Morning. Welcome, everyone, to this fireside chat with Fulcrum Therapeutics. I'm Joe Schwartz from the Biotech Equity Research Team at Leerink Partners, and it's my pleasure to welcome Alex Sapir, CEO, and Iain Fraser from the company. I guess maybe we can start by having you give us your high-level view of things just to level set, and then we'll jump into the various aspects of development.
Sure. Sure. Happy to do that. Again, thanks for having us. Yeah, I think 2025 is poised to be an important year for the company. We're having two important clinical readouts in our Phase 1 b study with pociredir for the treatment of sickle cell disease. We have a 12mg cohort, which will read out approximately 10 patients, which will read out mid-year, and then by the end of this year, we will also have a 20mg cohort, again, approximately 10 patients, and that will read out the end of this year. Two very, very important data points.
Essentially, it is a Phase 1b study, so it is a safety study, but one of the key things that we're going to be looking at, and something I'm sure we'll get into and talk about in just a little bit, is pociredir's ability to increase levels of fetal hemoglobin in these sickle cell disease patients. Really important year, and we're certainly excited to see that data mid-year and end of year.
Great, as are we. Yeah, it seems to be a really important year for the company. Before we get into that trial, can we just talk a little bit about the mechanism, given this is a distinct kind of HbF inducer?
Sure.
How does it work?
Yeah.
How is it differentiated from other HbF inducers?
Sure. Iain, you want to take that one?
Yeah, absolutely. Pociredir is an inhibitor of the PRC2 complex, and that complex is responsible for the methylation of histone residues and regulates gene expression by altering the compaction of the chromatin. Pociredir itself binds to the EED subunit of PRC2, which is distinct from the catalytic subunit, which is EZH2. Tazverik, or tazemetostat, which is an approved drug for the treatment of advanced malignancies, inhibits the EZH2 subunit. Pociredir inhibits the EED subunit, so non-catalytic. It is the area of the complex that positions the complex over the trimethylated residues on the histones. It positions the complex there, and if you inhibit the complex through EED, you reduce the methylation of those histones, and you alter gene expression by virtue of that.
It turns out that one of the most highly upregulated genes in the setting of EED inhibition is HBG, which is the gene that encodes fetal hemoglobin and is normally repressed. You're relieving the repression of that fetal hemoglobin and allowing it to be expressed.
Okay.
Yeah. The second part of your question was in relation to how that's different from other modulators of HbF.
Yeah.
Hydroxyurea itself, which is the original one, inhibits ribonucleotide reductase and seems to induce HbF by inducing a stress erythropoiesis. It causes suppression in the bone marrow, and then you get this rebound effect during which HbF is induced. There are some other agents now that are just entering the clinic, particularly from BMS and Novartis, and those two compounds target transcription factors that are involved in maintaining the normal repression of fetal hemoglobin expression. By inhibiting that, you relieve the repression of it, but it is through a somewhat different mechanism. There are degrader compounds that increase the degradation of two transcription factors, one in the case of Novartis, which is BCL11A, and two in the case of BMS, which is a combination of BCL11A and LRF or ZBTB7A, two transcription factors involved in that process. Lastly, I will mention the DNMT1 inhibitors.
That's another mechanism for induction of fetal hemoglobin. They're focused not on histone methylation, but rather on DNA methylation directly. There are two main compounds in development for that. One is Novo's NDec, which is a combination of decitabine and THU, and GSK is just entering the clinic now with a novel inhibitor of DNMT1. There are a number of different ways to get induction of fetal hemoglobin, and we just reviewed those various aspects.
Yeah, no, that's a very helpful perspective for my next question, so thank you for that. I was going to ask next about the clinical hold that you had, and what did you do to get that resolved, and who are you enrolling in the pociredir study now? What kinds of patients are these?
Yeah, absolutely. The clinical hold was imposed in early 2023, and there were really two strands of evidence that FDA cited around their reason for the hold. One was related to pociredir itself and to preclinical data, not to any of the clinical data that we generated to date with that compound, and that was the observation in a subset of the toxicology studies that had been performed. A small percentage of animals developed hematological malignancies in those studies. That was the pociredir-related piece of it, and then the non-pociredir-related piece was related to Tazverik, which I mentioned earlier, approved for the treatment of advanced malignancies. The observation there was evidence of malignancy in their preclinical toxicology studies.
In their pivotal clinical trials, again, this is in patients with advanced malignancies, all of whom have received either chemotherapy or radiation in addition to having a primary malignancy, they had a secondary malignancy rate of 0.7% in that study, which is not really unexpected given the patient population, but nonetheless, FDA took the view that these were related to the drug therapy. There was no control group in that study, and it was that concern of the link between what had been observed preclinically and what they were seeing in the clinic there. Those are the two pieces of the clinical hold. Really, in order to get back into dosing pociredir to patients, FDA did not require us to do any additional preclinical studies or any additional clinical studies for that matter.
It really was a question of redefining the patient population for the clinical trial. I think the attitude of FDA was, you know, we have, FDA has some concerns about this mechanism of action. This is an early-phase clinical trial. We're not sure what the upside benefit is. Given that you're still developing the potential benefits of this therapy, we think you should restrict your studies to more severely impacted patients who don't have a lot of therapeutic options available to them. That's really the genesis of where those inclusion-exclusion criteria were changed in order to accommodate that. Again, no wet lab work, no preclinical work, just redefining that patient population. The way that that's worked is there are two categories of how that patient population is defined.
One is related to disease severity, and so we're focused on a patient population that has more severe disease, and you can get in either by having frequent acute events like vaso-occlusive crises, and it's four in the preceding 12 months, and there's some variance depending on how severe they are and whether it's an acute chest or a sequestration event, but a number of acute events. There is also a category of end-organ disease where you need not have frequent acute events, but you have renal insufficiency, right-sided heart failure, or pulmonary hypertension related to your sickle cell disease, and those are typically the older, more experienced patients, and those could enter based on severity criteria.
That's the severity bucket, and then the second bucket is related to prior experience with therapies, and all of these patients are required to have had some experience previously with hydroxyurea and have either not succeeded with that, so failed therapy, or developed some intolerance to it and are now no longer taking it, and they also may not be continuing on hydroxyurea in combination with pociredir. Those are the main criteria. There were some exclusions around the more recently approved therapies, which in practice was mostly Oxbryta, rather than crizanlizumab and L-glutamine, which were also more recently approved but are not used that frequently. Now with the withdrawal of Oxbryta, that particular requirement has largely fallen away, and so that's less of an intrusion.
The requirement was to have tried HU plus one of the other more recently available therapies or not have access to those therapies, and that's why that sort of dropped out, if you like.
Right. Great. Very helpful. Thank you for that perspective. Iain, the company's done a nice job of activating sites. Enrollment's been following, and it seems like things are accelerating, and that puts you in a good position to be reporting data this year. Can you give us some insight into where you stand in terms of site activation and enrollment and the data that we'll get throughout the year?
Sure, absolutely. We have a total of 15 sites that are activated. We plan to activate a couple more over the next couple of weeks, so we will probably have a total of 20 sites fully activated for this Phase 1b study. We did announce in our last earnings call that we just recently had enrolled our 10th patient, so we do remain on track. Feel very confident of having the data for that third cohort, cohort 3, the 12mg cohort, by mid-year. There is a very good chance that we could have more patients by that point that we will have data for, and the reason that I say that is there could be a period of time in which the 20-mg cohort has not yet opened, but there are still patients that are actively screening.
For those that are meeting the inclusion-exclusion criteria, I think given the interest level in this study, it's very possible that we could see an over-enrollment, not intentionally, but we could see 14, 15 patients enrolled in the 12 mg cohort, and there's nothing currently in the protocol that would preclude us from being able to do that.
Okay. Great. When we think about the 12mg data mid-year, what's the bar for success in your mind?
Yeah, it's a great question, and I think, obviously, I think because of the cell and gene therapies, there's been this renewed interest in fetal hemoglobin, and I think that is why there are so many products, fetal hemoglobin inducers that are currently in development, ours, but also some of the other big players like GSK, Novartis, BMS. I think what we know about fetal hemoglobin is that any increase in fetal hemoglobin, even a 1% increase in fetal hemoglobin, is beneficial to the patients. Novo shared some data at ASH last December, which showed that a 1% increase in fetal hemoglobin results in anywhere from a 4-8% reduction in these vaso-occlusive crises, these pain crises that many times patients wind up in the hospital, in the emergency room, for excruciatingly challenging pain crises.
You know, I think that I would say that the minimal threshold that I think you need to achieve is a mid-single-digit increase in fetal hemoglobin because if you can get a patient's absolute fetal hemoglobin up by, say, 5%, 6%, 7%, that will result in a reduction in VOCs that is going to be clinically meaningful for the patients. I think ultimately what we're all trying to shoot for is to get fetal hemoglobin levels north of 25% because I think what we know about the data is that once you can get patients to a 25% fetal hemoglobin levels, at that point you see a near complete abolition of VOCs. Now, the cell and gene therapies, actually, we're able to get to 40%, and we know the curative nature of the cell and gene therapies. You don't necessarily need to get that high.
Once you get to that 25%, that's really where you see full abolition. Do you need to get to that 25% in order for the patients to benefit from these therapies? I don't think so. I would say it's anywhere from a maximum of 25% to a minimal sort of threshold that we're trying to hit of a mid-single-digit increase in fetal hemoglobin compared to where their current baseline is coming into the study.
Okay. The data is somewhat limited, but it looks like you have a nice dose response based on the difference between the 2 and the 6-mg data that we saw earlier. How do you think about the effect of more time and also higher dose as we advance?
Yeah. Great question. You're absolutely right. We did see a very nice dose response as patients went from 2 mg to 6 mg to 12 mg. The longest patient that was enrolled in the 12 mg cohort was only on drug for a total of six weeks, and for that one patient, again, I just want to caveat that this is one patient, but their baseline fetal hemoglobin was 15, and at the end of that six weeks, you did see an absolute increase in their fetal hemoglobin of 10%, so they were actually able to get up to that 25. If you look at that curve, it looked like the curve, the slope of that curve was still increasing, so it is quite possible that you could see very nice levels, nice increases in fetal hemoglobin with the 12 mg.
We did do a healthy volunteers study which showed that there was a dose response as patients went from 10 mg to 20 mg. That was not measuring the fetal hemoglobin protein; that was measuring HBG mRNA. It looks like you could possibly see even more with the 20 mg, but again, we will need to sort of activate that cohort, get those patients enrolled, and then we will have that data by year-end to share with everyone.
Okay. Great. We look forward to that. Can you remind us of how the process works with the DSMB in order to be able to advance from 12 to 20 mg?
Sure. Yeah, absolutely. The DMC evaluation was baked into the protocol right from the beginning, the dose escalation in patients and after every cohort prior to going to the next highest dose. There is a DMC review of the data. They are reviewing just the general safety and tolerability data to move forward, and the trigger for convening the DMC is when the eighth patient reaches four weeks of dosing, and that triggers the meeting, the gathering of the data, and so on. They will meet prior to going ahead with the 20 mg cohort based on the sort of real-time reporting of AEs that we get and the knowledge from the previous cohorts. There is nothing unremarkable, untoward, or obviously drug-related that is being observed, so we are not expecting anything unusual to arise from that, but that is the process that we need to undergo to go to the next cohort.
Right.
We will be sharing once that 20-mg cohort is open for enrollment. Our plan is to share that just in our normal sort of regular sort of updates to the market. That would probably be in our next earnings call, which would be sometime in early May.
Okay. Super. That's great to know. Thanks. It seems like based on the types of, or based on the inclusion-exclusion criteria, you should be probably enrolling pretty severe patients. I know that the Pioneer data that we'll be getting is fairly short follow-up, but do you think it's possible that we could see any directional changes on VOCs relative to their baseline history either in the short duration? Is that a possibility? How long can you treat these people, and maybe over a longer period of time, that's a possibility?
Yeah. Three months is a really short period to get an observation on VOCs itself. We are collecting all of that data as adverse events. The study is not powered around that as an event, obviously, for obvious reasons, small numbers and short duration, but we will also be capturing much more so now than we did in the previous iteration of the protocol what those patients' VOC history was coming into the study, so we'll have a better handle on that than we did for the first cohort of patients. There might be something there. I think it's just a really short period of time they need to get that fetal hemoglobin up in order to see those benefits. We might have a rough read on it, but I think it's not really powered for that.
I think traditionally for a VOC-powered study, that's usually a one-year study or 48-week study. I would expect you start to see effects after about six months or so, but I think we'll have to see what the data reveal.
Yeah. That makes sense. Is there an open-label extension that these patients can go into?
Not currently. It's something that we're actively working on. Coming off the clinical hold, the context was around reactivating the Pioneer study, which is always designed as a total duration of three months of dosing. We have heard anecdotally from some of the sites that patients and the investigators are very keen to continue, and anecdotally there have been some reports where patients have said they feel better and they would like to continue. At the moment, that's not possible, but we're certainly working on making that a possibility.
Okay.
There would certainly be an open-label extension for our next study, which we would kick off in 2026. I think in light of some of the anecdotal feedback that we've been hearing from sites, the idea of possibly starting that open-label extension potentially earlier and allowing maybe some of those patients to roll over. I think that the 12-mg patients would clearly have a drug holiday. Some of those have already completed the study and are off drugs, so it would probably be afforded maybe to some of those 20-mg patients that would start getting enrolled in the second half of the year.
Okay. Very helpful. How are you thinking about the development path from here? Right now, the enrollment criteria is fairly narrow. I guess I'll break this into two parts. For the first part, at what point does it make sense to go to the FDA, and what do you think they'll want to see in order to entertain the conversation that you can broaden that?
Yeah. We broached this already with them at the time of the discussions around the clinical hold for obvious reasons, and I think the feedback from them at the time was that they view this as a context of risk and benefit. Part of the discussion we were having at the time, this was prior to the approval of the gene therapies, was, "Hey, these gene therapies are moving forward. They do not have quite as restrictive inclusion criteria. What's your thinking on that?" The feedback was, "We understand that gene therapy is potentially curative, has significant upside, and so we, FDA, are willing to tolerate the risks associated with gene therapy, which include malignancy and even mortality as evidenced more recently." They contextualized that as upside benefit balancing out the potential risk.
The implication, as we discussed with them, was they want to see the data coming out of the Pioneer study to provide further evidence that there really is some benefit to these patients, which we then understand will help us to, A, relax the inclusion-exclusion criteria, B, increase the duration of dosing, and C, potentially consider the dropping of the prohibition on the HU co-administration. Those are the sort of general approaches. Going back to them with the Pioneer data to review that, when we probed them on, "So what's the specific bar?" the answer was, "As you might expect, bring us the data and we'll have the discussion." That is exactly what we're preparing for.
Okay. Great. That makes sense. Now onto the second part of that question. What does a phase III development program look like? We know the Agios study is enrolling over 200 patients. Is that a reasonable rubric to envision?
Yeah. Yeah, I think so. One of the things that sort of feeds into this is whether the agency has appetite for using fetal hemoglobin as a surrogate endpoint for the basis of approval, and that's something that we intend interacting with them over, separate from the data that's coming out of Pioneer, but just reviewing with the agency all the data that exists. There really are very abundant data that are genetic and epidemiologic and pharmacologic and non-gene therapy related that really speak to the association between HbF induction and clinical meaningfulness. In the context of that, that opens the door potentially for a six-month duration in order to get an approval based on HbF because that's a reasonable timeframe for that, as opposed to the more traditional 12-month duration, which is the type of study that you mentioned previously.
That's another aspect that we'll be interacting with the agency over.
Yeah. I know this is a tough one to answer, but do you think that HbF is still viewed as a valid surrogate endpoint with a VOC or something as a confirmatory thing to capture longer term?
I think that's a reasonable proposition to make, and again, that's exactly what we'll be reviewing with the agency. I think some folks bring up the fact that Oxbryta was approved on a surrogate endpoint or at least conditionally approved on a surrogate endpoint, but that particular endpoint, which was a total hemoglobin endpoint, an increase of 1 gram per deciliter, I think is very, very different than HbF in terms of the data that support that as being related to something that's clinically meaningful. It's not really an apples-to-apples comparison there. On the other hand, will the agency feel burned by their conditional approval of Oxbryta just on the surrogate endpoint in general, excluding the specifics of it? That we don't know, but there clearly is a larger unmet need now than there was before, and I'm sure that that'll factor into their decision-making as well.
Yeah. The only thing I would add to that is I think that we certainly believe that fetal hemoglobin could be an appropriate surrogate endpoint simply because the abundance of the data, both reduction in VOCs but also reduction in mortality above certain HbF thresholds, the data is very compelling, much stronger than the data that exists out there with total hemoglobin, and that obviously was a surrogate endpoint that they used for the approval of Oxbryta. Whether they agree with us, I think, remains to be seen, but I think the data is extremely strong and very compelling, connecting increases in fetal hemoglobin with not only reductions in morbidity but also reductions in mortality as well.
Okay. Great. Thanks. Moving to some of the earlier pipeline opportunities where you're working on things in Diamond-Blackfan anemia and inherited aplastic anemias, can you give us some insight into when we will start to see these programs gain traction?
Sure. Yeah, absolutely. What we've stated publicly is that we expect to file an IND for a compound for the treatment of Diamond-Blackfan anemia by the end of the year, and we anticipate being in the clinic for that next year. We've also said that there are some commonalities across other inherited aplastic anemias such as Shwachman-Diamond syndrome, Fanconi anemia, 5q-, and others, and we're doing much of the preclinical work on that at the moment. The initial IND will be for Diamond-Blackfan anemia, which, as a reminder, there are about 2,000 patients in the US. There's no disease-modifying therapy available for them, and they are reliant on corticosteroids and blood transfusions.
The blood transfusions are complicated by all the usual complications of blood transfusions, including iron overload that often shortens the lifespan of those patients, and corticosteroids associated with all the known complications of steroid therapy. There is really not much available for these patients, and we are really looking forward to that.
Yeah. Interesting. If I think back to early trials for pociredir, you incorporated some very interesting target engagement assays. Is that possible in these settings in order to see early assays?
Yeah. We haven't yet revealed the exact mechanism of action of the drug, and we will be doing that at a later date, but part of that will be what are the target engagement type biomarkers that we can use to address it. I would say also, though, that in an anemia like DBA, where these patients are really very transfusion dependent, you can detect efficacy of a drug in a really short period of time, and by short, I mean three to four weeks. You would expect to see reticulocytes increasing in these patients. That's the sort of responsiveness that you see with corticosteroids. Even in the absence of a direct target engagement biomarker, there's still potential to evaluate that side of the efficacy of the drug pretty early on in patients.
Super. I think we covered a lot of ground, so we can leave it there. Thank you so much for the update.
Yeah. Thank you, Joe. Appreciate it.
Next time.