Earnings Call Transcript - FULC Q4 2025

Operator, Operator

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. 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.

Alexander Sapir, CEO

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.

Unknown Executive, Unknown

Welcome.

Alexander Sapir, CEO

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 pociridir 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, pociridir continues to be generally well tolerated at this higher dose. Taken together, the 20-milligram data reinforce our belief that pociridir 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.

Iain Fraser, Head of Clinical Development

Thank you, Alex. This slide serves as a reminder that sickle cell disease is a serious and life-threatening condition impacting millions worldwide, with a significant unmet medical need. Despite progress in clinical care, mortality rates are still high, and life expectancy is lower. The next slide highlights the importance of fetal hemoglobin (HbF) in influencing the severity of sickle cell disease. As HbF levels increase, patients report fewer vaso-occlusive crises (VOCs) annually, and even slight increases in HbF correspond with fewer occurrences of these episodes. Now let's discuss the PIONEER study's 20-milligram cohort. This overview covers the trial's design, and today we share an update on the partial cohort data presented at ASH in December 2025. We'll go over the full 12-week treatment data for the 20-milligram subgroup, with a cutoff date of December 23, 2025. A key point to note is the inclusion criteria for participants, which reflect a high severity of disease among the sickle cell patient group. Regarding patient enrollment, 13 patients participated, and 12 were evaluable for the pharmacodynamic analysis. One individual unfortunately discontinued due to a death on day 1, which was not related to the drug. A significant focus today will be on the full 12-week treatment data, as prior ASH presentations only covered the first 6 weeks. Moving on to the baseline characteristics, this data remains consistent with what we shared at ASH. The cohorts at both 12 and 20 milligrams are well matched, with a slightly lower number of males in the 20-milligram group, and one patient from South Africa in the 20-milligram cohort, along with new participants from Nigeria not included in the 12-milligram group. Looking at baseline fetal hemoglobin, the 12-milligram cohort showed 7.6% while the 20-milligram cohort was slightly lower at 7.1%. The baseline hemoglobin values were 7.8 grams per deciliter for the 12-milligram cohort versus 7.3 grams per deciliter for the 20-milligram cohort, with the 20-milligram group reflecting a more severely impacted patient population. The next slide illustrates the increase in fetal hemoglobin during the 12-week treatment period. For the 20-milligram cohort, the baseline started at 7.1% and rose to a mean of 19.3% at the 12-week mark, indicating a 12.2% increase over the period. Notably, no patients in the 20-milligram cohort required transfusions during this treatment phase. We now display individual patient data, showing significant HbF increases across the cohort, with 58% achieving at least a 20% increase by the 12-week cutoff, and every patient showing a minimum increase of 6.5%. Analyzing the F cells in the 20-milligram group, we noted a doubling from around 31% at baseline to 63% at week 12. The decline from week 10 to week 12 in F-cell percentages, affecting patients that weren’t included at every checkpoint, likely accounts for that dip, but we still observe an overall doubling in F-cell percentage during the treatment phase. We then examine additional markers associated with rising HbF, focusing on markers of hemolysis; specifically, LDH decreased by 34% and indirect bilirubin decreased by 40% by week 12, confirming reduced hemolysis from rising HbF levels. It’s important to point out that the 20-milligram cohort started with higher baseline values for both markers, indicating this group's increased severity. The following slide investigates erythropoiesis and red cell morphology markers, showing a 42% reduction in reticulocyte count, which represents less bone marrow stress due to reduced hemolysis. The right side of the slide shows a normalization in RDW, indicative of a more uniform red blood cell population, similar to the 12-milligram cohort. Regarding total hemoglobin, at the 20-milligram cohort by week 12, there was a mean increase of 1.1 grams per deciliter compared to 0.9 in the 12-milligram group. The absolute value for the 20-milligram cohort was lower due to increased severity but showed consistent rises over the treatment period, and no patients in this cohort had transfusions. Turning to VOCs, we captured baseline data for these in the inclusion criteria. Interestingly, 7 out of 12 patients in the pharmacodynamic analysis portion reported no VOCs during treatment, despite high initial baseline rates. Although the study isn't sufficiently powered for VOCs, this trend is promising and aligns with what was observed in the 12-milligram cohort. The expected VOCs, based on initial reports, would be around 16 events over 12 weeks, but only 6 events were seen among 5 patients. Regarding safety, pociridir at the 20-milligram dose continues to be well tolerated, with no serious treatment-related adverse events. Overall, the safety profile is consistent with our previous December 2025 update, with three patients experiencing treatment-related adverse events, all resolved with ongoing dosing. Importantly, there have been no treatment-related discontinuations in this updated cohort. In comparing the 12-milligram and 20-milligram cohorts, the adverse event profiles align with expectations for a severely affected sickle cell population, witnessing no dose-limiting toxicities. Additionally, pociridir has now been administered to nearly 150 adults. To conclude, I’d like to summarize the comprehensive data we've presented today as we look across this slide. The findings from the 20-milligram dose represent a cohesive series of biological events expected from a drug designed to increase fetal hemoglobin. We're observing a strong induction of HbF, reaching a mean of 19.3% by week 12, with over half of patients achieving levels of 20% or more. As HbF levels increase in the red blood cell population, they gain greater protection, which corresponds with a reduction in hemolysis. This decreased hemolysis leads to normalized red blood cell production and improved anemia, evident with roughly a one gram per deciliter rise in total hemoglobin. Furthermore, the VOC trends in this short-term study align well with this biological framework. Overall, the clinical indicators we've seen correspond accurately with the HbF induction mechanism and the biology of sickle cell disease. Now, I'd like to turn the call over to Dr. Steinberg for his expert insights on the clinical data regarding pociridir and its potential role in treating sickle cell disease. Dr. Steinberg?

Unknown Executive, Unknown

Thank you, Iain, for sharing these insights. Overall, experts agree that sufficient fetal hemoglobin levels can significantly improve or potentially cure the effects of sickle cell disease. While gene therapy has this potential, it currently faces challenges in reaching a large patient population effectively. Therefore, there is a significant unmet need for an oral treatment that can elevate fetal hemoglobin levels. The results we've seen are quite promising as they indicate that this drug could effectively reduce both acute vaso-occlusive crises and hemolytic anemia in sickle cell patients. Currently, hydroxyurea is the standard treatment, typically initiated before the age of one, with positive outcomes, particularly in younger patients. Comparing Iain's findings with the multicenter hydroxyurea trial is important, as this was one of the few studies conducted under controlled settings leading to FDA approval for the drug. In that trial, out of 150 patients, fetal hemoglobin levels rose to around 10%, with about 35% being F cells, although individual responses to hydroxyurea varied. Overall, there was an average increase in fetal hemoglobin of 0.5 grams, and acute vaso-occlusive events decreased by approximately 50%. In the pociridir study, after 12 weeks, fetal hemoglobin was reported at around 20% F cells, slightly over 60%. If we analyze the MSH study further by quartiles, the top responders achieved levels comparable to hydroxyurea's best quartile, with similar F and F cell percentages. Over time, F cell counts grew due to sustained treatment, showing greater longevity for F cells. This aligns with observations in a 20-milligram cohort. It’s noteworthy that the lowest quartiles in the MSH trial showed minimal long-term fetal hemoglobin increases. A significant distinction between the trials lies in the fact that the MSH trial saw a 16% increase in mean corpuscular volume and hemoglobin for those with high fetal hemoglobin responses, while in the pociridir trial, the increase was about 5%. Consequently, this indicates that, at equal fetal hemoglobin levels, pociridir patients achieved higher hemoglobin F per F cell concentration. This is crucial since our analysis indicates that higher F cell counts correlate with fewer acute vaso-occlusive events, reduced hemolysis, and lower mortality rates. Furthermore, the pociridir trial data included a diverse patient demographic, many of whom likely exhibited CAR haplotypes associated with sickle cell disease. In contrast, the MSH trial found that the absence of this haplotype correlated with better fetal hemoglobin responses. The key takeaway is that if these findings are confirmed in later clinical trials, pociridir could emerge as a primary treatment option. Given its different mechanism compared to hydroxyurea, it may also be beneficial in combination therapies for synergistic effects. Its more uniform distribution of fetal hemoglobin could be advantageous, in contrast to the variable distribution seen with hydroxyurea. I am optimistic about these findings as they point to new avenues for treatments aimed at increasing fetal hemoglobin, which remains a crucial approach for managing sickle cell disease effectively. Thank you.

Alexander Sapir, CEO

That's great. Thank you so much, Dr. Steinberg. I'm sure many of you will have questions for both Dr. Steinberg and Iain. Before we start the Q&A, I want to share why 2026 is such an important year for Fulcrum. We will provide an update on the next trial design in Q2 of this year after we receive the FDA meeting minutes. Based on the feedback from the FDA, our current plan is to begin 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 next trial's design. Finally, we are currently activating sites for an open-label extension study for PIONEER patients to evaluate the longer-term safety and durability of response of pociridir. With that overview, Gigi, let's open the call for questions.

Operator, Operator

Our first question comes from Joe Schwartz from Leerink Partners.

Joseph Schwartz, Analyst

Congratulations on the excellent update today. The VOC data is quite encouraging. Could you provide any additional insight into which patients experienced VOCs and when they occurred during the study?

Alexander Sapir, CEO

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

Iain Fraser, Head of Clinical Development

Yes, thanks, Joe. The VOCs were distributed throughout the treatment period. I want to highlight that this 12-week treatment period is relatively short. During this time, we observed increases in HbF, indicating that these patients had not yet reached their steady state. Therefore, it's not surprising to have seen VOCs during the treatment period. Additionally, there were more VOCs observed in patients with lower increases in HbF, but we have not disclosed further details on individual patients.

Joseph Schwartz, Analyst

Okay. That makes sense. And it's a good segue to my next question. Given the response to pociridir 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?

Alexander Sapir, CEO

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

Iain Fraser, Head of Clinical Development

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 Arab or Indian haplotype, which is the opposite end from the CAR. So those are the ones with the highest baseline HbF and the best responses to hydroxyurea. 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 skew high end. So I think 20-milligram likely more representative of the sort of global population.

Joseph Schwartz, Analyst

Very helpful. Thank you.

Alexander Sapir, CEO

Thanks Joe, Gigi next question.

Operator, Operator

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

Anupam Rama, Analyst

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?

Alexander Sapir, CEO

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.

Iain Fraser, Head of Clinical Development

Yes, that's a great question. HbF induction is the main mechanism of action here, and we're measuring the increase in HbF levels in these cells. As HbF rises and more cells with higher HbF circulate, those cells are better protected against hemolysis, resulting in a longer lifespan. Consequently, the cell population evolves over time. Immediate effects include reduced hemolysis, which we can see through markers such as LDH and bilirubin, reflecting a downstream impact from HbF. We observe decreases in these markers, though it's important to note that LDH is also linked to tissue damage, which could influence these markers, and bilirubin can be affected by liver function as well as hemolysis. Additionally, the normalization of RDW is encouraging as it trends toward normal levels, and we notice a significant decline in reticulocyte counts, although they do not return to baseline levels. This trend is evident even in successful gene therapy patients, where reticulocytes remain slightly elevated two or three years post-treatment, suggesting inherent biological factors at play. Lastly, total hemoglobin showcases the culmination of these effects, indicating an increase in the population of cells with fetal hemoglobin in circulation, which enhances protection and facilitates a new steady state. All of these markers are anticipated to reflect changes lagging behind HbF, possibly taking more time to reveal their full effects.

Anupam Rama, Analyst

Thanks so much for taking the question and congrats again.

Alexander Sapir, CEO

Thanks Anupam, Gigi next question.

Operator, Operator

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

Kristen Kluska, Analyst

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?

Alexander Sapir, CEO

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.

Iain Fraser, Head of Clinical Development

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.

Alexander Sapir, CEO

Kristen, regarding the total addressable market, studying a more severe patient population is beneficial from both a regulatory and clinical success perspective. For example, if a patient has four vaso-occlusive crises, achieving a 25% or 50% reduction to three or two crises is more attainable than for a patient with only one or two crises. Our assumption is that if we focus on a more severe population, the label will likely not specify the exact number of crises. Instead, it may state the treatment is for sickle cell disease in patients with recurrent vaso-occlusive events or crises, or it may qualify for patients with severe sickle cell disease. Ultimately, this leaves it to physicians to communicate with payers to demonstrate that a patient qualifies as severe or has recurring vaso-occlusive events, no matter how many events they experienced in a given year. This is our current mindset as we plan the next study and consider how this may influence the overall total addressable market.

Kristen Kluska, Analyst

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?

Alexander Sapir, CEO

Great question. I can say that the percentage of patients who currently meet our inclusion/exclusion criteria is around 20%. If the label were specific to recurrent vaso-occlusive events or patients with severe disease, that percentage would likely be much higher than the 20% we are currently studying. This reflects a key point made by Iain in his introductory slides, highlighting that sickle cell disease is very severe. Patients with severe sickle cell disease face a ninefold increased risk of mortality and typically have their lifespan reduced by about 20 years. Overall, sickle cell disease is a very serious condition. Gigi, next question.

Operator, Operator

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

Matthew Biegler, Analyst

I wanted to follow up on the pancellularity data and the comment made by Dr. Steinberg regarding hydroxyurea, noting that F cells tend to increase over time as the non-F cells decrease. I think I understand that, but could you confirm if we should expect pancellularity to rise as patients continue on pociredir for more than 12 weeks? Additionally, I have a quick follow-up regarding the two patients who did not have the 12-week assessment. Will we receive that information? It seems like their absence may have affected the average negatively. Thank you.

Alexander Sapir, CEO

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?

Unknown Executive, Unknown

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 are 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.

Alexander Sapir, CEO

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

Iain Fraser, Head of Clinical Development

Thanks, Matt. In response to the second part of your question, we will not have the missing data that was mentioned earlier. This particular assay is conducted at a single location, and there have been logistical issues regarding the shipping of samples to the analysis sites, which has resulted in the data not being representative of all patients at all time points. This is simply a characteristic of this specific assay at this time. However, I want to highlight that the two patients who were absent at week 12 had F cell percentages of 63% and 57% at week 10. This contributed to the relatively higher F cell percentage observed at that time. Additionally, two patients with lower HbF levels of 38% and 35% were represented at week 12 but were missing from the week 10 data. These two patients had baseline levels below 15%. I believe this conveys an important message across the entire group; even those with low baseline F cell percentages showed a response. We are observing responses in F cells across the board in these patients, and the numerical values at individual time points are somewhat affected by the missing data, as I mentioned earlier.

Alexander Sapir, CEO

Thanks Matt, Gigi next question.

Operator, Operator

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

Corinne Jenkins, Analyst

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.

Alexander Sapir, CEO

Yes. You asked two important questions. For your first question about dose response, Iain will address that. Iain, could you also provide some insight on patient 10? Dr. Steinberg, I'd like to hear your thoughts on patient 10 as well, considering at the previous time point their level was at 34, and now it's down to 29. How significant is it to you that this particular patient experienced about a 5% to 6% absolute decrease in their fetal hemoglobin? I'll start with Iain and then pass it to Dr. Steinberg.

Iain Fraser, Head of Clinical Development

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.

Unknown Executive, Unknown

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.

Alexander Sapir, CEO

That's great. To wrap up, regarding your comment about dose response, the 20-milligram data is extremely strong. This is the dose we plan to present to the agency as part of our strategy to discuss the upcoming study, which will begin in the second half of this year. Currently, there is significant interest in HbF induction for clear reasons, as mentioned by Iain and Dr. Steinberg. We believe we have about a 2-year lead over the next competitor, likely from the WIZ degraders. We aim to maintain that head start before other players enter the market. We are excited about the 20-milligram data, and we will recommend this dosage in our upcoming discussions with the agency scheduled for the first half of the year. Gigi, next question.

Operator, Operator

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

James Condulis, Analyst

Thank you for taking my question and congratulations on the data. I have a question about safety. I understand the cutoff is set for late December, so I assume there will be some additional safety follow-up. Could you provide any further insights beyond what we've seen in this presentation? Also, this drug has been tested on a large group of people, so I am interested in your confidence that this data set is sufficient for the FDA to consider expanding the study population over time. Thank you.

Alexander Sapir, CEO

Sure. Iain, do you want to take those?

Iain Fraser, Head of Clinical Development

Yes, absolutely. Even though our data cutoff is December 23rd, we receive safety information in real time. If any significant safety events occur after that date, we will report them. At this time, we have not identified any concerning safety events that need to be reported. We remain confident in the well-tolerated profile of pociridir at the 20-milligram cohort, which is consistent with the lower doses we've tested, showing no dose-related toxicities. This is a key point regarding the updated safety information. Regarding broadening the patient population, it’s crucial to consider both the severity of sickle cell disease and the unmet needs of patients. Despite some promising developments in recent years, patients have fewer treatment options available now than they did a few years back. Therefore, it’s vital to move forward with a promising therapy, given the serious nature of the disease and the unmet medical need. We feel confident in proposing our advancement into a registration-enabling study as part of our discussions with the agency, which will be a significant topic in our upcoming talks with them.

Alexander Sapir, CEO

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?

Unknown Executive, Unknown

I believe the unmet need is significant. Currently, hydroxyurea is the only treatment that has demonstrated sustained disease-modifying effects over many years, and even throughout a lifetime for some patients. However, we also recognize the variability in how patients respond to hydroxyurea. As a standalone treatment, it's often insufficient. Even patients who respond well to hydroxyurea can still experience severe sickle cell-related complications and increased mortality. The development of therapies that act downstream of polymerization, such as voxelotor, crizanlizumab, and mitapivat, has yielded mixed results. Given the current lack of effective treatments, these drugs may serve as supplementary options to hydroxyurea. However, what we truly need are better methods to induce increased fetal hemoglobin and red blood cells. The industry is aware of this need, and promising advancements are being made with agents like pociridir and potentially molecular glue degraders, which may hold significance in treatment. Therefore, the need remains substantial, and oral medications appear to be the most viable solution for effective therapy.

Alexander Sapir, CEO

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

Operator, Operator

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

Gregory Renza, Analyst

Great. Thanks Alex 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.

Alexander Sapir, CEO

Yes, that's a great question, Greg. To set the context, we know there are approximately 7.7 million patients with sickle cell disease globally, with many in Sub-Saharan Africa. In the U.S., there are about 100,000 patients, but research suggests it could be closer to 125,000. Europe has around 50,000 patients. We're currently working on operationalizing our Phase III study, and we're proceeding with some risks as we await guidance from the agency. This global study will involve sites not only in the U.S. but also in Europe and possibly in Sub-Saharan Africa, such as Nigeria. We believe that making this study global will allow many more physicians, beyond those just in Nigeria and the U.S. who have experience with pociredir, to gain firsthand knowledge of this drug in a clinical trial environment. There is definitely a market opportunity in the developed world, but if we have an oral agent capable of raising fetal hemoglobin levels, it's our responsibility to ensure access for all patients globally, whether in developing or developed countries. We are actively considering ways to ensure that every patient around the world can access this potentially transformative medication like pociredir.

Gregory Renza, Analyst

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 WIZ degraders. Thanks again and congrats guys.

Alexander Sapir, CEO

Yes, that's a great question. Before I hand it over to Dr. Steinberg, I want to remind everyone that we conservatively estimate we have about a two-year advantage over the next closest class of fetal hemoglobin inducers, which we believe are the WIZ degraders. Dr. Steinberg mentioned the glues, which are still in earlier stages. Dr. Steinberg, could you provide a more comprehensive overview of the different mechanisms of fetal hemoglobin induction and their current development status?

Unknown Executive, Unknown

Sure. Well, there's been a very limited amount of published material on this. The molecular glue degraders include degraders of the transcription factors WIZ and BCL11A and perhaps some other ones. And this is a way of decreasing the repressors that are responsible for turning off fetal hemoglobin gene expression. As far as I know, these are in very early phase clinical studies, but there certainly hasn't been any published information on this. The effects of these drugs in cell-based studies and animal studies have been profound. But of course, it's a big leap from there to human development, especially given the nature of the action of the transcription factor degraded. All I could do is agree with Alex. I don't know any other agents that are in this phase of clinical development. So I think there is an advantage for the development of this agent right now. But as a physician, I welcome the field to develop as many agents as possible because we know from experience that 1 or 2 aren't enough. We like to have choices of different ways of attacking the fetal hemoglobin gene so that it's robustly expressed into adulthood.

Alexander Sapir, CEO

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

Operator, Operator

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

Luca Issi, Analyst

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.

Alexander Sapir, CEO

Yes. Before passing it over to Iain, based on the baseline VOCs that these patients had, we would have anticipated 16 VOCs among the 12 patients during the 12-week treatment period. However, we actually observed 6 VOCs in 5 patients. If you recall the data we shared at ASH, there were 5 VOCs in 4 patients. Therefore, we did see a slight increase in the number of VOCs with this complete data set. I would like to hear from both Iain and Marty regarding this encouraging trend in VOC reduction, despite the small increase in the number of VOCs. Does this raise any concerns as we consider our path forward? Iain, why don't you start?

Iain Fraser, Head of Clinical Development

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.

Alexander Sapir, CEO

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.

Unknown Executive, Unknown

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.

Alexander Sapir, CEO

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

Unknown Executive, Unknown

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

Alexander Sapir, CEO

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

Operator, Operator

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

Alexander Sapir, CEO

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 physicians 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.

Unknown Executive, Unknown

Thank you. Bye-bye.

Alexander Sapir, CEO

Bye-bye.

Operator, Operator

This concludes today's conference call. Thank you for participating. You may now disconnect.