Fulcrum Therapeutics at Goldman Sachs Conference: Strategic Updates and Future Plans

On Wednesday, 11 June 2025, Fulcrum Therapeutics (NASDAQ:FULC) presented at the Goldman Sachs 46th Annual Global Healthcare Conference, offering a comprehensive overview of its strategic initiatives. The company highlighted its progress on key clinical trials and financial health, while addressing challenges and future plans in the competitive healthcare landscape.

Key Takeaways

• Fulcrum’s lead asset, losvidir, is in Phase Ib trials for sickle cell disease, with promising early results.
• The company plans to submit an IND for a Diamond Blackfan Anemia compound by year-end.
• A strong cash position of $226 million supports a projected cash runway extending into 2027.
• Clinical trial readouts for losvidir’s 12mg and 20mg cohorts are expected in early Q3 and by year-end, respectively.
• Fulcrum is exploring regulatory strategies, including using fetal hemoglobin as a surrogate endpoint for accelerated approval.

Financial Results

• Cash Position: Fulcrum ended Q1 with $226 million in cash.
• Projected Burn: The company anticipates burning $55 million to $65 million in 2024.
• Cash Runway: Current projections indicate a cash runway extending into at least 2027, supporting continued development of their pipeline.

Operational Updates

• PIONEER Trial:

- Phase Ib study with cohorts at increasing dosages: 2mg, 6mg, 12mg, 20mg.

- Enrollment completed for the 12mg cohort (16 patients); ongoing for the 20mg cohort.

- Readouts expected in early Q3 for the 12mg cohort and by year-end for the 20mg cohort.

- Focus on patients with severe sickle cell disease who have failed hydroxyurea treatment.

• Clinical Hold: Lifted six months after being instituted in early 2023, allowing trial progression.
• Diamond Blackfan Anemia: IND submission expected by year-end for a new compound.

Future Outlook

• Regulatory Strategy:

- Fulcrum plans to meet with the FDA following data readouts to discuss trial expansion and potential accelerated approval.

- Considering fetal hemoglobin as a surrogate endpoint for expedited regulatory pathways.

• Clinical Trial Design:

- A pivotal study may involve a six-month readout for accelerated approval or a one-year study focusing on VOC endpoints.

- The study would likely require several hundred patients for efficacy and 100 patients for safety over a year.

Q&A Highlights

• Fetal Hemoglobin Targets: Aiming for a mid to high single-digit increase, potentially halving VOCs.
• Polypharmacy: The necessity will depend on the efficacy of oral HbF inducers; monotherapy could suffice if HbF levels reach mid-20%.
• Competitive Landscape: Continued interest in fetal hemoglobin induction as a treatment mechanism for sickle cell disease.
• Market Size: Approximately 100,000 patients in the U.S., with global estimates ranging from 4 million to 8 million.

In conclusion, Fulcrum Therapeutics’ strategic focus on clinical advancements and financial stability positions it well for future growth. For a detailed understanding, refer to the full transcript below.

Full transcript - Goldman Sachs 46th Annual Global Healthcare Conference:

Alex, Interviewer, Goldman Sachs: Good morning, everyone. Thanks for joining us here on day three of the Goldman Sachs Global Healthcare Conference. I’m thrilled to be joined this morning with the team from Fulcrum Therapeutics. Maybe I’ll let you guys introduce yourself and then provide a brief overview of the company.

Alex Zapier, President and CEO, Fulcrum Therapeutics: Sure. Alex, thank you all for joining. I’m Alex Zapier. I’m the President and CEO of Fulcrum. I’ve been there for about two years and have a long history of leading previous biotech companies focused on rare disease.

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: Yeah, my name is Ian Fraser. I head up early clinical development at Fulcrum, and I’ve been there just a little over two years.

Alex Zapier, President and CEO, Fulcrum Therapeutics: And Fulcrum, just as by way of background, Fulcrum is a biotech company that is using small molecule technology to modify gene expression for rare diseases. And we’ve really decided to focus very much on nonmalignant hematology. So we have a Phase Ib, very interesting Phase Ib asset in sickle cell disease, which I’m sure we’ll talk a little bit about over the next half hour or so. By the way, the clock is not winding down. And then in addition to that, we also have some other there we go.

And then we also have some really earlier stage assets, but for some other very, very interesting benign hematological conditions such as diamond black band anemia, Schwachman Diamond syndrome, but I’m sure we’ll talk a little bit about that after we talk about our lead asset.

Alex, Interviewer, Goldman Sachs: Absolutely. Okay. So maybe let’s start with pasire dirham, the lead asset, as you said, in sickle cell disease. And let’s start with, like, a brief refresher. What is the mechanistic rationale that underpins Poseidia in sickle cell?

Alex Zapier, President and CEO, Fulcrum Therapeutics: Sure. Ian, you want to take that? Yeah, so

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: Poseidia fundamentally is an inducer of fetal hemoglobin. And that is a key mechanism in sickle cell disease that over many years now with genetic and pharmacological evidence has been shown to be protective in sickle cell disease and reducing the severity of the disease. How it does that? It inhibits an enzyme called PRC2, which is responsible for regulating gene expression because it methylates histones and compacts the DNA in the nucleus. And by inhibiting that PRC2 complex, you get less methylation of the histones, alterations in gene expression, and it turns out that one of the most highest upregulated genes under those circumstances is the gene that encodes fetal hemoglobin to get a robust induction of fetal hemoglobin.

Alex, Interviewer, Goldman Sachs: So maybe talk to us about the role of fetal hemoglobin in sickle cell disease, and what do we know about kind of the thresholds at which patients with sickle cell have fetal hemoglobin? At what point do they kind of reach normal activity and sort of the clinical manifestations of that?

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: Yeah, it’s long been known now that increased fetal hemoglobin decreases the severity of sickle cell disease. Initially genetic evidence, patients who co inherit sickle cell disease gene along with the gene for hereditary persistence of fetal hemoglobin, which is normally switched off, after birth. Some individuals have continued expression of that. They have a fundamentally much milder course of their sickle cell disease. We then move into the pharmacology drugs that induce fetal hemoglobin and hydroxyurea is the main example of that.

Induced fetal hemoglobin reduce the severity of the disease, not only the severity of the disease, but also the mortality associated with sickle cell disease. And then more recently genetic evidence where interfering with the mechanisms that suppress fetal hemoglobin with gene therapy and stem cell transplantation, you can induce very high levels of fetal hemoglobin and essentially abolish the manifestations of the disease. In terms of what the actual threshold numbers are, we know that for any individual patient, any increase in fetal hemoglobin is beneficial to them, makes their disease less severe. We also know that once you get into the range of about 25%, so that’s of all the total hemoglobin, 25% is fetal hemoglobin, that’s when it becomes significantly transformative for these patients. Going above that doesn’t hurt, but it doesn’t incrementally change it.

Things flatten out there. So small increases for individual patients are still clinically meaningful. At around the mid-20s, transformational.

Alex, Interviewer, Goldman Sachs: Right. So you mentioned posterior as a fetal hemoglobin inducer, but what have you shown in preclinical or clinical settings in terms of that increase in fetal hemoglobin?

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: Yeah, so preclinically we’ve been able to show using CD34 positive cells that we differentiate, that you get a dose or an exposure related increase in fetal hemoglobin as you increase the concentration of Poseridir. That was reaffirmed in our in human study. So not sickle cell disease patients, but healthy volunteers where you can look at the gene expression in the peripheral blood, that HBG gene, and we showed a dose response in that gene as you went up from placebo, which is flat, two milligrams gives you a little bump, and then as you go up from two to six, six to ten, ten to 20 at each of those doses, incremental bumps in the hpg mRNAs, the mRNA encoding fetal hemoglobin. Twenty to thirty in that two week dosing period didn’t show an incremental bump, but between two and twenty clear dose response. Moving to the patients where we now measure the protein in the cells in sickle cell disease patients.

To date we’ve dosed two milligrams, six milligrams, and a few patients at twelve. We have a cohort of twelve milligrams that’s fully enrolled, a new cohort, that is 16 patients and that readout will be in the third quarter of this year. We had a few patients before that were dosed with 12 And in those patients, we were able to show two to six, six to 12 dose responsive increases in fetal hemoglobin measured at the protein level.

Alex, Interviewer, Goldman Sachs: Okay. So obviously, you had a couple of patients treated, two to six. You said a couple at 12. But then there was a clinical hold that was put on the program. So can you talk to us about the history of that clinical hold and sort of what then had to happen in order to resolve it?

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: Yeah, absolutely. So the clinical hold was instituted by the agency in February of twenty twenty three, was not based on any clinical data from the program. And at that point, we’d had about 100 healthy volunteers in our initial study and we’d had sixteen patients in the sickle cell disease study. So no clinical findings that were of concern. The concern from the agency was that in the preclinical toxicology studies or in a subset of those preclinical toxicology studies, there was an observation of hematological malignancies in some of those animals.

And that information coupled with what the agency knew about an approved drug that is also a PRC two inhibitor called Tazemetostat or Tazveric. It’s approved advanced synovial sarcoma and lymphoma. And in their preclinical studies, they had had some hematological malignancies in their preclinical animals. And then in their pivotal clinical trial in patients treated for malignancy, they had a zero point seven percent rate of secondary malignancies. So these are patients who’d already had chemotherapy and or radiation for their primary malignancy, and then developed it during the exposure to Tasemetastak.

Not a controlled study, and in a patient population that’s predisposed to those particular hematological secondary malignancies. Nonetheless, FDA attributed those to drug. Because of that said, we FDA believe that there’s a risk associated with this mechanism, even though the exact molecular mechanisms are different. Tasemetastat inhibits a catalytic subunit, EZH2, Pulseria inhibits an accessory or guide subunit called EED, but they both inhibit PRC2. Because of that FDA said, we believe that early on in your development program, you should confine your studies to those patients that are most severely impacted by sickle cell disease and who don’t have a lot of therapeutic options.

It was not a request to do additional studies in order to get back into the patient population. It was largely or exclusively a matter of redefining the patient population from what had been an all comers sickle cell patient population to one with more severe disease with no therapeutic options.

Alex Zapier, President and CEO, Fulcrum Therapeutics: And then so where we are now is, as Ian mentioned, in early ’twenty three, clinical hold was put in place. Six months after that, because the FDA was not requiring us to do any additional studies, we were off clinical hold six months, into 2023, so third, fourth quarter of twenty twenty three. Spent a lot of time in 2024, identifying new sites that met this new, more severe inclusionexclusion criteria for patients. So it really wasn’t until, I would say, the fourth quarter of twenty twenty four where we were able to really start, actively enrolling in, as Ian mentioned, this new twelve milligram cohort followed by a twenty milligram cohort, which we’re currently enrolling in.

Alex, Interviewer, Goldman Sachs: Okay, great. So you have mentioned now a couple of times this ongoing twelve mg cohort. There’s a twenty mg cohort as well. Maybe you could just provide an outline of the current trial protocol and what you guys are evaluating in those studies. Sure.

I can take that one.

Alex Zapier, President and CEO, Fulcrum Therapeutics: Yes, so the study that we keep referring to is the PIONEER trial. It is a Phase Ib study open label, four cohorts in, increasing dosages. So as Ian mentioned, we started with a two milligram cohort, escalated to a six, escalated to a twelve, and we’re currently enrolling in a twenty milligram cohort. The cohort, the twelve milligram cohort, recently completed enrollment. We had a total of 16 patients in that cohort, And we will be sharing the results of that, data, and we’ll talk maybe in a little bit about what data we’re planning to show.

We should have that data to share with everybody in early in the third quarter of this year. And then that twenty milligram cohort, Cohort four, which is currently screening and actively enrolling patients, we should have that data by the end of the year. So really important year for Fulgrum in that we’ll have not one, but two very important clinical readouts in patients during the next really during the next six months.

Alex, Interviewer, Goldman Sachs: Okay, great. And then maybe you can talk a little bit about the patient. Obviously, you’ve narrowed the patient population down. What are some of the other key inclusionexclusion criteria in the patient population that you’re enrolling? Yeah.

So

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: so in the bucket of disease severity, the most common and frequent requirement for for disease severity is based on counting acute events, these vaso occlusive crises. And in order to get into the study, patients need to have experienced at least four of those episodes over the preceding twelve months or two over the preceding six months in order to get into the study. There are some variants on that. So there’s an acute crisis called an acute chest that’s more severe than a VOC. So that gets counted as two VOCs essentially.

Alex Zapier, President and CEO, Fulcrum Therapeutics: But

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: but basically it’s it’s those four VOCs. There’s also disease severity based on end organ disease. So there are some patients who have severe sickle cell disease may not be having frequent acute events, but they do have manifestations of the chronic hemolytic anemia. So they have renal insufficiency, right sided heart disease, pulmonary hypertension. So criteria are also permitted.

And then in addition to the disease severity, there’s therapy related criteria in order to get into the study and these patients need to have at least tried hydroxyurea in the past. So that’s the current standard of care and has been for over thirty years now. And they might have tried it and failed because they didn’t get increases in fetal hemoglobin or an improvement in their clinical disease, or they may have had adverse events to hydroxyurea and been intolerant to it. They need to have tried and failed in some respect. They also may not be on concurrent HU during the study.

So those are the main inclusion exclusion criteria.

Alex, Interviewer, Goldman Sachs: Can you explain why people who are on concurrent HU are not included and what the impact might be in terms of the patient outcome?

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: Yeah, absolutely. So this was something that came out of the clinical hold from the agency. It was not based on any experimental preclinical or clinical data. It was really governed by concern from FDA that HU itself is labeled as a carcinogen and has a black box warning for malignancy. And so what the agency said is given that there are potential concerns about PRC two mechanism, and I think they’re concerned about other epigenetic mechanisms as well, because as we see other compounds that induce fetal hemoglobin by that mechanism coming into the clinic, they too seem to have this restriction on concomitant HU.

So it’s this theoretical concern around the mechanism of action. There’s no reason that patients who are on HU or cells that are exposed to HU would not also still respond to posterity. On top of that, we have both preclinical and some early clinical data to support that because in the initial cohorts of patients that we studied, there were some of those on concomitant AU because the restriction was not in place at that time. And those patients responded to Poseidia Okay. Pretty much as well as those that that were not.

Alex, Interviewer, Goldman Sachs: Okay. You mentioned that you had to activate new sites. Enrollment’s now complete in the twelve mg, ongoing in the 20. I guess, could you talk about, like, the pace of enrollment into this study and sort of what you’ve seen, what you’re seeing today, and let us know if you feel confident in the twenty mg kind of timelines as you’ve laid them out.

Alex Zapier, President and CEO, Fulcrum Therapeutics: Sure, sure. Yeah, I think what we experienced, Corinne, was a very sort of typical type of enrollment curve for a study of this type. So you start off very sort of like I would say the enrollment curve is very flat initially as physicians start to get experience with the trial and putting patients on drug and then getting feedback from those patients. Again, this is an open label study where all patients are receiving drug. And then I think because of that sort of positive feedback that some of those physicians may be getting from their patients, they start to get more excited about the study.

They start to understand the operational nuances of the study, and they start to enroll patients. So what we saw end of last year, beginning of this year was a very much of a change in the slope of the enrollment rate that we’ve been seeing. And so in terms of your question about level of confidence of twenty milligram cohort readout by year end, we feel very confident based on where we are with that twenty milligram that we will be able to hit that previous guidance that we provided.

Alex, Interviewer, Goldman Sachs: Okay, great. I think you have shared some things around the baseline patient characteristics in the twelve minute cohort. Maybe you can remind us what that is and just how you should we expect something similar in the twenty, or what should we be paying attention to there?

Alex Zapier, President and CEO, Fulcrum Therapeutics: Yeah. Yeah, so the what we did disclose in our most recent earnings call was that those 16 patients had a baseline fetal hemoglobin level of 7.6, and that was the average. The median was 7.7, so very similar. In terms of what to expect at the end of that study, I think as Ian mentioned, any increase in fetal hemoglobin is beneficial to There’s been some recent data that came out at ASH last year that essentially concluded by looking retrospectively at previous studies that have shown that for every 1% increase in fetal hemoglobin, you see about a 4% to 8% reduction in VOCs. That if you can essentially increase that baseline fetal hemoglobin level from where it is today at sort of 7.6 to an absolute increase in what I would call the mid to high single digits.

So essentially, call it a doubling of where they are today, that could be very sort of meaningful for the patients. And the way that I the way that we think about that is, let’s just take an average patient that has a 7.5. If you can double that from 7.5 to 15, call that seven times an 8% reduction in VOCs in that 4% to 8%, that sort of gets you that 50% reduction in vaso occlusive crises, which again, many of the other drugs that have been approved for the treatment of sickle cell looking at reduction in VOCs were right around that fifty percent reduction in vaso occlusive crises at the one year part at the one year mark.

Alex, Interviewer, Goldman Sachs: Okay. It’s my understanding that there’s also a function of time on therapy that drives the absolute change that you see in fetal hemoglobin. So with that in mind and considering the dose that you guys are doing, the baseline hemoglobin, like, what would be a reasonable outcome for the twelve mg data, and then what would be reasonable at 20?

Alex Zapier, President and CEO, Fulcrum Therapeutics: Yeah, you wanna take that?

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: Yeah, so we see at the earlier doses, we see that the fetal hemoglobin seem to be plateauing around the three month mark. We haven’t dosed longer than that, so we haven’t defined that completely, but it seems to rise fairly steadily during that period. And I think that that’s a reflection of the turnover of the red cells. It’s not a pharmacological parameter. Right.

It’s just that the the drug needs to act in the red cells, and they need to undergo several cycles. So during that three month period, you’re seeing an increase in the fetal hemoglobin, and that seems true irrespective of the dose. What I think is different between the doses is the magnitude of change, where you net out at the end of that period. And that seems to be what’s different across the cohorts. And as I said earlier from the healthy volunteers, we’ve previously seen that dose response from two to six to 10 to 20.

And so we would expect to see that as we get the protein data from the patients.

Alex, Interviewer, Goldman Sachs: Okay. And in terms of, like, obviously the primary endpoint or the thing we’re trying to understand is the change in fetal hemoglobin. Will vaso occlusive crises be counted in the study? Is there any reason to expect you’d see a benefit? Or is that is it too early for that?

Alex Zapier, President and CEO, Fulcrum Therapeutics: Yeah. So just as a quick reminder, so this is a Phase Ib study, open label for cohorts, as I mentioned. So the primary endpoint of the study is obviously safety. So we will be that’ll be the one thing that we will really be focusing on, to make sure that the drug is safe for patients. But then in addition to that, we will also be showing changes in fetal hemoglobin as you mentioned.

We’ll also be looking at some other really important markers of hemolysis such as red cell distribution width, bilirubin, total hemoglobin. So we’ve been looking at those as well. In terms of your question about will we be showing VOC data, the simple answer to that is we will be. It is an important baseline characteristic, as Ian mentioned earlier. So these patients will have had to have had a minimum of 12 VOCs during a sorry, sorry, sorry, four VOCs during a twelve month during the previous twelve months prior to enrolling in the study.

So we will share those baseline characteristics. And then obviously, if a VOC happens during the three months that they are on study drug, that will obviously be reported in the AE table. I would caution people not to read too much into the VOC data because, again, it’s not an endpoint in the study. We don’t have an adjudication committee. The way in which we were defining a VOC using medical records prior to initiation of the study is different than the criteria that we’re using to define VOCs during the study.

But the simple fact of the matter is data in early Q3 when we read out the twelve milligram and then at the end of the

Alex, Interviewer, Goldman Sachs: year with the 20. Okay.

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: Sorry. Maybe just one additional point is, you know, traditional VOC study is usually a one year study.

Alex, Interviewer, Goldman Sachs: Mhmm.

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: We are looking at a three month endpoint. And so essentially during that entire three months, the fetal hemoglobin’s gonna be going up. So we’re we’re not seeing the maximal effect

Alex Zapier, President and CEO, Fulcrum Therapeutics: Right.

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: Until at least the end of that time. But as we said earlier, even small increases are expected to have some benefit. Okay. So just to bear that in mind as as that data come out.

Alex, Interviewer, Goldman Sachs: Okay. So with that in mind, EC 12, EC 20, let’s assume for the case of this question that they show what you were hoping to see. What comes next from there in terms of the next kind of studies that you would be running?

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: Yeah, and this goes back to coming off the clinical hold and the discussions with the agency where the focus was on generating additional data to indicate whether or not this mechanism provides benefit to patients. Because I think that it’s a question of what is the risk and benefit for patients who have this disease that’s really still pretty significant in terms of not only morbidity, but also mortality where the lifespan reduction is still about twenty years even in The US. So it’s understanding the risk benefit potential and what the agency, discussed with us at that time was, let’s complete this study, let’s finish the twelve milligram, let’s finish the twenty milligram cohort, go back and discuss then what the next steps will be. And those next steps include, you know, can we lessen the inclusion exclusion criteria to broaden it to less severely impacted patients? That’ll be based on the data from the study.

Is there potential evidence of benefit to allow that to occur? Let’s increase the duration of the study and potentially that study could be a pivotal study. So it’ll be discussions around can we do that? In addition, there’s also the potential we believe for fetal hemoglobin in and of itself to act as a surrogate endpoint potentially for an accelerator approval. There’s no precedent for fetal hemoglobin playing that role in sickle cell disease as yet from from an approval standpoint, but there is really abundant evidence that links fetal hemoglobin to reductions in disease severity in sickle cell disease.

And so that’s another strand of the conversation that we’ll be having with the agency.

Alex, Interviewer, Goldman Sachs: Okay. So I want to clarify both of those points separately. You mentioned that based on your conversation with the agency previously, you think it’s possible that these studies, the Phase 1B that’s ongoing, would be sufficient to expand the patient population. Do you have any sense for kind of like what level of benefit or what they’re going to be paying attention to that you can go Yes.

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: So there are no pre established or predefined bars. And the response, as you might expect, was bring us the data, we’ll look at the data and make a decision there. That’s where it is. I think based on what we know about fetal hemoglobin induction and its benefits in sickle cell disease that, you know, the data might be sufficient to drive that decision. And obviously it depends on there being adequate acute safety and tolerability, which is what we’ve observed to date.

And so it’ll be viewed both as the fetal hemoglobin induction but also the overall safety of the drug.

Alex, Interviewer, Goldman Sachs: Okay. And then I guess the other question from there is just, like, how quickly can you kind of meet with regulators and get some of these answers? When should we expect an update?

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: Yeah. So so as I said, it’ll it’ll be driven by the data coming out of the study if we need to complete the twenty milligram data. We’ve said that twenty milligram data, we will release publicly around the end of the year. Mhmm. And so that gives a rough timing for when we expect to have that, and then that will trigger an end of phase one meeting with the agency.

So that’ll likely be early in 2026 Okay. Based on on the conduct of the study.

Alex, Interviewer, Goldman Sachs: Okay. So you mentioned that another key question is whether changing fetal hemoglobin is a good surrogate endpoint for a registrational study. Talk to us about, like, what a pivotal design would look like in the case they do agree to a surrogate versus what it would look like if you are required to run sort of a full outcome study.

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: Yeah, and I think those possibilities are still there. They haven’t been decided yet. If you do just in general use surrogate endpoint for a conditional approval, the rules are that you need to also conduct a confirmatory study. Mhmm. And so whatever your design is, it can either be a separate study

Alex, Interviewer, Goldman Sachs: Mhmm.

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: With the accelerated approval in one study, or it can in fact be part of the same study where you do an initial data cut around the surrogate endpoint and then continue the study, in order to get, the support of evidence, the support of clinical evidence to do that. So how might that look for sickle cell disease, so HBF as a surrogate endpoint, you might expect that at the six month mark you could potentially get a read on that, that would be sufficient as a surrogate endpoint. We know that traditionally, historically, the one year mark has been used for clinical readouts like VOCs. And so, you know, base case without an accelerated approval, it would be a one year study with a VOC like primary endpoint for an accelerated approval could be a six month readout on that. Yeah.

And then either a separate study or the same study continued in order to to derive the one year data.

Alex, Interviewer, Goldman Sachs: In terms of, like, roughly the number of patients that you think there’ll be both an efficacy component and a safety component, what do you understand in terms of maybe both?

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: Yeah. So a little early to say without the fine details of the design, but from an efficacy standpoint, a few 100 patients typically would be required to drive that. So 200, 300 patients in that sort of broad range. From a safety point of view, that’s something again that we’ll be discussing further with the agency. Base case in these types of diseases is agency typically looking for 100 patients exposed for a year on treatment, but they’ve shown, some variability around that.

So that’s a key topic that we’ll be discussing. Okay.

Alex, Interviewer, Goldman Sachs: Maybe we could spend some time on the market size. you could talk about kind of the overall sickle cell population. And then can you help us understand the carve out that you’re currently limited to versus what sort of unlocks if you’re able to go into a broader patient population?

Alex Zapier, President and CEO, Fulcrum Therapeutics: Sure. I’m happy to take that. Yes, so I think just in terms of the prevalence of the population, in The U. S, there’s approximately one hundred thousand patients, that suffer from sickle cell disease. Globally, the estimates are anywhere from four million.

I’ve actually seen all the way up to eight million. A large percentage of the non U. S. Prevalent population obviously resides in Sub Sahara Africa. About ninety five percent of all sickle cell patients are black.

I will say before I talk in more detail about some of the other questions that you asked about, I think that the other thing that’s also really important to mention is the unmet need is extremely high in this patient population. There was, about a year ago, there was a recent withdrawal, a product called Voxelotor, which was a product that was being marketed by Pfizer. Unfortunately, that got withdrawn from the market. The cell and gene therapies really have not seen the uptake that people would have expected, and I think that obviously has to do with the complexity of the treatment, the cost of the treatment, the risk associated with myeloablation. So this market is really one in which I think there’s a very, very high unmet need.

As Ian mentioned earlier, there’s a lot of interest in fetal hemoglobin induction. There’s a number of other companies that are also approaching this from a fetal hemoglobin induction perspective, albeit with different mechanisms of action. So I think over the next couple of years, what you will probably see is continued sort of interest in investment around the fetal hemoglobin sort of mechanism as opposed to the anti polymerization, mechanism which others are studying, such as the Voxelotor drug that I mentioned had been withdrawn and probably the next, latest stage asset is mitapivat by Agios.

Alex, Interviewer, Goldman Sachs: Okay. Maybe then you could talk a little bit about the competitive landscape as you see it. Maybe let’s talk about, like, how do you see the sickle cell market evolving with the advent of potentially new therapies? Is this going to be polypharmacy, sequential use? And where would an HBF inducer fit in that context?

Alex Zapier, President and CEO, Fulcrum Therapeutics: Do you want to start, and then I can

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: Yeah, sure. I think there’s certainly a recognition that HBF induction really is a key mechanism in the disease. I think the gene therapy, CRISPR vertex therapy, which specifically induces fetal hemoglobin, has really confirmed that. So I think there’s a lot of interest in that as being a holistic treatment, if you like, for sickle cell disease. I think there’s likely a place for drugs like the PK activators that do not induce fetal hemoglobin.

They bind directly to the hemoglobin, or they alter the environment within the red cells to to change the affinity of the hemoglobin for oxygen. And those those, PK activators have clearly been shown to decrease hemolysis and also to increase total hemoglobin. And so that’s clearly the mechanism of action there. The impact on the other manifestations of the disease, particularly the acute events associated with sickle cell disease are a little more questionable. And I think that’s a key focus for what will be coming out there.

So those compounds might be particularly efficacious for patients whose total hemoglobin doesn’t seem to be rising. That might be the niche for that and we’ll have to see. But I think the fetal hemoglobin, mechanism really offers the potential to really reduce the hemolysis as well as have an impact on, on these acute events.

Alex Zapier, President and CEO, Fulcrum Therapeutics: Yeah. And I think ultimately, in answer to your question about polypharmacy, I think ultimately it’ll come down to how strong the data is with the oral HBF inducers. As, Ian mentioned at the outset, if some of these oral HBF inducers such as Posiridir at the twenty milligram can get those patients to a sort of mid-twenty percent. And as Ian mentioned, that’s essentially transformative for patients. Monotherapy may be adequate.

If they’re not able to do that, it could be a combination of multiple HBF inducers targeting different pathways. So I think ultimately I think we’ll learn a lot over the next couple of years based on the data that’s going to be generated by us this year and by others in subsequent years.

Alex, Interviewer, Goldman Sachs: Okay. I know we only have a few minutes left, so maybe you can briefly do the pipeline.

Alex Zapier, President and CEO, Fulcrum Therapeutics: Sure. Sure. Do you wanna talk a little bit about some of the inherited plastic anemias we’re looking at?

Ian Fraser, Head of Early Clinical Development, Fulcrum Therapeutics: So so what we’ve, disclosed is that, by the end of the year, we expect to be submitting an IND for a compound that is targeted at a disease called diamond black fan anemia. That’s a genetically inherited aplastic anemia and affects about two thousand five hundred to three thousand individuals in The US and is very underserved in terms of what therapies are available. They typically treat it with transfusions or red cell transfusions which have all the complications associated with repeated transfusions including iron overload and corticosteroids, some of which some of the patients respond to and then lose responsiveness. And then of course that’s associated with its own complications over time. So this would be targeting the mechanism of action of that disease.

We haven’t yet disclosed the molecular basis of that mechanism, but we believe that that is also likely to be applicable in some of the other inherited genetic aplastic anemias such as Schwachman Diamond syndrome, Fanconi anemia, 5q minus. So there’s a number of these rare genetically inherited conditions that all end up with affecting the bone marrow and its ability to produce red cells and this mechanism might be applicable there. So that’s the next step in terms of getting into the clinic. We also have a robust discovery effort looking at other induces of fetal hemoglobin and that continues to be a focus in the lab. Maybe

Alex, Interviewer, Goldman Sachs: final question here. Just remind us the cash balances and the runway. In particular, what activities are embedded in that runway? What what? What activities?

Yep. Yep.

Alex Zapier, President and CEO, Fulcrum Therapeutics: Okay. Yeah. I think in in today’s market, we’re in a very enviable position in terms of our balance sheet. At the end of Q1, we had a balance sheet of $226,000,000 of cash. We’ve guided that this year, we will burn somewhere between $55,000,000 and $65,000,000 So take the sort of midpoint of that of, call it, dollars 60,000,000.

First quarter, we burned slightly under $15,000,000 So we have a balance sheet or sorry, a cash runway that takes us out into at least 2027, and that is assuming success on the pocereidir program in terms of advancing to the next clinical trial in 2026 as well as bringing some of the other products that are currently in discovery, for which we’re going to be filing our IND at the end of this year, bringing those into the clinic as well. So essentially assume success of the entire pipeline that we’re

Alex, Interviewer, Goldman Sachs: currently working on. Beautiful. Well, you guys for the time this morning.

Alex Zapier, President and CEO, Fulcrum Therapeutics: Yeah.

Alex, Interviewer, Goldman Sachs: Appreciate it. Thanks everyone joining us here on online.

Alex Zapier, President and CEO, Fulcrum Therapeutics: Thank you all. Thanks so much.

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