2025 RBC Global Healthcare Conference. My name is Greg Brunzo, one of the Biotech Analysts, and we're pleased to close out our day with Fulcrum Therapeutics. Joining us from the company is the CEO, Alex Sapir. Alex, great to see you. And of course, the Head of Early Development, Iain Fraser. Iain, it's great to see you as well. We're certainly at a really important point for Fulcrum 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. Yeah, sure. Absolutely. Thank you all for joining us. Yeah, Fulcrum is a smidget Biotech Company. We are very focused in rare, benign hematological conditions. Our latest stage program is a program called Pociredir 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. In addition to that, we have a very robust discovery pipeline targeting other novel HBG inducers, but also some very ultra-rare inherited aplastic anemia, such as Diamond-Blackfan anemia, Shwachman-Diamond syndrome. 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-Blackfan anemia or DBA. Great, great. You mentioned the lead asset, Pociredir, for the treatment of sickle cell disease. Certainly a market that some are rather familiar with, especially given that unmet need in the space. 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. Yeah, so just to ground everybody in some numbers, sickle cell affects about 100,000 people here in the U.S., about 4.4 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 20-25 years. The 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. 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. I think while five years ago, I think there was a lot of excitement given some of these more recently approved therapies, unfortunately, we are very much back to where we were 20 years ago when patients really have Hydroxyurea 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 is why so many people are excited about what we are doing with Pociredir. Yeah, it certainly leaves the door open, especially for oral options, not just stateside, but even globally. Maybe that's a good place for you, Iain, to maybe walk us through the history of Pociredir, the origination of the assets, as well as just the rationale behind the fetal hemoglobin mechanism. Yeah, absolutely. Happy to do that, Greg. So Pociredir 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. 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, your phenotype is much milder than if you do not have that elevation of fetal hemoglobin. It is known fetal hemoglobin not only dilutes out the abnormal sickle hemoglobin in the cell, but actually actively prevents the sickling from occurring, which occurs under hypoxic conditions, essentially. That is the rationale for going after fetal hemoglobin in sickle cell disease, and we can come back to that. Turns out that Pociredir 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 Pociredir binds EED, and EED is responsible for positioning that complex over the histones. 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 it results in an altered gene expression profile. 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. It allows for reactivation of fetal hemoglobin expression. That is how Pociredir is working, inducing fetal hemoglobin and the fetal hemoglobin acting in the red cells to counteract the effect of the sickle hemoglobin and give rise to a milder phenotype. At high levels, essentially abolishing the manifestations of the disease. Iain, as Alex mentioned, with data points coming up and as investors getting comfortable with the readouts, they're looking back at the history and the rationale that you're alluding to. 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 clinical hold lifted. Yeah, yeah, happy to do that, Greg. The clinical hold was instituted by FDA early in 2023. 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. At that point, about 100 subjects in the Healthy Volunteer First in Humans study, and we had 16 subjects having been dosed or being dosed in a sickle cell phase 1B study. That was the timing of it. It was that preclinical finding coupled with the knowledge that FDA had of another compound, another molecule called tazemetostat or Tazverik, 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. The observation with the tazemetostat development program was an observation in their preclinical toxicology studies of hematologic malignancies. 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 0.7% 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 tazemetostat added onto that. That low frequency of secondary malignancies in that study, which may or may not have been attributed to drug, there wasn't a control group in the study. That was an open label study. It is known in that particular patient population that they are predisposed to getting those secondary malignancies like AML and MDS, which were observed. Nonetheless, FDA was concerned that drug may have contributed to that. Those two strands of evidence were the underlying reason for the hold. Coming off the hold and getting back into the sickle cell patients, which took about six months overall back and forth with the agency, did not 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, phase 1B study, it was open to all with sickle cell disease. There was no requirement for any minimal severity. As long as you had sickle cell disease and met 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 impacted patient population and also a prohibition on the concomitant use of Hydroxyurea in that patient population. 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. The agency saying, you know we need to see some evidence of benefit to balance out the potential risk. In order to do that, the safest way is to restrict your study to more severely impacted patients who do not have a lot of therapeutic options. That is the genesis of that. Indicated as part of that process how the agency's thinking of this in terms of risk-benefit. That's very much how we've approached that. We redefined the inclusion-exclusion criterion. 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 and is labeled in the label as HU is a carcinogen. 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. That's the genesis of how that all unfolded and how we came off of that. That's helpful. Alex, to you, with Iain characterizing the new inclusion-exclusion 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 criteria? 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? Yeah, no, it's an excellent question, Greg. I'll go back to what I said earlier. In the US, there's about 100,000 patients that have sickle cell disease. Based on the inclusion-exclusion criteria that Iain spoke about, we believe currently about 10% of patients meet that inclusion-exclusion criteria. 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? 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 10% that we have, that will ultimately come down to what benefit has the drug shown in terms of increasing levels of fetal hemoglobin. 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 Pociredir 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 inclusion-exclusion criteria was actually less restrictive than ours. 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. If we can come to them with very robust levels of fetal hemoglobin at the end of this 12 and the 20 milligram cohort, we believe that there's very strong rationale to potentially relax that inclusion-exclusion criteria for the next study and thus broaden that patient population that we go after. That makes sense. The thought of that loosening in mind in those future interactions, maybe before we talk about sort of your expectations on the data in the cohorts three and four, maybe we can cover a little bit of what you've learned from the earlier cohorts, from the six meg and the two meg from an efficacy and safety standpoint now that those are. Yeah, absolutely. Just to ground everybody, 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 6 milligram once daily oral, a 2 milligram. Did I say 6 first? Six. Yeah, six milligram. We did a six milligram, a two milligram, and now we are in the process of completing enrollment in the 12 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. We dosed the six. We saw very modest increases in fetal hemoglobin. In the two, as we escalated to the six, we saw more robust increases in fetal hemoglobin. Then we had a couple of patients in the 12 milligram prior to the initiation of the hold that Iain spoke about. Even in those small number of patients, we saw an even more impressive higher induction of fetal hemoglobin. Where we are right now is in cohort three, which is essentially redoing those patients in that 12 milligram cohort. Maybe to take it a step further, when you quantify those bars of clinical meaningfulness, numbers that are being thrown around in the% way, and I'll leave it to you to maybe help characterize that. 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 about that. I'm not sure whether that was my fault or your fault, but I apologize nonetheless. Yeah, there is a very strong correlation between increases in fetal hemoglobin and reduction in vaso-occlusive crises. 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, in many cases, IV opioids to try to control that pain. 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 4%-8% reduction in vaso-occlusive crises. That then begs the question, what reduction in VOCs is considered clinically meaningful? To answer that question, I think you can look at some of the more recently approved therapies that have been approved by the agency. 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. If you take that 4%-8% range, right, 4%-8% reduction in VOCs, and you're trying to get to a minimum of 25%, you 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. If you look at cohort three, which is a 12 milligram 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. 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. Absolutely. Alex, you mentioned some of the data in the landscape and other players looking at competitive MOAs across fetal hemoglobin. Maybe Iain, to you, just lay out some of the pros and cons as you look at the landscape and how you believe the EED inhibition via Pociredir actually better sets up to address that underlying phenotype. 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 Voxelotor, which is a hemoglobin polymerization inhibitor and maybe a focus away from that particular mechanism, and also reinforced by the gene therapy, particularly the Vertex CRISPR therapy, which specifically also increases fetal hemoglobin. It goes up into the 40% range, which is well above the flattening of the curve in terms of symptom relief. It probably doesn't need to be that high, but certainly showing and confirming dramatic reductions in these acute events in those patients. Resurgence of interest. We're seeing now a number of players entering the field and entering the clinic. We have BMS that has a dual degrader, a WIS and ZBTB7A degrader. Novartis has a WIS degrader in development. GSK has a DNMT1 inhibitor that is in development. They have all entered the clinic recently. Novo has a decitabine-THU combination that is in phase two that is expected to read out later this year, although there has not been much data flow around that. There is 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 study, so they are somewhat behind where we are at. We do not yet have any of the clinical data to understand the profiles there. Obviously, what we would be looking for is extent of HBF induction as well as safety and tolerability profiles there. We will be following those closely. Clearly, a renewed interest in HbF as a central mechanism 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, US globally 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. Yeah, it's a great question. 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 starting from scratch. I think a lot of investors were wondering, will we ever be able to enroll this study? Because the enrollment early on was very, very slow. 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 going to see an inflection in that enrollment. I think that's exactly what we've seen given some of the over-enrollment that we saw in cohort three and excitement that we have around the enrollment potential trajectory for cohort four. 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. 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. That makes sense. I just want to pitch it to the audience here in New York if we have any questions for Alex and Iain. If not, I can keep going. Good. Good. I think what we will do, Alex, just to close it out, just when it comes to your resource allocation, you mentioned BD, sort of the early pipeline, the investment in Pociredir and existing trial and even in future potential trials. Just remind us of your cash position. Certainly, monetizing losmapimod last year is a big boost to give you some cushion as well. Just remind us of that. Yeah. Greg is mentioning a deal that we did with Sanofi last year for the ex-U.S. rights for a program that unfortunately failed in phase three clinical trials. What that did was that brought in about $88 million in non-dilutive financing for the company. At the end of Q1, we ended with $236, $226, I apologize, $226 million. We're burning somewhere between $55-$65 million a year. 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? Do you have aspirations to become more than just a sickle cell company? I think our goal over the next five years is to really become a leader in benign hematological rare conditions. We are certainly looking at a number of interesting opportunities outside of our core areas of focus right now. Our main focus and 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. We certainly have our eye on other rare benign hematological conditions that maybe at some point in the future we may transact on. Our focus right now is really executing what we have. Absolutely. We look forward to the posterior updates and the company updates throughout the year. Iain and Alex, thank you very much. Good to see you. Thanks, Greg. Thank you. Thanks, everybody.