Welcome, everyone, to the 44th Annual J.P. Morgan Healthcare Conference. My name's Anupam Rama. I am one of the Senior Biotech Analysts here at J.P. Morgan. I'm joined by my squad: Ratih Pinhei, Priyanka Grover, and Joyce Zhou. Our first presenting company of the day is Fulcrum Therapeutics, and presenting on behalf of the company, we have CEO Alex Sapir. Alex? Thank you. Thank you, Anupam. Thank you, J.P. Morgan, and thank you for your excellent report that you issued earlier this week. If you haven't had a chance to read it, it's really, really very well done, and thank you all for joining us this morning at 7:30 A.M. As Anupam said, I'm Alex Sapir. I'm the CEO at Fulcrum Therapeutics. I will be making several forward-looking statements throughout the next 20 or 25 minutes, so I would encourage you to please read the full listing of the risks and uncertainties in our recent filings with the Securities and Exchange Commission. So, Fulcrum's strategic focus has always been to develop oral small molecules designed to modify gene expression for rare diseases where there continues to be a very high unmet need. Our initial focus is in benign hematology, and even more specifically, our focus today is in sickle cell disease. Our lead asset is a product called pociredir. It is a fetal hemoglobin inducer, and we'll talk a lot about fetal hemoglobin over the next 20 minutes or so. It is, we believe, a best-in-class HbF inducer for the treatment of sickle cell. It does have Fast Track and Orphan designation, composition of matter and method of use patents out until 2040. We are in the process of wrapping up a phase Ib study in patients, but a lot of that data has been presented in 2025, in July and December, and we'll go through that data in some detail. We do have an end-of-phase meeting planned with the agency, sometime scheduled in the first half of this year, and we believe that we will be kicking off our next study, which we believe has the potential to be a registrational study sometime in the second half of this year. A lot of activity going on with Fulcrum in 2026. Beyond that, we have a very rich discovery effort and a very deep early-stage pipeline with a very strong cash runway of $352 million at the end of last year, which takes us out into at least 2029. Here is our pipeline. You can see here we are just wrapping up our phase Ib study for pociredir, but we have a number of very interesting and early discovery efforts looking at other benign hematological conditions such as Diamond-Blackfan anemia, Fanconi anemia, Shwachman-Diamond, which all fall into the bone marrow failure syndromes. You see that articulated here. We also have a number of efforts ongoing to really develop and discover the next generation of fetal hemoglobin inducers for the treatment of sickle cell disease. We've also done a little bit of work in the field of oncology as well. Let me spend a little bit of time and talk about sickle cell disease. Prevalence is very high. About 7.7 million people worldwide suffer from sickle cell disease. Within the more developed nations, about 100,000 people in the US, about half of that are 55,000. In In Europe, it is a rare genetic disorder primarily affecting Black and brown population. The disease is really caused by this sickling of the red blood cell. When you have this sickled red blood cell, it, in essence, can prevent that red blood cell and the oxygen that is associated with that red blood cell from getting to the tissues. By not being able to get to the tissues, these patients experience not only chronic pain throughout every day of their life, but also these acute manifestations of pain, which we call vaso-occlusive crises. Most of the time, these VOCs essentially wind people up in the hospital or the intensive care for days on end. These VOCs contribute to about 75% of the sickle cell-related hospitalizations. In addition to that, there are many other comorbidities: stroke, leg ulcers, pulmonary hypertension, splenic sequestration. Really, the message that I want to leave you with on this slide is that these patients face a very substantial reduction in life expectancy, greater than 20 years, so worse than many of some of the worst forms of cancer, with a mortality rate that's 9X higher than any of us. The road for sickle cell has been very bumpy over the last couple of years. 2019 through 2022, there was a tremendous amount of promise in sickle cell disease. There were four products approved: Adakveo, Oxbrita, and then two cell and gene therapies, Casgevy and Lyfgenia. Unfortunately, that road has not been as well paved as the patients would have hoped. In 2023, Adakveo failed in their confirmatory study to show a reduction in these vaso-occlusive crises and was subsequently withdrawn from the European market. In 2024, Oxbrita was withdrawn globally. And the cell and gene therapies, as innovative and as much as a scientific breakthrough as they are, they really have not reached their potential as a commercial opportunity. About 100 patients within the U.S., of the 100,000 patients, are currently receiving Casgevy or Lyfgenia. And so the conclusion here is that the unmet need remains very, very high in sickle cell. Here's how we think about this market along these two axes and along these four different types of products used to treat sickle cell. You have the anti-polymerization inhibitors, so that would be the PK activators, mitapivat, etavopivat, voxelitor, GBT-601, which is the follow-on product. And you also have these adhesion and inflammation modulators, such as crizolizumab. And they all act on the mature red blood cell. Gene therapies, on the other hand, act much more upstream. So they're acting within the bone marrow as those red blood cells are being formed. And if you can get enough fetal hemoglobin in those red blood cells, they emerge from the bone marrow very healthy. They do not sickle, and you essentially, therefore, get the prevention of these vaso-occlusive crises. The challenge with cell and gene therapy is the risks, costs, and complexities of the therapy. I think for those three reasons, that is one of the key reasons why a very, very small number of patients have received those therapies, despite being on the market for more than 2 years. That's really, I think, where the opportunity comes in with a novel oral, once-a-day fetal hemoglobin inducer, such as pociredir. I want to leave you with two messages here, and I think these are really important messages to remember, because as we go into the data, I want you to remember this. If you can get a patient's fetal hemoglobin levels up to 20%, you essentially are curing that patient. They have 94% of those patients are VOC-free. However, you don't need to get every patient to 20% in order to see a benefit. That's the evidence on the right-hand side of this slide. This is data that was presented by one of our competitors in ASH of 2024, and what they demonstrated is that for every 1% increase in fetal hemoglobin, or HbF, you see a 4%-8 reduction in VOCs. Let's just imagine for a minute, if you can take a patient from an HbF level of 1%- 8, that's a delta of 7, you're going to see somewhere between a 30% or 60 reduction in VOCs during that year. That is very, very meaningful for the patient, so I want you to remember those two numbers as we get into the data in just a minute, so when we set out on this journey in 2021, 2022, we had what we believed was the ideal product profile. We wanted a once-a-day oral that was well tolerated, demonstrated a robust and rapid increase in HbF at a pan-cellular level. We also wanted to see reductions in the markers of hemolysis, an increase in total hemoglobin, a reduction in anemia, and ultimately a reduction in VOCs. That's exactly what we saw in these two data sets that we presented, one in July and one in December last month at the ASH Conference. There's a lot of text on here, but I'm going to walk through this data very quickly in the following slides. Here's the study that we are in the process of wrapping up. It was a 12-week open-label study in sickle cell patients, roughly about 10 patients per arm. We tested 6 doses, sorry, we tested 4 doses: 2 mg, 6 mg, 12 mg, and 20 mg. Primary endpoint, obviously, was safety and tolerability, but we also looked at some other very important parameters, such as HbF induction, hemolysis markers, anemia, and so forth. I'm going to talk now. I'm going to walk you through the data from these 2 cohorts: the cohort 3B, which was 12 mg, and cohort 4, 20 mg. These 2 cohorts were fairly consistent. Slightly more females in the 20 mg cohort. About 60% of the patients came from the US,the remainders came from outside of the U.S. Baseline total hemoglobin levels were about 7% across the 2 arms. I'm sorry, fetal hemoglobin, I apologize. Total hemoglobin was 7.3 and 7.6. Total fetal hemoglobin was 7.1 and 7.6. And here you can see the number of VOCs that these patients experienced historically prior to coming into the study. So about almost seven VOCs in the 20 mg cohort over a 12-month period of time, and about 2.5 VOCs in five of those patients over a 6-month period of time. The 20 mg cohort we're going to spend most of the time on, because that was the data that we just presented weeks ago at the ASH Conference. It was a total of 12 patients. The data that I will show you is all patients getting through day 42, so only 6 weeks of treatment. 6 of those patients got all the way through to day 84, or 12 weeks of treatment. And we will complete this study and report out the full cohort this quarter. So here, I think, is probably one of the most important slides of the presentation. And this is showing the induction of fetal hemoglobin over time. Each one of these slides has a similar look and feel. The blue is the 12 mg. The green line is the 20 mg cohort. You can see it's truncated at 42 days, or 6 weeks. What you're seeing here is a very, very robust and rapid increase in fetal hemoglobin from about 7%- 16.9 in the 20 mg cohort after only 6 weeks. If you just look at that data from a change from baseline, what I want to call your attention to is that the 20 mg cohort was able to achieve a greater level of HbF induction at 6 weeks than what the 12 mg cohort was able to achieve at 12 weeks. These are the individual patients. These are the 12 individual patients. The gray line is where those patients' baseline HbF levels were. The green is the increase that they saw. If the green bar is solid, that is a patient that went all the way out to day 84, or 12 weeks. If it is dashed, as you see here, they had not yet completed the full day 84. So I want to leave you with two messages on this slide. The first message (and remember that 20% that we talked about earlier) after only 6 or 12 weeks of treatment, we were able to get seven of those 12 patients above 20% with an oral once-a-day therapy. And all patients achieved at least a 6.5% increase in their HbF, or greater. So more than 50% were able to reach that 20%. We know that 20% is transformative. But we also know that all patients were able to increase their fetal hemoglobin levels to a point where it became clinically meaningful. So like if you just look at patient number 5, they were at 1.5. They got to 9 at the end of 12 weeks. That's a delta of 7.5. That 7.5, when multiplied by those earlier numbers that I showed you, a 4%-8 reduction in VOCs, that patient, over time, will see anywhere from a 30%-60 reduction in their VOCs, clinically meaningful for those patients, so the other thing we also wanted to look at is, because this is operating in the bone marrow, while those red blood cells are being formed, as those red blood cells come out of the bone marrow, because they now have the presence of fetal hemoglobin, they should be healthier, they should not sickle, and as a result of that, you should see less hemolysis or bursting of those red blood cells, and so there's four markers that we look at: LDH, bilirubin, red cell distribution width, and reticulocyte count. You can see across both the 12 and the 20. You see LDH going down, bilirubin going down, reticulocytes going down, red cell distribution width going down. That should all translate if you're seeing less destruction of the red blood cells because they have the presence of fetal hemoglobin. You should see an increase in total hemoglobin, which should improve factors like anemia and fatigue for these patients. That's exactly what we saw. An increase in total hemoglobin. Patients in the 20 mg started at about 7.3, and at the end of only six weeks, got up to 8.1, or a delta of 0.8g/dL. So the other thing that we wanted to look at, but I will caution you that this is a 3-month study, and I think that this relationship between increasing HbF and reduction in VOCs takes time, but we did want to look at, were we seeing an impact in VOCs in this very short study? And so if you remember the baseline VOCs that these patients had, seven of them had baseline VOCs of 6.7, almost 7 VOCs in the previous 12 months. Five of these patients had 2.5 VOCs over 6 months. So you would have expected to observe 16 VOCs across these 12 patients during this 12-week study had they not have received pociredir. What we have observed as of the data cut of November 11th, we've observed 5 VOCs across 4 patients, or 8 of these patients experienced no VOCs during the course of this study. It is early. I will caveat it that this VOCs was not an endpoint in the study. There was no adjudication committee. We probably would not have been disappointed if we did not see any reduction in VOCs, given the fact that this was only a 3-month study, but the fact that we did see a very meaningful reduction from what we expected to see versus what we observed left us very, very encouraged, and finally, safety was the primary endpoint of this study. You can see here that the 20 mg looked very similar to the 12 mg. We had 3 treatment-related AEs in the 20 mg cohort and 3 treatment-related AEs in the 12 mg cohort, with the exception of one of those AEs, which maybe we can talk about during the Q&A. All of those treatment-related AEs were grade 1 and resolved while on study drug. So the drug is, again, met our target product profile of an oral once-a-day, very well tolerated. So as we look forward into 2026, I mentioned that it was going to be a very important year for Fulcrum. We've got a number of important milestones coming up over the next 12 months. We will be completing this 20 mg cohort and will be reporting that out to all of you sometime in the of this year Q1 Armed with the strength of this data, we intend to engage with the agency as part of our official end-of-phase meeting in the first half of this year, share with them the data, and gain alignment on what we believe that next study should look like. In addition to that, for these patients that have just participated in the study that I just talked through with you, these patients will have the option to go into an open-label extension study, which we expect to operationalize and begin enrolling patients in the 1st half of this year. We believe there's going to be very, very strong interest from many of these patients based on the anecdotal evidence that we were hearing from investigators about how well these patients were feeling while on study drug. And then in the 2nd half of this year, we believe we have the possibility to begin enrolling in a global registrational of study that will serve as the basis for an approval of pociredir. And with that, we have a very strong cash runway of $352 million. We have cash to get us all the way through that registrational of study with additional cash runway on the back end of that. So we are fully funded to support many of the anticipated regulatory milestones over the next couple of years. And with that, I thank you, and I will turn it over to Anupam to start running through some questions. Yep. Thanks so much, Alex. I'm going to ask the first couple of questions, but there'll be an opportunity for the audience to ask a question too, so just raise your hand. So Alex, just quickly, when you were at ASH when these data were presented, maybe you can just orient us to some of the KOL feedback you were getting at the conference as kind of the most de-risking data that de-risked the kind of program and next steps. And then I think you wanted to maybe comment on that discontinuation as well. Sure. Absolutely. Yeah. And maybe, Iain, I'll have you know the details of the discontinuation a bit better than I do. Yeah, I think, obviously, the physicians, as you probably have witnessed yourselves from seeing this data, some of you maybe for the 1st time, highly, highly encouraged across the totality of the data. The robust increase in fetal hemoglobin, the reduction in all of those markers of hemolysis saying that these red blood cells are not rupturing because they're coming out of the bone marrow in a much healthier state. You're seeing then, as a result, an increase in total hemoglobin. The trends toward VOCs, I think, again, physicians were saying it's interesting, but obviously, it's a hypothesis, and we need to test that in a much larger study. But I would say the 1 piece of evidence of all of the totality of this data, which again was very strong. I think the one thing that the physicians are most impressed about was that very robust and rapid increase in fetal hemoglobin and the fact that we were able to get seven of those 12 patients above 20% again after only 12 weeks of dosing. So Iain, do you want to maybe talk about the one discontinuation, the grade 3 reticulocytopenia? So the reticulocytopenia, not dis gone from the study? Yes, yes. The grade 3. Yes. So there was one patient that you'll see under the list of treatment-related adverse events that includes a reticulocytopenia. That patient had a year prior to enrolling in the study an experience of depressed blood counts, including neutropenia in the context of a viral infection and sinusitis that was treated with an antibiotic. When that infection resolved and the antibiotic was discontinued, those counts came back. After enrolling in the study with pociredir at the 20 mg dose, a few weeks into the study, experienced symptoms of a viral infection and sinusitis. They were started on amoxicillin. Their counts were noted to be depressed, including neutrophils and reticulocytes and monocytes. At that point, we discontinued the pociredir because we weren't certain about the overall clinical picture with the patient. Their viral infection got better. We did a workup there. They had a positive Parvovirus IgM, although the DNA PCR on that was negative. As that infection resolved, the counts started to come back up. We clearly thought that this was the depression of the counts was related to that intercurrent event, and so we restarted the Pociredir after a two-week pause. And at that point, the counts continued to remain elevated and did not go down further, therefore indicating that the drug was not related to those events. It was more the intercurrent illness. The reticulocytopenia is listed as still related to drug. The investigator indicated that that was because the reticulocytes did not come back to their pre-study baseline at that point. If you recall, and Alex is projecting this now here, that a reduction in reticulocytes is part of the therapeutic response to Pociredir because the red cells are surviving longer and they're healthier, there's less stress on the bone marrow, and so the reticulocytes come down as a therapeutic response. You wouldn't expect somebody who had responded to the therapy to go back to their pre-treatment baseline. Nonetheless, that's the attribution that's listed there. The overall events clearly not related to drug. They went back on drug. Counts came back. They did well, and they completed the study. You have sort of updated data coming for the 20m g cohort this quarter. What's going to be the size and scope of the data relative to what we learned at Ash? How are you broadly defining a win scenario for that 1 Q update? Sure, sure. Maybe I'll just, for the people in the room, maybe I'll just go back to the presentation. So what you will see at the release of the full data on the 20 mg cohort is each one of these green lines will extend all the way out to 12 weeks. So we'll show you the data on fetal hemoglobin induction. We'll look at individual patients. We'll look at all those markers of hemolysis. We'll look at the total hemoglobin. We'll look at VOCs, and of course, we'll look at safety as well. The way I would answer the question in terms of a win, I would say we've already won based on the data that we've just released and that I've just shared with all of you this morning. I think if and we were able to achieve 16.9 in the 20 mg after only six weeks, if we can get that to, on average, across all patients of a 19% or 20 at week 12, I mean, that would be extremely, extremely powerful for these patients. But that data will be imminent. That data will be coming out in the very, very, very near future. There is not a medical conference, so it won't be shared in the medical conference sort of ecosystem, if you will, but we will share that as part of one of our regular corporate updates. Question from the audience? Yep, go ahead. Have you tried the treatment with a higher dose like a survey? The question is, have you tried a higher dose? Yeah, it's a great question. Yeah. Question is? Do you have any biomarkers to show the target engagement? Sure. So let me answer the first question, and then the biomarker question, I'll turn that over to Iain. So we have tested higher doses in healthy volunteers looking at HBG mRNA at day 14. So this is not the protein in healthy volunteers. And what we saw, we tested 2 mg, 6 mg, 10 mg, 20 mg, and 30 mg, so 5 different doses. We saw a very, very elegant dose response as patients went from 2- 6, 6- 10, and 10- 20. We did not see a dose response as patients went from 20- 30. So, I think based on what we saw in the healthy volunteers and based on the robust nature of the data that we've seen with the 20 mg, we don't, even though we have the option in this protocol to go higher, we don't believe that we do need to go higher. And so once we finish this cohort, we will wrap that up and get ready for an end-of-phase meeting with the agency sometime in the first half of this year. Iain, do you want to comment on the biomarker? Yeah. So there is a biomarker of target engagement. The PRC2 complex is responsible for trimethylation of one of the lysine residues on histone H3. And you can measure that. We did that in that first-in-human study that Alex referenced earlier, measuring it in the peripheral blood of those healthy volunteers. The assay, unfortunately, doesn't offer a very fine level of discrimination across doses. And what that showed is you saw some inhibition of that effect by measuring that trimethyl mark at doses as low as two mg once a day. So there was indication of target engagement at that level. At the higher doses of a 6 and all the way to the 30, very difficult to discriminate the actual magnitude of induction. The assay maxes out at about 80% inhibition. But clearly, seeing inhibition of that over the course of the 2 weeks and then reversion back to baseline pretty rapidly after that ceased. Additional questions from the audience? On the key endpoint of vaso-occlusive crises, that's commonly used in clinical trial. What gives you confidence here based on the early totality of data that you know and then put it into context of what we're going to learn in 1 Q as well? Yeah. Iain, do you want to maybe take that one? Yeah. So there really is a large body of evidence that links increased levels of fetal hemoglobin with reductions in clinical manifestations of sickle cell disease, and particularly that of VOCs. And when I say a large body of evidence, it's normal human development evidence. It's genetic evidence with naturally occurring mutations that increase expression of HbF. It’s pharmacological evidence, mostly with hydroxyurea, and then more recently, gene therapy experience showing induction of fetal hemoglobin essentially abolishing VOCs. There’s that very tight link between increased HbF and improved clinical symptoms like VOCs. The other piece that’s very reassuring to us in the dataset is that as the fetal hemoglobin goes up, you would expect to see evidence of decreased hemolysis, evidence of decreased stress on the bone marrow, and evidence of increasing total hemoglobin as the red cells survive for longer. All of those were directionally consistent across these. We’re seeing LDH, bilirubin go down as a marker of less hemolysis, the reticulocytes going down. We mentioned that earlier, and the total hemoglobin going up. In totality, everything that you’d expect from an HbF inducer is occurring there. And then this large historical and current dataset supporting that link between increased HbF and decreased VOCs. Maybe another one for me. You've got this end-of-phase one meeting coming up with the FDA. What are the key points of discussion with the agency? And in your mind, what's kind of a base case trial design for pivotal pending regulatory feedback for SCD? Yeah, yeah. Great, great question. Iain, maybe I'll start, and then please add to what I'm saying. So I think for us, the way that we're thinking about going into this meeting with the agency is more than likely what the agency will require is a clinical endpoint in sickle cell disease as opposed to a biomarker such as HbF for a full approval. So we believe that we will need to design a one-year VOC study. We understand there's a lot of variability around VOCs, and we've done a lot of effort to try to reduce some of that variability, not only across centers within a geography, but across geographies. So we believe that we will need to design a phase three registrational study that has VOCs as an endpoint at one year, probably two to one. Numbers of patients, we're still going through some of those powering calculations, probably a couple hundred patients. But based on everything that Iain said and everything that I walked through and the strength of the evidence showing this very strong relationship between HbF and VOCs, we think there is a path forward to look at fetal hemoglobin at an earlier time point, say at 6 months in a smaller number of patients as a surrogate endpoint for the basis of an accelerated approval. So that essentially is the, we think that there is a clear path forward for that. We feel that the strength of the evidence is there to propose that, and that's essentially will be kind of what we will be at a high level taking to the agency and seeking feedback on. Iain, anything you would add? I think that's pretty clear. Okay. Any final questions from the audience? And I have one more. Maybe my final question for the session here. The gating factors to starting that OLE portion of the pioneer, and any thoughts? Could we get some OLE data later in the year? And obviously, some of the key measures you're going to be monitoring. Great, great question. So the only gating factor with the OLE study is getting those sites activated with that study. And so we are very active in getting those sites initiated. I believe as of last week, we had one site that had already initiated, so it was available to start enrolling patients. We are going to initially be focusing on the US patients. There is a total of 17 US patients that participated in either the 12 mg cohort or the 20 mg cohort. And so once those sites get activated, we will be enrolling those patients. We do believe, based on the anecdotal feedback that we've heard from investigators, from talking with their patients of how well they felt while on therapy, we think we will have a fairly decent number of those 17 opting to go into the OLE. Some of them may be lost to follow-up or maybe on other clinical trials. So I'm sure we won't get the full 17, but we think we'll get a decent number of that 17. And so as we start enrolling those patients on a go-forward basis, we'll provide more guidance with respect to when we'll have data to share. But we'll be looking at fetal hemoglobin. We'll be looking at VOCs. We'll probably be looking at that at a sort of monthly basis or every other month as those patients go from three months to six months to 12 - 18 months. But that's going to be a really interesting and nice dataset to see as we're enrolling in what we believe will be our registrational study, which will be our next big study. So there'll be sort of a 2- 2.5 data gap there. So this OLE data that we'll have that we'll be able to present in a fairly sort of regular cadence will be really important because I think it'll show a couple of things. It'll show, number 1, safety, and number 2, the durability of effect of the drug over time because all we know now is how well the drug performs at three months. We believe that the drug could perform better after a 3-month period of time, and that's one of the things, that's one of the hypotheses that we'll be able to test as part of the OLE study. Iain, anything you would add there? No, I think that's it. Okay. All right. Iain, Alex, thank you so much. Thank you. Thanks, Anupam.