Okay, good afternoon, everybody. Thank you so much for being here. Very happy to be hosting Fulcrum Therapeutics today. From the team, we have Alex Sapir, the CEO, and we have Dr. Iain Fraser, the SVP of Early Development. Thank you both so much for being here. Really appreciate it. Thank you for having us. To start, I'm just going to ask you the very basic question of providing us an overview of the company, and then we'll get into some details. Sure, I will give you a very sort of simple, straightforward answer so that we can get into what people do want to talk about, which is our recently announced data with our latest stage program. Fulcrum Therapeutics, we are a clinical stage biotech company that is focused in the area of benign hematological conditions. Since our founding nine years ago, we have always taken the approach to develop oral small molecules to modify gene expression for some of these rare benign hematological conditions. We feel that's a much more sort of simple, straightforward, elegant way, as opposed to using some more complex cell and gene therapies. We've chosen to really focus exclusively on oral small molecules to modify gene expression in some of these benign hematological conditions where there continues to be a very high unmet need. Our latest stage asset in the pipeline is a product for sickle cell, which I'm sure we'll talk about. In early discovery, we have a couple of very interesting programs targeting some bone marrow failure syndromes, again, orphan, rare disease. We should be filing an IND by the end of this year for our next wave of assets that will be hitting the clinic next year. Okay. Before we jump into your data, I always find it important to understand some of the aspects of the disease because that really helps us bring it all together and understand how clinically meaningful these are. On sickle cell, I understand your team's taken the advantage, especially this year, to meet with some leaders throughout the world, literally. I would love to hear some of the consistent comments you're hearing as you speak to the community and maybe what are some of the things that surprised you the most? Yeah, it's a great question. I will define leaders as both physicians and patients. The way I would describe the last, call it, eight years is a bit of a roller coaster for both physicians as well as patients. I think if you look at the period from 2019- 2023, there was a lot of excitement and a lot of hope for these patients. You had four approved therapies. Two of those were cell and gene therapies. One of them was an oral small molecule. One of them was a monoclonal antibody. Fast forward to where we are today, I would say that we're in probably a little bit of a state of despair for patients and for physicians. Unfortunately, one of those four products that was approved was withdrawn from the global market. That was voxelotor or Oxbryta. The other product, crizanlizumab, is a product that failed to demonstrate a reduction in VOCs in their confirmatory study. That drug was subsequently pulled from the European market, is continued to be available in the U.S., but really has not seen many patients put on that therapy. I think that the promise of the cell and gene therapies certainly has simply not materialized for patients. It is risky. It is very complex. It is very cumbersome. If you look at the number of patients that have either gone on Casgevy or Lyfgenia since those drugs were approved in late 2023, it's probably in the hundreds versus a prevalent patient population of 100,000. I think as we look towards the future, 2025 and beyond, I think patients and physicians are returning to this sort of state of hope and excitement given the number of products that are currently in development for the treatment of sickle cell. We see Fulcrum with our lead asset, pociredir, very much leading the charge and hoping to bring some of these treatment options to patients over the next couple of years. Thank you for that. Vaso-occlusive crises, or VOCs for short, are often described as one of, if not the most debilitating aspect of sickle cell for patients. How should we be thinking of what would be deemed clinically meaningful? I know we often talk about frequency, but what about duration and severity of attacks as well? Yeah, it's a really, really great question. I think it's fair to say that it's the frequency that's most commonly captured as an endpoint in a clinical trial. Sometimes it's the annualized frequency, sometimes just the frequency over the course of the study. Duration and severity are important aspects of that. There aren't, unlike in other diseases or with other endpoints, good, well-established scales that capture aspects like the severity of an individual crisis or the duration of an individual crisis. It's often left to adjudication committees to understand, for instance, if a patient has two events close to each other, is that one event that just took longer and maybe had a slight improvement in the middle, or are they two distinct separate events? That's part of the challenge of VOCs. I think trying to capture other aspects of that ultimately will be an important part of characterizing the disease. In terms of what's precedented and what's most commonly used, it's the frequency. Okay. What would be considered clinically meaningful? Absolutely. If we look historically at what the FDA has approved drugs on the basis of VOCs, the lowest improvement rate is probably the L-glutamine approval. They showed a 25% reduction in VOCs. Hydroxyurea, which has been around for a lot longer, has around a 45% reduction in VOCs. In that 25%- 50% range is sort of the minimally clinically meaningful bar that we know historically the FDA has accepted. I think there is an important aspect to this, and it relates to this issue of severity and frequency. That is, in patients who are having very frequent VOCs, even small percentage reductions can be clinically meaningful. For example, a patient has four VOCs per year, and you reduce it by 25%. That's one less VOC per year, one less hospitalization potentially. I think most people would regard that as clinically meaningful. On the other hand, if somebody has one VOC per year, and it's a 25% reduction, that's a little harder to contextualize as clinically meaningful. I think we do have to appreciate the baseline severity of the patients, the baseline frequency when we think about what's clinically meaningful for the patients. Why is fetal hemoglobin induction the mechanism behind pociredir thought to be a good approach for sickle cell disease? How does the mechanism work, and why is having a higher oxygen affinity critical? Yeah, yeah, no, it's a great question. I think there's growing appreciation for the centrality of HbF induction as an effective way to treat sickle cell disease. We see that by the number of new entrants into the clinic and the pipelines of companies that are focused on that. It goes back a ways to even before hydroxyurea, where the initial observations were that patients who had sickle cell disease but also co-inherited genes that encoded for hereditary persistence of fetal hemoglobin, so that they had higher levels of fetal hemoglobin than their counterparts with sickle cell disease, generally had a milder course, not as frequent VOCs, not as severe disease. There was that initial genetic observation. Along comes hydroxyurea. The predominant mechanism of action is induction of fetal hemoglobin. We show induction of fetal hemoglobin, reduction in VOCs, reduction in the number of other endpoints, and ultimately even a reduction in mortality associated with that. That's the pharmacological piece. More recently, we've seen gene therapies being approved, some of which directly target induction of fetal hemoglobin. The Vertex CRISPR gene therapy, the Beam gene therapy directly do that. We see dramatic increases in fetal hemoglobin in those patients, accompanied by an equally dramatic reduction in the VOCs. That linkage between induction of fetal hemoglobin, whether it's genetic, whether it's small molecule pharmacology, whether it's gene therapy, is associated with beneficial outcomes. That's the association, if you like. Getting back to how it works, the issue of oxygenation is important to the extent that it's the deoxygenated sickle hemoglobin that sickles. If you have sickle hemoglobin but it remains oxygenated, it doesn't sickle. That's the mechanism of action behind products like, as well as to some extent the PK activators, which alter the hemoglobin-oxygen dissociation curve. If you can keep that sickle hemoglobin in a more oxygenated state, it doesn't sickle. It's a little different with fetal hemoglobin. Fetal hemoglobin itself does not sickle, even under deoxygenated conditions. If you have increased fetal hemoglobin in the cell, you have less sickle hemoglobin there, and also the fetal hemoglobin itself doesn't sickle. You prevent those cells from sickling even under deoxygenated conditions. That's the mechanism of action of the fetal hemoglobin. Thank you. Linking those two factors together, we have a great sense out there of how HbF induction ultimately addresses the VOCs. What are some of the very specific trends that these large data sets have been able to give us some context into? Yeah, I can take that one, Iain. I think that, as Iain said, there is this incredibly strong relationship between fetal hemoglobin and VOCs, such that as you increase fetal hemoglobin, you see a corresponding reduction in VOCs. I think there's really, there's two dimensions to that, which I'll speak about individually. I think the first is that any increase in fetal hemoglobin is going to be beneficial to patients. Data that was presented by one of our competitors at the ASH conference last year demonstrated that even a 1% increase in fetal hemoglobin leads to a 4%- 8% reduction in VOCs. As Iain said, a 25% reduction in VOCs can be clinically meaningful for a patient. You could, in essence, get a mid-single-digit increase off of whatever that baseline fetal hemoglobin is, and that could be clinically meaningful for the patient in terms of reduction in VOCs that the patient is experiencing. That's one dimension. I think the other dimension is that what we've also seen, and the data supports this, this is some data that we'll actually be presenting at the ASCAT meeting coming up in just a couple of months' time. We looked at a real-world data set, and what we found is that when patients' fetal hemoglobin level gets to the high teens to low 20s, you're essentially seeing a 90% reduction in VOCs during the course of that year. Once you get patients to 25%, anything beyond that, you're seeing almost a complete abolition of VOCs. One of our goals with pociredir is not only to increase the patient's fetal hemoglobin from where they are at baseline, but to try to get a meaningful number of those patients into that sort of high teens, low 20s. Ideally, if we could get patients to, you know, the mid-20s and beyond and be able to do that with a once-daily oral therapy, that is transformative for patients. Okay, thank you for that. Let's switch gears to your phase 1B data. About five weeks ago, I think now you had your most recent cohort of data. Before we jump into what you saw there, can you remind us why this patient population was a bit different from the ones you traditionally looked at? Yeah, absolutely. The patients that we studied in the data set that we just released five weeks ago, that Kristen spoke about, that was a more severe patient population. These patients had to have, and the severity was very much determined by the number of these vaso-occlusive crises that these patients were having. These patients had to enter the study having at least two VOCs over a six-month period of time or four VOCs during a 12-month period of time. Certainly a more severe patient population. These patients as well could not have been on hydroxyurea when entering the study. The patient population that we studied early on was a less severe patient population that could be on hydroxyurea at the time. The reason for the difference was discussions that we had with the FDA after we got taken off of hold, which was in late 2023, in which we agreed with the agency for this phase 1B study, let's study this drug in a more severe patient population. Let's demonstrate the risk-benefit. Let's come back to you with that data once we've established the risk-benefit of the drug. Then we can talk about broadening the patient population from there. We're sort of, we finished the 12 milligram, and our plan is to complete the last cohort of this study, which is a 20 milligram by year-end, and then take that data back to the agency and have that discussion sometime in the first quarter. A dogma in general across all of medicine is typically that when you have more severe patients, it's tougher to get them to respond to therapy. Why does this hold true for sickle cell disease, and what evidence do we have? Yeah, no, it's a great question. Thinking about this, there are obviously pieces that are related to the underlying disease itself, and then there are pieces related to the therapy. Are the patients more severe because, you know, they didn't respond to the therapy, and the disease progressed because they didn't have a response to therapy, and that's why they appear more severe, or is it just that intrinsically their disease is more severe? I think one of the interesting observations that we've noted as we've gone through the data that we've collected is that if we look at the patients in our study, the 16 patients at the 12 mg dose, and we look at those that had the lowest baseline fetal hemoglobins and the lowest responses to the therapy, it turns out that a majority of those patients, so four out of the five on that far end of that response curve, were from a region in Africa, which is known to have a very high prevalence of a sickle cell haplotype that's called CAR, sometimes called the Bantu haplotype. The haplotype is not the genetic mutation that causes sickle cell because that's conserved across all sickle cells, but it's the haplotype of the beta globin gene locus. We know that the CAR haplotype is very prevalent in the Democratic Republic of Congo, which is where these South African patients actually came from. We also know that haplotype is associated with very low baseline HbFs and more severe disease. Those are more severe disease patients. There are also studies that suggest that those patients have less responsiveness to hydroxyurea. It's interesting that we see those patients that seem to have a lower response to pociredir in our study. We don't have the genetic data back yet. We have this epidemiological association, which is very strongly suggestive of that. In addition to having the sickle cell mutation, the haplotypes of the beta globin gene locus can play into baseline HbF and disease severity and potentially also responsiveness to therapy. We're exploring that further as we go along, and that's one of the aspects that we've encountered. The one other point I would mention, and we've spoken about HbF, which is clearly a modulator of disease severity in these patients, is the other aspect of HbF is that for a given level of HbF, how that's distributed across the red cells is an important indicator of how effective that's going to be at preventing the manifestations of sickle cell disease. The more widely distributed it is, or the more pancellular it is, the more beneficial it is. We were very encouraged to see in these 16 patients that level of pancellularity going up from about 34% at baseline to close to 70% at the end of the 12 weeks. Modulating that sort of intrinsic factor that modulates disease severity, but being able to do that therapeutically with pociredir, which is a little different than hydroxyurea, which doesn't have the same level of pancellular distribution. Okay, so you knew you were dealing with a tougher patient population here, yet you still had some pretty remarkable data. 100% of patients had an increase in their HbF, a little under half showed their total HbF levels over 20%. What do we make of that? Yeah, I think you really have to go back to a comment that I made just a minute ago, which is patients that can get their HbF levels to 20% are going to see a dramatic reduction in their vaso-occlusive crises over time. The fact that we got, after only 12 weeks, 50% of the patients above 20%, and the fact that all patients showed, 100% of patients showed an increase in fetal hemoglobin, coupled with, I think, the comment that Iain made, which is the people that tended to be on the sort of lower response side, I think we have a fairly good idea as to why they didn't respond, and we can obviously make modifications in the next cohort and the next study. I think this data, and from speaking with a lot of physicians, I think based on the three points that I just mentioned, the physician community, the thought leaders, the investigators are as, if not more, excited than we are at the company. Yeah, I know it was a short study, so you were never really looking to see a hard data point on VOCs, but you did share some early trends that you were able to articulate. Can you share that? Yeah, absolutely. What we would have expected to see, given the severity of this patient population, what we would have expected to see during the three months' study duration is that these patients, on average, would have experienced about one and a quarter VOCs during that 12-week period of time. Again, small study. I think your point is very well taken, Kristen, which is small study, not powered, but what we did see, what we observed in that 12 weeks is that these patients, on average, were experiencing about half a VOC. About a 60% reduction in what we would have expected to see in those patients had they not have gone on pociredir. Furthermore, of the 16 patients that were enrolled, eight of those patients experienced zero VOCs during the study. VOCs is certainly going to be something that we will have to look at in our registrational study. That will be a clinical endpoint that I believe the FDA will continue to ask companies developing drugs for sickle cell to continue to focus on. I think some of these early signs that we're seeing in what was a relatively small study with short duration leave us very, very encouraged by what we may see in a pivotal study. You have some brand new analyses fresh off the weekend, I think, showing how you looked at the data to essentially account for the different baseline characteristics. At least from our eyes, it's very clear there's also a dose response, which is something people were asking about. Help us understand that. You really are talking about a harder patient population with this last cohort, yet you're still seeing that. Yeah, absolutely. I think it's important to remember the more severe patient population on average is going to have a lower baseline HbF. It turns out for the 12 mg cohort, that baseline HbF was 7.6, the mean. If we look back at our previous 6 mg cohort, which did not have the severity criteria imposed at that point, that baseline was 10.8. It was a much higher baseline HbF that we were looking at. When you compare the response that you see over the 12-week period, you need to consider where those patients were starting out. If we normalize it by looking at the fold change from baseline, you can very clearly see a dose response as you move from the 6 mg dose in the patients to the 12 mg dose in the patients. That's very consistent with what we'd seen previously in healthy volunteers, where instead of looking at the HbF protein in the red cells, we looked at HBG mRNA because you can do that over a shorter timeframe in the context of a healthy volunteer study. In that study, again, using fold change from baseline, because healthy volunteers, their baseline is essentially zero. You saw a dose response in that study as we went from 6 to 10. There wasn't a 12 mg dose. From 6 to 10, there was that dose response. Again, from 10 to 20, there was additional dose response, which is the reason we're going to 20 mg now in the patients to see if that continues to replicate that dose responsiveness. Okay. Before we talk about what's next, anything else that we should really take away from these recent data you shared? I think those are the key things. We didn't touch on the transfusion patients, which we flagged in the deck. The only comment there really to make is that not that those patients don't respond to the therapy. It's just you underestimate the HbF response in those patients, because when you're measuring HbF, you measure it as a proportion of the total hemoglobin. If you're a sickle cell patient, it's either HbS or HbF. That's the denominator. When you transfuse them, you're giving them HbA, so normal healthy adult hemoglobin. That goes into the denominator. It doesn't go into the numerator. Your HbF level gets falsely depressed. We're seeing an underrepresentation of what their true HbF response is. We did all the calculations in our presentation based on the full 16 patients, but we have flagged those two for that very reason. Yeah, and maybe the only other thing I would add, Kristen, is I think, you know, in the physicians that I've talked to, when I've shared this data, I say, you know, here's the data. What do you think? I think across the board, what they're most impressed by is the totality of the data. We, in a very rapid fashion, robustly increased fetal hemoglobin. We did that in a pancellular way. In addition to that, we also saw a reduction in many of those markers of hemolysis, meaning the red cells simply aren't dying off as quickly as they were before. As a result of seeing less hemolysis, you are seeing an increase in total hemoglobin as well, which is something we did not talk about. We saw a 0.9 g/ dL increase in total hemoglobin, which should also help improve patients' feeling of fatigue. On top of all that, we also had an AE profile that was extremely well tolerated, which maybe we can talk a little bit about, you know, taking this data to the FDA and how do we position it for the next study. I just think across the board, the totality of the evidence is what physicians found most compelling. Thank you. Thinking about what's next, you have some 20 meg data expected around year-end. You're also going to meet with the agency, I believe, early next year to discuss the data. Maybe first, how should we be thinking about what's good data for this upcoming cohort? You already have some good data with 12 here. Yes. I would say that I think the data with 12 was very strong, very compelling. It's probably better than good. What we do know from healthy volunteer data is that there is a clear dose response as healthy volunteers go from 10 mg to 20 mg. What we also know, as Iain mentioned, is that there is a clear dose response in patients when patients go from 2 mg to 6 mg to 12 mg. We don't know yet what response we will see in patients who are currently enrolling in the 20 mg because we have not yet enrolled patients in the past in a 20 mg. Based on the healthy volunteers, we would expect to see an improvement in what we saw in the 12. That being said, I want to come back really to where I started, which is the 12 mg data in and of itself is very, very strong. Okay, thank you for that. Thinking about the FDA dialogue, I know you obviously don't have these 20 meg data to talk about, you know, which you're going to talk to them about. What are the biggest arguments you think you're going to make to the FDA just to understand the risk-benefit profile of this drug? Sure. As Kristen said, we are focused right now on finishing the 20 mg cohort. We will have that data read out by the end of this year. We will then take that full package of data for the entire study and engage with the agency in the first quarter as part of our end-of-phase one meeting with them. The agency looks at every drug from a risk-benefit perspective. What we clearly have demonstrated with the 12 is this drug benefits this severe patient population. I think that's a really important message that we need to convey. I think with the benefit that we've shown in this severe patient population and a rebalancing of that risk-benefit in the minds of the FDA, we believe that there's a possibility in our next study, which very likely could be a pivotal study to be able to expand to a broader patient population. Currently, we're targeting with the patient population that we have, we're targeting about 20% of the total market. We believe that there is a possibility based on the benefits that we've been able to see in this severe patient population to potentially broaden that in those discussions with the agency. That obviously is contingent on the agency weighing in on that as well. Okay, thanks. Just curious how you're viewing the market opportunity as well. I know it's going to depend on ultimately which patients you can go after, but maybe the most conservative scenario and a bigger one. Yeah, I mean, the way that I think about this, there's a huge unmet need in this market, number one. Number two, there's a prevalent population in the U.S. of 100,000 sickle cell patients. Number three, it is considered a rare disease, and therefore for a rare disease, I believe that drugs that come to this market will command rare disease-like pricing. The way that I think about this is that for every 5% of the market, you're essentially looking at a $1 billion product opportunity. That simply just scales from there. I think even with a modest gain of share, a drug like pociredir could easily become a $1 billion opportunity relatively soon post-launch. Okay, maybe to close, we'd love to just hear a recap of the current financial situation of the company and anything else you'd like our audience to take away. Great. As of the end of Q2, our balance sheet was at $214 million. We're currently burning somewhere between $55 million and $65 million, and we expect to end the year with roughly about $180 million of cash. That gives us a very comfortable runway into 2028. That's assuming success not only on the pociredir program, advancing that to the next trial, but also bringing some of these inherited and acquired bone marrow failure drugs into the clinic. I would say just the last thing that I would ask people to walk away with is really the way that I started. I think the next five years for this market are going to be really, really dramatic for patients in terms of the therapies that are currently in development. We are just so excited to be doing the great work that we're doing to potentially be able to deliver therapies that could transform these patients' lives. Okay, okay, thank you so much, Iain and Alex. We're rooting for you and appreciate your time today. Yeah, thanks so much, Kristen. Appreciate it.