Fulcrum Therapeutics Q3 2025 Earnings Call Transcript

Quartr
Provided by Quartr
October 29, 2025

Key Takeaways

  • Positive Sentiment: FTX‑6058 Phase 1B (12 mg) produced dose‑dependent, clinically meaningful increases in fetal hemoglobin with near pan‑cellular induction, improved hemolysis markers, higher total hemoglobin and a trend toward fewer VOCs, with only grade‑1 treatment AEs reported.
  • Positive Sentiment: Enrollment in the 20 mg cohort is complete (12 evaluable); roughly half of patients should have day‑84 data by the ASH cutoff and cohort results will be presented at ASH in December, creating an imminent clinical catalyst.
  • Positive Sentiment: Fulcrum submitted a protocol to the FDA and is operationalizing an open‑label extension (OLE) to continue treatment for Pioneer participants, enabling longer‑term safety and durability data that will inform regulatory discussions.
  • Positive Sentiment: The company ended Q3 with $200.6M in cash, cash equivalents and marketable securities and expects this to fund operations into 2028, which management says covers planned development of FTX‑6058 and other programs.
  • Neutral Sentiment: Fulcrum plans an IND in Q4 2025 for bone marrow failure syndromes and presented preclinical efficacy for FTX6274 in prostate cancer, but these programs are earlier‑stage and less likely to move the needle near term.
AI Generated. May Contain Errors.
Earnings Conference Call
Fulcrum Therapeutics Q3 2025
00:00 / 00:00

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Operator

Good morning and welcome to the Fulcrum Therapeutics third quarter 2025 financial results and business update conference call. Currently, all participants are in a listen-only mode. This call is being webcast live and can be accessed on the Investor section of Fulcrum's website at www.fulcrumtx.com and is being recorded. Please be reminded that remarks during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about the company's future expectations and plans, clinical development timelines, and financial projections. While these forward-looking statements represent Fulcrum's views as of today, this should not be relied upon as representing the company's views in the future. Fulcrum may update these statements in the future but is not taking on any obligation to do so.

Operator

Please refer to Fulcrum's most recent filings with the Securities and Exchange Commission for discussions of certain risks and uncertainties associated with the company's business. Leading the call today will be Alex Sapir, CEO and President of Fulcrum. Joining Alex on the call are Alan Musso, Chief Financial Officer, and Dr. Iain Fraser, Senior Vice President, Clinical Development. After providing updates on the company's key programs, there will be a brief Q&A in which the Fulcrum management team will be available for questions. With that, it's my pleasure to turn the call over to Alex.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

That's great. Thanks, Shannon, and good morning, everybody, and thank you all for joining us today. The past several months have certainly been a busy, but more importantly, a very exciting time for Fulcrum, marked by significant progress with our lead program, pociredir, for the treatment of sickle cell disease, which is an inherited blood disorder with a high unmet need afflicting approximately 100,000 people in the U.S. and approximately 7.7 million people worldwide. There is an ever-increasing need for better treatment options for sickle cell disease patients who face not only an impaired quality of life due to chronic pain, fatigue, and acute complications like vaso-occlusive crises, but also very high rates of mortality. Patients with sickle cell disease face a greater than 20-year reduction in life expectancy with a mortality rate that is nine times higher than the general population.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

As we continue on our journey to find better treatment options for these patients, we were very encouraged with the data presented this past July from the 12-milligram dose cohort of the Phase I-B PIONEER trial, which demonstrated a potential for pociredir to meaningfully improve outcomes for people with sickle cell disease. Now, digging into that data a little bit more at a high level, pociredir demonstrated a dose-dependent and clinically meaningful increase in fetal hemoglobin, near pan-cellular induction of that fetal hemoglobin or HbF, improvement in key biomarkers of hemolysis resulting in a subsequent increase in total hemoglobin, and finally, encouraging reduction in vaso-occlusive crises or VOCs. Equally as important, pociredir continued to be well tolerated with all treatment AEs being grade 1 in severity and all resolving during the treatment period without any disruption in study drug.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

These encouraging results achieved our target product profile criteria and positioned pociredir as a potentially best-in-class once-daily oral therapy for sickle cell disease. In August of this year, we submitted a protocol to the FDA to initiate an open-label extension or OLE trial, which will allow patients to continue receiving pociredir after completing the PIONEER trial, enabling thus longer-term evaluation of safety and durability of response. We're also pleased to share today that we have completed enrollment in the 20-milligram dose cohort with a total of 12 evaluable patients and will present data from this cohort at the American Society of Hematology, or ASH, conference in early December. The over-enrollment seen in the 12-milligram and 20-milligram cohorts is a testament to the enthusiasm from the physicians involved in the study.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Now, with a number of these 12 patients starting drug in September, we expect approximately half of the 12 patients will have completed their day 84 visit, and all patients will have completed their day 42 visit at the time of our data cutoff for the ASH meeting. Approximately 60% of the patients enrolled in this 20-milligram cohort have come from the U.S., with the remainder coming primarily from sites in Nigeria, which are newer sites that were not yet activated in time to participate in the 12-milligram cohort. The mean and median HbF levels at the start of the study for this cohort were 7.1% and 7.3%, respectively. We're also pleased to see patients remaining in the study with a greater than 90% adherence to the once-daily oral drug regimen. We continue to believe that inducing fetal hemoglobin is the optimal strategy for treating sickle cell disease.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Evidence for this approach continues to grow, as highlighted in our recent presentation earlier this month at the annual conference for the Academy for Sickle Cell and Thalassemia, or ASCAT for short, where we demonstrated a quantitative correlation between increased fetal hemoglobin levels and reduced vaso-occlusive crises in sickle cell disease. This data, together with the 12-milligram cohort data that we shared in July, gives us confidence that pociredir has the potential to provide a differentiated therapeutic option for people living with sickle cell disease. We look forward to sharing additional results from the PIONEER trial at the upcoming ASH conference in December, and we plan to engage with the FDA for an end-of-Phase I meeting in Q1 of 2026 to align on the next stage of our clinical development for pociredir.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Now, outside of pociredir, we continue to advance our program for the potential treatment of bone marrow failure syndromes such as Diamond-Blackfan anemia, 5q deletion syndrome, Shwachman-Diamond syndrome, and Fanconi anemia, and we plan to submit an IND for these benign hematological conditions in the fourth quarter of 2025. Additionally, we recently presented preclinical data at ESMO this month for FTX6274, an oral EED inhibitor, which demonstrated robust efficacy in castration-resistant prostate cancer models. We are encouraged by these findings, which highlight the potential of EED inhibition beyond our current hematology programs. With that overview, let me now turn it over to Alan Musso, our Chief Financial Officer, to run through the numbers for the quarter. Alan, over to you.

Alan Musso
Alan Musso
CFO at Fulcrum Therapeutics

Thank you, Alex. I'll now go over our results for the third quarter ended September 30th, 2025. Our research and development expenses were $14.3 million for the third quarter of 2025 compared to $14.6 million for the third quarter of 2024. The decrease of $0.3 million was primarily due to decreased employee compensation costs as a result of the workforce reduction we implemented in September of last year, as well as a decrease in costs associated with our discontinued losemepamide program, partially offset by increased costs relating to advancing our pociredir program. The general administrative expenses were $7.6 million for the third quarter of 2025 compared to $8.4 million for the third quarter of 2024. The decrease of $0.8 million was primarily associated with decreased professional services costs.

Alan Musso
Alan Musso
CFO at Fulcrum Therapeutics

The net loss was $19.6 million for the third quarter of 2025 compared to a net loss of $21.7 million in the third quarter of 2024. Now, turning to the balance sheet, we ended the third quarter of 2025 with cash, cash equivalents, and marketable securities of $200.6 million compared to $241 million as of December 31st, 2024. The decrease of $40.4 million is primarily due to the cash used to fund our operating activities. Finally, turning to cash guidance, based on our current operating plans, we expect our existing cash, cash equivalents, and marketable securities will be sufficient to fund our current operating requirements into 2028, providing sufficient runway to substantially progress the clinical development of pociredir. With that, Alex, let me turn the call back over to you.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Great. Thanks so much, Alan. Before opening it up to Q&A with all of you, let me just conclude with just a couple of final comments. Fulcrum has achieved meaningful milestones in the first three quarters of this year, with one of two planned data readouts for our lead program, pociredir, yielding very encouraging results in sickle cell disease. We are excited about the upcoming data readout at ASH and the opportunities ahead. We are fortunate to have a committed and talented team coupled with a strong balance sheet, which positions us well to achieve our goal of delivering transformative therapies. With the opening remarks concluded, Shannon, let's go ahead and open up the line for questions.

Operator

Thank you, Alex. To ask a question at this time, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Our first question comes from the line of Kristen Kluska with Cantor Fitzgerald. Your line is now open.

Kristen Kluska
Kristen Kluska
Equity Research Analyst at Cantor Fitzgerald

Hi, good morning, everybody. Thanks for taking the questions and for the updates today. I appreciate you disclosing the baseline characteristics for this cohort, and it looks pretty similar to what we saw for cohort three. I'm wondering, now that we know the baseline characteristics are relatively similar, now that we know the inclusion-exclusion criteria is more appropriate to compare apples to apples to these, how are you internally thinking about what is a win here and whether ways to measure if there's a dose response?

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, Kristen, it's a great question. We're going to handle that in two parts. I'll start, and then I'll turn it over to Iain because I do think there is a nuance for the approximately 50% of the patients for which we have full day 84 data. In terms of, I guess, your question about what is a win, I would argue that we've already won. If you go back and you look at the 12-milligram cohort, we essentially achieved that target product profile that we felt like we needed to achieve. We saw robust and rapid increases in fetal hemoglobin. We saw we were nearing levels of pan-cellularity. We were seeing all of the markers of hemolysis going down as we would have expected, and a subsequent increase in total hemoglobin nearing one gram per deciliter at the end of that 12 weeks.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

We saw a trend toward a reduction in VOCs, which obviously we need to confirm in a registrational study, and the drug was extremely well tolerated with all of the treatment emergent AEs being grade 1 in severity. I would argue that I think we have won with the 12-milligram cohort. Now, do we expect to see an increase in efficacy for the 20 relative to the 12? I think to answer that question, we really have to look at the healthy volunteer data in which we did show a dose response, again, in healthy volunteers at day 14 when measuring the fold induction of not the protein, not fetal hemoglobin, but the HBG mRNA.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

I think based on that healthy volunteer data alone, we would expect 20 to outperform the 12, but we will obviously know that in just a matter of weeks when we present this data at ASH. Iain, I do think it is probably important to talk a little bit about what we've seen with basically the first half of patients that started on the study and what we plan to present at ASH coming up in December.

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

Yeah, absolutely, Alex. Happy to address that question from Kristen. Based on when the last patients enrolled in the study, which was really towards the end of September, we expect that about half of the cohort will have completed the day 84 treatment visit at the time of the data cutoff that will serve the ASH meeting data presentation. We expect that we should have a 42-day visit available for all the patients, all 12 patients in that 20-milligram cohort. Interestingly, for those patients that have completed the full 84-day treatment period, and these were the earliest patients enrolled in the cohort, their baseline HbFs have tended to skew on the lower end of the range. When we present that data, once we have the exact number of patients for that cutoff, I think it'll be very important to accommodate the baseline for those 50% or so of the patients.

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

Obviously, when we release the full day 84 data, once everybody's completed the full treatment period, that'll reflect the 7.1%. I did just want to highlight that piece for the partial cohort data that we'll be sharing later this year.

Kristen Kluska
Kristen Kluska
Equity Research Analyst at Cantor Fitzgerald

Okay, thanks for that color. The OLE study, I know in the past you've noted it was something you're looking into, but I think this is the first time you've officially announced plans to start that. I'm curious if there was interest from the patients that were in the trial, the physicians that have been investigators in the study, and also how this study may also help with some of your future FDA discussions. Thanks again.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, great question, Kristen. You're absolutely right. I think that the timing of starting the OLE study was, quite frankly, really born out of discussions that I had had with several of the investigators in which they were expressing to me some of their patients' anxiety as those patients were getting closer and closer to day 84 and that we really didn't have anything at the time to offer them once the 12 weeks of dosing was up. In light of that, we really decided to kick off this OLE study earlier than we had initially planned in order to allow some of those patients in the PIONEER trial, once they come off of drug, to be able to roll into an open-label extension.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

I will tell you that in the conversations that I've had with the investigators, they were quite happy that their voice was heard, and as a result of their voice being heard, we reacted accordingly. In terms of how this, Iain, maybe in terms of how this data may help inform future discussions with the agency, do you want to comment a little bit on that?

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

Yeah, happy to do that, Alex. That study is now being operationalized at the moment, and I think one of the key aspects of that allowing us to continue treatment in those patients who previously were restricted to the three months contained within the PIONEER study allows us to generate additional safety data in that patient population, which I think overall for the program is going to be an important piece.

Kristen Kluska
Kristen Kluska
Equity Research Analyst at Cantor Fitzgerald

Thanks a lot.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Thanks, Kristen. Next question, Shannon.

Operator

Our next question comes from the line of Joseph P. Schwartz with Leerink Partners. Your line is now open.

Joseph P. Schwartz
Joseph P. Schwartz
Senior Research Analyst at Leerink Partners

Great, thanks so much, and congrats on the progress. I was wondering if you can give us any insight into the baseline level of HbF for the patients in the first half of the 20 mg cohort that we'll get data on first and how it compares to the second half of patients who were enrolled?

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, great question, Joe. I think to answer that, let me turn that one over to Iain. He's obviously been very, very close to each of these patients and very close to the study as well.

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

Yeah, as we said, Joe, the initial patients enrolled have trended lower than that 7.1% mean that reflects the entire 12 patients in the cohort. Because we don't know exactly where the cut is going to be with the 50%, depending on which samples get to the lab in time for the data cutoff, we haven't given the precise number there. We will obviously have that when we have those exact data, and we'll reveal that at the time of the data disclosure. I think it is important, just thinking ahead, that overall the trend there was just by chance the initial patients enrolled in the cohort were on average lower than the 7.1% mean.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, and maybe just to sort of add a little bit on what Kristen said earlier, you know now we can look at sort of apples to apples, and the fact that we now have a lower baseline for the roughly 50% of patients that will have completed day 84 by the time of ASH, we're looking really more at like apples to oranges, and the way to account for differences in baselines is to really look at that fold induction curve. That is one of the slides that we've included in our investor presentation comparing the 6-milligram to the 12-milligram.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

I encourage everybody to look at that because the fact that these patients, the first half of patients, tended to be on the lower end of that average, we'll certainly look at that sort of fold induction because that is one way to essentially sort of normalize for differences in the baselines. I think suffice it to say, Joe, clearly the first half of the patients had a lower baseline, and then obviously the second half of those patients tended to be a bit higher than the 7.1% and the 7.3% that we mentioned in our opening remarks.

Joseph P. Schwartz
Joseph P. Schwartz
Senior Research Analyst at Leerink Partners

Okay, great. Thanks for the insight. How are you currently thinking about the addressable market following Oxbryta's withdrawal, and can you give us some insight into your assumptions that go into your current estimate? Thanks.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, it's a great question. We really have sort of evaluated the market based on the data that exists out there in terms of what per cent of patients have what number of VOCs in the course of a given year. Our belief is that about 25% of patients have either four VOCs during a 12-month period of time or two VOCs during a six-month period of time. Obviously, because our drug at present cannot be concomitantly used with hydroxyurea, some of those patients are currently on hydroxyurea, and we've taken a bit of a haircut. What we estimate right now is that roughly about 20% of the 100,000 patients in the U.S. currently meet the inclusion-exclusion criteria as defined in the PIONEER trial.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Obviously, when we get to those conversations with the agency, certainly one of the questions that we will be asking them is the potential to expand to a broader set of patients. I will say, overarchingly, our overarching goal with this program is to get this drug to the market as quickly as possible because, as you mentioned, patients don't have the treatment options that they did several years ago with the withdrawal of Oxbryta. The cell and gene therapy is really not being too terribly successful commercially because of the costs and risks and the complexities of that therapy.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Our overarching goal and something that I continue to stress to this team is, we have to make sure that we get this drug to the market as quickly as possible to help as many patients as we possibly can, not just in the U.S., but globally for the 7.7 million patients who have sickle cell disease outside of the U.S.

Joseph P. Schwartz
Joseph P. Schwartz
Senior Research Analyst at Leerink Partners

Makes sense. Thank you.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, thanks, Joe. Thanks for the question. Shannon, next question.

Operator

Our next question comes from the line of Corinne Johnson with Goldman Sachs. Your line is now open.

Corinne Johnson
Corinne Johnson
Equity Research Analyst at Goldman Sachs

Thanks. Maybe two from us. As you think about kind of the 20 mg dose cohort, and maybe think about the full data set that you get later, what do you need to see from that for that to be the go-forward Phase III dose, considering your point earlier that you've kind of already won with 12 mg? What's included in the cash runway guidance with respect to the scope of a Phase III program? Maybe you could speak about duration and endpoints that would be included in that guidance. Thank you.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, great. Two great questions, Corinne. Maybe I'll turn it over to Iain for the first half of that question and then turn it over to Alan for your second question.

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

Yeah, thanks, Corinne. I think importantly, we'll be looking across the totality of the data in the 20 mg cohort, and we obviously would be delighted to see that the efficacy endpoints in the study are indicating improvement with an ongoing favorable tolerability and safety profile and ongoing good adherence to the study drug. We'll obviously be paying close attention to the HbF levels with a particular emphasis, as we've alluded to in some of the comments that we've made this morning, on the dose response as measured by a fold induction of HbF. Based on the induction of HBG mRNA that we observed at 14 days in the prior healthy volunteer study, we do expect that the 20 mg dose cohort could well outperform that which we observed at the 12 mg cohort.

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

I think one of the key learnings from the 12 mg data readout, as we compare the 12 mg to the previous 6 mg readout, it really was very important to look at that as a fold induction because the baselines across those cohorts were different, and that plays a big role. We'll also be looking to ensure that we are seeing a response in HbF across all patients. We're focused on the extent to which we achieve pan-cellularity. We're looking at improvements of markers of hemolysis, improvements in anemia, and trends of improvements in VOCs, while obviously the study isn't powered specifically around the VOCs. Overall, we expect and will be looking for continued safety and tolerability as we've observed across both the healthy volunteers and the patients that we've treated to date.

Alan Musso
Alan Musso
CFO at Fulcrum Therapeutics

Yeah, and Corinne, on your question on cash runway and guidance, that is a full success sort of forecast for the organic program. We basically anticipate moving forward with pociredir to the next trial. We've talked to a number of CROs who have mapped out what we think that could look like and feel very good that that is fully accounted for as we move forward with the cash guidance. We also anticipate moving forward with the program for DBA and some of those other bone marrow failure syndromes, as well as continued progression of work that's in the preclinical phase. It's sort of an all-in, full success of what we have going on in the pipeline at this time.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

That's great. Thanks for the question, Corinne. Shannon, next question.

Operator

Our next question comes from the line of Edward Tenthoff with Piper Sandler. Your line is now open.

Edward Tenthoff
Edward Tenthoff
Biotech Equity Research Analyst at Piper Sandler

Great, thank you. Good morning, everybody. Thanks for all the detail that you provided. Really excited to see the results down in New Orleans in just a couple of weeks. My first question really has to do with what do you think is actually going to be published in the ASH abstract release? It probably won't be the full data set, but I just want to get a sense for what you think might actually be in the abstract versus what you've sort of laid out in terms of what you'll be presenting at ASH. Do you think that'll be a poster or an oral presentation? Thank you.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, great. Two great questions, Ted. The abstract that will be made public by ASH next Monday, November 3rd, does not include any of the data from the 20-milligram cohort. It does include data from the 12-milligram cohort, but there's no data in the 20-milligram cohort. It was really a placeholder to ensure that we could get a spot at the ASH conference. In terms of whether it's a poster or an oral, that will get released by ASH on Monday. We think it's just to respect the process that ASH has, we feel like it's probably most appropriate and prudent to really let ASH share all of the abstracts in sickle cell and hematology that have been accepted and then which of those have been accepted for poster and which of those have been accepted for an oral presentation. Stay tuned. We'll know a lot more on Monday.

Edward Tenthoff
Edward Tenthoff
Biotech Equity Research Analyst at Piper Sandler

Great. One quick follow-up, if I may, and I appreciate the extra color with respect to the early patients maybe being on the lower baseline side, and we saw that the higher the baseline, the more HbF, the more response. When you look at all of these factors, what really is most important, both to KOLs, regulators, and yourself, in terms of really defining the activity of pociredir? Is it the per cent HbF? Is it the percentage of patients above 20%? Is it the total HBG? What is really the most important, or is it the totality of all of that data?

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, it's a great question, and I'll start, but Iain will probably have a better answer than I will. I've had a lot of conversations with a lot of investigators, not only in the U.S. but outside of the U.S., since the data we released in July around the 12-milligram. When I sort of pressure-tested your question with them, which is, if you look across these five parameters, right, increasing levels of fetal hemoglobin, the pan-cellularity, the decrease in markers of hemolysis, number four, the subsequent increase in total hemoglobin, and then a trend toward a reduction in VOCs, and doing that all with a once-daily oral that obviously is shown to be very well tolerated, I've asked that question, which of those five criteria are most important to you? They essentially have all come back to me and said it's really the totality.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

You can't really pinpoint one versus another. We know fetal hemoglobin will reduce VOCs. We know that increasing total hemoglobin will reduce fatigue that patients feel, which is very important for them. We know that the increase in fetal hemoglobin, it's imperative that that happens at a pan-cellular level, right? That's one of the knocks on hydroxyurea, is that they're not able to get to 70% of all the red blood cells having the presence of HbF. I really think it's each one of those criteria that we shared in July that they find impressive with the overall profile of the product. Iain, anything you'd like to add?

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

Oh, yeah, sorry, go ahead. Go ahead, please. No, the only thing I would add is that getting patients into that 20%+ range is obviously associated with really very dramatic benefits in the outcomes of the disease, and I think that's important. What we showed at the 12 mg dose, where about half of the patients were able to achieve that, I think is particularly encouraging. I do want to also recognize, and we've heard this as well, that there are some patients who really have very low baseline HbFs in the 2%, 3%, 4% range, often associated with very severe disease. For those patients to get right up into the 20s is a much bigger climb. Providing them with a threefold induction, an increase over their baseline, really is considered to be associated with significant benefit for those patients.

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

I think both aspects are operational here, that we will be able to get some of the patients into that really transformative range. For those starting out really low, you can make a dramatic impact on their disease, even though you may not quite get them up to that fully transformative range.

Edward Tenthoff
Edward Tenthoff
Biotech Equity Research Analyst at Piper Sandler

Lastly, when would we get the final PIONEER data set? Do you think that would be all the way at EHA next year?

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, it's a great question, Ted. Based on, from what I can remember, most patients should be wrapped up with their dosing sometime very much to the very end of this year. We would expect to have the full data set to share with everybody sometime in the first quarter of next year.

Edward Tenthoff
Edward Tenthoff
Biotech Equity Research Analyst at Piper Sandler

Great. Thanks, guys, and really excited for all the upcoming data.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, thanks, Ted. We appreciate the questions. Shannon, next question?

Operator

Our next question comes from the line of Matthew Biegler with OppCo. Your line is now open.

Matthew Biegler
Managing Director at OppCo

Hey, guys, thanks for the update. I had a follow-up on the demographics. I know we've talked about it a bit, but it sounds like, if I'm reading between the lines from Iain's comments earlier, that the Nigerian patients might be a bit sicker, or would you say overall the two cohorts are largely similar in terms of baseline severity, and like maybe the heterogeneity in baseline hemoglobin is just random variation?

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, it's a great question.

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

Yeah, Matt, thanks. I wouldn't take away from this the assumption that it's the Nigerian patients specifically that are more severe. It's really just the way in which patients came into this cohort. I think it's by chance that that's the case, that some of the patients enrolling earlier just happened to have those lower baselines. I don't think it's a geographic aspect related to that.

Matthew Biegler
Managing Director at OppCo

Maybe a bigger picture question for me is, and assuming 20 mg looks good or maybe marginally better than 12, do you keep dose escalating, or do you think that 20 is your recommended Phase II dose?

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, Iain, you want to take that?

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

Yeah, I think what we've indicated previously is that the current version of the protocol does allow us to dose escalate up to 30 milligrams. Based on what we saw at the healthy volunteer level, looking at the HBG mRNA, we didn't see much of an increment at the 14-day mark when we escalated there from 20 milligrams to 30 milligrams. Based on that, along with the promising data that we've already seen at the 12-milligram cohort and our expectations around the 20-milligram cohort, we're not planning to proceed with that 30-milligram dose.

Matthew Biegler
Managing Director at OppCo

Got it. Makes sense. Appreciate it.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, thanks, Matt.

Operator

Our next question comes from the line of Andres Maldonado with HC Wainwright. Your line is now open.

Andres Maldonado
Andres Maldonado
Senior Biotechology Analyst at HC Wainwright

Hi, guys, thanks for taking my question and congrats on the progress. One quick one for me. I guess when you have the 20-milligram data in hand, the question becomes, you know, how do you feel how generalizable pociredir's efficacy will be in the less severe patients? Can you maybe walk us through the mechanistic argument for why that will be? Thank you very much.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, it's a great question, Andres. Iain, you want to take that?

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

Yeah, and I think, thanks, Andres. I think, you know, we do have some data from the early part of the study in the less severe patient population, or at least in the patient population that didn't have the same severity criteria that the 12 and the 20-milligram cohorts have had. That early part of the study was an all-comers, sickle cell disease patient population, including some patients who were on concomitant HU at the time. We observed, albeit at the lower end of the dosing scale, so 6 milligrams and 2 milligrams and a few at 12 in that cohort, that we saw very robust effects on HbF induction. We don't expect that there would be a difference in the ability of pociredir to induce HbF based on the patient disease severity.

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

We have that, and then in addition, we have preclinical data, CD34 cells differentiated in vitro and so on, showing robust induction of HbF across a range of different donors. We also see induction, obviously, in healthy volunteers who don't have sickle cell disease, and we see induction in individuals with sickle traits, so the heterozygous for the sickle mutation, and seeing robust induction there. We're not expecting that the disease severity per se is going to impact the ability of pociredir to induce HbF.

Andres Maldonado
Andres Maldonado
Senior Biotechology Analyst at HC Wainwright

Great, thank you very much.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, thanks, Andres. Thanks for the question. Shannon, next question.

Operator

Thank you. As a reminder, to ask a question at this time, please press star one one on your touch-tone telephone. Our next question comes from the line of Luca Issi with RBC. Your line is now open.

Luca Issi
Luca Issi
Senior Biotechnology Analyst at RBC

Oh, great. Thanks so much for taking my question. Congrats on all the progress. Maybe, Iain, a quick one actually on safety. Obviously, we appreciate that it is really, really hard to prove a negative here, but what is the FDA telling you about how many patients and maybe how long of a follow-up are they hoping to see in order to feel comfortable about safety here? Again, any context there much appreciated. Maybe just a quick one on the plan going forward here. Can you just talk about the clinical plan beyond this Phase I-B? Should we assume that you start directly a registrational trial after this, or is it still possible that you will need to run intermediate Phase II before you go into registrational trial? Any color there much appreciated. Thanks so much.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

That's great. Yeah, Luca, two great questions. Great to have you on the call as well. Iain, maybe I'll turn that one over to you.

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

Yeah, thanks, Luca. As we've indicated previously in our discussions with the agency, there's obviously a context of risk and benefit. In our discussions with them, the plan was to complete the PIONEER study, as we're coming towards the end of that now, and to bring those data, as well as all the data from our Phase I program, back to the agency to discuss next steps with them. There's no specific numerical criteria provided around that. We expect that the ongoing favorable safety and tolerability profile is going to be important, but that also needs to be contextualized with the potential benefit that the therapy is bringing. No specific criteria outlined there, but certainly the plan to bring that back to the agency for that discussion.

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

The design of the next study is obviously going to be based on our discussions with the regulators and will be influenced very much by the data emerging from the PIONEER study, along with our other Phase I studies. We do believe that there is the potential for the next study to be a registrational study in the context of what's previously being used in the setting of an agent that induces HbF. We would expect that a clinical endpoint, such as VOC reduction, would likely be the primary clinical endpoint in that study. There's also the potential, as we've discussed previously, about the association between increasing HbF levels and the association between that and beneficial clinical outcomes. A potential there for an earlier look at the study, an interim look potentially, where HbF could be evaluated as a surrogate endpoint for a potential accelerated approval in sickle cell disease.

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

Of course, all of this is something that we'll be discussing with the regulators with the context of the full PIONEER data set and prior to initiating the next study.

Luca Issi
Luca Issi
Senior Biotechnology Analyst at RBC

Got it. Thanks so much.

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

Yeah, thanks, Luca.

Operator

Our next question comes from the line of Tazeen Ahmad with Bank of America. Your line is now open.

Tazeen Ahmad
Tazeen Ahmad
Managing Director at Bank of America

Hi, guys. Good morning. Thanks for taking my questions. I have a couple. Just in terms of the rules regarding embargo for ASH, when the abstracts do get released on Monday, is there a requirement that you would not be allowed to talk about the additional data that would be shown at the meeting itself? Would you be in a position to potentially release the new data before the actual presentation slot, whether it be a poster or an oral at the meeting? Just to clarify a couple of points from earlier, what additional data from prior cohorts are you expecting to show, if any, at your presentation at ASH? Basically, I just want to get a sense of what metrics to expect beyond what we saw for cohort three. Thanks.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Yeah, two great questions, Tazeen. I'll start, and then I'll turn it over to Iain for maybe additional color. As I mentioned in the question that Ted asked, the abstracts, when they get released by ASH, or specifically the PIONEER pociredir abstract that gets released on Monday, will not have any of the 20-milligram data, and we will not be sharing any of that data until such time as that data gets obviously either presented in the poster session or in the oral session that you mentioned. We'll find out on Monday whether that data has been accepted for an oral presentation or a poster. There won't be any data that we'll share until such time.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

However, there may be an opportunity for us to do a call maybe after that data gets presented, either over the weekend or at some point in the not-too-distant future, so we can provide a little bit more sort of color on that information. Stay tuned for that. I think in terms of additional data, I'll have Iain answer that question, but I do just want to say that the data that we would plan to share, either in that oral or poster, followed by what may be a more sort of type of a video call or a conference call, we would try to be as forthcoming and transparent with the 20-milligram data as we were with the 12-milligram. We'll share with you all the data that we have up until that ASH cut point. If it's only approximately half of the patients, we'll share that.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

If it's all the patients, we'll share that. We'll be very, very specific in terms of what data we have at the different time points for the 20-milligram. In terms of additional data that we'll share on the 12-milligram, Iain, do you want to take that one?

Iain Fraser
Iain Fraser
SVP of Clinical Development at Fulcrum Therapeutics

Yeah, sure. Happy to do that. Thanks, Tazeen. As you will recall, for the 16 patients in the 12-milligram cohort we previously presented at the end of July, the data for the full day 84 treatment period, we did not have the follow-up data. There is a four-week safety follow-up where those patients are no longer on drug, and those data were not all available at that time. That will be presented at the time of the ASH presentation. In addition, we will provide the full safety data set. We did provide all of the safety data that was available at the time of our previous data release, including some AEs that occurred during that safety follow-up period. We will round that out to make that a more complete data set around the 12-milligram cohort.

Alex Sapir
Alex Sapir
CEO and President at Fulcrum Therapeutics

Great, thanks for the question, Tazeen. Shannon, are there any more questions in the queue?

Operator

Currently, showing, no further questions at this time. This does conclude today's conference call. Thank you all for your participation. You may now disconnect.

Executives
    • Alan Musso
      Alan Musso
      CFO
    • Iain Fraser
      Iain Fraser
      SVP of Clinical Development
    • Alex Sapir
      Alex Sapir
      CEO and President
Analysts
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