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Good morning, and welcome to the Fulcrum Therapeutics conference call to discuss 12-week data from the 20-milligram cohort of the Phase 1b PIONEER trial of pociridir in sickle cell disease. [Operator Instructions] This call is being webcast live and can be accessed on the Investors section of Fulcrum's website at www.fulcrumtx.com, where a replay will be available. I'll now turn the call over to Alex Sapir, CEO and President of Fulcrum Therapeutics.

That's great. Thanks so much, Gigi, and good morning, everybody, and thank you all for joining us on the call. So, for those of you who know this management team well, you know we are not ones to use superlatives all that often. But this morning, we are very, very excited to share with you the full 12-week data from the 20-milligram cohort of the Phase 1b PIONEER trial, building off of the strong data that we presented at ASH in December of last year. This data set has been years in the making, and we simply could not be more pleased to share it with you this morning because of the potential that it has to help many sickle cell patients around the world. So before we jump in, I do just want to remind everybody that today's presentation does include 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 FCC. I'd like to start by welcoming our guest speaker today. We're very fortunate to be joined by Dr. Martin Steinberg, who is also with us when we presented the interim data at ASH last December. Dr. Steinberg is a Professor of Medicine, Pediatrics, Pathology, and Laboratory Medicine at Boston University School of Medicine. It is his pioneering work that has helped shape much of our modern understanding of sickle cell disease biology and clinical care. Thank you for joining us this morning, Dr. Steinberg.

Welcome.

Thank you. I'm also joined by Iain Fraser, our Head of Clinical Development;, and Alan Musso, our CFO. Many of you know Alan and Iain quite well. So here's the agenda for the call. I will provide some brief introductory remarks. Iain will then quickly provide an overview of sickle cell disease and the clinical relevance of HbF, and then take us through the clinical data from the 20-milligram cohort in some detail. Next, we'll turn to Dr. Steinberg for his expert perspective on the clinical data and what this means for his patients and for the field in general. And then lastly, we'll open it up for Q&A. So let me start with a high-level takeaway of the data that Iain will walk through in just a couple of minutes. With 20 milligrams of pociredir dosed over a 12-week period, we are seeing rapid and robust HbF induction with a 12.2 mean absolute increase beginning from a baseline of 7.1% and ending at 19.3% at week 12. Importantly, more than half of the patients achieved HbF levels at or above 20%, a threshold historically associated with clinically meaningful protection. We're also seeing progression towards pancellularity alongside reductions in key markers of hemolysis, resulting in a greater than 1 gram per deciliter increase in total hemoglobin after only 12 weeks of treatment. At the same time, we continue to observe encouraging trends in vaso-occlusive crisis reduction over the 12-week treatment period, with 7 of these 12 severe SCD patients reporting no VOCs. And finally, pociredir continues to be generally well tolerated at this higher dose. Taken together, the 20-milligram data reinforce our belief that pociriedir is demonstrating the biological profile we would expect from a best-in-class oral HbF inducer for sickle cell disease. And so with that brief overview of the data, I'll now turn it over to Iain to walk through the data in some more detail. Iain, I'll kick it over to you.

Thanks, Alex. This slide, which is familiar to you all on the call today, is a reminder that sickle cell disease is a debilitating, life-threatening condition that affects millions of individuals globally. Importantly, there remains a very significant unmet medical need. In spite of advances in clinical care, mortality rates remain elevated, and overall life expectancy is reduced. Similarly, the next slide you have seen before, again, just to emphasize that fetal hemoglobin or HbF has long been identified as an important modulator of disease severity in sickle cell disease. As HbF levels increase, the number of VOCs reported by patients on an annual basis decreases, and even modest increases in HbF have been associated with reductions in the frequency of these VOCs. We turn now to the PIONEER study 20-milligram cohort itself. This is the overview of the trial design. And today, we're providing an update to the partial cohort data that was previously presented at ASH in December of 2025. We'll be discussing today the full 12-week treatment period from the 20-milligram dose cohort, which represents a data cutoff of December 23, 2025. The main highlight that I want to mention here, as we move into the data itself, is that on the bottom left, the inclusion criteria for these patients indicate a very high degree of disease severity in the sickle cell disease patient population. Moving to the disposition of patients across the study. There were 13 patients enrolled. There are 12 evaluable patients in the pharmacodynamic analysis subset. We had previously disclosed discontinuation due to a death on day 1 of the study for one of the individuals. This was deemed unrelated to the study drug. The main feature that we'll be discussing today is that we have data now for the full 12-week treatment period. At the time of the ASH presentation, we had full data for the cohort only through week 6 of treatment. Going to the next slide, the baseline characteristics. Since this is the baseline, this is exactly the same as we presented at ASH. Again, you'll see that the cohorts of 12 and 20 milligrams are quite well matched. There were fewer males in the 20-milligram cohort than in the 12-milligram cohort. And as we previously discussed in the 20-milligram cohort, there are fewer patients from South Africa, just one patient, and there are now patients from Nigeria who were not enrolled in the 12-milligram cohort. We just focused briefly on the baseline fetal hemoglobin. The 12-milligram cohort came in at 7.6% baseline. The 20-milligram cohort was similar, but slightly lower at 7.1%. Similarly, baseline hemoglobin, 7.8 in the 12-milligram cohort versus slightly lower at 7.3 grams per deciliter in the 20-milligram cohort. And then lastly, baseline VOCs represent a slightly more severely impacted patient population at 20 milligrams. Go to the next slide. This shows the increase in fetal hemoglobin that occurred across the 12-week treatment period. On the left-hand side of the slide, you will see that the increase in the 20-milligram cohort was from a baseline of 7.1% to a 12-week mean of 19.3%, which represents a delta of 12.2% for the entire cohort over the 12-week period. I do want to highlight that, for the 20-milligram cohort, unlike the 12-milligram cohort, there were no transfusions in patients in this particular cohort. We turn now to the patient-level slide. This shows each individual patient in the cohort, stacked by their increase in HbF across the 12-week treatment period. What you will see here is that all 12 patients showed substantial increases in HbF and that 7 of the 12 patients, or 58%, achieved at least a 20% absolute level of HbF at the time of the 12-week cutoff. All patients in the 20-milligram cohort showed an increase of at least 6.5%. Turning now to the F cells at the 20-milligram cohort, what we see is a doubling of the F cells from a baseline of around 31% to a 12-week percentage of 63%. I do want to make an important comment about the time point from week 10 to week 12 and the dip that we are seeing there is a factor of the fact that not all patients are represented at every time point and that two patients who were represented at week 10 with relatively high F-cell percentages of 63% and 57% who were not represented at the 12-week time point and I think that likely accounts for the dip that you're seeing there, but nonetheless, all patients responded in terms of an increase in their F-cell percentage, and overall, we see at least a doubling over the 12-week treatment period. We then move on to other markers that are associated with the increase in HbF in these patients and what we're seeing here on this slide are markers of hemolysis: LDH on the left and indirect bilirubin on the right. You'll see a 34% reduction in LDH and a 40% reduction in indirect bilirubin at week 12. This is consistent with the reduced hemolysis that is occurring in these cells as a result of the increase in HbF. I do want to comment here that the 20-milligram cohort did have slightly higher baselines for both markers, again reflecting the slightly increased severity of the 20-milligram cohort versus the 12-milligram cohort. The next slide looks at markers of erythropoiesis and red cell morphology. What you see at the 20-milligram cohort is a 42% drop in reticulocytes. We will see the increase in hemoglobin on the next slide. The reduction in reticulocytes reflects a reduction in the bone marrow stress that is caused by hemolysis. As hemolysis decreases, there is less stress on the bone marrow, and the reticulocytes decrease accordingly. We also see on the right that the RDW, which is a measure of the heterogeneity of red cell size, is essentially normalizing, which is what we saw in the 12-milligram cohort, which indicates a more uniform red blood cell population. Then as mentioned before, if we look at total hemoglobin, we see here that at 20-milligram cohort at week 12, we are seeing a 1.1 gram per deciliter mean rise in total hemoglobin versus 0.9, 12-milligram cohort. On the left, you see that the absolute value was lower for the 20-milligram cohort, again reflecting the severity -- increased severity of that 20-milligram cohort population, but you can see the rise that occurs over the 12-week treatment period. And again, I would emphasize that in the 20-milligram cohort, unlike the 12-milligram cohort, there were no patients with transfusions during the treatment period. Turning now to the VOCs, or acute events, we have indicated this before. We capture baseline VOCs as part of the [inclusion] [indiscernible]. What we are seeing here is that 7 of the 12 patients in the PD analysis subset had no VOCs at all during the treatment period, despite having a high level of baseline VOCs coming into the study. Study is not powered for VOCs, but this trend is obviously encouraging, and we observed this trend in the 12-milligram cohort. The expected VOCs based on the baseline VOCs reported by these patients was in expectation 16 events over 12 weeks, and we observed 6 in 5 patients during the treatment period. Turning now to safety, pociredir at the 20-milligram dose continues to be generally well tolerated, with no treatment-related serious adverse events. Overall, the pociredir safety profile similar to that described in the December 2025 presentation. There were three patients with treatment-related adverse events. All of these resolved with continued dosing of pociredir, and we have mentioned some of the details of these patients previously. Again, we will note that with the updated 20-milligram cohort, there have been no discontinuations due to treatment-related adverse events. The next slide looks at the 12-milligram and the 20-milligram cohort next to each other. I think at a very high level, the adverse event profile that we see is consistent with what you would expect in a severely impacted sickle cell disease patient population. There have been no dose-limiting toxicities and no treatment-related discontinuations. An overall, pociredir has been dosed in almost 150 adults to date. And then just to wrap it up, I would like to take a step back and evaluate the totality of the data that we presented today as we move left to right across this slide. What I would emphasize is that what we are seeing at the 20-milligram dose is not really a collection of isolated data points, but rather it reflects an expected biologically relevant cascade of events that you would expect with a drug that increases fetal hemoglobin. So we start with a robust induction of HbF on the far left, reaching a mean of 19.3% at week 12, and with more than half of the patients achieving an HbF level of 20% or higher. As HbF rises across a broader population of red cells, we expect there to be more of the red cells protected as a result of now having fetal hemoglobin within them and that is what we see as we see markers of hemolysis reduce. With less hemolysis, we also see a normalization of erythropoiesis and improvements of anemia with approximately a 1 gram per deciliter increase in total hemoglobin. And ultimately, while exploratory, the VOC trends that we've observed to date in this relatively short-term study are consistent with this overall biological framework. So importantly, the clinical signals that we're seeing align very nicely with the mechanism of action of induction of HbF and on the biology of sickle cell disease. With that, I'd now like to turn the call over to Dr. Steinberg to provide his expert perspective on the clinical data for pociredir and its potential for treating sickle cell disease. Dr. Steinberg?

Yes. Thank you very much, Iain, for presenting these data. So I think generally, all experts in the field believe that enough fetal hemoglobin in most sickle cells can cure or greatly ameliorate the phenotype of sickle cell disease. So gene therapy could do this, but for many reasons, of course, it's ineffective because it can't reach a population of patients and it's unlikely to do so for a very long time, if ever. So the major unmet need for treating sickle cell disease and other beta hemoglobinopathies is an orally available agent that will induce high levels of fetal hemoglobin. I think these results are very impressive because they suggest strongly that this drug will be efficacious and decrease both acute vaso-occlusive events and the hemolytic anemia of sickle cell disease. So the standard of care now in sickle cell disease is hydroxyurea, which has started before the end of the first year of life with excellent results at least in very youngest patients. I think it's useful to compare the results that Iain suggested with the multicenter study of hydroxyurea trial. Hydroxyurea, of course, the standard of care. And the trial is one of the few studies where the drug was administered under controlled conditions. And this is the trial that led to FDA approval of hydroxyurea. And at the end of the study, in all 150 patients, fetal hemoglobin increased to about 10% with about 35% F cells. And this was in the totality of the patients. And the reason for this, of course, is that the patients responded differentially to hydroxyurea. Now the whole group had about 0.5 gram increase in fetal -- in total hemoglobin and the acute sickle cell-related vaso-occlusive events decreased by about 50%. Then the pociredir study at 12 weeks, fetal hemoglobin was about 20% F cells, a little bit more than 60%. If you look at the MSH study, and divide the people into quartiles, this is about equal to the highest quartile of hydroxyurea treated patients in the MSH after 12 weeks. So in this top quartile of responders, which is the most stringent comparative for the pociredir trial, they had about 20% F and about 60% F cells. Of course, over time, the amount of F cells increased because they continued to get the drug and F cells have a preferential survival. And these results are similar to the 20-milligram cohort. Now the thing to remember is the 2 lowest quartiles of the MSH trial had little long-term increment in fetal hemoglobin. Now I think the key difference between these trials is in the MSH trial, the mean corpuscular volume and mean corpuscular hemoglobin increased by about 16% in these high fetal hemoglobin responders, whereas in the pociredir trial, they increased somewhere around 5%. And therefore, the importance is that similar mass fetal hemoglobin concentrations, the hemoglobin F per F cell in pociredir patients is higher. And I think this is critical because in our analysis of the cooperative study data and MSH databases, it's F -- the F cell that's associated with the reduction in acute vaso-occlusive events, less hemolysis and reduced mortality. In addition, the pociredir trial that Iain reported gave the results of all patients. And many of these patients are likely to have CAR haplotypes of sickle cell disease. And in the MSH trial, it was the absence of this haplotype that was associated with better fetal hemoglobin response. So I think the takeaway point is that if these results are replicated in late phase clinical trials. Pociredir could be used as a first-line stand-alone therapy. Now as its mechanism of action is different from hydroxyurea, it could also be part of a combination chemotherapy where there might be synergistic or additive effects. And I think its tendency towards pancellularity, which we're seeing to be especially useful as the increase in fetal hemoglobin caused by hydroxyurea is heterocellular, which is less efficacious than a pancellular distribution. So I'm excited by these results because of the possibilities that they will give us for additional fetal hemoglobin inducing agents, which at this moment in time is the way to impact the phenotype of sickle cell disease in a clinically important manner. Thank you.

That's great. Thank you so much, Dr. Steinberg. And I'm sure many of you will have questions for both Dr. Steinberg as well as Iain. So before we open it up for Q&A, I would just like to share why 2026 is such an important year for Fulcrum. So we'll be providing an update on the next trial design in Q2 of this year following receipt of FDA [meeting] minutes. And then pending that feedback from FDA, our current plan is to initiate a potential registration-enabling trial in the second half of 2026. We also plan to engage with the European Medicines Agency in mid-2026 to obtain protocol assistance and feedback on the design of the next trial. And finally, we're currently activating sites for an open-label extension study for PIONEER patients to evaluate the longer-term safety and durability of response of pociredir. And so with that -- with those brief comments as an overview, Gigi, let's go ahead and open up the call for questions.

[Operator Instructions]. Our first question comes from the line of Joe Schwartz from Leerink Partners.

Congrats on the excellent update today. The VOC data is pretty encouraging. I was wondering if you can give us any additional insight into when -- into which patients had VOCs and when during the study they occurred?

Yes. Joe, it's Alex. Thanks so much for that. Yes, let me turn that over to Iain to answer.

Yes. Thanks, Joe. So the VOCs were spread throughout the treatment period. I think I do want to emphasize that this 12-week treatment period is relatively short. And throughout that period, we see increases in HbF so that these patients have not reached their steady state by any means during -- during the study. So it's not unexpected to have seen them throughout the treatment period. Having said that, there were more VOCs occurring in the patients who had lower increases in HbF, but we haven't revealed further details of individual patients there.

Okay. That makes sense. And it's a good segue to my next question. Given the response to pociredir seems to depend somewhat on the underlying sample type, I was wondering if you have a sense of how well the 20-milligram cohort represents the population of sickle cell patients who might enroll in a Phase III as well as how well it represents the population of sickle cell patients who are living with the disease in the U.S. and other major markets?

Yes. Great question, Joe. Iain, do you want to take that one as well?

Yes, absolutely. And you may recall from the 12-milligram cohort where we had a number of patients from South Africa who, in fact, turned out to have originated in the Democratic Republic of Congo, where we know epidemiologically, there's a very high prevalence of the CAR haplotype or the CAR allele that Dr. Steinberg referenced earlier. And we noted that 5 of those 6 patients in that cohort tended to have lower responses in their HbF. We have gone back and we're looking at haplotyping those to get the actual genetic data, but that was an epidemiologic observation. In the 20-milligram cohort, we had just the one patient from South Africa and enrolled more patients from Nigeria. Epidemiologically, we know that there's more heterogeneity across the haplotypes in Nigeria. And in some ways, that's more representative, I think, of the heterogeneity that you see within the U.S. We did not have any patients who were expected to be of the ArabIain IndIain haplotype, which is the opposite end from the CAR. So those are the ones with the highest baseline HbF and the best responses to HU. We do not expect that there were any of those patients enrolled here. And so I think the 20-milligram cohort likely represents a sort of middle slice, if you like. It's not over on the low end and it doesn't [indiscernible] high end. So I think 20-milligram likely more representative of the sort of global population.

Very helpful. Thank you.

Thanks Joe, Gigi next question.

Our next question comes from the line of Anupam Rama from JPMorgan.

Hi guys. Congrats on the update. When you look at the totality of the biomarker updates, which ones would you highlight that would take a little bit more time, let's say, beyond 12 weeks to kind of show a clear dose response and then sort of an increased depth of effect?

Yes. Great question, Anupam. And I think in terms of the biomarkers, maybe, Iain, I'll turn this over to you, but maybe I think just focus specifically on some of those biomarkers that look at the markers of hemolysis.

Yes, absolutely. Thanks, Anupam. I think that's a really important question. HbF induction is the primary mechanism of action here, and that's the sort of proximal effect and we capture that as we measure the HbF increasing in these cells. As HbF increases in cells and there are more cells in the circulation that have increased levels of HbF, those cells are relatively protected against hemolysis, their lifespan increases. And so the population changes over time. Some of the more immediate effects include the reduction in hemolysis, which are reflected by the LDH and the bilirubin. And those are sort of more immediately downstream, if you like, from the HbF, and we see those markers coming down. Importantly, there are other sources of those particular markers. LDH, of course, associated with tissue damage as well. And so that might have an impact on how those particular markers move and the bilirubin impacted by the liver function in addition to the hemolysis. So I think those are 2 comments there. As we look at some of the other markers, essentially a normalization of the RDW, which I think is encouraging that goes down to levels that are more or less normal. And then with the reticulocytes, you see them coming down quite dramatically. They don't reach baseline levels. And if you look even at the successful gene therapy patients, even out to, I think, about 2 or 3 years after that gene therapy, those reticulocytes don't normalize completely to baseline. So there might be something about the biology there. And then lastly, with the total hemoglobin, that sort of -- view that as the end of the cascade, if you like, and that needing to reflect increased populations of cells with fetal hemoglobin in the circulation, greater protection and allowing it to reach a new steady state. And so I think those are all expected to be lagging indicators behind the HbF. They may take longer to see the full manifestations of the effect.

Thanks so much for taking the question and congrats again.

Thanks Anupam, Gigi next question.

Our next question comes from the line of Kristen Kluska from Cantor Fitzgerald.

Hey, good morning, I'll also add my congratulations on these data. So I had a couple of regulatory questions. I guess, first and foremost, now that the Fulcrum team has seen the full data set here, I'm curious how you're going to approach your meeting with the agency in terms of what you're going to ask for on your wish list? And then for a registrational trial, how do you think about wanting to expand the TAM as much as possible, but also keeping a good balance of the patients that you do enroll to ensure that the trial is successful, just given some of the recent unfortunate failures we've seen in the space?

Yes. It's a great question. Maybe, Iain, if you want to talk about the first one, and then I'm happy to cover the second one.

Yes. Yes. Thanks, Kristen, for the question. Based on the strength and the consistency of the data that we've generated to date, with the robust induction of HbF and this progression towards a broader pancellular distribution along with the improvements of biomarkers of hemolysis and anemia, we really think that it's appropriate to advance into a study with the potential to be registration enabling. And that will certainly be a topic for our discussion with the FDA at the end of Phase meeting. Of course, there is substantial published literature that demonstrates an association between higher HbF levels and improved clinical outcomes in sickle cell disease. And that biological relationship is obviously a key part of the underlying rationale for our program. And of course, whether HbF could play a role in an accelerated approval framework will ultimately be a regulatory determination, but we very much look forward to discussing the totality of the PIONEER data set with the FDA in order to understand their perspective on the appropriate path forward.

And then, Kristen, in terms of -- in terms of the TAM, I think from a regulatory standpoint and from a probability of clinical success standpoint, I think certainly studying a more severe patient population like we have here helps from not only a powering standpoint, but also helps from a probability of clinical success. If you have a patient with 4 VOCs seeing a 25% or 50% reduction down to 3 or 2 is going to be easier to achieve compared to a patient that may only have 1 to 2 VOCs, so a less severe patient. I think our assumption as well is that if we were to study a more severe patient population, ultimately -- and that severity is measured by the number of VOCs, I think it would be pretty unlikely for the label and specifically the indication statement in the label to specify the number of VOCs. Now it may say something along the lines of for the treatment of sickle cell disease for patients with recurrent vaso-occlusive events or vaso-occlusive crises, or the qualifier could be for the treatment of patients with severe sickle cell disease. And I think really in either one of those cases, I think then it's really left up to the physicIain to have that conversation with the payer and demonstrate to the payer that this patient represents a severe patient or a patient with recurring VOEs, regardless of the number of VOEs that, that patient has had within a -- within a given year. So that's kind of how we're -- that's kind of how we're thinking about the approach the next study, and the impact that that may -- that approach may have on the overall total addressable market.

And just to follow up on that, assuming that is indeed what it ultimately looks like, what would you say, just roughly what percent of these patients would fall under that umbrella of having recurrent VOCs or something along that criteria that makes them more on the moderate to severe spectrum?

Great question. So, what I can say is that the percent of the patient-- of the patients who currently meet our inclusion/exclusion criteria, we believe it's around 20%. If the label was specific in terms of recurrent VOEs or patients with severe disease, that 20% would obviously go up much higher than the 20% that we're currently studying. And I think it really goes back to, I think, a point that Iain made in one of his first introductory slides. This is a very severe disease. Patients have -- patients with severe -- with sickle cell disease have a 9x greater chance of mortality, and 20 years are typically shaved off of their life. So, this is in whole, sickle cell disease is a very, very severe disease to begin with. Gigi, next question.

Our next question comes from the line of Matthew Biegler from Oppenheimer & Company.

I wanted to ask a follow-up on the pancellularity data and the remark by Dr. Steinberg. -- that on hydroxyurea, F cells tend to increase over time as the non-F cells die out. I think I understand that. But just to confirm, does that mean we should expect pancellularity to increase as patients stay on pociredir for longer than 12 weeks? And I just had a quick follow-up on those 2 patients that didn't have the 12-week assessment. Are we going to get those? Or because that does seem like it kind of swayed the average downward? Thank you.

Matt, great questions. I think, obviously, to answer your first question, I'll turn that one over to Dr. Steinberg. And then the second question, I can have Iain cover. Dr. Steinberg?

Sure. Well, yes, I would expect that it's going to increase. If you look at the results of the MSH trial that I referred to. At 12 weeks, they similarly had about 60% F cells, but it increased over time to over 85%. And we know, of course, that the mechanism of F cell induction in hydroxyurea is different than the mechanism of F cell induction with pociredir. So, I think this provides some optimism that over time, the F cell levels is going to increase and there will be increased in the cellularity. And these F cells not only have fetal hemoglobin in them, but have important levels of fetal hemoglobin in them enough to protect them almost fully from sickle hemoglobin polymerization. Because in F cells all F cells aren't alike. You could see an F cell because it has some fetal hemoglobin in it. And whatever it has is protective, but not protective enough. And this is the reason to try to achieve both pancellularity with a concentration of fetal hemoglobin that protects the cell nearly fully, as the cells in successful gene therapy treated patients are. And you can see the results from those patients.

That's great, Dr. Steinberg. Iain, second part of Matt's question.

Thanks, Matt. So, in response to the second part of your question, we will not get those data -- the missing data that was mentioned earlier. This particular assay is performed at a single site, and there have been some logistics around shipping of samples to the analysis sites that have caused the data to be not represented of all patients at all time points. And so that's just a feature of that particular assay at this particular time point. But I do want to emphasize that the 2 patients that were missing at week 12 had a 63% and 57% F cell percent at the week 10 mark. And so we're contributing to that somewhat higher F cell percent at that time point. In addition, there were 2 patients who were represented at week 12 with rather lower-end HbF, so 38% and 35%, respectively, but who were missing at the week 10 time point. Those 2 patients, the 38% and 35% started out from baseline that were below 15%. And I think that's perhaps the important message across the entire cohort that even those with low baseline F cell percent responded. So, we're seeing a response in F cells across the board in these patients, and that the numerical value at individual time points is somewhat sensitive to the missing data, as I alluded to earlier.

Thanks Matt, Gigi next question.

Our next question comes from the line of Corinne Johnson from Goldman Sachs.

Good morning. Maybe a couple of follow-up questions for me. One, I guess, now that you've seen the 20 mg data and the 12 mg, et cetera, do you feel confident that you've fully explored the dose range to move forward into registrational study here, both with respect to what the FDA might require and for purposes of just realizing the full value or benefit of this agent. And this is a bit nitpicky, but on the patient level, it looks like patient 10 kind of achieved a higher percent HbF earlier on at day 56 and then came back, obviously still having a good response. But could you provide any color on what happened with that individual? Thanks.

Yes. Two great questions. And I think in terms of your first one around dose response, I'll have Iain answer that. Maybe, Iain, if you also want to touch on patient 10. But then Dr. Steinberg, I would like also to get your sort of thoughts on patient 10 at a prior time point was at 34 and now they're down to 29. How -- like how much does that matter to you that for that one particular patient, we saw about a 5% or 6% absolute drop in their fetal hemoglobin. But maybe I'll start with Iain and then turn it over to Dr. Steinberg.

Thanks, Corinne. And based on the first question, so what we've articulated previously is even at the 12-milligram cohort based on the robustness of the increases of HbF and the consequent hemolysis and anemia biomarkers that we saw downstream of that, we felt very comfortable that those were robust and relevant responses that we were seeing. The 20 milligram certainly expands upon that, and we're very encouraged by that. The PIONEER protocol did allow for an increase to a dose as high as 30 milligrams once daily. That dose had been explored previously in our first-in-human study in healthy volunteers. We observed as a pharmacodynamic biomarker in that study, the HBG mRNA, which is the gene that encodes HbF. We saw inductions of HBG in a dose-responsive fashion all the way from 2 milligrams up to 20 milligrams at each of those dose increments seeing an increase in HBG mRNA at the 2-week mark. As we went from 20 to 30, we did not see further induction there. And so based on the robustness of the clinical data in the sickle cell disease patient population in PIONEER at the 12- and the 20-milligram dose, and the lack of incremental HBG1 mRNA induction earlier on, we decided not to go further on to the 30-milligram dose. That's the first part of the question. Second part of the question relates to the individual patients who achieved a higher level of HbF earlier on. We've gone back and looked at all the individual data. This is an anomaly in terms of the overall trend of HbF across the patients across the entire PIONEER study, where we have not seen declines in HbF occurring during the treatment period. There's been no clear explanation for that, no clear lab error or mixup of the data. I think it's just likely a reflection of small numbers of patients and some variability in the assay that contributed to that. But I would remark that, that patient started out with a baseline of around 8%, ended up at 29%, which by any measure is a very robust induction of HbF. So I think that small difference to the 34% and the 29%, we don't consider that to be clinically meaningful.

Yes. Dr. Steinberg, anything you want to add on that individual patient #10?

No, I think Iain said it all. The assay has a certain coefficient variation and it's going to vary from time to time. And so in a single patient in a small study, I wouldn't make anything of.

Okay. That's great. Yes. And then maybe, Corinne, just to sort of conclude, going back to your point about dose response. I mean, as I said at the outset, this 20-milligram data is extremely robust. And therefore, this is the dose that we will be taking to the agency as part of our plan to discuss the next study, which will be kicking off in the second half of this year. We right now have -- there's a lot of interest in HbF induction for obvious reasons, as Iain and Dr. Steinberg have mentioned. We believe right now that conservatively, we have about a 2-year head start over the next competitor. That's probably coming from the WI

Thank you. Our next question comes from the line of James Condulis from Stifel.

Hey! Thanks for taking my question and congrats on the data. I just had one on sort of safety. I know that the cutoff here is late December. So presumably, there's some additional kind of safety follow-up. And -- just curious if there's any color you can provide kind of beyond sort of what we've seen in this deck. And then more broadly, this drug has been studied in a lot of people now and just curious sort of your comfort that this is enough of a data set you think to get the FDA comfortable with kind of expanding the study population here kind of over time. Thanks so much.

Sure. Iain, do you want to take those?

Yes, absolutely. And I think, James, even though data cutoff is 23rd of December, we do get safety information in real time. And if there were any important safety events that occurred after the data cutoff, those would be relevant and we present those. So we don't have any untoward safety events that we have become aware of through that process that need to be reported. So I think we're -- we remain comfortable that the overall generally well-tolerated profile that we've seen with pocerdir at the 20-milligram cohort, similar to that at the lower doses with no dose-related toxicities that we've seen. So I think that, that's the key feature around updated safety, if you like. The second question relates to broadening the patient population and how comfortable do we feel about this. I think the important thing to recognize here is not only the disease severity of sickle cell disease, but also the unmet need that exists for patients. And we've seen despite what were some encouraging developments over the past several years. We've seen those being peeled back now. And so patients have fewer therapeutic options available to them now than they did just a few years ago. So I think it's very important to contextualize moving forward with an encouraging therapy in terms of the severity of the disease and the unmet medical need and we certainly feel very comfortable about at least proposing our move forward into a registration-enabling study as part of our discussions with the agency. And naturally, that will be an important topic for our discussions upcoming with them.

Yes. And maybe, Dr. Steinberg, I'd love to get your thoughts on how significant is the degree of unmet need for somebody like yourself who has treated a large number of patients with sickle cell disease, obviously, with the withdrawal of Oxbryta, crizanlizumab not showing a reduction in VOCs in its confirmatory studies. And despite Lyfgenia and Casgevy both being approved, they really haven't seen much uptake in the market. Maybe if you could just help the group here really contextualize how significant is the degree of unmet need in sickle cell disease?

Well, I think it's huge. We only have hydroxyurea that has shown sustained disease-modifying effects over many years and even over a lifetime in some patients. And we also know the heterogeneity of response to hydroxyurea. And as a single therapy, it's almost never good enough. There's patients who even are good responders to hydroxyurea because of the heterocellular nature of the response, continue to have severe sickle cell-related events and increased mortality. Now the whole field of developing agents that work downstream of polymerization, and this includes [indiscernible], voxelotor, crizanlizumab, mitapivat, they've all had really unimpressive effects. It's not that there isn't -- given our current dearth of therapy, there's some role for these drugs as adjuncts to hydroxyurea. And I've written about this and discussed this in the past. But what we really need is better ways of inducing more fetal hemoglobin and more red cells. And so that is -- obviously, the industry has taken this to heart and the most promising developments are agents like pociredir and who knows about the molecular glue degraders, but they are also show to have the potential being important agents. So I think the unmet need is great and oral agents are the way to go if any type of therapy is going to be effective.

Thanks for the color, Dr. Steinberg. Gigi next question.

Our next question comes from the line of Gregory Renza from Truist Securities.

Great. Thanks Alex [indiscernible] congratulations on the updates as well, and I appreciate you are taking my question. Alex, as you're looking towards a potential registrational trial and certainly international implications when it comes to trialing and exploring next steps. Just curious if you can comment perhaps on how you're thinking about just optimizing the strategic value of pociredir globally, this may be the time to think about the best way to perhaps penetrate commercially to do that work internationally. I'm just curious how you're thinking about going global, especially with markets of high unmet need ex U.S. Thanks so much.

Yes. Great. Really, really good question, Greg. And maybe just to orient folks. So what we know, and Iain talked about this at the outset, about 7.7 million patients worldwide with sickle cell disease. A lot of those patients exist in Sub-Sahara Africa. In the U.S., about 100,000, although we actually have done some research, which I think it could actually be closer to 125,000 in the U.S., about 50,000 in Europe. We are in the process of operationalizing that Phase III study, and we're obviously doing a lot of that work right now at [risk] because we've yet to have guidance from the agency in the form of those -- in the form of those meeting minutes. And obviously, that global study will include not only sites in the U.S., but many sites in Europe, potentially some sites in Sub-Sahara Africa, like Nigeria. And we feel that, that sort of having this to be a global study will certainly give many other physicIains besides just the physicIains in Nigeria and the U.S. that have had experience with pociredir. We really feel that that will give many more physicIains the opportunity to have experience with this drug in a clinical trial setting. Clearly, the market opportunity very much exists, I would say, in the developed world. But that being said, I think that if we have an oral agent that can induce levels of fetal hemoglobin like what we're seeing, it really is incumbent on us as an organization to make sure that all patients around the world, regardless of whether they're in the developing world or the developed world, can have access to this drug. And so obviously, we're thinking strategically about ways that we can maximize the uptake and the revenue of this drug, but also to make sure that we don't lose sight of the fact that there are many, many patients in the developing world that might not otherwise have access to potentially a transformative therapy like this. And so, we're clearly thinking about ways that we can ensure that all patients around the world, regardless of where they reside, can get access to a potentially transformative medication like pociredir.

Great. That's very helpful. And then Alex, maybe just one more and perhaps for Dr. Steinberg. Alex, as you mentioned, the criticality of maybe maintaining a lead over next fetal hemoglobin inducer of oral options. Maybe to ask Dr. Steinberg to help put into context the oral scalable options that are in development now, how you break down pociredir and EED inhibition versus other HbF induction EED [indiscernible] WI

Yes. Great. Great question. And before turning it over to Dr. Steinberg, just to remind folks, again, conservatively, we believe we have about a two-year head start over the next closest class of HbF inducers, and we believe those are the WI

Sure. Well, there's been a very limited amount of published material on this. The molecular glue degraders include degraders of the transcription factors WI

Yes. Thanks so much, Dr. Steinberg, and thanks for the question, Greg. Gigi, next question.

Our next question comes from the line of Luca Issi from RBC Capital Markets.

Okay, team, this is Shelby on for Luca, and congrats on all the progress. It looks like the total number of VOCs when we look at the treatment period plus the safety follow-up went from 6 at ASH to 9 today. Appreciate that it's a very sick population, as you've highlighted in the baseline characteristics. So how should we think about that increase in such a short period of time? And does that modestly decrease your confidence that this drug can lower VOCs in a pivotal trial? Any color to it much appreciated.

Yes. Maybe before kicking that over to Iain. So, based on the baseline VOCs that these patients were coming in with, we would have expected to see 16 VOCs in these 12 patients over that 12-week treatment period. What we did observe during that treatment period was 6 VOCs in 5 patients. And if you remember the data that we presented at ASH, it was 5 VOCs, I believe it was in 4 patients. So we did see a very small uptick in the number of VOCs with this full data set. I guess maybe to-- I'd love to hear maybe from Iain, but also from Marty as well, when you sort of think about this encouraging trend in VOC reduction, albeit a small increase in the number of VOCs, does that give us any sort of pause or concern from a path forward? Iain, maybe start with you.

Yes. I'm happy to take that. I just want to make one clarification. So the slide that indicates the reduction of VOC, Slide #19, that is within the PD analysis set of patients. So that's in the 12 patients. And there, there were 6 VOCs observed in the 5 patients during the treatment period. And then, in addition, 3 VOCs were observed during the safety follow-up period. So that represents 9. On the following slide, Slide #20, which is the safety slide, that includes the entire safety analysis set for the study, and that's where the 10 VOCs are reported, which includes the patient who came into the study experiencing a VOC and who ultimately experienced a Grade 5 SAE and was discontinued. So that's where the 9 and the 10 come from. I don't think that the observation of the increase from the time of the ASH presentation to this presentation, different data cut in any way changes our view of the effect on VOCs here. Again, this is a very short study to observe that clinical endpoint. The patients are not at a steady state of maximum effect of the drug. They're increasing their HbF throughout the treatment period. And given that they are a severe patient population to start with, it's not unexpected that they would have VOCs during that early treatment period. So we do not feel in any way dissuaded or discouraged by that fact and remain, in fact, very encouraged by these trends.

Yes. And maybe, Dr. Steinberg, your take on Slide 19. And I think it's really important to remind everybody that even though we reported this data, we've always been really cautious for people to say, I wouldn't overinterpret this data. It is a short-term study. VOCs were not an endpoint in this study. There was no adjudication committee, but we decided to report the data out as we did on Slide 19 without too much overinterpretation. But maybe Dr. Steinberg would love to get your sort of perspective, with all the caveats that I just mentioned, on what you think about the data on Slide 19.

Well, I don't think you could make anything of that. If fetal hemoglobin is going to be increasing to the levels we're seeing, and if the hematologic changes are going to be similar. And based on 40 or 50 years of understanding pathophysiology and fetal hemoglobin, when the F goes up, the events go down. And so one patient in a short period of time means absolutely nothing for the ultimate efficacy of the agent.

Yes, that's very helpful. Gigi, next question?

I think I have to go off because I have some other calls. Is that okay? Or how do you want to do?

Gigi, can you see if there are any more calls in the queue?

At this time, I'm showing no further questions.

All right. Timing is perfect. That's great. So thanks, Gigi. And Dr. Steinberg, thanks for joining. Maybe just very quickly, in closing, I do want to thank all of you for joining us this morning. More importantly, I do want to thank the sickle cell warriors and their caregivers. None of what we do would be possible if it weren't for the warriors who enrolled in the study and their physicIains and families who supported them along the way. We're deeply grateful for their passion and partnership, and we remain steadfastly committed to advancing this important work in the months and years to come. Thanks, everybody, for joining us on the call.

Thank you. Bye-bye.

Bye-bye.