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 yourselves first and then provide a brief overview of the company.
Sure. Alex, thank you all for joining. I'm Alex Sapir. 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.
Yeah, my name's Iain Fraser. I head up early clinical development at Fulcrum, and I've been there just a little over two years.
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. We have really decided to focus very much on non-malignant hematology. We have a phase IB, very interesting Phase 1b 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. In addition to that, we also have some other, there we go. We also have some really earlier stage assets, but for some other very, very interesting benign hematological conditions, such as Diamond-Blackfan anemia or Shwachman-Diamond syndrome. I'm sure we'll talk a little bit about that after we talk about our lead asset.
Absolutely. OK, so maybe let's start with P ociredir, the lead asset, as you said, in sickle cell disease. And let's start with a brief refresher. What is the mechanistic rationale that underpins P ociredir in sickle cell?
Sure. Iain, you want to take that?
Yeah. So Pociredir fundamentally is an inducer of fetal hemoglobin. 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. 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 highly upregulated genes under those circumstances is the gene that encodes fetal hemoglobin. You get a robust induction of fetal hemoglobin.
Great. Maybe talk to us about the role of fetal hemoglobin in sickle cell disease. 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? Sort of the clinical manifestations of that.
Yeah, now 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, induce fetal hemoglobin, reduce the severity of the disease, not only the severity of the disease, but also the mortality associated with sickle cell disease. 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. It 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. Small increases for individual patients are still clinically meaningful at around the mid-20s, transformational.
Great. You mentioned Pociredir as a fetal hemoglobin inducer, but what have you shown in preclinical or clinical settings in terms of that increase in fetal hemoglobin?
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 Pociredir. That was reaffirmed in our first 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 twenty, at each of those doses, incremental bumps in the HBG mRNA, so the mRNA encoding fetal hemoglobin. Twenty to thirty in that two-week dosing period did not 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 12. We have a cohort of 12 mg 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. In those patients, we were able to show two-six, six-12 dose responsive increases in fetal hemoglobin measured at the protein level.
OK. So obviously, you had a couple of patients treated, two, six, you said a couple at 12, but then there was a clinical hold that was put on the program. 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?
Yeah, absolutely. The clinical hold was instituted by the agency in February of 2023. It was not based on any clinical data from the program. At that point, we'd had about 100 healthy volunteers in our initial study, and we'd had 16 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. That information, coupled with what the agency knew about an approved drug that is also a PRC2 inhibitor called tazemetostat or Tazverik, to improve the treatment of synovial sarcoma and lymphoma. In their preclinical studies, they had had some hematological malignancies in their preclinical animals.
In their pivotal clinical trial, in patients treated for malignancy, they had a 0.7% rate of secondary malignancies. These are patients who had already had chemotherapy and/or radiation for their primary malignancy and then developed it during the exposure to tazemetostat. 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, FDA said, we believe that there's a risk associated with this mechanism, even though the exact molecular mechanisms are different. Tazemetostat inhibits the catalytic subunit, EZH2. Pociredir 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 do not have a lot of therapeutic options.
There 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-common sickle cell patient population to one with more severe disease with no therapeutic options.
Where we are now is, as Iain mentioned, in early 2023, 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 2023. Spent a lot of time in 2024 identifying new sites that met this new, more severe inclusion-exclusion criteria for patients. It really was not until, I would say, the fourth quarter of 2024 where we were able to really start actively enrolling in, as Iain mentioned, this new 12 mg cohort followed by a 20 mg cohort, which we are currently enrolling in.
OK, great. You have mentioned now a couple of times this ongoing 12-mig cohort. There is a 20-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. Yeah, so the study that we keep referring to is the PIONEER trial. It is a Phase 1b study, open label, four cohorts in increasing dosages. As Iain mentioned, we started with a two milligram cohort, escalated to a six, escalated to a 12, and we are currently enrolling in a 20 mg cohort. The third cohort, the 12 mg cohort, recently completed enrollment. We had a total of 16 patients in that cohort. We will be sharing the results of that data, and we will talk maybe in a little bit about what data we are planning to show. We should have that data to share with everybody early in the third quarter of this year. That 20 mg cohort, cohort four, which is currently screening and actively enrolling patients, we should have that data by the end of the year.
Really important year for Fulcrum in that we'll have not one, but two very important clinical readouts in patients really during the next six months.
OK, great. 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 inclusion-exclusion criteria in the patient population that you're enrolling?
Yeah, so in the bucket of disease severity, the most common and frequent requirement for disease severity is based on counting acute events, these vaso-occlusive crises. In order to get into the study, patients need to have experienced at least four of those episodes over the preceding 12 months or two over the preceding six months in order to get into the study. There are some variants on that. There is an acute crisis called an acute chest that is more severe than a VOC. That gets counted as two VOCs, essentially. Basically, it is those four VOCs. There is also disease severity based on end-organ disease. There are some patients who have severe sickle cell disease who may not be having frequent acute events, but they do have manifestations of the chronic hemolytic anemia. They have renal insufficiency, right-sided heart disease, pulmonary hypertension. Criteria are also permitted.
In addition to the disease severity, there is therapy-related criteria in order to get into the study. These patients need to have at least tried hydroxyurea in the past. That is the current standard of care and has been for over 30 years now. They might have tried it and failed because they did not 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. Those are the main inclusion-exclusion criteria.
Can you explain why people who are on concurrent HU are not included and what the impact might be in terms of the patient outcomes?
Yeah, absolutely. 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. What the agency said is, given that there are potential concerns about the PRC2 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. It is this theoretical concern around the mechanism of action. There is no reason that patients who are on HU or cells that are exposed to HU would not also still respond to Pociredir.
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 HU because the restriction was not in place at that time. Those patients responded to Pociredir pretty much as well as those that were not.
OK. You mentioned that you had to activate new sites, enrollment is now complete in the 12-minute, ongoing in the 20. I guess, could you talk about 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 20-minute kind of timelines as you've laid them out?
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. 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. 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.
What we saw end of last year, beginning of this year, was very much of a change in the slope of the enrollment rate that we've been seeing. In terms of your question about level of confidence of the 20 mg cohort readout by year end, we feel very confident based on where we are with that 20 mg that we will be able to hit that previous guidance that we provided.
Great. I think you have shared some things around the baseline patient characteristics in the 12-minute cohort. Maybe you can remind us what that is and just how should we expect something similar in the 20, or what should we be paying attention to there?
Yeah, yeah. What we did disclose in our most recent earnings call was that those 16 patients had a baseline fetal hemoglobin level of 7.6. That was the average. The median was 7.7, so very, very similar. In terms of what to expect at the end of that study, I think, as Iain mentioned, any increase in fetal hemoglobin is beneficial to patients. There has 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%-8% reduction in VOCs.
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. 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- 15, call that seven times an 8% reduction in VOCs in that 48%, 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 50% reduction in vaso-occlusive crises at the one-year part, at the one-year mark.
OK. It's my understanding that there's also just a function of time on therapy that drives the absolute change that you see in fetal hemoglobin. With that in mind and considering the dose that you guys are doing, the baseline hemoglobin, what would be a reasonable outcome for the 12-minute data? What would be reasonable at 20?
Yeah, you want to take that?
Yeah, so we see at the earlier doses, we see that the fetal hemoglobin seemed to be plateauing around the three-month mark. We have not dosed longer than that, so we have not defined that completely. It seems to rise fairly steadily during that period. I think that that is a reflection of the turnover of the red cells. It is not a pharmacological parameter. It is just that the drug needs to act on the red cells, and they need to undergo several cycles. During that three-month period, you are seeing an increase in the fetal hemoglobin. 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. That seems to be what is different across the cohorts.
As I said earlier, from the healthy volunteers, we'd previously seen that dose response from two to six to 10 to 20. We would expect to see that as we get the protein data from the patients.
OK. In terms of, 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 it too early for that?
Yeah, so just as a quick reminder, this is a Phase 1b study, open label, four cohorts, as I mentioned. The primary endpoint of the study is obviously safety. That will be the one thing that we will really be focusing on to make sure that the drug is safe for patients. In addition to that, we will also be showing changes in fetal hemoglobin, as you mentioned. We will also be looking at some other really important markers of hemolysis, such as red cell distribution width, bilirubin, total hemoglobin. We have 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 Iain mentioned earlier.
These patients will have had to have had a minimum of four VOCs during the previous 12 months prior to enrolling in the study. We will share those baseline characteristics. 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.
The simple fact of the matter is VOC data in early Q3 when we read out the 12 mg, and then at the end of the year with the 20.
Sorry, maybe just one additional point is traditional VOC study is usually a one-year study. We're looking at a three-month endpoint. Essentially during that entire three months, the fetal hemoglobin is going to be going up. We're not seeing a maximal effect until at least the end of that time. As we said earlier, even small increases are expected to have some benefit. Just bear that in mind as that data come out.
OK. So with that in mind, AC12, AC20, let's assume for the case of this question that they show what you are hoping to see. What comes next from there in terms of the next kind of studies that you would be running?
Yeah, yeah. 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. 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 20 years, even in the U.S. It's understanding the risk-benefit potential. What the agency discussed with us at that time was, let's complete this study. Let's finish the 12 mg. Let's finish the 20 mg cohort. Go back and discuss then what the next steps will be. Those next steps include, 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. Potentially, that study could be a pivotal study. It will 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 accelerated approval. There's no precedent for fetal hemoglobin playing that role in sickle cell disease as yet from an approval standpoint. There is really abundant evidence that links fetal hemoglobin to reductions in disease severity in sickle cell disease. That is another strand of the conversation that we'll be having with the agency.
OK. 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 what level of benefit or what they're going to be paying attention to that you can go out and?
Yeah, there are no pre-established or predefined bars. 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, the data might be sufficient to drive that decision. Obviously, it depends on there being adequate acute safety and tolerability, which is what we've observed to date. It'll be viewed both as the fetal hemoglobin induction, but also the overall safety of the drug.
OK. I guess the other question from there is just how quickly can you kind of meet with regulators and get some of these answers? When should we expect an update?
Yeah, so as I said, it'll be driven by the data coming out of the study. We need to complete the 20 mg data. We've said that 20 mg data we will release publicly around the end of the year. That gives a rough timing for when we expect to have that. That will trigger an end of phase I meeting with the agency. That'll likely be early in 2026 based on the conduct of the study.
OK. You mentioned that another key question is whether change in fetal hemoglobin is a good surrogate endpoint for a registrational study. Talk to us about what a pivotal design would look like in the case they do agree to a surrogate versus what it would look like if you're required to run sort of a full outcome study.
Yeah, and I think those possibilities are still there. They haven't been decided yet. If you do, just in general, use a surrogate endpoint for a conditional approval, the rules are that you need to also conduct a confirmatory study. Whatever your design is, it can either be a separate study 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 supportive clinical evidence to do that. How might that look for sickle cell disease? 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, a one-year mark has been used for clinical readouts like VOCs. Base case without an accelerated approval, it would be a one-year study with a VOC-like primary endpoint. For an accelerated approval, it could be a six-month readout on that. Either a separate study or the same study continued in order to derive the one-year data.
In terms of roughly the number of patients that you think there would be both an efficacy component and a safety component, what do you understand in terms of maybe both?
Yeah, so a little early to say without the fine details of the design. From an efficacy standpoint, a few hundred 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. They've shown some variability around that. That's a key topic that we'll be discussing.
OK. Maybe we could spend some time on the market size. First, you could talk about kind of the overall sickle cell population. 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?
Sure, I'm happy to take that. Yeah, so I think just in terms of the prevalence of the population, in the U.S., there's approximately 100,000 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-Saharan Africa. About 95% 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. About a year ago, there was a recent withdrawal of a product called Voxelotor, which was a product that was being marketed by Pfizer. Unfortunately, that got withdrawn from the market.
The SelG1 therapies really have not seen the uptake that people would have expected. I think that obviously has to do with the complexity of the treatment, the cost of the treatment, the risk associated with myeloablation. This market is really one in which I think there's a very, very high unmet need. As Iain 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. 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.
Probably the next latest stage asset is mitapivat by Agios.
OK. Maybe then you could talk a little bit about the competitive landscape as you see it. Maybe let's talk about 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?
Do you want to start? I can sort of jump in.
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, particularly the CRISPR/Vertex therapy, which specifically induces fetal hemoglobin, has really confirmed that. 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 change the affinity of the hemoglobin for oxygen. Those PK activators have clearly been shown to decrease hemolysis and also to increase total hemoglobin. 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.
I think that's a key focus for what will be coming out there. Those compounds might be particularly efficacious for patients whose total hemoglobin does not seem to be rising. That might be the niche for that. We will have to see. I think the fetal hemoglobin mechanism really offers the potential to really reduce the hemolysis as well as have an impact on these acute events.
Yeah. I think ultimately, Iain answered your question about polypharmacy. I think ultimately it will come down to how strong the data is with the oral HBF inducers. As Iain mentioned at the outset, if some of these oral HBF inducers, such as Pociredir at the 20 milligram, can get those patients to a sort of mid 20%, and as Iain 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. 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.
OK. I know we only have a few minutes left. So maybe you can briefly do the pipeline?
Sure, sure. You want to talk a little bit about some of the inherited aplastic anemia you're looking at?
Yeah, 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-Blackfan anemia. That's a genetically inherited aplastic anemia. It affects about 2,500-3,000 individuals in the U.S. and is very underserved in terms of what therapies are available. They're typically treated with transfusions, so 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. Of course, that's associated with its own complications over time. This would be targeting the mechanism of action of that disease. We haven't yet disclosed the molecular basis of that mechanism.
We believe that that is also likely to be applicable in some of the other inherited genetic aplastic anemias, such as Shwachman-Diamond syndrome, Fanconi anemia, 5q minus. There are a number of these rare genetically inherited conditions that all end up with affecting the bone marrow and its ability to produce red cells. This mechanism might be applicable there. That is the next step in terms of getting into the clinic. We also have a robust discovery effort looking at other inducers of fetal hemoglobin. That continues to be a focus in the lab.
OK. Maybe final question here. Just remind us the cash balances and the runway. In particular, what activities are embedded in that runway?
What?
What activities?
Yep, yep, OK. Yeah, I think 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 million of cash. We've guided that this year we will burn somewhere between $55 million-$65 million. Take the sort of midpoint of that, call it $60 million. First quarter, we burned slightly under $15 million. We have a balance sheet, or sorry, a cash runway that takes us out into at least 2027. That is assuming success on the Pociredir 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 first IND at the end of this year, bringing those into the clinic as well.
Essentially assume success of the entire pipeline that we're currently working on.
Beautiful. Thank you guys for the time this morning. I appreciate it. Thank you for joining us here on Online.
Yeah, thank you all. Thanks so much.