Fulcrum Therapeutics Inc (FULC) 2025 Q3 法說會逐字稿

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 investors section of Fulcrum's website at www.ulcrumtx.com, and it's 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.

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.

Follow may update these statements in the future, but it's not taking on any obligation to do so.

Please refer to Fulcrum's most recent filings with the Securities and Exchange Commission for discussions of certain risk 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 Allie Musso, Chief Financial Officer, and Dr. Ian Frasier, 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.

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 Poser 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 US 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 crisis, but also very high rates of mortality.

Patients with sickle cell disease face a greater than twenty-year reduction in life expectancy with a mortality rate that is nine times higher than the general population.

And so, 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 12mg dose cohort of the phase 1B 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 pancellular induction of that fetal hemoglobin or HBF.

Improvement in key biomarkers of homolysis 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 one in severity and all resolving during the treatment period without any disruption in study drugs.

These encouraging results achieved our target product profile criteria and position 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 20mg dose cohort with a total of twelve valuable patients, and we'll present data from this cohort at the American Society of Hematology, or ASH conference in early December.

The over enrollment scene in the 12mg and 20mg cohorts is a testament to the enthusiasm from the physicians involved in the study.

Now with a number of these twelve patients starting the drug in September, we expect approximately half of the twelve patients will have completed their day 84 visit and all patients will have completed their day 42 visit at the time of our data cut off for the ASH meeting.

Approximately 60% of the patients enrolled in this 20mg cohort have come from the US, with the remainder coming primarily from sites in Nigeria, which are newer sites that were not yet activated at the in time to participate in the 12mg cohort. The mean and median HPF levels at the start of the study for this cohort. 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.

Evidence for this approach continues to grow as highlighted in our recent presentation earlier this month at the annual conference of 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 12mg 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 one meeting in Q1 of 2026 to align on the next stage of our clinical development for pociredir.

Now outside of pociredir, we continue to advance our program for the potential treatment of bone marrow failure syndromes such as diamond black fan anemia, 5Q deletion syndrome, Schwachman 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 ESO this month for FTX 6274, 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.

And so 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.

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 losmapimod 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.

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 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 cash to the cash used to fund our operating activities.

And finally turning into cash guidance, based on our current operating plans, we expect our existing 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 Bay here.

And with that, Alex, let me turn the call back over to you.

Great, thanks so much, Alan. So 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're 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.

And with the opening remarks concluded, Shannon, let's go ahead and open up the line for questions.

Thank you, Alex. To ask a question at this time, please press *11 on your telephone and wait for your name to be announced. To withdraw your question, please press *11 again.

Our first question comes from the line of Kristen Kluska with Cantor Fitzgerald, your line is now open.

Hi, good morning, everybody. Thanks for taking the questions and for the updates today. So, I appreciate you disclosing the baseline characteristics for this cohort, and it looks pretty similar to what we saw for cohort three. So, 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?

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 Ian because I do think there is a there is a nuance for the approximately 50% of the patients for which we have full day 84 data. But 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 12mg 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 pancellularity. We were seeing all of the markers of homolysis going down as we would have expected, and a subsequent increase in total.

Nearing 1g per liter at the end of that twelve weeks. We saw a trend toward a reduction in BOCs, which obviously we need to confirm in a in a registrational study, and the drug was extremely well tolerated with all of the treatment emerging AEs being grade-1 in severity. So, I would argue that I think we have one with the 12mg cohort. Now, do we expect to see an increase in efficacy?

For the twenty relative to the twelve, 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 HPG mRNA. So, I think based on that healthy volunteer. Data alone we would expect twenty to outperform the twelve, but we will obviously know that in just a matter of weeks when we present this data at Ash and I do think it is probably important to talk a little bit about what we've seen with the Basically the first half of patients that that started on the study and what we plan to present at ASH coming up in December. Yeah.

Absolutely happy to address that question from Kristen. So 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 84day treatment visit at the time of the data cutoff that'll serve the ASH meeting data presentation. And we expect that we should have 42day visit available for all the patients, All twelve patients in that 20mg cohort.

Interestingly, for those patients that have completed the full 84day 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. And so, 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 and then obviously when we release the full 84day data once everybody's completed the full treatment period, that'll reflect the 7.1%. So, I did just want to highlight that piece for the partial cohort data that we'll be sharing later this year.

Okay, thanks for that color. And then 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. So, 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.

Yeah, great question, Kristen, and you're absolutely right. I think that the timing of starting the OLE study was, quite frankly, it was 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 84day and that we really didn't have anything at the time to offer them once the twelve weeks of dosing was up. And so, in light of that, we really decided to kick off this OLE study.

Than we had initially planned in order to allow some of those patients in the Pioneer trial to come off once they come off a drug to be able to roll into an open label extension. So, I will tell you that in the conversations that I've had with the investigators they were quite happy that You know their voice was heard and as a result of their voice being heard, we reacted accordingly in terms of how this, 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?

Yeah, happy to do that. So that 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.

Thanks a lot.

Thanks, Christian.

Next question, Shannon.

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

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 20mg cohort that we'll get data on first and how it compares to the second half of patients who are enrolled.

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

Yeah, and as we said, Joe, the initial patients enrolled have trended lower than that 7.1% mean that reflects the entire twelve 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 times of the day to cut off. 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, but I think it is important just thinking ahead that that overall the trend there was just by chance, the initial patients enrolled in the cohort were on average lower than the 7.1%.

Yeah, and that maybe just to sort of add a little bit on what Kristen said earlier, 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 data before by the time of Ash, we're looking really more like apples to R. And the way to account for differences and baselines is to really look at that fold induction curve. So, that's one of the slides that we've included in our investor presentation comparing the 6mg to the 12mg. So, I encourage everybody to look at that because the fact that these patients, the first half of patients had tended to be on the lower end of that average we'll certainly look at that sort of fold deduction because that is one way to essentially sort of normalize for differences in in in the baselines. But 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 than the 7.1% and the 7.3% that we mentioned in our opening remarks.

Okay, great, thanks for the insight. And then how are you currently thinking about the addressable market following Ori's withdrawal and can you give us some insight into your assumptions that go into your current estimate?

Thanks.

Yeah, it's a great question. So, we really have sort of evaluated the market based on. The data that exists out there in terms of what percent of patients have what have what number of VOCs in the course of a of a given year and our belief is that about 25% of patients have either four VOCs during a 12-month period of time or two VOCs during a 6-month period of time, but obviously because Our drug at present cannot be concomitantly used with hydroxyurea. Some of those patients are currently on hydroxyrhea, and so we've taken a bit of a haircut. So, what we estimate right now is that roughly about 20% of the 100,000 patients in the US currently meet. The inclusion exclusion criteria is defined in the Pioneer trial. Now, 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, but 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 cost and risks and the complexities of that of that therapy. So our overarching goal is 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 US but globally for the $7.7 million patients who have sickle cell disease outside of the US.

Makes sense. Thank you.

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

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

Thanks, maybe to from us if you think about kind of the 20mg dose cohort 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 three dose considering your point earlier that you've kind of already won with 12mg and then what's included in the cash runaway guidance with respect to the scope of the phase three program? Maybe you could speak about duration and end points that would be included in that guidance.

Thank you.

Yeah, great, two great questions. Maybe I'll turn it over to Ian for the first half of that question and then turn it over to Allan for your for your second question.

Yeah, thanks, Corinne. So, I think importantly we'll be looking across the totality of the data in the 20mg cohort, and we obviously would be delighted to see that the efficacy end points in the study are indicating improvements, 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 full induction of HBF based on the induction of HPG mRNA that we observed at 14 days in the prior healthy volunteer study, we do expect that the 20mg dose cohort could well out. That which we observed at the 12mg cohort. I think one of the key learnings from the 12mg data readout as we compare there the 12mg to the previous 6mg readout, I think it really was very important to look at that as a fold induction because the baselines across those cohorts were different and that places, 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 pancellularity. 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. And then overall, we expect, and we'll be looking for continued safety and tolerability as we, as we've observed across both the healthy volunteers and the patients that we've treated to date.

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

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

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

Great, thank you. Good morning, everybody. Thanks for all the detail that you provided.

I'm really excited to see the results down in Orlando in just a couple of weeks. My first question has to do with what do you think is actually going to be published in the abstract release?

And 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 sort of laid out in terms of what you'll be presenting at Ash and do you think that'll be a poster or an oral presentation?

Thank you.

Yeah, great two questions. Yeah, so the abstract that will be made public.

By Ash next Monday, November 3rd, does not include any of the data from the 20 mg cohort. It does include data from the 12mg cohort, but there's no data in the 20mg cohort. It was really a placeholder to ensure that we could get a spot at the at the ASH conference. And then in terms of whether it's a poster or an oral that that will get released by Ash on Monday so, 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. So, stay tuned we'll know more we'll know a lot more on Monday.

Great. And then one quick follow-up if I may, and I appreciate sort of 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 sort of all of these factors, what really is most important both to KOLs, regulators and yourself in terms of really defining the activity of this? Is it, the percentage HbF, is it the percentage of patients above? 20, is it the total Hb? What is really the most important or is it the totality of all of that data?

Yeah, it's a great question, and I'll start, but Ian will probably have a better answer than I will, in the conversation and I've had a lot of conversations with a lot of investigators not only in the US but outside of the US since the data. We released in July around the 12mg and when I sort of pressure tested, you were very, your question with them, which is, if you look across these five parameters, right, increasing levels of fetal hemoglobin, the pancellularity, the decrease in markers of ammolysis, the subsequent increase, number 4, the subsequent increase in total hemoglobin, and then a trend toward a reduction of 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 sort of five criteria are most important to you? And they essentially have all come back to me and said it's really the totality. 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, and we know that the increase in fetal hemoglobin. It's imperative that that happens at a at a pan-cellular level, right? That's one of the sort of knocks on hydroxyurea is that they're not able to get to sort of 70% of all the red blood cells having the presence of that. So, I really think it's each one of those criteria, that we shared in July that they're, that they find, impressed with the overall sort of profile of the of the product in anything.

Oh yeah, sorry, go ahead, please. Oh.

The only thing I would add is that, getting patients into that 20% plus range is obviously associated with really very dramatic benefits in the outcomes of the disease, and I think that's important and what we showed at the 12 mg dose where about half of the patients were able to achieve that, I think is particularly hurting, but I do want to also recognize, and we've heard this as well, is that there are some patients who really have very low baseline HB's in the, 23.4% range, often associated with very severe disease. And for those patients to get right up into the 20% is a much Bigger climb, but providing them with, a threefold induction, an increase over their baseline really is considered to be associated with significant benefit for those patients. So. I think they're both aspects are operational here that we will be able to get some of the patients into that really transformative range and 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 transformed range.

And then lastly, when would we get the final pioneer data set? Do you think that would be all the way at EHA next year?

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

Great, thanks guys. I'm really excited for all the upcoming data.

Yeah, thanks, Ted. So are we. I appreciate the questions.

Shannon, next question.

Our next question comes from the line of Matthew Begler with Oco. Your line is now open.

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 Ian's comments earlier that the Nigerian patient 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 and baseline hemoglobin is just a random variation.

Yeah, it's a great question.

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

To mention okay.

Gotcha. Like maybe a bigger picture question for me is then assuming 20 mg looks good or maybe marginally better than 12 mg, do you keep dose escalating or do you think that 20 mg is your recommended phase two dose?

Yeah, and you want to.

Take that? Yeah, and I think what we've indicated previously is that the current version of the protocol does allow us to dose escalate up to 30 mg. But 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 14day mark when we escalated there from 20 mg to 30 mg. So based on that, along with the promising data that we've already seen at the 12 mg cohort and our expectations around the 20 mg cohort, we're not planning to proceed with that 30 mg dose.

Got it makes sense. I appreciate it.

Yeah.

Thanks, Matt.

.

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

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

Thank you very much.

Yeah, it's a great question, Andres. Ian, you want to take.

That? Yeah, and I think thanks Andreas. I think you know we do have some data from the early part of the study in a less severe patient population, or at least in a patient population that didn't. Have the same severity criteria that the that the 12 mg and the 20 mg cohorts have had. So 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. And we observed, albeit at the lower end of the dosing scales of 6 mg and 2 mg and a few at 12 mg in that cohort that we saw very robust effects on HBF induction. So, we don't expect that there would be a difference in the ability of posterior to induce HBF based on the patient's disease severity, and we have that and then in addition, we have pre-clinical data, CD34 cells differentiated in vitro and so on, showing robust induction of HPF 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 heterozygote, for the sickle mutation and seeing robust induction there. So, we're not expecting that. The disease severity per se is going to impact the ability of posteria to induce HPF.

Right, thank you very much. Yeah, thanks Andreas. Thanks for the question. Shannon, next question.

Thank you. As a reminder to ask a question at this time, please press *11 on your touch tone telephone. Our next question comes from the line of Luca Issi with RBC. Your line is now open.

Oh great, thanks so much for taking my question. Congrats on all the progress. Maybe a quick one actually on safety. Obviously we appreciate that it's 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 and any context there, much appreciated. And then maybe just take a quick one on the plan going forward here.

Just talk about the clinical plan beyond this phase 1b like, should we assume that you start directly registration or trial after this, or is it still possible that you will need to run intermediate phase two before you go into registrational trial? You got any call there, much appreciated. Thanks so.

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

You. Yeah, thanks. And as we've indicated previously in our discussions with the agency, there's obviously a context of risk and benefit, and, 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 one program back to the agency to discuss next steps with them.

There's no specific. Numerical criteria provided around that. Obviously 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 benefits that the therapy is bringing. So, no specific criteria outlined there, but certainly the plan to bring that back to the agency for that discussion. 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 one studies. We do believe that there is the potential for the next study to be. 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. But 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. So, a potential there for an earlier look at the study and interim look potentially where HPF. Could be evaluated as a surrogate endpoint for a potential accelerated approval in sickle cell disease. But 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.

Got it. Thanks so.

Much. Yeah, thanks, Luca.

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

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? And then 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.

Yeah, two great questions to Zan. I'll start and then I'll turn it over to Ian for maybe additional caller. Yeah, so, as I mentioned in the question that that Ted asked, the abstracts when they get released by Ash on or specifically the Pioneer. Poster de abstract that gets released on Monday will not have any of the 20 mg 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 and and we'll find out on. Monday whether that whether that data has been accepted for a for an oral presentation or a poster so there won't be any data that we'll share until such time. 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 in in the not too in the not too distant future so we can provide a little bit more sort of color on that information. So, stay tuned for that. I think in terms of. Additional data I'll have I answer that question, but I do just want to say that the data that we would plan to share either in that or poster followed by what may be a more sort of type of like a. A video call or a conference call, we would TRY to be as forthcoming and transparent with the 20 mg data as we were with the 12 mg so we'll share with you all the data that we have up until that Ashcu point if it's only, approximately half of the patients will share that if it's all the patients will share that, so we'll be very specific in terms of.

What data we have at the different time points for the 20 mg in terms of additional data that we'll share in the 12 mg. Ian, do you want to take that one? Yeah.

Sure, happy to do that. Thanks. So, as you as you will recall for the 16 patients in the 12 mg cohort we previously. Presented in the end of July, the date for the full 84day treatment period, we did not have the follow-up data, so, there's a four week safety follow-up where those patients are no longer on drug, and that those data were not all available at that time, so that will be presented. At the time of the ASH presentation, and 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, but we'll round that out to make that a more complete data set around the 12 mg cohort.

Great, thanks for the question, Tazeen.

Shannon, are there any more questions in the queue?

I'm 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.