Hey, good afternoon, everyone. Thanks for joining the Oppenheimer & Co conference. Pleased to do our next fireside. It's with Fulcrum Therapeutics. Fun team, Alex, Alan, and Iain are here. Guys, thanks for joining us. Thanks for having us, Matt. Yeah, I mean, it's a pretty simple story, right? I mean, we're consolidating around pociredir right now. I know you're working on some other pipeline assets that, you know, we might hear more about this year and into next, but the story is really about pociredir. Now, back to sickle cell, I think a lot of investors probably wrote the program off when it went on clinical hold. You resolved that clinical hold really quickly. I don't know why it wasn't. It was really a preclinical hold. But I, you know, what do you think it's going to take to get people to start believing in this story again and to kind of rejuvenate the enthusiasm that we had seen prior to the hold? Yeah, Matt, thanks so much for the question, and thanks so much for the invitation to the conference as well. I think, like with any story, what will cause people to get re-engaged and thus excited again about the Fulcrum story is data. And let me sort of back up a little bit. I think one of the reasons that people were so excited about the Fulcrum story in advance of the clinical hold is some really impressive data that we had showed in about 15 patients in a very dose-dependent manner. So, as patients were going from 2 mg orally once a day to six to 12, we saw a very, very elegant dose response in patients' levels of fetal hemoglobin. One of the things that we know about fetal hemoglobin, and we can go into this in more detail, is that any increase in fetal hemoglobin, even if it's one percentage point, it's beneficial to the patients. Once you're able to reach fetal hemoglobin levels of about 25% of total hemoglobin, you're seeing a complete abolition of VOCs. In that 12 mg cohort, for which we had enrolled three patients, we were seeing really, really nice and very, very robust increases in fetal hemoglobin after only about four to six weeks. I think, you know, now that we're off hold, we've got a great number of sites that are enrolling patients. We've guided now to having the 12 mg cohort mid-year and the 20 mg cohort by end of year. You know, potentially, if a patient is on 12 mg for a period of three months, you know, we may be able to see fetal hemoglobin levels that are getting in that sort of mid-20% range. And if that actually comes out to be true, that could be truly transformative for patients, not only in the U.S., for which there's 100,000, but for the 4 million patients around the world that still to this day suffer from sickle cell with very, very few, if any, treatment options. Yeah. I think, I mean, sickle cell has been a tough market to sell drugs in. And I think historically it's been because drugs don't work very well, right? Like, they don't make patients feel better. And pociredir, to me, seems like one of the few out there, outside of maybe gene therapy. No one wants to get gene therapy because of all the other downstream consequences. But pociredir, to me, seems like one that actually can have that impact on making people feel better. Could you just kind of discuss how you think about the landscape for sickle cell treatments right now, especially with Oxbryta being pulled from the market? Yeah, absolutely, Matt. And what I'll do is let me just pull up our investors' deck, because I think we added a slide at the beginning of this year really around the competitive landscape. And I think this is the way we view the competitive landscape. And I'll hit on a couple of points and maybe turn it over to Iain to see if he wants to add anything. You know, one of the advantages of gene therapy is that you're able to get to that fetal hemoglobin level, which is north of that mid-25%. In fact, after about 12 months of dosing, Lyfgenia and Casgevy, we're able to get to 40%. And that is truly transformative for patients. But as you said, these two drugs have now been approved for the better part of a year, and we're seeing very, very little uptake because of the cost, complexity, of the risks associated with it. You also have the polymerization inhibitors such as Oxbryta, mitapivat, etavopivat, temopivat, and all of these essentially sort of, in essence, work in a very similar way. They help the disease through an anti-polymerization effect, and they've been able to measure the effect of an increase in total hemoglobin. I think in light of the Oxbryta withdrawal, there's been a really sort of a renewed interest in the HbF inducers, and that's what you see here in the upper right-hand side, so there's a number of companies, obviously Fulcrum being one of them, that are targeting this HbF induction, albeit through different mechanisms of action, so BMS has a product. It's a combination WIZ degrader and ZBTB7A degrader. Novartis also has a WIZ degrader. GSK has a product, which is a DNMT1 inhibitor. Again, all focused on increasing fetal hemoglobin. These three programs are all a little bit earlier than Fulcrum. And so, Fulcrum in very, you know, in many regards, is the latest program that is targeting this HbF induction pathway. And I think because of some of the, you know, hiccups that we've seen with some of the polymerization inhibitors, I think there really has been a renewed sense of interest in the HbF inducers. And some of that obviously is born of the fact that what we've seen with the cell and gene therapies, in terms of being able to get fetal hemoglobin levels north of that 25%. But again, very little sort of commercial uptake because, as we said, the cost and risk and complexity associated with those therapies. Iain, anything you'd want to add around the current landscape? Yeah, other than to say, you know, standard of care with the withdrawal of Oxbryta is really back to primarily hydroxyurea as really the only agent that's being used extensively. Obviously, Adakveo P-selectin inhibitor is still being used. It hasn't had huge uptake, and there've been some variability in some of their confirmatory clinical trials, and it's not on the market in the EU, for example. So, that's a very limited slice of the market. And L-Glutamine, likewise, not many folks take that. So, we're really back with HU as the standard of care. And there's clearly huge unmet need. And I think that's reflected in all these various competitors that you see on the slide that are developing drugs. I think also the renewed interest in HbF, which has really been given something of a boost from the gene therapy data, particularly from Casgevy, which induces HbF as its mechanism of action and has shown very dramatic associated reductions in VOCs with that induction of HbF, but of course limited by being a low throughput type of therapy that's only going to be available for small numbers of patients. Right, and a lot of the gene therapies work with like some kind of siRNA interference or upregulation, but pociredir's mechanism of action is different as an epigenetic modifier. Can you just talk about how we think it kind of opens up chromatin around the HbF region to allow for expression? Yeah, absolutely. And Alex is projecting the slide that shows that top right is the cartoon illustration there where we're targeting the EED subunit of the PRC2 complex. That complex is an enzymatic complex that's responsible for methylating histone H3 at lysine 27. And by doing that, it alters the conformation of the DNA as it's wrapped around the histone proteins. And we know that by inhibiting the activity of this methylase, you get a reduction in the methyl marks on the histones, and you get an opening up of the chromatin in those areas. And that results in alterations of gene expression. And one of the most highly upregulated genes in response to that inhibition of PRC2 is HBG, which is the gene that encodes fetal hemoglobin. And it's probably not a direct effect on the HBG gene itself. We have some data showing that it acts at least in part through downregulation of BCL11A, which is an important regulator of HbF repression, and which is the specific target of the Vertex gene therapy. So, the alterations in gene expression with this upregulation of the gene encoding fetal hemoglobin is modulated through a downregulation of the repressors that normally keep fetal hemoglobin repressed in healthy adults. Not to go on a tangent here, but inhibiting PRC2, yesterday, Pfizer just showed some data from mevrometostat that effectively it could work in prostate cancer by increasing expression of androgen signaling. I'm wondering if you guys see maybe an angle for outlicensing this drug in cancer applications. Yeah. So, we're obviously aware of that. And before that, tazemetostat also in EZH2. So, EZH2 is the catalytic subunit of the PRC2 complex that is being targeted there. And that drug, tazemetostat or Tazverik, is approved for advanced synovial sarcoma and lymphoma. So, also an oncology indication. So, that certainly we're well aware of and know of that activity. I think the unmet need in sickle cell and the results that we've seen to date are really encouraging us down that particular pathway. But we obviously are aware of what's going on in the broader universe of PRC2 inhibition. What level of, I mean, back to sickle cell, what level of HbF do you think regulators would allow for? I was always remembering back to GBT days with Oxbryta that basically just increased regular hemoglobin, and they got away with a 1 g/ dL improvement, which is like basically nothing. Yeah. Any of the bars higher now or? Well, yeah. So, important to remember that that was a total hemoglobin increase. And part of their reasoning behind that was that if you transfuse a unit of blood, you get about a 1 g/ dL increase in total hemoglobin. And that's a therapy used in particularly sickle cell patients who've had strokes. Yeah. The data that support that as being a beneficial level in sickle cell disease is really not that abundant compared to that for fetal hemoglobin, which is really quite different and much more extensive, and there's both genetic data from patients who co-inherit a sickle cell genotype along with a hereditary persistence of fetal hemoglobin phenotype, where their disease is much less severe because they're making fetal hemoglobin in the adult state, and then there's also pharmacological data, and it's summarized nicely in this slide that Alex is projecting here. On the left is a poster that Novo presented at ASH this last December. They went back and did some modeling on older data, older sickle cell trial data, and really the bottom line of this was for every one percentage point increase in fetal hemoglobin, you got about a 4%-8% reduction in VOCs. A pretty meaningful reduction in VOCs at that level of fetal hemoglobin induction. On the right of the slide is some modeling work that we've done on a real-world data set that we got from patients with sickle cell disease. Really what that curve shows, it's plotting out HbF on the x-axis against the probability or the percentage of patients who have zero VOCs during the year. As you see on the graph, as your fetal hemoglobin goes up, the likelihood that you'll have zero VOCs goes up pretty dramatically. It sort of flattens out at about 25%. Even, you know, leading into that 25% absolute range in the 10%-20% range, there's still very, very significant reduction in the likelihood of having a VOC, which is consistent with the data on the left. Even these smaller increases, even though they're not getting into that totally transformative zone, are likely to be beneficial. And this is something that we'll be probing with the agency this year as an interaction, not related specifically to the data from our PIONEER study, which will be a separate interaction, but we are going to be approaching them around the ability to use fetal hemoglobin as a potential surrogate endpoint. Right. And these patients, sickle cell patients, already have a higher proportion of baseline HbF, just given their condition, the fact that their body wants to express more of it. Normally, there's less than 1% or maybe less than 2% if you don't have sickle cell, but in the setting of sickle cell disease, they tend to have higher levels of HbF at baseline, and it depends on what other genetics they've co-inherited as to how high that baseline is, but absolutely, yes, it's a response to the disease to some extent. But I guess what I'm trying to get at is really the delta in terms of percentage, the absolute percentage increase in HbF that you need to show is much lower. I mean, if you assume on average patients start out around 4% or 5%, to get to 20%, you only need 15%, right? Yeah, and the range across patients is around 5%-10%, I think, across the entire sickle cell patient population. You can see here, this is from the initial 16 patients in the PIONEER study. And it's perhaps best illustrated with the 6 mg cohort. If you look at the top middle graph there at baseline, those are the baseline HbF. So the lowest patient there came in at 3%, and the highest was at 20%, which is pretty high. You can see a pretty broad spread there. But the encouraging piece, I think, for us was that even if you started out low, the rate of rise of HbF on pociredir was still pretty dramatic. And in fact, the patient with the lowest baseline HbF had the steepest curve in this particular case. Got it. So, right now, we're continuing to enroll at 12, that cohort. And you want to have data around that mid-year. And that was in around 20 patients, you said? No, it's 10 patients per study, 10 patients per cohort. We've restarted the 12 mg cohort, so the three that you see represented here are not included in the 10, so it's about 10 additional patients on top of those three, and then we plan to move to the next cohort, which will be 20 mg once a day, and that'll be another 10, so it's 10 at 12 and 10 at 20. Got it. Interesting. So, expectations for the 12 mg group, really, can we get to kind of that 20% absolute level? But then, I mean, to put it into context, any percentage is, yeah, I'm just trying to, like, what do you think expectations should be for the mid-year readout? Yeah. So, if you take the 1% HbF, it gives you a 4%- 8% reduction in VOCs. The question then becomes, well, what's a meaningful reduction in VOCs? And if you have about a 25% reduction in VOCs, that's likely to be clinically meaningful. And so, if you back it out, that's around 6% or 7% increase. So, if you want to map VOCs to HbF, that's a reasonable approximation, if you like. And that's the sort of thing that we'll be discussing with the agency. Got it. And that, I mean, that meeting wouldn't happen until like the end of phase II, which would be more of like a early 2026? No, no, no. We intend to have that meeting this year. That meeting is independent of the data from the PIONEER study. That's more a sort of a cross-divisional interaction with FDA around surrogate endpoints. They have a separate track, if you like, for discussion of surrogate endpoints. It's largely a review of the literature and the existing data to support this as the endpoint rather than specifically the data from the study. Obviously, there is definitely an interaction with the agency around the data coming out of PIONEER as we move on to the next piece of the development program. But that's a separate interaction. The HbF interaction is focused on the potential for using that as a surrogate endpoint based on the existing overall data set out in the literature. Got it. And so, I guess for anyone that still maybe has some reservations based on because of the clinical hold, just go over again, the clinical hold, that was driven just by maybe preclinical findings or the fact that mechanistically, as you mentioned, we know tazemetostat works similarly. There is a black box warning of a small incidence of secondary cancers. It sounds like the FDA was fine with what you provided them and really just made you kind of hone in on the risk-to-benefit in terms of who you were enrolling into the trial. Is that right? Yes. So, we were not required to do any additional experimentation or additional studies to get back into the sickle cell patient population. It was all around redefining the severity of the patient population, given that we're at an early stage of development and still defining the potential benefit of this new therapy. So, it was all around a risk-benefit calculus at that time. And the reason for the hold was based on preclinical data, as you indicate with pociredir, not based on any of the clinical data that we generated. And then, in conjunction, their reference to drugs like Tazverik, which is the approved drug that we mentioned earlier, which had some hematological malignancies in their preclinical program. And then, in their pivotal clinical trial, which was an open-label study in patients with advanced malignancy, a secondary malignancy rate of 0.7% in that study, which, given the patient population, underlying malignancy, previous chemotherapy, radiation, and so on, is not an unexpected percentage, but nonetheless was potentially attributed to drug by the agency. So, that was the clinical piece of it, if you like, from another drug. I guess. Not exactly the same subunit. Yeah. I mean. And then. Oh, go ahead. Matt, I was just going to make one other point, and it's somewhat related to your last question about the clinical hold and the question before that about, you know, what is the agency expecting from a regulatory standpoint in terms of HbF levels? I think what's really important to remember is that the patients that we're recruiting now, as Iain mentioned, tend to be more severe because we were required to target a more severe patient population in order to get off clinical hold. Those more severe patients may end up having a lower fetal hemoglobin at baseline compared to the patients that you're seeing here. So, if a patient is, let's say, at 3% or 4%, it may be after three months of dosing on a 12 mg, it may be more difficult to get them to 20% or 25% than a patient that maybe is starting at a baseline of 10%. So, I felt that was an important point that I just wanted to highlight. Yeah. That makes sense. Yeah. I mean, it seems like the safety stuff is maybe a bit aggressive. I mean, I'm happy that they allowed you to get off hold so fast. But patients with sickle cell have a higher risk of malignancy anyway. So, at the end of the day, how are we really going to be able to deconvolute if it was caused by a drug versus just the fact that you have sickle cell in the first place? Yeah. I think that's a potential concern. The epidemiology does indicate an increased relative risk of malignancy for patients with sickle cell disease. The absolute risk is still relatively low, so it's not a massively increased absolute risk, but the relative risk is somewhat higher, but I think you want to offset that against the severity of the disease and the fact that even in an era of hydroxyurea therapy, lifespan is reduced by about 20 years in these patients. So, it has a significant impact on lifespan, quite aside from all the morbidity, which is what we've been talking about in terms of VOCs and other manifestations. So, this is a life-shortening disease as well, and I think that's an important piece of the context around benefit-risk assessment. Yeah. I agree. As we look forward to the data, can we maybe just talk a little bit about the efforts you've made to improve patient compliance? Because that was an issue, particularly at the lower doses and the earlier readouts from the trial, and we just don't want to make sure that that is another confounding variable going forward. Yeah. Yeah. That's a great, it's an excellent point, Matt. So, you're 100% right. We did have issue with certain patients adhering to study drug during the duration of the trial prior to the initiation of the hold. And so, what we really attempted to try to solve for is how do we make sure that we don't see those issues as we get this study off hold and back up and running. And we think we have solved for it with this AI tool that is put out by a company called AiCure. And essentially, what happens is when the patient goes into the clinic for their first dose and to receive their drug that they're then going to take home, they get a 30-day supply. While they're there on that initial drug initiation visit at the site, this app is downloaded onto their smartphone. And if for whatever reason they don't have a smartphone, the one is provided to them through the CRO. And at that time, they have to designate when they actually want to get an alert in terms of when it's time to take their medication. So, in this case, the patient has chosen 8:00 A.M. So, at 8:00 A.M. for the next three months, there'll be this little pop-up, and the patient hits the start button. They have to, before they can move forward, they have to confirm that they actually have drug in hand available to take. Once they hit this continue button, there's a quick facial recognition that this is the actual sort of patient that is enrolled in the trial. There's a quick capsule recognition. The patient actually has to hold the capsule up to the smartphone, and it can recognize that that is actually the capsule of pociredir. The patient puts that in their mouth. They swallow it. They open their mouth to show that it's been ingested. Then, to compensate the patient for going through this each and every day, and it takes about 10-1 5 seconds to go through, patients receive a modest compensation for that. In this case, in the U.S., it's $15. Of the patients that have enrolled to date, no patient is less than 90% adherence. And I'd say that more than half of the patients that we've enrolled so far are 95% adherent or greater. So, we really feel like we have solved for some of the adherence issues that we had seen in sort of early 2022, late 2022, in those 15 patients for which the data that we showed you just a couple of minutes ago. Pay me $15. I'll take that pill every day. All right. So, Alex, I mean, I think I understand the catalyst here, right? Mid-year for the 12 mg cohort, year-end for the 20 mg, and in between, we'll get some feedback from the FDA on maybe a path to approvability. That's right. Yep. Yep. That's 100% right. Yep. And I guess we've got maybe two more minutes if you guys just want to talk about some of the other things you're working on in the pipeline. I know we didn't talk at all about the core capabilities and why the company was funded, but you have a pretty robust drug discovery engine there. We do. And I think, you know, in light of the success that we've been seeing with pociredir, we really have redoubled our efforts around benign hematology, again, developing oral medications in certain benign hematological conditions where there continues to be a high unmet need. And the one that is farthest along is the work that we're doing with a product for the treatment of Diamond-Blackfan anemia. And we would expect to have the IND submitted sometime in Q4 using the oral agent that is currently in IND-enabling studies right now for the treatment of Diamond-Blackfan anemia. It's not a huge market in the US. It's probably somewhere between 2,500- 3,000 patients. But there are some other inherited aplastic anemias, such as Shwachman-Diamond syndrome or Fanconi anemia. And they all are around a prevalent population of somewhere between 2,000- 3,000 patients. We do believe that in some of the discovery work that we've done, each one of these inherited aplastic anemias, including Diamond-Blackfan, share a common pathway. We have not disclosed what that common pathway is. So, you know, it could potentially be that this oral agent that we're developing for the treatment of Diamond-Blackfan anemia could also have application in a couple of these other rare inherited aplastic anemias, some of which I mentioned previously. That'd be really cool. Yeah. I'm looking forward to hearing more about that this year, as well as keeping tabs on the progress of the sickle cell program. So, it sounds like a lot of exciting stuff, guys. Yeah. 2025 is certainly going to be an important year for Fulcrum, for sure. Appreciate the time. Thanks so much again, Alex, Alan, and Iain. Yeah. Thanks, Matt. Thanks, Matt. Appreciate your time. Bye. Take care. Bye-bye.