be the go-forward dose.
Yeah, it's a really good question, and I think the same way that this is an open- label study, and so we get to see the data almost in real time. I think investors also wanna see the data as quickly as they possibly can.
I think the fact that we showed in that 12 mg cohort in a handful of patients, one patient was on drug for only a total of six weeks and their fetal hemoglobin went from a baseline of 15- 25, and so it is quite possible that that 12 mg cohort at that three-month mark may be enough to reach that threshold that Iain talked about, which was north of this mid- to high- 20, where you really see a dramatic decrease in the rates of VOCs that these patients experience.
So I think it's for that reason that we intend to share those two datasets independent of one another, b ut even if the 12 mg data looks really strong and very robust, and maybe it's enough information to then have that follow-on discussion with the agency, which we do need to have, we would still continue with the 20 mg cohort as well.
Okay. Just to be clear, you're gonna meet with the FDA after cohort three and then after cohort four?
No, I think so. So what the agency came back and said to us was, "Come back to us when you have the data." S o I think, in very, you know, this is somewhat dependent on how strong the data is in that initial 12 mg cohort a nd if that 12 mg cohort is replicating what we were seeing in that handful of patients that were only on drug for four to six weeks.
If that data is strong enough that you are getting a large percentage of those patients that are getting, you know, north of that mid- to high-20s, I think at that point we certainly have the ability to have an internal discussion of whether we wanna approach the agency at that point and share with them the data that we have.
But there's no sort of hard and fast that the agency said, "Come back to us after the 12, come back to us after the 20." The only governing body that we have to go back to prior to initiating the 20 mg is the Drug Safety Monitoring Committee of the study a nd we have to approach that group once the eighth patient in the 12 mg cohort has completed 30 days of dosing.
We then reconvene the Drug Safety Monitoring Committee. They look at the data in its totality, and then they essentially are advising us whether to proceed with the 20 mg or not.
Eight patients in the twelve?
In the twelve.
Okay.
Is that?
Yeah. Yeah. When the eighth patient has reached four weeks of dosing that, that's the trigger.
Okay. Eighth patient, four-week dosing. Okay. Let's, if we fast forward to, latter part of 2025 where you have now both cohort three and cohort four data, it's not really your fault, but FDA nevertheless issued a clinical hold based on some ancillary data and data points that they triangulated on, and so there is this underlying mechanistic question around safety.
The dose, if we were to think about a dose-dependent effect, so cohort four gives you, say, like almost a 30% induction of fetal hemoglobin, 20% with the 12 mg. How do you go about deciding the go-forward dose, bearing in mind this was a limited 90-day dosing and you just have this unresolved, you know, disproving the negative scenario in terms of going forward?
Yeah. No, it's, it's an excellent question a nd just to reemphasize the pociredir data that drove the hold was all preclinical data. T hen the triangulation was with tazemetostat, which is approved for, you know, end-stage sarcoma and lymphoma. So patients with existing malignancies where they had also seen some preclinical malignancy signal.
T hen in a small percentage, 0.7% in their pivotal study, of those patients developed secondary malignancies, bearing in mind that those patients already had a primary malignancy and had received either chemotherapy or radiation therapy or in some cases both.
S o whether it really was the drug that, that caused those malignancies, secondary malignancies or not, I think is questionable 'cause they are the types of malignancies that occur in these treated patients, anyway. So a different patient population, a different risk factor.
The earliest time point that they developed a secondary malignancy was, I believe, 14 months, and the other piece, from that dataset, was in their preclinical studies, there wasn't a clear dose-response. So to the extent that this might be related to drug, the mechanism is probably not a dose-responsive mechanism, and so that probably doesn't factor in, in the same way that like a liver toxicity signal or some of these more traditional type of safety signals that you might see in drug development occur.
So not a clear dose or exposure-related response, and so I think it's what's the tolerability and safety in the clinical program that we've observed to date and what's the efficacy that we're demonstrating, what's the potential benefit for those patients bec ause we're balancing out the potential efficacy in this disease that even to this day with the therapies that we have is really devastating with the reduction in lifespan, increased mortality in addition to the increased morbidity.
But presumably 90 days is really not long enough to show any kind of malignancy effect, right?
Yeah.
So I would imagine you're gonna have to go off on a limb on 90-day safety, which is not going to be all that material. Efficacy will be, I guess, more direct, in a dose-dependent kind of fashion, hopefully. So is that really going to be your deciding factor, just going off on a limb and saying we didn't see anything on safety, so let's decide on efficacy?
Yeah. So I think going into it, our expectation is that we don't expect three months to resolve that issue if that issue is a real issue a nd even if you extended the dosing, this is a low-frequency event if you follow the tazemetostat data. Y ou know, I don't wanna extrapolate too much because of the totally different patient populations and circumstances.
But if you take that as an example, takes a long time and it's a low-frequency event. So you're never really going to resolve that in the context of the clinical trial a nd so I think that's where you have to look really at the efficacy a nd, you know, we can look at the gene therapies, which are approved now.
W e've heard about the malignancies that have occurred in some of those programs, and even more recently, a death of one of the patients in one of the gene therapy studies. So clearly significant adverse events associated with those therapies, which are known. But yet you balance that out with well, if you come through that process on the other end, there's a potential for a cure. I t's that risk-benefit that drives that calculus a nd I think that's the way that the agency thinks of it as well a nd they've articulated that to us.
Okay. At this point, I mean, last time we chatted, you guys haven't met with the FDA post Oxbrita withdrawal. Presumably you'll next go up to them after, like you mentioned, Alex, once you have data. What's sort of the argument you're planning on making to now completely loosen this inclusion-exclusion criteria, bearing in mind risk-benefit calculus is completely flopped?
Yeah. Yeah. So the, I mean, the voxelotor withdrawal has clearly increased the unmet need in the patient population. We know the FDA knows that and is using that as part of their calculus as well. They know that there's more need in this patient population. They did approve voxelotor on an accelerated basis using a surrogate endpoint, in this case, total hemoglobin.
You know, perhaps they might feel that that was a little overhasty on their part, but that's a very different surrogate endpoint than fetal hemoglobin, which has behind it all the evidence that I spoke of earlier, that speaks to the benefits of raising fetal hemoglobin and the knock-on effects on clinical endpoints. The total hemoglobin aspect was really novel and not well mapped out.
That's why they ended up choosing for their primary confirmation Phase III study, this transcranial Doppler ultrasound, rather than the more traditional VOC or other clinical endpoint. I think it's clearly will be increased need in the patient population that the agency will be aware of.
Maybe some reflection on, you know, accelerated approval based on a surrogate, but then also to different potential surrogate endpoints. I think they'll balance those out. Those are some of the discussions that I think we'll be having in the context of, "Hey, this is the type of efficacy that we've observed in the study. These are the effects that we're seeing, and this is the potential benefit that it accrues."
Yeah. So maybe just put a finer point on that, Daegon. I think the way I'm sort of thinking about this is there's sort of two separate ways in which we can engage with the agency, one of which you, you articulated well, which was once we have the data, come back to them and have a more comprehensive conversation about the risk-benefit of pociredir in this patient population that still has very high rates of mortality.
The other path that we're intending to engage the agency around is around this idea of fetal hemoglobin as a surrogate endpoint for an accelerated approval a nd the group that you approach, unlike the data workstream, which is you go directly to the hematology division, there is a sort of cross-functional, departmental cross-functional group that just looks at these surrogate endpoints.
A s Iain mentioned, the abundance of evidence out there to show this strong connection between increase in levels of fetal hemoglobin and very dramatic reductions in VOCs and an increase in survival, the data out there is beyond reproach. It's very strong.
S o in addition to the workstream of approaching the agency about the data, the other idea, which we're under discussions with internally, is around approaching this broader surrogate endpoint group within the agency around considering using fetal hemoglobin as a surrogate endpoint for an accelerated approval based on the abundance of data that's out there right now. So it's really a question of when we would actually approach the agency on that, a nd that's still something that's under discussion internally.
Presumably that would be two different sets of meetings if you were to meet the surrogate endpoint meeting with that division as well as the hematology division to just walk them through your data.
Absolutely. Yeah. So there is the hematology division, and then there is a cross-divisional group that looks at these surrogate endpoints. The hematology division is probably one division that sits on that, but it is across many of the different divisions within the agency. So yes, two very, very separate streams of activity and ways that we could engage with the FDA in the coming months.
Okay. On that surrogate endpoint idea, another forward-looking, so subject to change, obviously, surrogate endpoint when it comes to fetal hemoglobin, I think I agree with you in terms of correlation being pretty stark, fairly obvious to track given the track record of the gene editing gene therapy guys.
Yep. Yep.
But we also know those trials also tracked VOEs as they were followed for multiple years. So given you have this, again, safety overhang, however theoretical it is, do you envision a trial design that the FDA, kind of pushes you into not only exceeding 100 patient enrollment, just to get it on the safety side, but also a longer duration, just to kind of check that off?
Yeah. So I think because there is the link between fetal hemoglobin and the clinical outcomes, there's no reason not to bake the study in from the beginning as including the VOCs. The question is, can you do an earlier cut on the data on the fetal hemoglobin in order to get an accelerated approval while you're continuing the study to gather the VOC data along the way and then, you know, update the label later on with those data?
So I think it's different than the Oxbrita scenario where that link between the increased hemoglobin and the clinical outcome is really not there. But I think in this case, there's a very clear link between them a nd it's more like a time-dependent event.
S o I think that would be the thought process is, there's high unmet need in the patient population. If we can get an effective therapy to them based on HbF earlier and then confirm it pretty rapidly with the continuation of that study, that's the most efficient way to get it early to patients. So that's the type of thought process that we're going through at the moment.
Okay, so something like a Phase II, III, get a, you know, earlier one-year cut on fetal hemoglobin and then two, three.
Yeah, o r even potentially earlier than a year, you know, if the, I was just rereading the Vertex briefing document and they had a 20% fetal hemoglobin cut and their 20% cut at six months, I think almost completely predicted the VOC free at 12-month endpoint. So very high correlation between that. So potentially earlier than, almost certainly earlier than a year for an HbF endpoint.
Okay, just talking about these trial sites that are gonna be participating in pociredir, quickly remind for us how many of them actually participated in prior trials, whether criz, voxelotor, or anything else that haven't really panned out? Do we know?
I think there's a fairly, yeah, I don't know exactly, but I think most of the sites that were represented at an investigator meeting that we had a week and a half ago, most of those were also involved in some of the other Vox and criz studies as well. So I don't know the exact overlap of the Venn diagram, but I would imagine it's pretty high.
Okay, and we're getting pretty close to 2025, so Happy New Year to you guys.
Thank you.
So when it comes to that update you're gonna be providing for us of what to expect in 2025 , I, I guess any, any sense of what exactly you're gonna communicate? Is it just going to be a brief timeline on when to expect cohort three and four? Is it other endpoints that you're looking at, other broader strategies? What other kind of info?
Yeah. It's really gonna be, it's really gonna be time. So what we said up until now is that we plan to have data in 2025 to share with folks. I think once we continue to enroll patients and we get that critical mass, and I feel like we're reaching that, we're approaching that critical mass now, essentially what we'll be providing is more definitive timelines in terms of like what quarter in 2025 will we have data to share with people. So that's really, I think, the main purpose of early 2025, giving more specifics around the timing of that.
Okay. One last question. I know Alan's in the audience.
Yep.
But Alex, cash question. Cash runway.
Sure. Yep. Absolutely. Very strong balance sheet as of the end of Q3, $257 million. We expect to have $240 million by the end of this year. Next year we'll be burning somewhere between $55 million and $65 million. So that cash runway, assuming full success of all of our programs, takes us out into at least 2025.