Fulcrum Therapeutics at RBC Capital: Strategic Steps in Sickle Cell Treatment

On Wednesday, 21 May 2025, Fulcrum Therapeutics (NASDAQ:FULC) presented at the RBC Capital Markets Global Healthcare Conference 2025, offering a detailed strategic overview. The company highlighted its commitment to addressing unmet needs in sickle cell disease while acknowledging challenges like regulatory hurdles and competition. Fulcrum’s financial stability and focused research efforts position it as a potential leader in benign hematological rare conditions.

Key Takeaways

• Fulcrum’s lead asset, Posiridir, targets sickle cell disease by inducing fetal hemoglobin.
• The company overcame an FDA clinical hold by refining patient criteria for its PIONEER study.
• Fulcrum maintains a strong cash position with a financial runway until at least 2027.
• Enrollment in the PIONEER study has accelerated, driven by high unmet needs in the market.
• Competition from major players like BMS and Novartis is acknowledged.

Financial Results

• Cash Position:

- Fulcrum ended Q1 with $226 million in cash.

- Completed an $88 million non-dilutive financing deal with Sanofi for ex-US rights to the losmapimod program.

• Burn Rate:

- Annual expenditure is between $55 million and $65 million.

• Financial Runway:

- Current funds are expected to last until at least 2027.

• Capital Allocation:

- Focus on executing programs in sickle cell and inherited aplastic anemias.

- Exploring opportunities in other rare benign hematological conditions.

Operational Updates

• Posiridir Phase 1b Study (PIONEER):

- Study includes four cohorts: 2mg, 6mg, 12mg, and 20mg doses.

- Enrollment nearing completion for 12mg cohort; 20mg cohort enrollment starting.

- Data readout for the 12mg cohort expected in early Q3.

• Clinical Hold:

- FDA hold due to toxicology data was lifted after redefining patient criteria.

- Criteria now focus on severely impacted patients, excluding hydroxyurea users.

• Fetal Hemoglobin Induction:

- Dose-dependent increase in fetal hemoglobin observed in early cohorts.

- Preliminary data from the 12mg cohort shows promising HbF induction.

Future Outlook

• Strategy:

- Aim to lead in benign hematological rare conditions.

• Expansion of Patient Population:

- Plans to broaden Posiridir’s eligible patient population based on Phase 1b data.

- FDA discussions will guide future study designs and criteria adjustments.

• Data Expectations:

- Anticipate a mid-single-digit percentage increase in fetal hemoglobin to reduce VOCs.

Q&A Highlights

• Market Opportunity:

- High unmet need due to current treatment limitations.

• Regulatory Considerations:

- FDA’s risk-benefit assessment requires evidence of clinical benefit.

• Enrollment Challenges and Strategies:

- Accelerated enrollment due to increased patient interest post-clinical hold.

Readers are encouraged to refer to the full transcript for an in-depth understanding of Fulcrum Therapeutics’ strategic initiatives and future plans.

Full transcript - RBC Capital Markets Global Healthcare Conference 2025:

Greg Renzo, Biotech Analyst, RBC Global Healthcare Conference: Twenty twenty five RBC Global Healthcare Conference. My name is Greg Renzo, one of the biotech analysts, and and we’re we’re pleased to close out our day with, with Fulcrum Therapeutics. Joining us from the company is the CEO, Alex Saber. Alex, great great to see you, and and, of course, the the head of, early development, Ian Frazier. But, Ian, it’s great great to see you as well.

We’re we’re certainly at at a really important point for for Fulcrum in in 2025 with some data coming, but maybe, Alex, we can just take a step back. And for those less acquainted with Fulcrum, just give a brief introduction to the company, please.

Alex Saber, CEO, Fulcrum Therapeutics: Yeah. Sure. Absolutely. And thank you all for joining us. Yeah.

So Fulcrum is a SMIDGAP biotech company. We are very focused in, rare benign hematological conditions. So our, latest stage program is a program called Posiridir for the treatment of sickle cell disease currently in phase 1b studies, two important data readouts coming up this year which we’ll talk about, and then in addition to that we have very robust discovery pipeline targeting other novel HBF inducers, but also some very ultra rare inherited aplastic anemia, such as diamond black van anemia, Schwachman diamond syndrome, and we’ll be submitting our first IND later this year for the first of what we hope will be many inherited aplastic anemias, the first one being diamond black vein anemia or DBA.

Greg Renzo, Biotech Analyst, RBC Global Healthcare Conference: Great, great. And you mentioned the lead asset, post serative, for the treatment of sickle cell disease. Certainly a market that some are rather familiar with, especially given that unmet need in this space, and frankly, there’s just been a great deal of even evolution in the last several months as well. Just walk us through where you see the market opportunity in sickle cell and that unmet need.

Alex Saber, CEO, Fulcrum Therapeutics: Yeah. So just to ground everybody in some numbers, sickle cell affects about one hundred thousand people here in The U. S, about four million four point four million people globally. The mortality rates are very, very high for sickle cell disease. In fact, most patients with sickle cell have a decreased life expectancy of about twenty to twenty five years.

So mortality rates are very, very high. I think over the last five years, there was a lot of hope in light of some of the more recently approved drugs. You had Voxelotor approved, or you also had Adakveo or crizanlizumab approved by Novartis. You also had the two cell and gene therapies that were more recently approved. Unfortunately, if you look at where we are today, Voxelotor unfortunately, has been pulled from the market.

Crizanlizumab, because of their inability in their confirmatory study to show a reduction in vaso occlusive crises, which are these acute pain crises that these sickle cell patients suffer, they did not show a difference compared to placebo. And some of the more recently approved cell and gene therapies, I think because of the cost, risk, and complexity, really have not become the commercial success that many people thought. So I think, well, five years ago, think there was a lot of excitement, given some of these more recently approved therapies. Unfortunately, we’re very much back to where we were twenty years ago, when patients really have hydroxyurea and and nothing else. I think, to get back to your sort of final question about the unmet need, I think the unmet need is extremely high today, which I think why so many people are excited about what we’re doing with, with posiridar.

Greg Renzo, Biotech Analyst, RBC Global Healthcare Conference: Yeah. It certainly leaves the door door open, especially for for oral options, not just stateside, but even even globally. Maybe that’s a a good place for you, Ian, to maybe walk us through the history of of Poseidia or the the origination of of the assets, as well as just that the rationale behind the fetal hemoglobin mechanism.

Ian Frazier, Head of Early Development, Fulcrum Therapeutics: Yeah. Absolutely. Happy to do that, Greg. So Poseidia was identified in house at Fulcrum, we developed the molecule ourselves and it emerged from our screening efforts to seek out compounds that induce fetal hemoglobin. And the reason for doing that is that we know and we’ve known for a long time that if you inherit sickle cell disease, but also inherit the genes that leave you with an increase in fetal hemoglobin expression in adulthood, that your phenotype is much milder than if you don’t have that elevation of fetal hemoglobin.

So it’s known fetal hemoglobin not only diluting out the abnormal sickle hemoglobin in the cell, but actually actively preventing the sickling from occurring, which occurs under hypoxic conditions essentially. And so that’s the rationale for going after fetal hemoglobin in sickle cell disease and we can come back to that. Turns out that posterior inhibits an enzyme complex called PRC2 and it does that by binding to one of the subunits of that complex that’s known as EED. That’s not the catalytic subunit, the catalytic subunit is EZH2. There are some other drugs that are targeting EZH2, but posterior binds EED and EED is responsible for positioning that complex over the stones and it regulates gene expression by methylating those histones causing compaction of the DNA by inhibiting that activity, you release that inhibition of expression in the DNA and results in an altered gene expression profile.

And it turns out that one of the most highly upregulated genes in response to PRC2 inhibition is HBG, which is the gene that encodes the fetal hemoglobin protein. It doesn’t do that directly on the HBG locus, it does it through some of the repressors that are responsible for repressing fetal hemoglobin expression after the fetal period in life. And so it allows for reactivation of fetal hemoglobin expression. So that’s how posterior is working, inducing fetal hemoglobin, the fetal hemoglobin acting in the red cells to counteract the effect of the sickle hemoglobin and give rise to a milder phenotype. And at high levels, essentially abolishing the manifestations of the disease.

Greg Renzo, Biotech Analyst, RBC Global Healthcare Conference: And and Ian, as Alex mentioned, with with data points coming up and as investors are getting comfortable with with the the the readouts, they’re they’re looking back at the history and and and the rationale that that you’re alluding to. And as investors are looking at a clinical hold that occurred just some time ago, maybe you can just brief us on when that did happen and how the company really worked in an expeditious way to have that hold lifted?

Ian Frazier, Head of Early Development, Fulcrum Therapeutics: Yes, happy to do that, Greg. The clinical hold was instituted by FDA early in 2023. And the reason for the hold was based not on clinical data from the program, but rather from some preclinical data where in a subset of the preclinical toxicology studies, there was an observation of hematological malignancies. There’d be nothing in the clinical program and at that point, about 100 subjects in the healthy volunteer first in human study and we had 16 subjects being having been dosed or being dosed in the sickle cell Phase 1b study. So that was the timing of it.

So it was that preclinical finding coupled with the knowledge that FDA had of another compound, another molecule called Tasemetastat or Tasbaric, which is an approved compound now for the treatment of advanced malignancies. Now that compound also inhibits PRC2 does it slightly differently in that it inhibits the catalytic subunit that EZH2 subunit. And the observation with the Tazemetostat development program was an observation in their preclinical toxicology studies of hematologic malignancies and then in their pivotal clinical trials, which is in patients or was in patients with advanced malignancies, so advanced synovial sarcoma and lymphoma, an observation of a zero point seven percent rate of secondary malignancies. These are patients who’ve already had a primary malignancy, received chemotherapy and or radiation to treat that and then had tasmetostat added onto that. And so that low frequency of secondary malignancies in that study, which may or may not have been attributed drug that was in a control group in the study that was an open label study.

And it’s known in that particular patient population that they’re predisposed to getting those secondary malignancies like AML and MDS which were observed. But nonetheless FDA is concerned that drug may have contributed to that. So that was the those two strands of evidence with the underlying reason to hold. And coming off the hold and getting back into the sickle cell patients, which took about six months overall back and forth with the agency didn’t involve us needing to do additional preclinical or clinical work. It was really around redefining the patient population for the sickle cell study that was underway.

When the study started, the PIONEER study, 1b study, it was open to all with sickle cell disease, so there was no requirement for any minimal severity. As long as you had sickle cell disease and other criteria, you were eligible. There was also no restriction on the concomitant use of hydroxyurea. Coming off the clinical hold, we ended up with an inclusion criteria that included a more severely patient and more severely impacted patient population and also a prohibition on the concomitant use of hydroxyurea in that patient population. And the reason for that really in discussions with the agency was around early stage of development with a novel mechanism of action, not yet clear what the benefit to patients might be and this potential risk based on a preclinical signal and maybe a clinical signal with another molecule.

And the agency saying, well, we need to see some evidence of benefit to balance out the potential risk. And in order to do that, the safest way is to restrict your study to more severely patients who don’t have a lot of therapeutic options. And so that’s the genesis of that. But indicated as part of that process how the agency is thinking of this in terms of risk benefit. And that’s very much how we’ve approached that.

So we redefined inclusion exclusion criteria and the restriction on concomitant use of HU was not based on any specific data, but rather on the fact that HU carries a black box for malignancy.

Greg Renzo, Biotech Analyst, RBC Global Healthcare Conference: Sure.

Ian Frazier, Head of Early Development, Fulcrum Therapeutics: And is labeled in the label as HU is a carcinogen. And so from the perspective of the agency, again, early on in development, you shouldn’t be administering something that’s labeled as a carcinogen, something where there’s a potential. So that’s the genesis of how that all unfolded and how we came off of that.

Greg Renzo, Biotech Analyst, RBC Global Healthcare Conference: That’s helpful. And Alex, to you, with Ian characterizing the new inclusionexclusion criteria, maybe help us contextualize, how that translates into the market, into the patient population. What percentage of the overall market may meet this more severe And frankly, as a follow-up, how could that be changing, and how validated are those numbers? Could it even be bigger than what you had been initially quoting?

Alex Saber, CEO, Fulcrum Therapeutics: No, it’s an excellent question, Greg. So I’ll go back to what I said earlier. In The U. S, there’s about one hundred thousand patients that have sickle cell disease. Based on the inclusionexclusion criteria that Ian spoke about, we believe currently about ten percent of patients meet that inclusionexclusion criteria.

And I think that’s critical purely from a standpoint of can the study that we are currently executing on, can it even be completed? Are there enough patients? And clearly, with 10,000 patients and having 10 patients per cohort, there are clearly enough patients. I think as you talk about what can we do to expand the patient population beyond the current ten percent that we have, that will ultimately come down to what benefit has the drug shown in terms of increasing levels of fetal hemoglobin, And once we have that data in hand, we’ll come back to the agency as part of our end of phase 1B meeting, have that discussion, which ultimately will inform what the next study that we do with posterior looks like, and what that hopefully the more relaxed criteria, will look like for that study. Interestingly enough, we all know the risks associated with the cell and gene therapies, and yet their inclusionexclusion criteria was actually less restrictive than ours.

And I think what that gives us an indication on is that the FDA is really thinking about this as risk benefit, because they know the cell and gene therapies are curative, and so if we can come to them with very robust levels of fetal hemoglobin at the end of this 12 and the twenty milligram cohort, we believe that there’s a very strong rationale to potentially relax that inclusionexclusion criteria for the next study,

Greg Renzo, Biotech Analyst, RBC Global Healthcare Conference: and let’s broaden that patient population that we go after. That makes sense. So the thought of that loosening in mind in those future interactions, maybe before we talk about sort of your expectations on the data and the cohorts three and four, maybe we can cover a little bit of what you’ve learned from the earlier cohorts from the six mg and the two mg from an efficacy and staffy standpoint, now that those are

Alex Saber, CEO, Fulcrum Therapeutics: Yeah, absolutely. So just to ground everybody, so this is a phase 1b study. This is all in patients, and we have four cohorts. Cohort one and cohort two included patients in a six milligram, once daily oral a two milligram did I say six first?

Ian Frazier, Head of Early Development, Fulcrum Therapeutics: Six first.

Alex Saber, CEO, Fulcrum Therapeutics: Yeah, six milligram. We did a six milligram, a two milligram, and now we are in the process of completing enrollment in the twelve milligram, and now we’re kicking off enrollment in the 20. I think what we learned from the initial data from those early cohorts is that this drug can show increase in fetal hemoglobin, and we’ll probably talk a little bit about why does fetal hemoglobin matter. But this drug can show an increase in fetal hemoglobin in a very dose dependent manner. So we dosed the six, we saw very modest increases in fetal hemoglobin.

As we in the two, as we escalated to the six, we saw more robust increases in fetal hemoglobin. And then we had a couple of patients in the twelve milligram prior to the initiation of the hold that Ian spoke about, and even in those small number of patients we saw, and even more impressive, higher induction of fetal hemoglobin. And so where we are right now is in cohort three, which is essentially redoing those patients in that twelve milligram cohort. And and maybe to take it

Greg Renzo, Biotech Analyst, RBC Global Healthcare Conference: a a step further, when you quantify those bars of clinical meaningfulness, and numbers that are are being thrown around in in the percentage way, and I’ll leave it to you to to maybe help characterize that. And and and even the correlation of, quality of life benefits for patients, how does that all tie together with how investors should be and investigators should be evaluating the data? Sorry

Alex Saber, CEO, Fulcrum Therapeutics: about that. Not sure whether that was my fault or your fault, but I apologize nonetheless. Yes, so there is a very strong correlation between increases in fetal hemoglobin and reduction in vaso occlusive crises. And that’s in essence what patients are trying to avoid, these horrific, excruciating pain crises that wind these patients up in the emergency room and ultimately getting admitted and on, in many cases, IV opioids to try to control that pain. And what they’ve shown is that as you increase levels of fetal hemoglobin, you show reductions in VOCs.

One of our competitors presented data at ASH last year that showed that for every 1% increase in fetal hemoglobin, you’re seeing about a four to 8% reduction in vaso occlusive crises. That then begs the question, what reduction in VOCs is considered clinically meaningful? And to answer that question, I think you can look at some of the more recently approved therapies that have been approved by the agency, and the minimum bar there is around a 25% reduction in VOCs is considered clinically meaningful, and that has been the basis of approvals by the agency. So if you take that 4% to 8% range, right, 4% to 8% reduction in VOCs, and you’re trying to get to a minimum of 25%, take that 4% and simply do the math, a mid single digit, or 6% increase in fetal hemoglobin can get you a reduction in VOCs that is considered clinically meaningful. And so if you look at cohort three, which is a 12 cohort, in which we’ve enrolled a total of 16 patients, and we’ll be reading that data out in early Q3, the baseline fetal hemoglobin of those patients was around seven.

So if you can get those patients to see an absolute increase in their fetal hemoglobin in the mid single digits, that could be a result in a clinically meaningful reduction in VOCs. That’s ultimately what we’re aiming for here.

Greg Renzo, Biotech Analyst, RBC Global Healthcare Conference: Absolutely. And, Alex, you mentioned some of the data in the landscape and other players looking at competitive MOAs across fetal hemoglobin. Maybe, Ian, to you, just lay out some of the pros and cons as you look at the landscape and how you believe the ED inhibition via posterior dere actually better sets up to address that underlying phenotype.

Ian Frazier, Head of Early Development, Fulcrum Therapeutics: Yeah, yeah, yeah, absolutely. And what we’ve seen, I think, is a resurgence in the interest in fetal hemoglobin as being a really good way to address the pathogenesis of sickle cell disease and that’s been highlighted by the withdrawal of OXELETOR, which is a hemoglobin polymerization inhibitor and maybe a focus away from that particular mechanism and also reinforced by gene therapy particularly the Vertex CRISPR therapy which specifically also increases fetal hemoglobin goes up into the 40% range, which is well above the flattening of the curve in terms of symptom relief. So probably doesn’t need to be that high, but certainly showing and confirming dramatic reductions in these acute events in those patients. So resurgence of interest and so who we’re seeing now a number of players entering the field and entering the clinic. We have BMS that has a dual degrader, Wizz and ZBTB7A degrader.

Novartis has a Wizz degrader in development. GSK has a DNMT1 inhibitor that is in development. So they’ve all entered the clinic recently. Novo has a decitabine THU combination that’s in Phase II that’s expected to read out later this year, although there hasn’t been much data flow around that. So there a lot of interest and activity in that particular arena with the exception of the Novo compound, which I just mentioned, the others have just started with their first in human studies.

So they are somewhat behind where we’re at. We don’t yet have any of the clinical data to understand the profiles there and obviously what we’d be looking for is extent of HBF induction as well as safety and tolerability profiles there. So we’ll be following closely. But clearly, a renewed interest in HBF as a central mechanism

Greg Renzo, Biotech Analyst, RBC Global Healthcare Conference: for sickle cell. Maybe you could for us, you could tie it to just the enrollment and the pace of recruitment across the trials. As we appreciate a great deal of competition U. S. For such patients.

Alex, maybe just kick off how recruitment has gone as far as the enrollment with these cohorts and how you view maybe the impact of the need, but also the impact of the competition for you to meet your goals clinically or developmentally?

Alex Saber, CEO, Fulcrum Therapeutics: Yeah, it’s a great question. So when we got off clinical hold and we had this more narrowly defined inclusion exclusion criteria, essentially, what we were doing is creating a brand new protocol and and and starting from scratch. And I think a lot of, investors were wondering, will we ever be able to enroll this study? Because the enrollment early on was was very, very slow, and we reassured, investors that at some point, we can’t predict exactly when, but at some point, you’re going to see a hockey stick. You’re gonna see an inflection in that in that enrollment.

And I think that’s, exactly what we’ve seen given some of the over enrollment, that, that we saw in cohort three and excitement that we have around the enrollment, potential trajectory for for cohort four. I think that, I think in light of what I said earlier, Greg, about some of the real sort of disappointments that patients have seen in this market with cell and gene therapy being very risky, very, very complex, Voxelotor getting approved, crizanlizumab not being regularly used, I still think that that unmet need of patients wanting to find something that helps reduce these excruciating pain crises that many patients experience multiple times a year, I still think there’s a very, very high unmet need, and I do believe that that’s translating into, more and more patients wanting to get involved in clinical trials for the treatment of sickle cell disease.

Greg Renzo, Biotech Analyst, RBC Global Healthcare Conference: That makes sense. I just want to pitch it to the audience here here in New York if we have any any questions for for Alex and Ian. And if not, I can keep going. Good. Good.

So I I think what we’d do, Alex, just to to close it out, just when it comes to your resource allocation, mentioned BD, sort of the early pipeline investment in posterior in the existing trial and even in in, future potential potential trials. So just remind us of of, your cash position. Certainly, monetizing losmapimod last year is a big boost to give you some cushion

Alex Saber, CEO, Fulcrum Therapeutics: as well. So just remind

Greg Renzo, Biotech Analyst, RBC Global Healthcare Conference: us of that.

Alex Saber, CEO, Fulcrum Therapeutics: Yes. So Greg Greg is mentioning a deal that we did with Sanofi last year for, the ex US rights for a program that unfortunately failed in phase three clinical trials. But what that did was that brought in about $88,000,000 in non dilutive financing for for the company. So at the end of q one, we, ended with $238.26. I apologize.

226,000,000. We’re burning somewhere between 55 and $65,000,000 a year, so that’s giving us a very, very nice runway out until at least 2027. I think a lot of people ask us, how are you planning to sort of deploy that capital? And and do you have aspirations to become more than just a sickle cell company? And I think our goal over the next five years is to really become a leader in benign hematological rare conditions.

And so, we’re certainly looking at a number of interesting opportunities outside of our core areas of focus right now, but our main focus in the capital that we have is to really execute on the programs that we are currently focused on, both in sickle cell, as well as some of these inherited aplastic anemias. But we certainly have our eye on other rare benign hematological conditions that maybe at some point in the future we may transact on, but our focus right now is really executing what we have.

Greg Renzo, Biotech Analyst, RBC Global Healthcare Conference: Absolutely. And we look we look forward to the the SERDRA updates and and the company updates throughout the year. Ian and, Alex, thank you very much. Good to

Ian Frazier, Head of Early Development, Fulcrum Therapeutics: see you. Thanks. Ryan. Thanks, Greg.

Alex Saber, CEO, Fulcrum Therapeutics: Thank you. Thanks, everybody.

This article was generated with the support of AI and reviewed by an editor. For more information see our T&C.