Fulcrum Therapeutics at Leerink’s Global Healthcare Conference: Strategic Insights

On Tuesday, 11 March 2025, Fulcrum Therapeutics (NASDAQ: FULC) presented at Leerink’s Global Healthcare Conference 2025, outlining a transformative year ahead. The conference call focused on strategic milestones for Posiridir, a treatment for sickle cell disease, with both opportunities and challenges highlighted. Despite a recent stock dip, the company remains optimistic about its clinical and regulatory pathway.

Key Takeaways

• Fulcrum Therapeutics anticipates key Phase 1b study readouts for Posiridir in 2025, targeting mid-year for a 12mg cohort and year-end for a 20mg cohort.
• The company resolved a previous FDA clinical hold by redefining patient criteria, focusing on severe sickle cell cases.
• Plans for a Phase 3 development program are underway, potentially involving over 200 patients.
• Fulcrum is actively engaging with the FDA to use fetal hemoglobin as a surrogate endpoint for accelerated approval.
• An IND filing for a new compound targeting Diamond Blackfan anemia is expected by year-end.

Operational Updates

• Site Activation: 15 clinical sites are currently activated for the Phase 1b study, with plans to reach 20.
• Enrollment: The tenth patient has been enrolled, with potential over-enrollment in the 12mg cohort.
• Dose Escalation: The 20mg cohort will open for enrollment, with updates expected in the next earnings call.
• Open Label Extension: While not yet available, an extension is planned for 2026 to allow continued treatment.

Future Outlook

• Phase 3 Development: Fulcrum plans a large-scale Phase 3 program, akin to the Agios study.
• Regulatory Strategy: Discussions with the FDA focus on fetal hemoglobin as a surrogate endpoint, aiming for relaxed criteria and longer dosing durations.
• Pipeline Expansion: An IND for a new compound targeting Diamond Blackfan anemia is on track for the end of the year, with trials to begin next year.

Q&A Highlights

• Clinical Hold Resolution: The hold was lifted by targeting patients with severe disease, without needing additional studies.
• Target HBF Levels: Success is defined by a mid-single-digit increase in fetal hemoglobin, aiming for a 25% increase to reduce VOCs.
• Surrogate Endpoint Discussion: Fulcrum supports fetal hemoglobin as a surrogate endpoint, citing data linking it to reduced morbidity and mortality.

In conclusion, Fulcrum Therapeutics is optimistic about its strategic direction and ongoing discussions with regulatory bodies. For more detailed insights, please refer to the full transcript below.

Full transcript - Leerink’s Global Healthcare Conference 2025:

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: Good morning. Welcome, everyone, to this fireside chat with Fulcrum Therapeutics. I’m Joe Schwartz from the Biotech Equity Research Team at Lyric Partners. And it’s my pleasure to welcome Alex Sapir, CEO, and Ian Frasier 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

Alex Sapir, CEO, Fulcrum Therapeutics: of development. We’re happy to do that. Again, thanks for having us. Yeah, so I think 2025 is poised to be an important year for the company. We’re having two important clinical readouts in our Phase 1b study with posterior for the treatment of sickle cell disease.

We have a twelve milligram 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 twenty milligram cohort again approximately 10 patients and that will read out that will read out the end of this year. So 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, Posiridir’s ability to increase levels of fetal hemoglobin in these sickle cell disease patients. So really important year and we’re certainly excited to see that data mid year and end of year.

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: 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? And how does it work?

And how is it differentiated from other HBF inducers?

Alex Sapir, CEO, Fulcrum Therapeutics: Ian, you want to take that one?

Ian Frasier, Fulcrum Therapeutics: Yes, absolutely. So, Posiridir 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. Posiridar itself binds to the EED subunit of PRC2, which is distinct from the catalytic subunit, which is EZH2. Tazemetostat or Tazveric, which is an approved drug for the treatment of advanced malignancies, inhibits the EZH2 subunit. Posiridir inhibits the EED subunit, so non catalytic.

It’s the area that of the complex that positions the complex over the trimethylated residues on the histones. So 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. And 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. So you’re relieving the repression of that fetal hemoglobin and allowing it to be expressed.

Okay. So, yeah. So and the second part of your question was in relation to how that’s different from other modulators of HBF. Yeah. So hydroxyurea itself, which is the original one, inhibits ribonucleotide reductase and seems to induce HBF by inducing a stress erythropoiesis.

So 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 repression, the normal repression of fetal hemoglobin expression. So by inhibiting that, you relieve the repression of it, but it’s through a somewhat different mechanism there, degraded compounds that increase the degradation of two transcription factors, one in the case of Novartis, which is WIS, and two in the case of BMS, which is a combination of WIS and LRF or ZBTB7A, two transcription factors involved in that process. And then lastly, I’ll 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. And there are two main compounds in development for that. One is Novo’s Ndac, which is a combination of decitabine and THU. And then GSK is just entering the clinic now with a novel inhibitor of DADMT1. So there are a number of different ways to get induction of fetal hemoglobin and we just reviewed the various aspects.

Yes. No, it’s

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: 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 Paciridogor study now? What kinds of patients are these?

Ian Frasier, Fulcrum Therapeutics: Yes, absolutely. So the clinical hold was imposed in early twenty twenty three and there were really two strands of evidence that FDA cited around their reason for the hold. One was related to POCIRODR 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 have been had been performed, a small percentage of animals that developed hematological malignancies in those studies. So that was the Posardia related piece of it.

And then the non Posardia related piece was related to Taystemetostat, which I mentioned earlier, approved for the treatment of advanced malignancies. And the observation there was, evidence of malignancy in their preclinical toxicology studies. And then 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 zero point seven percent 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 so it was that concern of the link between what had been observed preclinically and what they were seeing in the clinic there. So those are the two pieces of the clinical hold. And really, in order to get back into dosing posterior 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. And I think that the attitude of FDA was, we have we, FDA, have some concerns about this mechanism of action.

This is an early phase clinical trial. We’re not sure what the upside benefit is. And 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. And that’s really the genesis of where those inclusion exclusion criteria were changed in order to accommodate that. So again, no wet lab work, no preclinical work, just redefining that patient population.

And 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 are 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 twelve months and there’s some variance depending on how severe they are and whether it’s an acute chest or a sequestration event, but number of acute events. And then there’s 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.

So 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 or 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 Posurdia. So those are the main criteria. There were some exclusions around the more recently approved therapies, which in practice was mostly Oxprida rather than Crizanlizumab and l glutamine, which were also more recently approved, but are not used that frequently.

And now with the withdrawal of OxBryta, that particular requirement has largely fallen away and so that’s less of an intrusion. But the requirement was 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.

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: Right. Great. Very helpful. Thank you for that perspective. And so, the company has done a nice job of activating sites.

Enrollment’s been following. And seems like things are accelerating and that puts you in a good position to be reporting data this year. So, 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?

Alex Sapir, CEO, Fulcrum Therapeutics: Sure, sure. Absolutely. So, 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’ll probably have a total of 20 sites fully activated for this Phase 1b study.

We did announce in our last earnings call that we did have we just recently had enrolled our tenth patient. So, we do remain on track feel very confident of having the data for that for that third cohort, cohort three, the twelve milligram cohort by mid year. There’s 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 twenty milligram cohort has not yet opened but there are still patients that are actively screening and for those that are meeting the inclusion exclusion criteria, I think given the interest level in the study, it’s very possible that we could see an over and over, but not intentionally, but we could see fourteen fifteen patients enrolled in the twelve milligram cohort and there’s nothing currently in the protocol that would preclude us from being able to do that.

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: Okay, great. And then, when we think about the twelve milligram data mid year, what’s the bar for success in your mind?

Alex Sapir, CEO, Fulcrum Therapeutics: Yeah, it’s a it’s it’s it’s a great question and I think obviously I think because of the Celadene 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. And 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 pneumoglobin results in anywhere from a four to eight percent 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, 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 567% 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, you at that point you see a near complete abolition of VOCs. Now the cell and gene therapies actually were able to get to forty percent and we know their curative nature of the cell and gene therapies. You don’t necessarily need to get that high, so once you get to that twenty five percent that’s really where you see full abolition. Do you need to get to that twenty five percent in order for the patients to benefit from these therapies? I don’t think so.

So I would say it’s anywhere from a maximum of twenty five percent 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.

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: Okay, and the data is somewhat limited, but it looks like you have a nice dose response based on the difference between the two and the six milligram data that we saw earlier. How do you think about the effect of more time and also higher dose as we advance?

Alex Sapir, CEO, Fulcrum Therapeutics: Yeah, a great, great question. So you’re absolutely right. We did see a very nice dose response as patients went from two milligram to six milligram to twelve milligram. The longest patient that was enrolled in the twelve milligram cohort was only on drug for a total of six weeks and for that one patient again, I just want to caveat this, 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 that get up to that 25.

If you look at that curve and look like the curve the slope of that curve was still increasing. So, it is quite possible that you could see, you know very nice levels nice increases in fetal hemoglobin with the twelve milligram. We did do a healthy volunteer study which showed that there was a dose response as patients went from ten milligrams to twenty milligrams. Now that wasn’t measuring the fetal hemoglobin protein that was measuring HBG mRNA. So So it looks like you could possibly see even more with the twenty milligram, but again we need to sort of we’ll need to activate that, activate that cohort get those patients enrolled and then we’ll have that data by year end to share with everyone.

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: Okay, great. We look forward to that. And can you remind us of how the process works with the DSMB in order to be able to advance from 12 to 20 kilograms?

Ian Frasier, Fulcrum Therapeutics: 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’s a DMC review of the data. They’re 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 so that triggers the meeting, the gathering of the data and so on. And so they will meet prior to going ahead with the twenty milligram cohort based on the sort of real time reporting of AEs that we get and the knowledge from the previous cohorts. There’s nothing unremarkable untoward or obviously drug related that’s been observed. So we’re not expecting anything unusual to arise from that. But that’s the process that we need to undergo to go to the next cohort.

Alex Sapir, CEO, Fulcrum Therapeutics: Right. And, we will be sharing once that twenty milligram cohort is open for enrollment. Our plan is to share that just in our normal sort of regular sort of updates to the market and that would probably be in our external base call which will be sometime in early May.

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: Okay. Super. That’s great to know. Thanks. And it seems like based on the types of or based on the inclusion, exclusion criteria, you know, 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? Or how long can you treat these people and maybe over a longer period of time that’s a possibility?

Ian Frasier, Fulcrum Therapeutics: Yes. 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. So 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. So 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 forty eight 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.

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: Yes, that makes sense. And is there an open label abstention that these patients can

Ian Frasier, Fulcrum Therapeutics: go into? So not currently, it’s something that we’re actively working on. The 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.

Alex Sapir, CEO, Fulcrum Therapeutics: Okay. So there would certainly be an open label extension for our next study, which we would kick off in 2026. But I think in light of some of the anecdotal feedback that we’ve been hearing from 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 twelve milligram patients would clearly have a drug holiday, some of those obviously have already completed the, some of those have already completed the study and are and are off drugs. So it would probably be afforded maybe to some of those twenty milligram patients that would start getting enrolled in the second half of the year.

Okay,

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: very helpful. And then how are you thinking about the development path from here? Right now the enrollment criteria is fairly narrow. I guess, you know, I’ll break this into two parts. For the first part, you know, 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?

Ian Frasier, Fulcrum Therapeutics: Yeah, and we brought 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. And 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 don’t have quite as restrictive inclusion criteria. What’s your thinking on that? And the feedback was, well, we understand that gene therapy, you know, is potentially curative, has significant upside.

And so we’re FDA are willing to tolerate the risks associated with gene therapy, which include malignancy and even mortality as evidenced more recently. And so they contextualize that as upside benefit balancing out the potential risk. And 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 co administration. So those are the sort of general approaches going back to them with the pioneer data to review that when we probe 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.

And so, so that’s, that’s exactly what we’re preparing for.

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: Okay, great. That makes sense. So, now on to the second part of that question, what does a Phase three development program look like? We know the Agios study is enrolling over 200 patients.

Ian Frasier, Fulcrum Therapeutics: Is that a reasonable rubric to envision? Yes, 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. And there really are very abundant data that are genetic and epidemiologic and pharmacologic and not gene therapy related that really speak to the association between HBF induction and clinical meaningfulness.

And so 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 twelve month duration, which is the type of study that you mentioned previously. So that’s another aspect that we’ll be interacting with the Agency over.

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: 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, you know, a VOC or something as a confirmatory thing to capture longer term?

Ian Frasier, Fulcrum Therapeutics: I think that’s a reasonable proposition to make. And again, that’s exactly what we’ll be reviewing with the agency. I think, you know, some folks bring up the fact that Oxbridge was approved on a surrogate endpoint or at least conditionally approved on surrogate endpoint. But that particular endpoint, which was a total hemoglobin endpoint, an increase of one gram per deciliter, I think it’s very, very different than HBF in terms of the data that support that as being related to something that’s clinically meaningful. And so it’s not really an apples to apples comparison there.

But on the other hand, you know, will the agency feel burned by their conditional approval of OXPRI just on a surrogate endpoint in general, excluding the specifics of it? That we don’t know. But there clearly is a larger unread need now than there was before. And I’m sure that that will factor into their decision making as well.

Alex Sapir, CEO, Fulcrum Therapeutics: Yeah. And 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 use for the approval of Oxprida. Whether whether they agree with us, I think, you know, 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 mortality as well.

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: Okay, great. Thanks. So, 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?

Ian Frasier, Fulcrum Therapeutics: Yes, absolutely. And 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 so 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 Schwackman Diamond syndrome, Fanconi’s anemia, five Q minus and others. And we’re doing much of the preclinical work on that at the moment.

So the initial IND will be for Diamond Blackfan anemia, which as a reminder, there are about two thousand patients in The U. S. Then there’s no disease modifying therapy available for them and they’re reliant on corticosteroids and blood transfusions and blood transfusions are complicated by all the usual complications of blood transfusion, including iron overload that often shortens the lifespan of those patients and corticosteroids associated with all the known complications of steroid therapy. So there’s really not much available for these patients. And so we’re really looking forward to that.

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: Yeah. Interesting. And, if I think back to early trials for Paciradir, you incorporated some very interesting target engagement assays. Is that Is that possible in these settings,

Ian Frasier, Fulcrum Therapeutics: in order to see early site? Yes. So, 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, you know, what are the target engagement type biomarkers that we can use to address it. I would say also though that in 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. So 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.

Joe Schwartz, Biotech Equity Research Team, Lyric Partners: Super. I think we covered a lot of ground. So, we can leave it there. Thank you so much for the update.

Alex Sapir, CEO, Fulcrum Therapeutics: Yeah, thank you Joe. Appreciate it.

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