Are you all ready to go? We are. Okay. Great. So I think we can go ahead and get started. Good morning everybody. Thank you all for joining us this morning. And I'd like to thank everybody who's online as well. We've got a fairly robust number of people online, so thank you all for joining us virtually as well. My name is Alex Sapir. I'm the chairman, I'm sorry, I'm the CEO and President at, not chairman, CEO and President of Fulcrum Therapeutics. This is a really exciting day for Fulcrum, but I think more importantly, it's an even more exciting day for patients and the sickle cell community at large, really because of the potential that this drug has to possibly truly transform patients lives around the world. And so I think for that reason we're so excited that you have been able to join us. Before we get started, I just wanted to remind everybody that today's presentation will include some forward looking statements which are based on current expectations and subject to risks and uncertainties. Actual results may differ materially, and we encourage you to review the full disclaimer on this slide. Together with the risk factors in Fulcrum's most recent filings with the SEC, so I'd like to introduce my fellow speakers up here. Many of you know Iain Fraser. Iain and I work together at Fulcrum. He is heading up all of development at Fulcrum. Dr. Sheinei Alan. Great to have you here. Dr. Alan is head of the Sickle Cell Center at Inova Fairfax and also the leading enroller of PIONEER. And so we're absolutely delighted to have her here as well. And to my left, someone who truly doesn't need any introduction, Dr. Marty Steinberg. Dr. Steinberg is professor of medicine, Pediatrics and Pathology at Boston University School of Medicine. And it's really his p ioneering work over the last 50 years that has really helped shape our modern understanding of sickle cell disease biology. I was talking to him earlier and was asking him how many ASHs he's actually been to. He started going to ASH, I think in 1968 and with the exception of COVID he's never missed one. So that's quite an impressive feat. So here's our agenda for the day. Iain and I will just give a couple of quick slides. I'll just give a very, very quick one slide overview on the data that Dr. Alan will go through in some detail. Iain has a couple of slides on the disease, the unmet need and why fetal hemoglobin induction is so important in the treatment of patients with sickle cell disease. Dr. Alan will really spend the bulk of the time going through the data in some detail. We'll have Dr. Steinberg give his expert perspective on really what this data means for the scientific community, the clinicians, and then ultimately for the patients. We will open it up for Q& A for all of you as well as. Anybody that's on the phone, if you are online. Just a quick reminder just to submit in the written text box, which you should see on your screen right now, and we'll take those questions as they come through, so moving on to the next slide, this is my only slide before turning it over to Iain, so the first two panels here should look relatively familiar to most of you. These are panels that we presented in July when we presented the 12 milligram data, and so if you look at that middle panel, we were very excited with the 12 milligram data primarily because the drug was very well tolerated. We saw a very rapid and robust induction of fetal hemoglobin at 5.6 at week six and 8.6 at week 12. 44% of the patients in the 12 milligram saw a greater than or equal to 20% fetal hemoglobin. At the end of the study, we saw a 2.4-fold induction in the 12 milligram. Really looking at dose response, all those markers of hemolysis were trending in the right direction. We were seeing trends toward pancellularity. We were seeing a really nice impressive increase in total hemoglobin as well. And although VOCs were not an endpoint in the study, we saw very encouraging trends in terms of reduction in VOCs. So we set what we thought was a very, very high bar with that 12 milligram. I'm incredibly excited to share that we have. We have exceeded that bar with the 20 milligram. And that's really what's reflected here on the right hand panel that you see on this slide. The drug, a nd Dr. Alan will go through all of these details, all of these data points in some detail, but just to hit them at a very high level, we continue to see evidence of this drug being generally well tolerated. We saw a 9.9% mean absolute increase in HbF at week six. As you remember, that compares to 5. 6% of what we saw with the 12 milligram at week six. And I think what's also important to note is that what the 20 milligram has been able to achieve at week six actually exceeds what the 12 milligram was able to show at week 12. 58% of the patients, or 7 out of 12, at the time of their last study visit had seen a greater than or equal to 20% fetal hemoglobin. And as Iain will speak about, that truly does have the potential to be transformative for these patients. In the 12 milligram we saw a 2.4 fold induction. With the 20 milligram we saw a greater than 3.75 fold induction. The drug continues to show trends towards pancellularity, improvements in anemia as because of the reduction in many of these markers of hemolysis that we've seen. And again, although not an endpoint of the study, we're continuing to see very, very encouraging trends in VOC reduction. So we could not be more delighted with the 20 milligram data that we shared in a poster form yesterday and the data that Dr. Alan will go through in just a couple of minutes. So with that, Iain, why don't I turn it over to you? I think Iain just has a couple of slides just at a very high level, the disease, the degree of unmet need and why fetal hemoglobin is so important for this patient population. So, Iain, I'll turn it over to you. Yeah, thanks Alex. Next slide please. Just a reminder that sickle cell disease is a debilitating disease with a very high unmet need. If we look globally, over seven million individuals affected, worldwide, in the U.S. around 100,000. As you know, the disease is driven by these abnormal sickle shaped red cells. They have a shortened lifespan because of the sickle hemoglobin that polymerizes. These cells rupture, they block blood vessels, causing extreme pain for the patient. Painful VOCs are a hallmark of the disease responsible for a majority of their hospitalizations. But there are a number of other acute manifestations that really have significant impact on patients' lives. Stroke, pulmonary hypertension, priapism, leg ulcers, splenic sequestration, just to name a few. And of course they also have chronic anemia related to the ongoing hemolysis that they experience and that leads to end organ dysfunction. I think important to note that even in the 21st century, patients with sickle cell disease face a substantial, substantial reduction in their life expectancy, probably more than 20 years overall with a mortality rate that's much higher than the general population. Next slide please. This slide speaks to the relationship between fetal hemoglobin levels and disease symptomatology in people with sickle cell disease. There's a long history of the relationship between increased levels of fetal hemoglobin and reductions in the manifestation of sickle cell disease. These are just two examples that we've illustrated here. Some of you will have seen these before. On the left is some modeling data from previous trials conducted with hydroxyurea, the MSH and the CSSCD. This analysis was presented last year by Novo at ASH. For every 1 percentage point increase in HbF there was an associated reduction of 4%-8% in VOCs. Then on the right, moving to a real-world data set that we analyzed from PicnicHealth, about 700 patients in the U.S. Illustrating this relationship in the patient population between increased levels of HbF and then the percentage of patients with no VOCs in the preceding year. Up on the Y axis, I think that one of the important points to bring out, and Dr. Alan was reminding us of this yesterday, is if you look at the low end of that curve, the patients who are coming in with very low fetal hemoglobins, even small increases for those patients, the curve is very, very steep and is likely to result in a clinically meaningful benefit for them. And then of course, on the bottom left, it's not just the VOCs, but it's also the impact on hemolysis of the cells. So reducing hemolysis, reducing anemia and reducing recurring events. Next slide please. This touches on the mechanism of action of pociredir. Again, many of you will be familiar with this. pociredir binds to the EED subunit of PRC2 and as a result of that inhibition, there's a reduction in the methylation of histone 3 at the lysine 27 position. And the net result of that is an increase in HbF. We know that that mechanism in part works through reductions in the activity of BCL11A, which is one of the master repressors of fetal hemoglobin. There are others involved as well, including MYB. But we do know that pociredir treatment leads to a reduction in BCL11A. It binds selectively to EED. It has a clean off target profile, and we've seen robust target engagement at doses as low as two milligrams once a day. Next slide please. This is just a snapshot, high-level overview of the development program to date, progressing on the left, from our in vitro work all the way through to the clinical work in sickle cell disease patients leading into this 20-milligram cohort data. So just very briefly, on the left, CD34-positive cells, whether from healthy volunteers, patients with sickle cell disease or with sickle cell trait, showing a robust induction of HbF when differentiated in vitro. In the middle panel is our early healthy volunteer data. Shorter term dosing. So two weeks of dosing, measuring the HBG mRNA in the peripheral blood in this case, and what you see is as you go up in the daily dose of pociredir, from 2 mg all the way up to 20 mg, you get a progressive increase in that HBG mRNA between 20 and 30. It flattens out at the two-week mark, but all the way up to 20, we've seen progressive increases and we've measured this as a fold increase in that mRNA in the peripheral blood. And it's been very reassuring and encouraging to see that initial mRNA translate well into the patient's measuring HbF protein over the three-month treatment period. And what we're showing here is the earlier data from the study leading into the 20 mg cohort that we'll discuss today, showing the 2, 6, and 12 mg doses, again expressed as a percentage change from baseline in order to evaluate that dose response. As you go up on the dose, as we saw in the mRNA, you go up on the induction of HbF protein in those p atients. Great. And the next slide, p lease. Super. All right, thanks, Iain. So obviously the moment many of you have been waiting for. I'm now going to turn it over to Dr. Alan to really run through in a fair amount of detail the data that was presented yesterday that we're going to kind of flesh out a little bit more today. So over to. Thank you so much. Good morning, everybody. So I'd like to. I'm not a sitting down behind a podium kind of person, so I'd like to kind of walk through it with you guys so we can all be on the same page about this. So the data we're presenting today is the 20 milligram cohort that we're showing you. The study is still in progress, but we're showing you all the data as of the data cut from November 11th. Again, this includes very sick patient population who are not on hydroxyurea or eligible to take it at the time of enrollment. These are patients predominantly of the more severe genotypes, ages 18 to 65. As I mentioned, hydroxy had to be discontinued for at least 60 days and the severity was defined either having had multiple VOCs leading to enrollment or an organ disease. The primary endpoint focused on safety and tolerability of the agent as well as the PK parameters, with the secondary endpoint looking at HbF induction, hemolysis and anemia, and exploratory endpoint looking at globin gene expression, the percentage of F cells, as well as the incidence of VOCs. I will point out, talk a little bit more about that down the line that they're not adjudicated VOCs. That's sort of observations in that period. Next slide please. What I want to highlight for you all is the number of patients enrolled which were 13. Patient 2 is included in the safety analysis but not in the PK analysis. This was an unfortunate event in which the patient experienced a grade 5 SAE on day one of treatment that was not deemed related to the study medication. But we felt it was important to include that assessment and everybody completed to day 42, so the data we're showing you is really of the day 42 analysis of all 12 patients and I want to highlight that also will include the. In July when we shared this data, we didn't have all the safety analysis for the 12 milligram. Not everybody has completed the full follow-up period, so that will be included as well as for the 20 milligram, and it's really important. I can't emphasize enough the degree of adherence: 97% of patients' adherence rate. This was using an AiCure app, so patients were actually documented of taking the medication, but it was really impressive to see that degree of adherence. Next slide please. Talking a little bit about the background of patients between the 12 and what's different in the 20 mg. Majority of females are 17% male compared to 44%, similar in age group in their early 30s. I was really excited now to see Nigeria involved in this study. This was a site that was activated for the 20 mg. Now we're not in the 12 mg. Again, more severe genotype HbSS, HbS beta 0 and beta+ baseline HbF a little bit lower 7.1% and baseline hemoglobin again a little bit lower 7.3%, and looking at VOCs for each patient enrolled, so either 2.4 VOCs over 6 months or 6.71 VOCs over 12 months. Next slide please. What this data is showing is that as you increase in dosage of pociredir there you see a dose dependent increase in the Cmax, meaning that you're seeing that exposure increasing as you increase the dose as one would expect. Next slide please. So what I want to highlight here is really looking at the HbF induction and this is day 42. Like I mentioned earlier, we're including all the patients in this study and as you can see, it's already absolute increase of 16.9% HbF, which is really impressive compared to the 16.2% that we saw at 12 weeks with a 20 milligram. So that was really phenomenal to see. And then looking at the percentage change in baseline here, again, the green going forward in the studies will be all the 20 milligrams and the blue is all the 12. So 9.9% increase compared to 8.6 at week 12. So pretty robust induction early on even doubled that of what we would see in the 12 milligram at half the time. So I think that's really interesting to see. Next slide, please. So here it's the individual patient breakdown. So I want to orient you. These are all the patients that were in the study, all 12, as I mentioned, that had follow up in the study. The gray bars present their baseline HbF. And the green% represents their increase in HbF level with the total percentages at the top. And the patients who are in solid green means they completed all 12 weeks of treatment, which is six patients. And then in the dashed green are patients that were still ongoing at the time of the data cut on November 11th. So we are showing all the data to the data cut in totality with the six patients. We'll break down a little bit further down the line. But as you can see, what I want to highlight is that seven of those patients, the 12 patients, achieve that HbF level greater than 20%. It's really important. I can't stress enough, as Iain mentioned earlier, that any induction of HbF is meaningful. I know I talked to some of you guys last night and everybody was like targeting the 20%. For me, you know, I won't go into it, but I really want to highlight that any improvement in HbF is really important. You can see everybody had a response, so that's really important. That basically everybody had at least greater than 6.5% increase in HbF. As Iain mentioned earlier, even a small increment of HbF isn't meaningful. Next slide, please. So this is looking at fold induction. Everybody who enters the study has different baseline HbF. Right. So we really need to kind of harmonize what that baseline looks like to really speak to the efficacy of the agent and thinking about dose-dependent response. And this is accounting for the 20 milligram patients, but the first six who completed the 12 weeks of treatment, as you can see, the baseline HbF is a little bit lower, 5% versus if you complete the whole 12 milligram, 12 patients, it's 7.1%. And if you compare that to the 12 milligram, it's 7.6%. So variable baseline. So we need to really harmonize for that and think about the fold induction accounting for that. And we can see there's about 3.75 fold induction in HbF in this first six patients who completed the 12 milligram. Next slide, please. Okay, so it's really important that we're looking at how many cells, or red blood cells, are getting that protection they need in terms of HbF protection, or using the term pancellularity, and as we're showing here, this data is not complete, and more information will come out once the whole data set is complete, but really showing that there's a nice robust increase in the amount of cells who are getting HbF even at day 42, similar to the 12 milligram in terms of pancellularity, certainly 60% or more. And we will have more information on that before, but again trending to more cells having this HbF induction and protection. Next slide, please. And so when you're getting an improvement in HbF, one would expect to then have more protection of the red blood cells and less cell breakdown as measured by lactate dehydrogenase and indirect bilirubin. And as we would expect, in the 20 milligram, there's a very robust, nice reduction in LDH even at week six or day 42, even compared to the 12 milligram cohort. And similar to the indirect bilirubin, you really robustly start to see these markers of hemolysis start to improve very early on in treatment. Next slide, please. Reticulocyte, and we'll talk a little bit more about this as well. It really measures the degree of erythropoiesis. As the hemoglobin improves and erythropoiesis improves, we would expect to see improvement in reticulocyte counts and kind of decline of that. That's what we see here. There's a 33% reduction in reticulocyte counts. Thinking through that, this is a highlight of improved stress erythropoiesis, because the marrow is no longer really hyperactivated. We also see that what we call red cell distribution width, where the cells are more uniform, being produced in a similar manner. Almost like a normalization of that. It's very robust and early in treatment that we start to see that. Next slide, please. If you have improved fetal hemoglobin induction, if you have improved hemolysis, what does this mean for the total hemoglobin? What we see early in the study is a rapid improvement in hemoglobin in patients. So, 8.1 grams per deciliter at day 42 as compared in this patient population. And what I want to highlight here is that in the 12 milligram cohort that we presented in July, there were two patients who had not infrequent blood transfusions because the severity of their disease, whereas we didn't have anybody transfused in the 20 milligram cohort. So this data is very clean in the sense that there's no confounding effects of transfusion. And again, this then kind of going back to the change from baseline, it really shows within six weeks we're seeing a nice change in baseline of hemoglobin at 0.8 grams per deciliter compared to 0.9 grams per deciliter at week 12. Next slide, please. Next slide, please. This is really important, so I think the computer really wants to stay here. I understand that. We're going backwards. We'll wait till that next slide comes up, but really that induction in hemoglobin and not having any of this very sick genotype and phenotype of patients not undergo transfusion, for me it's really profound. And if you think about it, especially the study being conducted in resource-limited areas of the world where the highest burden of diseases, I think the implications of that are something that it's really exciting to think about, so, as I mentioned earlier, patients needed to have VOCs as part of their inclusion criteria to enter this study. And so that's where we have that data, so 2.4 VOCs in some patients over six months or 6.71 VOCs over a 12-month period of enrollment. So based on that, statistically, then we would expect to see at least 16 VOCs that would be expected across 12 weeks of treatment in this very sick and severe population. However, at the time of the data cut on November 11th, there was only five VOCs observed in four patients, and that includes that first patient I mentioned earlier, who was not part of the overall assessment, so basically what I think is also really important is to highlight then eight of the 12 patients, or 67%, reported no VOCs during this treatment period, which I think is significant. So, combining the safety and tolerability of the drug, I do want to spend a little bit of time here. It was generally well tolerated. There is no discontinuation of the drug because of side effects in terms of treatment related adverse events. I will walk you all through it. Overall adverse events is what we would expect to see in this sick population. And depending on the areas of where they live, in terms of you see some VOCs, fatigue, malaria infection and arthralgias, treatment related adverse events. There were still. I want to talk a little bit about this reticulocytopenia. So as I mentioned earlier, we would expect to see some relative reticulocytopenia that will occur with improved erythropoiesis. This only one patient individual had a rapid reduction in their reticulocyte, hemoglobin, white blood cell counts, everything. Where we would expect that there's what we call like myelosuppression. This was in the context of being acutely ill with a Parvovirus B19 infection. Presumably that does add to the bone marrow as well as antibiotic use and this individual patient had a very similar profile going back almost a year before, who got sick and had similar antibiotics and had the same profile. There was a two-week hiatus to allow this patient to recover and then restarted the drug and everything continued to improve after that. They had nice, robust improvement in their hemoglobin and their white counts and those other cell parameters, so it's unclear if it's truly related to the drug, but we honor what the investigators write because I think, and that's why we need to kind of have highlight what the investigators deem possibly potentially related because they're in a study. There is also a degree of insomnia and iron overload that are still being reviewed, but probably less likely to be related in terms of treatment related serious adverse events. There are some. Okay. As I mentioned, there were six VOCs that were reported at the time of the data cut and that was one of them that occurred in the safety follow up period. Next slide, please. So again, this again highlights the safety profile. Overall, the AES are consistent with what we would expect in sickle cell disease, especially in this very severe population. These are patients who are really sick that would otherwise not be enrolled in a clinical trial. And so they're very sick. They've had no access to treatments before. And so it's not surprising that they would have some of these events that we observed. Overall, there is no dose limiting toxicities or dose discontinuation. And so these observations are really based on a total of 148 patients being exposed, 103 of them being voluntary, I mean healthy volunteers and then 45 patients being with sickle cell disease of that more severe genotype and phenotype. Next slide, please. So kind of, as Alex mentioned, this study slide, it's really highlighting what was done with the 12 milligram and then going on to see a similar trend, but even more robustly with the 20 milligram. So again, generally well tolerated, no discontinuation because of adverse events or side effects. Even more improvement in mean absolute HbF, 9.9% at week six compared to 5.6%. 58% of the patients reaching greater than 20% HbF at the time of the data cut. So that may even look different once we have the full total data. And then a 3.75 fold induction in HbF at week 12 of the patients, the first six patients that we analyzed. And there's this continued observation that more cells are getting HbF induction and that protection. So that pancellular distribution with that resultant improvement in anemia and hemolysis. While the study was not adjudicated for VOCs, but it was a very encouraging trend that we saw in terms of VOC r eporting. Okay, fantastic. Dr. Alan, thank you very much. Very comprehensive, very elegant, very, very well done. We covered a lot of data. I'd love to maybe hear a little bit from Dr. Steinberg, having been doing sickle cell biology for more than 50 years and knowing this disease. More than most. Maybe, Dr. Steinberg, if you could sort of share as you see this data, maybe give your perspective on what it means for the medical community, what it means for the treating physician, and ultimately what it means, in your opinion, what it means for the. Patient. Sure. Thanks. Well, I'm sure many of you have heard this from me before, but, you know, at the current state of the art, with our inability to directly correct the sickle mutation, which if it ever happens, is going to be a long time, inducing high levels of fetal hemoglobin in as many red cells as possible is the approach to really transformative treatment. There are a lot of other treatments in development, but I think they're nibbling about the edges, and we could really reverse the phenotype of the disease totally if we have enough fetal hemoglobin and enough cells. Nature has shown us that the gene therapy trials have shown us that the use of hydroxyurea has started us somewhat along the path. But what the field urgently needs is an oral fetal hemoglobin inducer that could be used as a single agent that possibly can be used in addition to other fetal hemoglobin inducers. So, you know, I find these results, which, you know, I saw yesterday and had heard about before, very encouraging. I mean, in a very short period of time, this agent has achieved fetal hemoglobin levels that are about twice the level that one would expect within the average patient with hydroxyurea. After all, the hydroxyurea trials showed an average fetal hemoglobin of only 9% after the trial was completed. And the hemoglobin rose about a half a gram, which one would expect, as Dr. Alan pointed out, as you induce fetal hemoglobin, and here we have. Almost twice as much fetal hemoglobin. The hemoglobin is going up more, so I think these results are really encouraging. And you know, if they continue along this trajectory, this will be a really valuable agent for the field and could have major effects on patient outcomes. You know, gene therapy won't, because as wonderful as it is, it's not an effective treatment. It can't reach people at scale, but an oral agent has that potential, so I'm very excited about these r esults. That's great. Thank you. Thank you so much. The good news is we have a lot of time for questions. I think before we get to those questions, I know a lot of you are wondering, so what's next? I really just want to touch on four things that we're planning to do in the near future. Obviously, as Dr. Alan mentioned, we're going to complete the 20 milligram cohort and we do intend to share that updated data set sometime in the first quarter of next year. We are continuing to very actively prepare for an end of phase meeting with the FDA which we would plan. We would submit that request to have a meeting with them so sometime in the first quarter and then have that meeting sometime in the first half of 2026. We are moving forward with operationalizing an open label extension study. Thanks very much to Dr. Alan's discussions that you and I had about the need or the desire for the patients to continue on therapy, so we would expect to be operationalizing that and we will actually begin enrolling patients that have been involved in Pioneer, enroll them in the open label extension study sometime in the first half of next year. And we are continuing obviously to finalize plans for a registrational study, obviously pending regulatory feedback. We need to have that discussion with the agency, but we think in light of the data, in light of Dr. Steinberg's comments about the importance of HbF, we feel like there is a potential pathway to go directly to a registrational study, which we would plan to kick off sometime in the second half of next year. So with that, I think we're going to go to the Q and A. We do have a microphone here. We've got a couple of hands up here in the room. So please state your name, your company affiliation, and then we'll check and see if there's any questions that are coming in online. Yep. Sam? Great. Thanks so much. Matt Biegler from Oppenheimer. Not a lot to pick at here, guys. So congrats on the data. Dr. Steinberg, my pointed question to you is, do you think that this can be a cure for some patients? Because you've published, I think, statistical modeling in Blood 2014. I think you came to the conclusion that you need maybe 30%-35%. We're seeing that in some patients. So can this be a functional c ure? Well, sure. You notice from the slide that patients respond differently. The fetal hemoglobin genes are poised to be reactivated. They're a peculiar gene compared to other genes in the body, and the control of them is very complex. And some people have the innate ability, with the proper push, to express large amounts of fetal hemoglobin. We saw that in hydroxyurea and you see it here. So there are some people who have the right genetics and the right cellular biology that will probably. There's the potential for inducing 20%, 30% or more fetal hemoglobin, which will be distributed fairly homogeneously among all the cells. So, you know, I mean, the aspirational goal is, you know, mimicking gene therapy. And I think, you know, it's possible. I doubt if it's going to happen to everybody because, you know, we're all different genetically and some people just can't do it. So, I think the potential is there, y es. Thank you. Kristen. Hi, good m orning. This is Kristen Kluska of Cantor. Congrats on these data. Very clear dose response that you've demonstrated. What can you tell us about what the slopes of the percent HbF data look like for those patients that did reach the 12 weeks? And, do you believe that you've reached a p lateau? Yeah. Iain, do you want to maybe take that one? Yeah. Yeah, happy to do that. So of those six that reached the full 12 weeks, remember, they all started out with the mean baseline that was somewhat lower than the overall cohort, so about 5.0. But their individual slopes are either upward sloping or flattening around the 12-week mark. We haven't seen anybody declining along the way. The one patient that we discussed earlier that had drug withheld for two weeks. They flattened out for that two-week period, maybe slightly down and then they bumped up again with their HbF after that. So we haven't seen that. And our expectation is that the 9.9% that we're seeing at the six weeks is going to end up for the full cohort as higher than that. We don't know exactly where that will be because of the patient still in transit. Great. Good morning and thank you for taking the questions Ted Tenthoff from Piper Sandler, so really remarkable results. I guess picking up on the last question. It seems like you've gone high enough, you don't need to go any higher. Is there any reason to potentially backfill. Between 12 and 18? And I guess the real question is when you go into registrational trial, do you envision doing more than one dose for potential titration or maybe even weight or age r elated d ifferences? Thanks. Yep. Iain, maybe I'll turn that one over to you. Yeah, absolutely. So I think the most important thing is we need to wait till the end of the 20-milligram cohort because we still have to finish that out before we can make those decisions. We've been really very much encouraged by the magnitude of change that we've seen at 20 with a very clear dose-response up from the 12-milligram dose. And to date again we haven't completed the cohort yet. But to date the safety has been pretty unremarkable relative to the other cohorts. So we haven't seen any clear treatment-related adverse effects emerging. So based on those considerations, I think 20 seems like a reasonable dose to take forward. But I think that discussion will be more fulsome once we have the full data set. We haven't seen anything in terms of PK-related changes relative to age and weight, for example, so I'm not sure that those factors in and of themselves w ill form an influence, but we'll continue to look at all of those d ata. Great. Couple more questions in the room h ere. Hi g uys. Congrats on the data. This is Andres Maldonado from H.C. Wainwright. One quick one from us. You know, how should we be thinking about the post-treatment observed HbF decay and how does that kind of durability correlate with pancellularity achieved on treatment? Maybe. Iain, we'll start with you and then Dr. Steinberg, I'd love to get your perspective on the latter half of that question. Iain, do you want to s tart? Yeah, and I think so. The data we showed for the 12-milligram cohort, which has the off-treatment period. We didn't have that available at the time of the July release. So that's new data for the 12-mg cohort. We don't have all of that for the 20 yet, but we will when we complete the cohort. And what you see, if you remember from the slides, is a gradual decline in the HbF once the drug has been stopped. It's not a precipitous decline. You wouldn't expect that to be the case. So the mechanism acting in the bone marrow to generate increased fetal hemoglobin, releasing those cells with the increased fetal hemoglobin into the circulation, those are then going to survive longer because they're not hemolyzing as readily. I'm not sure based on the trajectory that we're at a steady state at the three-month mark. So it's reflective of where we are at that time. There'll still be some cells that don't have the benefit of the HbF and others that do. And so the decline is going to reflect essentially the half-life of the red cells in the circulation at that time. But I think the important thing is that you don't see a precipitous drop, which is different than what you see with other mechanisms like the polymerization inhibitors or the PK activators which are acting on the mature red cells. You remove the drug and then they revert back immediately or pretty shortly thereafter back to their phenotype related to their hemoglobin in the cells at the time. I'm not sure if that addresses your question, but that's certainly the o bvious. Not much. I mean, you have two populations of cells. One is long-lived, the fetal hemoglobin cells. You have the intrinsic, the cells that don't have that much fetal hemoglobin in them and they're short-lived. So it's going to stay for a while. But of course you have to continue to take the agent to have continued fetal hemoglobin e xpression. Great. Greg. Great. Good morning, Alex and team. Congratulations on the data. Maybe a question for Dr. Alan. I think we sensed your appreciation for maybe some of those smaller absolute increases in hemoglobin with this cohort reaching a t least 6.5% i ncrease. Can you just talk a little bit about that appreciation, how that translates clinically, even those smaller increases certainly having a wider i mpact. Thank y ou. Absolutely. This is, you know, a very sick population who otherwise has no access to treatment. So being able to induce HbF, even in a small percentage of those cells, or even a small degree in more cells, it's really helpful and it improves outcome. There's a data set that Iain mentioned earlier, the PicnicHealth data set that we presented at ASH earlier this year. It's very real world data of consenting patients in the US and Canada. And what it looked at was percentage of HbF and the degree of like occurrence of VOCs. And as Iain mentioned, even a small percentage in HbF increase going from. So your chance of being VOC free at, for example, at 0% HbF is about 12% for the whole year. When you go to 5% HbF, that chance of being VOC free goes to nearly 60%. And so that even small increment in HbF and having that protection does lead to meaningful improvement in somewhat in reduction of hemolysis and improved hemoglobin in downstream vaso-occlusive events. For me as a practitioner, taking a very sick patient population who otherwise has no access to treatment to get on treatment, it's really exciting. Again, I think everybody's mentioned this is only a 12-week study, so long-term its implications could be even more p rofound. Tazeen has a q uestion. Thanks for taking my question. Good morning. Congrats on the data. I wanted to get the thoughts maybe from Dr. Alan first and then from the rest of the team about what you think the path to widening the adjustable patient population might be. You've shown convincing evidence that more severe patients are responding, at least in the early stages. But what do you see as the addressable patient population ultimately? And how are you going to take that into account when you design your registrational study and then just a follow up? Was there any difference in Cohort 4's baseline fetal hemoglobin level versus Cohort 3B? I just wanted to clarify that. Yeah. Thanks. You want to start and maybe Iain, I can pass it on to you and then Dr. Steinberg and myself. Yeah, great question T azeen. So in the 20 milligram cohort they had lower baseline hemoglobin compared to the 12 milligram, but the 20 milligram didn't have any transfusions throughout the treatment. So a little bit lower baseline. You know, as a clinician, I want to bring treatment to as many patients as I possibly can. And so for me, clinical trials, I would love to capture not only the disease severity based on genotype, but also phenotypic characteristics. So it's probably beyond the scope of what I can say because I'm not the one really running the studies, but you know, I do think based on what we see, if you have the more severe patient population responding as favorably then it kind of you could potentially think through expanding that to capture more patients and maybe see even more of a robust response. But I don't know what you guys plans a re. Yeah, I think it's a really important question. Based on the current severity criteria and also the hydroxyurea concomitant administration exclusion, we estimate it's about 20% currently of the total U.S. population, and the sort of levers to push to broaden that are on the one hand the patient severity itself, so decreased frequency of VOCs, for example, less end organ disease and then the second big one is the concomitant HU, and I think we consider both of those to be important and those will be issues that we'll be discussing with the regulators as we move forward with our plans for the next study and for studies beyond that p otentially. Yeah. So those questions we're certainly going to pose in our end of phase meeting with the agency sometime in the first half of next year. And I think the way I think about this is I think about it sort of speed to market versus. Time in the clinic, and I will favor speed to market, getting this drug to the market as quickly as possible. Having talked to people like Dr. Alan, having talked to patients and realizing that they really have very few treatment options today. I mean, we have hydroxyurea. voxelotor was pulled off the market. Gene therapy, as you said, is really not scalable. I think we estimate 200 patients of the 100,000 in the U.S. have actually gone on gene therapy, and crizolizumab, because of the failed confirmatory study, really is not being commercially used that much in the U.S. So, to me, if it was, you know, stay in the clinic longer, say for a year, year and a half, and broaden the patient population versus getting this drug to the market as quickly as possible and then look to expand that patient population. While you're on the market? I think we would opt for speed to market as opposed to more time on the development side. Any other thoughts you would add? Sure. You know, I think there's a general misconception of the severity of the pathophysiology of sickle cell disease, and historically sickle cell disease has been pain, but that's not the only thing, and you know, pain is a bad thing. That is the worst thing for most patients, but even when they don't have pain, the disease is relentlessly progressing, so the hemolytic anemia of sickle cell disease is a major cause of mortality and morbidity because it affects organs that. Necessarily immediately bring the patient to the clinic. Like they develop pulmonary hypertension, nephropathy, cerebrovascular disease. So expanding the treatment criteria to include patients who aren't totally crippled by pain, I think is very important. Patients, even when they're not having pain, have disease. We implicitly recognize this because we start every newborn nine months on hydroxyurea. Right. They're not sick, but we know that they're going to be sick and they're going to be sick in many different ways. So I think that really expands the market for treatments that have the potential to really have an impact on the d isease. James has a question. Great. James from Stifel, thanks so much for taking my question and congrats on the data. Maybe just one follow up on safety. I think the color you gave around the reticulocytopenia case is really helpful and makes a lot of sense of why it's not, you know, drug related. And prior cohorts, you've shown individual kind of patient curves, showing blood counts generally stay within the normal range. Is there any more color you can provide on some of these other patients in this cohort in terms of how their cell counts tracked and if there's any sort of outliers? Iain, you want to start? Yeah. So we haven't seen any treatment-related adverse events related to cytopenias. So neutropenia, lymphopenia, thrombocytopenia, and so on. As we discussed earlier, the decrease in counts here, certainly the neutropenia and the thrombocytopenia observed in this patient were almost certainly related to that intercurrent viral infection and the treatment, or the treatment with the antibiotics. And those counts came back once pociredir was reinstituted. So we don't think that those are drug related. I think you do see some movements on these counts. We've discussed the reticulocytes in particular. Those come down as a reflection of the decreased stress on the bone marrow. And so that's a sort of therapeutic response, if you like. A lot of these patients do come in with higher baseline white blood cell counts as well, and those tend to come down, but we haven't seen that manifest as neutropenia. AE as s uch. Great. Are there any more questions in the room? Okay. And I don't believe that there's any questions online, so just follow-ups. First of all, thank you all for joining us, and thanks so much for your interest in the data. Dr. Alan will actually be doing an oral presentation on this poster today at the Poster Walk from 11:15 A.M. to 12:15 P.M. in Lecture Hall B3B4. So if you all are heading over to the conference and are so inclined, there will be another opportunity for Dr. Alan to present the data and also to take questions. And then finally, I always like to end here, which is none of this would be possible. None of this really, really provocative and potentially transformative data would be possible if it wasn't for the patients that decided to enroll in these trials. So, really, our thanks go out to those patients, the caregivers, and then also, most importantly, the investigators that work so closely with their patients to shepherd them through these trials. So, on behalf of the entire team at Fulcrum, thank you all for joining.