Fulcrum Therapeutics Inc Aktie

Good morning, and welcome to Fulcrum Therapeutics First Quarter 2026 Financial Results and Business Update Conference Call. [Operator Instructions] This call is being webcast live and can be accessed on the Investors 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 may include statements about the company's future expectations and plans clinical development time lines 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 an obligation to do so. Please refer to Fulcrum's most recent files with the Securities and Exchange Commission for a discussion 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 full 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, everyone. We appreciate you all joining us today. The first quarter of 2026 was an important and exciting period for Fulcrum highlighted by the positive clinical data we reported from the Phase Ib PIONEER trial of Potero der in sickle cell disease.

Now as a reminder, sickle cell disease is a serious genetic blood disorder with a significant unmet need, affecting approximately 120,000 patients in the United States and millions more globally. Patients with sickle cell disease face a substantial disease burden, including chronic pain and fatigue as well as serious complications, such as vaso-occlusive crises, stroke and progressive end organ damage, all of which result in a substantial reduction in life expectancy of over 20 years.

Now we have known for decades that increasing levels of fetal hemoglobin or HBF and in patients with sickle cell disease leads to improvements in anemia and reductions in vaso-occlusive pain crises. And so it was for that reason that we were so pleased with the data that we reported in February, demonstrating that after only 12 weeks of treatment, 20 milligrams of Potero der taken once daily demonstrated a robust and clinically meaningful increase in HbF from 7.1% at baseline to 19.3% at week 12, along with improvements in markers of hemolysis and improvements in anemia.

We also observed continued progression toward pancellular expression of HBF, which we believe is critical for achieving meaningful clinical benefit. And importantly, we saw a reduction in the number of VOCs we would have expected in this severe patient population with 7 of the 12 patients experiencing no VOCs during the 12-week treatment period.

And importantly, pociredir has continued to be generally well tolerated with no treatment-related serious adverse events reported to date. And so taken together, these data reinforce our conviction in pociredir's potential to address the underlying biology of sickle cell disease. -- and support our belief that pociredir has the potential to represent a differentiated, once-daily oral treatment option for patients.

Now during the quarter, we also initiated an open-label, long-term dosing trial for patients in the PIONEER study, and we recently enrolled our first patient in this new study. All patients in this long-term dosing study previously completed 12 weeks of treatment as part of the PIONEER trial. Therefore, we expect to provide a distinct -- we expect this study to provide a distinct data set offering important insights into long-term safety, durability of response and the effects of reinitiating treatment with pociredir.

We also continue to support initiatives aimed at improving the care journey for people living with sickle cell disease, including our recent collaboration with medical alert and the Sickle Cell Disease Association of America, or SCDAA to help improve access to patient-specific care information in the emergency department setting.

Looking ahead, we are now focused on the next stage of clinical development for pociredir, and we expect to provide an update in the design of our next trial later this quarter following our upcoming end-of-phase meeting with the FDA and receipt of the final meeting minutes. Pending FDA feedback from that end-of-phase meeting, we plan to initiate a potential registration-enabling trial in the second half of 2026.

And so with a strong balance sheet that provides cash runway into 2029, we are well positioned to advance pociredir through the next phase of clinical development. Now before turning it over to Alan, I want to cover the 2 other important corporate updates. First, I want to welcome Josh Lehrer to our Board of Directors.

Josh brings to Fulcrum a deep experience and passion for sickle cell disease as well as a strong track record in advancing transformative therapies in this space, including his role in the development and approval of Oxbrina. We are honored to have Josh joined Fulcrum at this important stage.

And secondly, I would also like to thank Alan for his years of dedication and leadership as he looks towards retirement later in the year. Alan has played a critical role in strengthening our balance sheet and instilling financial discipline across the organization, and we are grateful for his continued commitment to Fulcrum as he remains in his role until a successor is named to ensure a smooth transition.

And so with that, let me now turn it over to Alan to review our financial results and again, I want to thanks...

Thanks, Alex, and thank you for the kind words. It's been a privilege to be part of Fulcrum's progress, and I'm proud of what we've accomplished together. With the impressive results from the PIONEER trial, a talented and motivated team and a strong capital base. The company is well positioned to deliver transformative therapy for sickle cell patients.

I look forward to continue working with the team over the coming months and ensuring a successful transition. And with that, I will now go over our results for the first quarter ended March 31, '21, '26. The research and development expenses were $14.1 million for the first quarter of 20 compared to $13.4 million for the first quarter of 2025. The increase of $700,000 was primarily driven by higher employee compensation costs, including $400,000 of increased stock-based compensation expense.

General and administrative expenses were $8.1 million for the first quarter of 2026 compared to $7 million for the first quarter of 2025. The increase of $1.1 million was primarily driven by higher employee compensation costs, including $300,000 of increased stock-based compensation expense as well as higher professional services costs. The net loss was $22.2 million for the first quarter of 2026 compared to a net loss of $20.4 million for the first quarter of 2025.

Now turning to the balance sheet. We ended the first quarter of 2026 with cash, cash equivalents and marketable securities of $333.3 million compared to $352.3 million as of December 31, 2025. The $19 million decrease was primarily due to cash used to fund our operating activities. And based on our current plans, we expect our existing cash, cash equivalents and marketable securities will be sufficient to fund our operating requirements into 2029, providing runway to advance pociredir through the next phase of clinical development. And with that, I'll turn it back over to you, Alex.

That's great. Thanks so much, Alan. So Fulcrum has reached an important inflection point with the positive clinical data from our PIONEER trial, reinforcing our conviction in pociredir's potential in sickle cell disease. We are focused on the next stage of development and look forward to providing an update on our plans following our upcoming end-of-phase meeting with the FDA.

And with a strong balance sheet and a dedicated team, we believe we are well positioned to advance pociredir through the next phase of clinical development. And so with those brief remarks, Shannon, why don't we go ahead and open up the line for questions.

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

Alan, congrats on your upcoming retirement, and thanks for your excellent stewardship of the company over the years. Alex, as you reflect on the experience gained through Pioneer, what are the most important things you've learned that you might not have fully appreciated going in? And how will those lessen to shape your Phase III design and execution?

Yes. It's a great question, Joe. And I may turn it over to Ian to see who wants to add anything. I mean, I think the 1 thing that I've really learned from Pioneer and talking with a lot of the investigators and hearing from those investigators, the conversations that they've had with their patients is that there continues to be continued high, high, high unmet need in this patient population, especially in the severe patient population that we studied in the PIONEER trial in the severe patient population that we would expect to continue in our next phase of clinical development.

I would say that's learning #1. I would say learning #2 is that there is such a strong connection between fetal hemoglobin and reduction of VOCs. And we've known this for a long time, but spending time as much as I have with people like Marty Steinberg, who has spent decades researching the underlying biology of fetalemoglobin. He said that just so succinctly and he's just so simple in his explanation in that if you can increase fetal-hemoglobin you're going to see a reduction in VOCs, you're going to see an improvement in anemia because of an increase in total hemoglobin because you're seeing less hemolysis.

And so I think it's really to me, Joe, it's those 2 things taken together, 1 related to the unmet need of the patient population. And secondarily is what we think is a very, very profound and robust induction of fetal hemoglobin that's really, I think, what continues to motivate me and make me excited for the next phase of this asset's journey along the clinical development time line.

Iain, you've obviously been pretty deeply involved with Pioneer as well. Anything you would want to add to that?

I think you captured it very well, Alex. It's the severity of the disease and the manifestations experienced by these patients coupled with the really high unmet need in terms of available therapies for the patients. And I think on a daily basis, we continue to be reminded of that.

Okay. Great. And then as you approach discussions with the FDA, what level of evidence do you think they might require in order to consider HPF as a reasonably likely surrogate endpoint for accelerated approval? And how do you plan to position what you've seen efficacy and safety wise for precede so far in terms of that clinical profile to support your case?

Yes, it's a great question, Joe. And obviously, Ian has been very, very deep in those preparation for our upcoming meeting. So I think to answer that, let me turn that 1 over to Iain.

Yes. Thanks, Alex. Thanks, Joe. I think there's really substantial published literature that demonstrates the association between higher HBF levels and improved clinical outcomes in sickle cell disease. And as we've discussed previously and again today, that biological relationship is really a key part of the underlying rationale for our program overall.

Of course, the role that HBF could play in terms of the regulatory framework is 1 that is going to be a topic of discussion with regulators to understand their perspective on the appropriate path forward. Our focus remains on designing a robust study that can meaningfully demonstrate clinical benefit, and we hope to align with the regulators on the optimal strategy around that.

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

Thanks and Alan best wishes on the retirement man. So at the sickle cell disease research symposium, will there be any new analysis that will be presented relative to the 1Q corporate update for Pioneer?

And I know second question, I know that the first patients have been dosed in the OLE portion of the Phase I what portion of the patient from PIONEER went to the OLE? And could we see that update maybe around ASH?

Yes. Maybe let me -- I'll answer the second question, and then Iain, I can turn it over to you to answer the first question. Yes. So we have enrolled our first patient in this open-label long-term dosing for pociredir -- right now, Anupam, we're targeting the 17 U.S.-based patients that were enrolled in either Cohort 3b and that was the 12-milligram cohort or Cohort 4, which was the 20-milligram cohort.

And so right now, really, our focus has really been on getting those sites activated. Unfortunately, this is not your sort of traditional OLE study where patients roll right over, this is considered a new study. And so it has to go through the same mechanics of any new protocol that gets introduced to an institution. So that obviously takes a bit of time.

I think it's a little difficult to project when we would have patients of those 17 patients enrolled in this open-label long-term dosing for pociredir. We don't think we'll get all of them. Some maybe lost a follow-up, some may be in other clinical trials. But I think given what we've heard from investigators in terms of the interest level and going back on therapy, we should expect to see a decent number of that 17%.

If you ask me to try to predict is as possible. I'd say it's probably going to be sometime in 2027 before we would have a critical mass of patients enrolled in order to be able to see a duration of therapy that is going to be a meaningful, interesting and new data point. We've seen what happens to this therapy when patients are dosed for 12 weeks. I think what's going to be really interesting is what happens when patients goes for longer 24 weeks or 6 months.

And so that would probably be the first data set that we would share with folks. And so more than likely, that probably would happen sometime in 2027 as opposed to ASH 2026.

There is a second question.

Yes, yes. This is Iain. I can handle that one. So we've indicated that we expect to provide a full similar parting of the entire PIONEER study. at a medical conference later this year. We have not provided details on that as yet. As we indicated in the press release, the FSCDR symposium oral abstract will include previously disclosed clinical data.

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

And let me also add my congrats to Alan for a great career in biotech and pharma, including the accomplishments at Fulcrum. The first question I had for you was just on broadly understanding the latest views coming from FDA. I know there's been several workshops, including at ASH. I know the team has met with some thought leaders in Washington, D.C. So bigger picture without specifically honing in on Fulcrum's path forward, what's the latest you've been hearing from these thought leaders about how they're thinking about sickle cell disease as an indication, the unmet need and just receptiveness to hearing about new drug classes.

Yes, it's a great question, Kristen. And I'll start, and Ian, you may want to add some thoughts as well. And I'll sort of -- I'll break the question up into 2 pieces. What are we hearing and what are we doing with folks on the hill -- and then what are we hearing and seeing at the I think what we -- and I personally have been spending a lot of time in Washington, D.C., Kristen is referencing a very interesting program that she attended in which we provided a congressional briefing to staffers of senators and congressmen just several weeks ago in Washington, D.C., where we really talked about the unmet need.

We had a couple of patients talk about their journey and it was standing room only and towards certain parts of the meeting, there were very few dry eyes in the house. And so I think that what the politicians understand is that sickle cell continues to be a disease with very high unmet need with shortened life expectancy of 20 years, not to mention during their time here, experiencing very debilitating pain crises and organ damage, leg ulcers, I could go on and on.

And so I think that it's important that the senators and congressmen on the sickle cell disease caucus on the rare disease caucus, on the dock caucus, they understand that and can help sort of lent their support in terms of how high the unmet need is in this patient population. So I'd say that's, I would say, on the -- more on the Hill side.

I think on the FDA side, I would point you to Agios' recent press release that showed that they will be moving forward with filing an NDA in the coming months for sickle cell disease with mitapivat. And we think that what that shows is an understanding of how high the unmet need is and potentially some regulatory flexibility to try to get drugs to patients as quickly as we can. These drugs obviously have to be not only effective, but they need to be safe.

And so we're obviously very excited and looking forward to engaging with the FDA in our upcoming end-of-phase meeting. Iain, anything you would want to add to that?

No, I think you covered the key points really well, Alex. Given the severity of the disease and the unmet need, I think the recent progress in the sickle cell disease landscape is very encouraging for the field, and we look forward to moving forward our program with pociredir.

Yes. And then my other question is just focusing in a little bit more on the open-label extension. Obviously, you want to understand the longer-term impacts on both safety and efficacy. But I'm curious if there are any end points in particular, you're really trying to understand the longer-term efficacy. So are there certain endpoints that maybe take a little bit longer for the benefits to occur where a trial longer than 12 weeks potentially might give you some insight.

Yes, Kristen, that's a great question. I think to answer that, I will turn that 1 over to Iain, who has been deeply involved in the design as well as the execution of the open-label long-term dosing study that -- for which we've enrolled our first patient. Iain?

Yes. Thanks, Alex, and thanks, Kristen. So as we've indicated before, at the 12-week treatment duration with pociredir the HBF levels are starting to flatten out, but we don't believe they've reached their peak level at that point. And so 1 of the outcomes of the study that we'll be very much interested in is to see the progression beyond that 12-week mark.

And then downstream of the HBF as we've seen with other hematological remarks of hemolysis in particular, but also the increase in total hemoglobin that we've seen. Those are probably not maxed out either at that point and with a longer duration of increased HBF, we would expect to see further improvements in those markets. So I think it's looking at how that response plays out over a longer treatment period.

Having said that, I think it is important and Alex alluded to this earlier, that these patients have been off pociredir for some time. So it's not the traditional open-label extension where they roll over immediately into that. So that will be starting from a new baseline, but it's the extended dosing duration in particular, that we're interested in tracking.

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

Congratulations to Alan as well from all of us in terms of the retirement. Maybe a question for us and just kind of the competitive landscape and evolving treatment landscape in sickle cell disease. I guess, could you help us think through the role you expect pociredir play, particularly if there's more kind of oral medications that come to market over the next couple of years?

Sure, absolutely. I'll start, and then Iain, you may want to add some additional points that I maybe leave off. So yes, I think the way we think about this, [ Kristin ], is there's sort of -- and it's interesting. This market is 1 that I think will grow exponentially over the next 5 to 10 years. If you look at just the sheer number of drugs in development for the treatment of sickle cell disease.

This is a market -- a very large market that has been underserved for years and years. And so I think the way that we see this market evolving is very much towards the oral treatment options. And there's really -- to us, we think about this as sort of 2 different approaches.

One is sort of operating downstream on the mature red blood cells like the PK activators to -- and the second is operating more upstream when those red blood cells are being formed in the bone marrow and ensuring that those red blood cells have enough fetal hemoglobin as they're being formed because once those red blood cells have enough fetalemoglobin and our form that do get spit out of the bone marrow.

Those red blood cells cannot and will not sickle. They maintain their soft flexible shape, thereby preventing vaso-occlusive crises, they have a lifespan of about 120 days versus a 30-day lifespan for a sickled hemoglobin -- and so for us, we think that really attacking the upstream underlying cause of the disease as we're doing with pociredir -- we believe that, that will ultimately be the treatment of choice as we look over the next 5 to 10 years as this market evolves, now where we are in relation to some of those other fetal hemoglobin inducers.

Conservatively, we believe that we have about a 24-month head start over the next closest competitor, and that next close is oral HBF inducer would be BMS's product, BMS 986, which is a wiz a dual degrader Wiz and ZBTB 7(a) or LRF for sure. So there They'll be -- they're currently in the clinic in a Phase I study, and they expect to announce the results of that Phase I study sometime in, I think it's the first quarter, the first half of 2027.

So we'll be well underway we believe with our Phase III study, while the next closest competitor, BMS, is reporting out their Phase I study results in 2027. And so maintaining that 2-year head start, so that when we come to market, we can have this market essentially without other oral HBF competitors, we believe that that's an important consideration that we want to make sure that we maintain that 24-month head start.

Iain, anything else you would want to add about the competitive landscape and how we see this market evolving over time?

I think you mentioned the key point, Alex. I think the focus of the PK activators is on the increases in total hemoglobin, resulting from a decrease in hemolysis and agree that the HBF mechanism, I think has emerged as a more central, more upstream mechanism to address more widely manifestations of sickle cell disease. I think we're seeing that reflected in the interest in the clinic in sponsors that are bringing forward oral HBF inducers.

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

And I'll add micrographs as well, Alan. Maybe just 1 sort of kind of on the competitive landscape and all these regulatory dynamics. Novo recently hit on a VOC endpoint. And -- just curious if you think that changes anything at all as it relates to the potential regulatory path for you? And if a drug were to be approved on VOC, does that sort of change what the FDA may be open to approving as it relates to the endpoints that are not a VOC endpoint? Just curious your perspectives there.

Yes, James, great question. Maybe just to orient everybody, they did have co-primary, total hemoglobin and VOCs and they hit on that. It was a 27% reduction in vaso-occlusive crisis. So very similar to the percent reduction in VOC that we saw with another product that's currently approved and generally not widely used a product called El glutamine that's all a 25% reduction in VOC.

So I wanted just to make sure that everybody was on the call was oriented to specifically what James was talking about. Iain, maybe I'll have you sort of take the heart of James' question, which is really around if there's any potential sort of read-through with pociredir and our path forward. Iain?

Yes, I think the fact that VOCs is an important clinical endpoint that I think remains the case. I don't think there's any change in that. I think as we've discussed before, the literature associating increases in fetal hemoglobin with reductions in VOCs certainly remains the case. And given the magnitude of HBF induction that we've seen in the PIONEER study to date, both at the 12 and the 20-milligram doses we would expect that, that would translate into a VOC benefit. And I think that remains an important clinical end point.

Our next question comes from the line of Matthew Biegler with Opco.

Congrats to you, Alan as well. Maybe just piggybacking on some of the -- an earlier comment that you made, Alex. I'm thinking about maybe potential future combination strategies here. And you mentioned PKR activators and some of the other downstream treatments where you guys are more upstream and maybe that makes logical sense.

So it sounds to me like maybe there might be a better partner for you than hydroxyurea. Have you given any thoughts to that?

Yes. It's a really good question, Matt. Ian, I may turn this over to you, but I think just maybe just a couple of initial thoughts. So hydroxyurea has been approved now for coming over 40 years. It is clearly the mainstay. I think that patients at times aren't crazy about it. It doesn't have a great sort of adherence to drug because of some of the side effects associated with it. But despite that, it is very much the main stand.

So I think our long-term development strategy has always been to figure out a path forward for us to be used in combination with hydroxyurea. We don't believe that, that will be part of the design that we will reach agreement on with the FDA as part of our upcoming end of phase meeting with them. But we do see that as an important part of the ongoing clinical development program for pociredir.

Yes, I think, Iain, maybe if you want to take kind of maybe just beyond HU, is there the idea of possibly combining an HBF inducer with potentially a PK activator or potentially operating on different mechanisms and potentially seeing greater efficacy than either 1 could achieve on their own.

Yes, absolutely. I mean we've certainly seen that in other fields, and that certainly remains a potential in this disease, which has so many manifestations that are so severe. I think as we think of those, however, our primary objective at the moment really is to generate an interpretable data set with pociredir that will support its registration.

And I think understanding in the context of monotherapy is really the first step in that journey so that we really have a full understanding of that and that we could then give serious consideration to how do we evaluate potential combination therapies down the road?

Yes, I think that's well said, Iain.

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

My congratulations to Alan on his service at Fulcrum and in the industry. I know, of course, the focus is on Posera there, but I'm just curious when you see the time being right to potentially advance or nominate some of the discovery programs and think about the novel HBF inducers that you may have in the library.

And then maybe secondarily, as we think about the FDA meetings upcoming, can you just give us an update on the engagement plans with respect to EMA and the global development.

Sure. I'll take the first question and Iain. I'll turn the second question over -- actually, Iain, why don't you -- if you want, do you want to take the second question first?

Yes. Yes, happy to do that. Thanks, Greg. So as we've indicated before, the context of a registrational sickle cell disease study is likely to be a global study and we've indicated that we will be interacting with EMA later this year as part of that process. So that's certainly the first step on looking more globally and getting additional feedback on the program.

Yes, it's great. And then yes, I think, Greg, in terms of your first question, our discovery efforts, we're a company of about 60, 65 people, we've got 20, 25 people focused entirely on discovery. And then within their discovery work, they are focused entirely on developing the second, third and fourth generation oral HBF inducer.

And so that has really been our key area a focus because we, again, going back to something that I said earlier, we do believe that this is a market that ultimately will be dominated by oral fetal hemoglobin inducers because of the reasons that I mentioned earlier. And so we're thinking about how can we develop a product that potentially could cannibalize pociredir once it's eventually hits it's the market.

I think at this point, it's a little bit premature, Greg, to how to estimate when we would start seeing things coming out of our discovery efforts and conducting those IND-enabling studies. But I will say that in the coming years, what we believe we will see is a number of new INDs almost entirely focused on trying to come out with an even better oral HBF inducer than what we currently have with pociredir given how we see this market evolving over the next 5 to 10 years.

And I'm currently showing no further questions at this time. Thank you, everyone, for your participation on today's call. This does conclude the conference. Thank you, and you may now disconnect.

Good morning, and welcome to the Fulcrum Therapeutics conference call to discuss 12-week data from the 20-milligram cohort of the Phase 1b PIONEER trial of pociridir in sickle cell disease.

[Operator Instructions] This call is being webcast live and can be accessed on the Investors section of Fulcrum's website at www.fulcrumtx.com, where a replay will be available. I'll now turn the call over to Alex Sapir, CEO and President of Fulcrum Therapeutics.

That's great. Thanks so much, Gigi, and good morning, everybody, and thank you all for joining us on the call. So, for those of you who know this management team well, you know we are not ones to use superlatives all that often. But this morning, we are very, very excited to share with you the full 12-week data from the 20-milligram cohort of the Phase 1b PIONEER trial, building off of the strong data that we presented at ASH in December of last year. This data set has been years in the making, and we simply could not be more pleased to share it with you this morning because of the potential that it has to help many sickle cell patients around the world.

So before we jump in, I do just want to remind everybody that today's presentation does include forward-looking statements, which are based on current expectations and subject to risks and uncertainties. Actual results may differ materially, and we encourage you to review the full disclaimer on this slide, together with the risk factors in Fulcrum's most recent filings with the FCC.

I'd like to start by welcoming our guest speaker today. We're very fortunate to be joined by Dr. Martin Steinberg, who is also with us when we presented the interim data at ASH last December. Dr. Steinberg is a Professor of Medicine, Pediatrics, Pathology, and Laboratory Medicine at Boston University School of Medicine. It is his pioneering work that has helped shape much of our modern understanding of sickle cell disease biology and clinical care. Thank you for joining us this morning, Dr. Steinberg.

Welcome.

Thank you. I'm also joined by Iain Fraser, our Head of Clinical Development;, and Alan Musso, our CFO. Many of you know Alan and Iain quite well. So here's the agenda for the call. I will provide some brief introductory remarks. Iain will then quickly provide an overview of sickle cell disease and the clinical relevance of HbF, and then take us through the clinical data from the 20-milligram cohort in some detail. Next, we'll turn to Dr. Steinberg for his expert perspective on the clinical data and what this means for his patients and for the field in general. And then lastly, we'll open it up for Q&A.

So let me start with a high-level takeaway of the data that Iain will walk through in just a couple of minutes. With 20 milligrams of pociredir dosed over a 12-week period, we are seeing rapid and robust HbF induction with a 12.2 mean absolute increase beginning from a baseline of 7.1% and ending at 19.3% at week 12. Importantly, more than half of the patients achieved HbF levels at or above 20%, a threshold historically associated with clinically meaningful protection.

We're also seeing progression towards pancellularity alongside reductions in key markers of hemolysis, resulting in a greater than 1 gram per deciliter increase in total hemoglobin after only 12 weeks of treatment. At the same time, we continue to observe encouraging trends in vaso-occlusive crisis reduction over the 12-week treatment period, with 7 of these 12 severe SCD patients reporting no VOCs.

And finally, pociredir continues to be generally well tolerated at this higher dose. Taken together, the 20-milligram data reinforce our belief that pociriedir is demonstrating the biological profile we would expect from a best-in-class oral HbF inducer for sickle cell disease. And so with that brief overview of the data, I'll now turn it over to Iain to walk through the data in some more detail. Iain, I'll kick it over to you.

Thanks, Alex. This slide, which is familiar to you all on the call today, is a reminder that sickle cell disease is a debilitating, life-threatening condition that affects millions of individuals globally. Importantly, there remains a very significant unmet medical need. In spite of advances in clinical care, mortality rates remain elevated, and overall life expectancy is reduced.

Similarly, the next slide you have seen before, again, just to emphasize that fetal hemoglobin or HbF has long been identified as an important modulator of disease severity in sickle cell disease. As HbF levels increase, the number of VOCs reported by patients on an annual basis decreases, and even modest increases in HbF have been associated with reductions in the frequency of these VOCs.

We turn now to the PIONEER study 20-milligram cohort itself. This is the overview of the trial design. And today, we're providing an update to the partial cohort data that was previously presented at ASH in December of 2025. We'll be discussing today the full 12-week treatment period from the 20-milligram dose cohort, which represents a data cutoff of December 23, 2025. The main highlight that I want to mention here, as we move into the data itself, is that on the bottom left, the inclusion criteria for these patients indicate a very high degree of disease severity in the sickle cell disease patient population.

Moving to the disposition of patients across the study. There were 13 patients enrolled. There are 12 evaluable patients in the pharmacodynamic analysis subset. We had previously disclosed discontinuation due to a death on day 1 of the study for one of the individuals. This was deemed unrelated to the study drug. The main feature that we'll be discussing today is that we have data now for the full 12-week treatment period. At the time of the ASH presentation, we had full data for the cohort only through week 6 of treatment.

Going to the next slide, the baseline characteristics. Since this is the baseline, this is exactly the same as we presented at ASH. Again, you'll see that the cohorts of 12 and 20 milligrams are quite well matched. There were fewer males in the 20-milligram cohort than in the 12-milligram cohort. And as we previously discussed in the 20-milligram cohort, there are fewer patients from South Africa, just one patient, and there are now patients from Nigeria who were not enrolled in the 12-milligram cohort.

We just focused briefly on the baseline fetal hemoglobin. The 12-milligram cohort came in at 7.6% baseline. The 20-milligram cohort was similar, but slightly lower at 7.1%. Similarly, baseline hemoglobin, 7.8 in the 12-milligram cohort versus slightly lower at 7.3 grams per deciliter in the 20-milligram cohort. And then lastly, baseline VOCs represent a slightly more severely impacted patient population at 20 milligrams.

Go to the next slide. This shows the increase in fetal hemoglobin that occurred across the 12-week treatment period. On the left-hand side of the slide, you will see that the increase in the 20-milligram cohort was from a baseline of 7.1% to a 12-week mean of 19.3%, which represents a delta of 12.2% for the entire cohort over the 12-week period. I do want to highlight that, for the 20-milligram cohort, unlike the 12-milligram cohort, there were no transfusions in patients in this particular cohort.

We turn now to the patient-level slide. This shows each individual patient in the cohort, stacked by their increase in HbF across the 12-week treatment period. What you will see here is that all 12 patients showed substantial increases in HbF and that 7 of the 12 patients, or 58%, achieved at least a 20% absolute level of HbF at the time of the 12-week cutoff. All patients in the 20-milligram cohort showed an increase of at least 6.5%.

Turning now to the F cells at the 20-milligram cohort, what we see is a doubling of the F cells from a baseline of around 31% to a 12-week percentage of 63%. I do want to make an important comment about the time point from week 10 to week 12 and the dip that we are seeing there is a factor of the fact that not all patients are represented at every time point and that two patients who were represented at week 10 with relatively high F-cell percentages of 63% and 57% who were not represented at the 12-week time point and I think that likely accounts for the dip that you're seeing there, but nonetheless, all patients responded in terms of an increase in their F-cell percentage, and overall, we see at least a doubling over the 12-week treatment period.

We then move on to other markers that are associated with the increase in HbF in these patients and what we're seeing here on this slide are markers of hemolysis: LDH on the left and indirect bilirubin on the right. You'll see a 34% reduction in LDH and a 40% reduction in indirect bilirubin at week 12. This is consistent with the reduced hemolysis that is occurring in these cells as a result of the increase in HbF. I do want to comment here that the 20-milligram cohort did have slightly higher baselines for both markers, again reflecting the slightly increased severity of the 20-milligram cohort versus the 12-milligram cohort.

The next slide looks at markers of erythropoiesis and red cell morphology. What you see at the 20-milligram cohort is a 42% drop in reticulocytes. We will see the increase in hemoglobin on the next slide. The reduction in reticulocytes reflects a reduction in the bone marrow stress that is caused by hemolysis. As hemolysis decreases, there is less stress on the bone marrow, and the reticulocytes decrease accordingly. We also see on the right that the RDW, which is a measure of the heterogeneity of red cell size, is essentially normalizing, which is what we saw in the 12-milligram cohort, which indicates a more uniform red blood cell population.

Then as mentioned before, if we look at total hemoglobin, we see here that at 20-milligram cohort at week 12, we are seeing a 1.1 gram per deciliter mean rise in total hemoglobin versus 0.9, 12-milligram cohort. On the left, you see that the absolute value was lower for the 20-milligram cohort, again reflecting the severity -- increased severity of that 20-milligram cohort population, but you can see the rise that occurs over the 12-week treatment period. And again, I would emphasize that in the 20-milligram cohort, unlike the 12-milligram cohort, there were no patients with transfusions during the treatment period.

Turning now to the VOCs, or acute events, we have indicated this before. We capture baseline VOCs as part of the [inclusion] [indiscernible]. What we are seeing here is that 7 of the 12 patients in the PD analysis subset had no VOCs at all during the treatment period, despite having a high level of baseline VOCs coming into the study. Study is not powered for VOCs, but this trend is obviously encouraging, and we observed this trend in the 12-milligram cohort. The expected VOCs based on the baseline VOCs reported by these patients was in expectation 16 events over 12 weeks, and we observed 6 in 5 patients during the treatment period.

Turning now to safety, pociredir at the 20-milligram dose continues to be generally well tolerated, with no treatment-related serious adverse events. Overall, the pociredir safety profile similar to that described in the December 2025 presentation. There were three patients with treatment-related adverse events. All of these resolved with continued dosing of pociredir, and we have mentioned some of the details of these patients previously. Again, we will note that with the updated 20-milligram cohort, there have been no discontinuations due to treatment-related adverse events.

The next slide looks at the 12-milligram and the 20-milligram cohort next to each other. I think at a very high level, the adverse event profile that we see is consistent with what you would expect in a severely impacted sickle cell disease patient population. There have been no dose-limiting toxicities and no treatment-related discontinuations. An overall, pociredir has been dosed in almost 150 adults to date.

And then just to wrap it up, I would like to take a step back and evaluate the totality of the data that we presented today as we move left to right across this slide. What I would emphasize is that what we are seeing at the 20-milligram dose is not really a collection of isolated data points, but rather it reflects an expected biologically relevant cascade of events that you would expect with a drug that increases fetal hemoglobin.

So we start with a robust induction of HbF on the far left, reaching a mean of 19.3% at week 12, and with more than half of the patients achieving an HbF level of 20% or higher. As HbF rises across a broader population of red cells, we expect there to be more of the red cells protected as a result of now having fetal hemoglobin within them and that is what we see as we see markers of hemolysis reduce.

With less hemolysis, we also see a normalization of erythropoiesis and improvements of anemia with approximately a 1 gram per deciliter increase in total hemoglobin. And ultimately, while exploratory, the VOC trends that we've observed to date in this relatively short-term study are consistent with this overall biological framework. So importantly, the clinical signals that we're seeing align very nicely with the mechanism of action of induction of HbF and on the biology of sickle cell disease.

With that, I'd now like to turn the call over to Dr. Steinberg to provide his expert perspective on the clinical data for pociredir and its potential for treating sickle cell disease. Dr. Steinberg?

Yes. Thank you very much, Iain, for presenting these data. So I think generally, all experts in the field believe that enough fetal hemoglobin in most sickle cells can cure or greatly ameliorate the phenotype of sickle cell disease. So gene therapy could do this, but for many reasons, of course, it's ineffective because it can't reach a population of patients and it's unlikely to do so for a very long time, if ever. So the major unmet need for treating sickle cell disease and other beta hemoglobinopathies is an orally available agent that will induce high levels of fetal hemoglobin. I think these results are very impressive because they suggest strongly that this drug will be efficacious and decrease both acute vaso-occlusive events and the hemolytic anemia of sickle cell disease. So the standard of care now in sickle cell disease is hydroxyurea, which has started before the end of the first year of life with excellent results at least in very youngest patients.

I think it's useful to compare the results that Iain suggested with the multicenter study of hydroxyurea trial. Hydroxyurea, of course, the standard of care. And the trial is one of the few studies where the drug was administered under controlled conditions. And this is the trial that led to FDA approval of hydroxyurea. And at the end of the study, in all 150 patients, fetal hemoglobin increased to about 10% with about 35% F cells. And this was in the totality of the patients. And the reason for this, of course, is that the patients responded differentially to hydroxyurea. Now the whole group had about 0.5 gram increase in fetal -- in total hemoglobin and the acute sickle cell-related vaso-occlusive events decreased by about 50%.

Then the pociredir study at 12 weeks, fetal hemoglobin was about 20% F cells, a little bit more than 60%. If you look at the MSH study, and divide the people into quartiles, this is about equal to the highest quartile of hydroxyurea treated patients in the MSH after 12 weeks. So in this top quartile of responders, which is the most stringent comparative for the pociredir trial, they had about 20% F and about 60% F cells. Of course, over time, the amount of F cells increased because they continued to get the drug and F cells have a preferential survival. And these results are similar to the 20-milligram cohort. Now the thing to remember is the 2 lowest quartiles of the MSH trial had little long-term increment in fetal hemoglobin.

Now I think the key difference between these trials is in the MSH trial, the mean corpuscular volume and mean corpuscular hemoglobin increased by about 16% in these high fetal hemoglobin responders, whereas in the pociredir trial, they increased somewhere around 5%. And therefore, the importance is that similar mass fetal hemoglobin concentrations, the hemoglobin F per F cell in pociredir patients is higher. And I think this is critical because in our analysis of the cooperative study data and MSH databases, it's F -- the F cell that's associated with the reduction in acute vaso-occlusive events, less hemolysis and reduced mortality. In addition, the pociredir trial that Iain reported gave the results of all patients. And many of these patients are likely to have CAR haplotypes of sickle cell disease.

And in the MSH trial, it was the absence of this haplotype that was associated with better fetal hemoglobin response. So I think the takeaway point is that if these results are replicated in late phase clinical trials. Pociredir could be used as a first-line stand-alone therapy. Now as its mechanism of action is different from hydroxyurea, it could also be part of a combination chemotherapy where there might be synergistic or additive effects. And I think its tendency towards pancellularity, which we're seeing to be especially useful as the increase in fetal hemoglobin caused by hydroxyurea is heterocellular, which is less efficacious than a pancellular distribution. So I'm excited by these results because of the possibilities that they will give us for additional fetal hemoglobin inducing agents, which at this moment in time is the way to impact the phenotype of sickle cell disease in a clinically important manner. Thank you.

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

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

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

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

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

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

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

Yes, absolutely. And you may recall from the 12-milligram cohort where we had a number of patients from South Africa who, in fact, turned out to have originated in the Democratic Republic of Congo, where we know epidemiologically, there's a very high prevalence of the CAR haplotype or the CAR allele that Dr. Steinberg referenced earlier. And we noted that 5 of those 6 patients in that cohort tended to have lower responses in their HbF. We have gone back and we're looking at haplotyping those to get the actual genetic data, but that was an epidemiologic observation.

In the 20-milligram cohort, we had just the one patient from South Africa and enrolled more patients from Nigeria. Epidemiologically, we know that there's more heterogeneity across the haplotypes in Nigeria. And in some ways, that's more representative, I think, of the heterogeneity that you see within the U.S. We did not have any patients who were expected to be of the ArabIain IndIain haplotype, which is the opposite end from the CAR. So those are the ones with the highest baseline HbF and the best responses to HU. We do not expect that there were any of those patients enrolled here. And so I think the 20-milligram cohort likely represents a sort of middle slice, if you like. It's not over on the low end and it doesn't [indiscernible] high end. So I think 20-milligram likely more representative of the sort of global population.

Very helpful. Thank you.

Thanks Joe, Gigi next question.

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

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

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

Yes, absolutely. Thanks, Anupam. I think that's a really important question. HbF induction is the primary mechanism of action here, and that's the sort of proximal effect and we capture that as we measure the HbF increasing in these cells. As HbF increases in cells and there are more cells in the circulation that have increased levels of HbF, those cells are relatively protected against hemolysis, their lifespan increases. And so the population changes over time. Some of the more immediate effects include the reduction in hemolysis, which are reflected by the LDH and the bilirubin. And those are sort of more immediately downstream, if you like, from the HbF, and we see those markers coming down.

Importantly, there are other sources of those particular markers. LDH, of course, associated with tissue damage as well. And so that might have an impact on how those particular markers move and the bilirubin impacted by the liver function in addition to the hemolysis. So I think those are 2 comments there. As we look at some of the other markers, essentially a normalization of the RDW, which I think is encouraging that goes down to levels that are more or less normal. And then with the reticulocytes, you see them coming down quite dramatically. They don't reach baseline levels. And if you look even at the successful gene therapy patients, even out to, I think, about 2 or 3 years after that gene therapy, those reticulocytes don't normalize completely to baseline.

So there might be something about the biology there. And then lastly, with the total hemoglobin, that sort of -- view that as the end of the cascade, if you like, and that needing to reflect increased populations of cells with fetal hemoglobin in the circulation, greater protection and allowing it to reach a new steady state. And so I think those are all expected to be lagging indicators behind the HbF. They may take longer to see the full manifestations of the effect.

Thanks so much for taking the question and congrats again.

Thanks Anupam, Gigi next question.

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

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

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

Yes. Yes. Thanks, Kristen, for the question. Based on the strength and the consistency of the data that we've generated to date, with the robust induction of HbF and this progression towards a broader pancellular distribution along with the improvements of biomarkers of hemolysis and anemia, we really think that it's appropriate to advance into a study with the potential to be registration enabling. And that will certainly be a topic for our discussion with the FDA at the end of Phase meeting. Of course, there is substantial published literature that demonstrates an association between higher HbF levels and improved clinical outcomes in sickle cell disease. And that biological relationship is obviously a key part of the underlying rationale for our program.

And of course, whether HbF could play a role in an accelerated approval framework will ultimately be a regulatory determination, but we very much look forward to discussing the totality of the PIONEER data set with the FDA in order to understand their perspective on the appropriate path forward.

And then, Kristen, in terms of -- in terms of the TAM, I think from a regulatory standpoint and from a probability of clinical success standpoint, I think certainly studying a more severe patient population like we have here helps from not only a powering standpoint, but also helps from a probability of clinical success. If you have a patient with 4 VOCs seeing a 25% or 50% reduction down to 3 or 2 is going to be easier to achieve compared to a patient that may only have 1 to 2 VOCs, so a less severe patient.

I think our assumption as well is that if we were to study a more severe patient population, ultimately -- and that severity is measured by the number of VOCs, I think it would be pretty unlikely for the label and specifically the indication statement in the label to specify the number of VOCs.

Now it may say something along the lines of for the treatment of sickle cell disease for patients with recurrent vaso-occlusive events or vaso-occlusive crises, or the qualifier could be for the treatment of patients with severe sickle cell disease. And I think really in either one of those cases, I think then it's really left up to the physicIain to have that conversation with the payer and demonstrate to the payer that this patient represents a severe patient or a patient with recurring VOEs, regardless of the number of VOEs that, that patient has had within a -- within a given year. So that's kind of how we're -- that's kind of how we're thinking about the approach the next study, and the impact that that may -- that approach may have on the overall total addressable market.

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

Great question. So, what I can say is that the percent of the patient-- of the patients who currently meet our inclusion/exclusion criteria, we believe it's around 20%. If the label was specific in terms of recurrent VOEs or patients with severe disease, that 20% would obviously go up much higher than the 20% that we're currently studying. And I think it really goes back to, I think, a point that Iain made in one of his first introductory slides.

This is a very severe disease. Patients have -- patients with severe -- with sickle cell disease have a 9x greater chance of mortality, and 20 years are typically shaved off of their life. So, this is in whole, sickle cell disease is a very, very severe disease to begin with.

Gigi, next question.

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

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

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

Sure. Well, yes, I would expect that it's going to increase. If you look at the results of the MSH trial that I referred to. At 12 weeks, they similarly had about 60% F cells, but it increased over time to over 85%. And we know, of course, that the mechanism of F cell induction in hydroxyurea is different than the mechanism of F cell induction with pociredir. So, I think this provides some optimism that over time, the F cell levels is going to increase and there will be increased in the cellularity.

And these F cells not only have fetal hemoglobin in them, but have important levels of fetal hemoglobin in them enough to protect them almost fully from sickle hemoglobin polymerization. Because in F cells all F cells aren't alike. You could see an F cell because it has some fetal hemoglobin in it. And whatever it has is protective, but not protective enough. And this is the reason to try to achieve both pancellularity with a concentration of fetal hemoglobin that protects the cell nearly fully, as the cells in successful gene therapy treated patients are. And you can see the results from those patients.

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

Thanks, Matt. So, in response to the second part of your question, we will not get those data -- the missing data that was mentioned earlier. This particular assay is performed at a single site, and there have been some logistics around shipping of samples to the analysis sites that have caused the data to be not represented of all patients at all time points. And so that's just a feature of that particular assay at this particular time point.

But I do want to emphasize that the 2 patients that were missing at week 12 had a 63% and 57% F cell percent at the week 10 mark. And so we're contributing to that somewhat higher F cell percent at that time point. In addition, there were 2 patients who were represented at week 12 with rather lower-end HbF, so 38% and 35%, respectively, but who were missing at the week 10 time point.

Those 2 patients, the 38% and 35% started out from baseline that were below 15%. And I think that's perhaps the important message across the entire cohort that even those with low baseline F cell percent responded. So, we're seeing a response in F cells across the board in these patients, and that the numerical value at individual time points is somewhat sensitive to the missing data, as I alluded to earlier.

Thanks Matt, Gigi next question.

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

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

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

Thanks, Corinne. And based on the first question, so what we've articulated previously is even at the 12-milligram cohort based on the robustness of the increases of HbF and the consequent hemolysis and anemia biomarkers that we saw downstream of that, we felt very comfortable that those were robust and relevant responses that we were seeing. The 20 milligram certainly expands upon that, and we're very encouraged by that.

The PIONEER protocol did allow for an increase to a dose as high as 30 milligrams once daily. That dose had been explored previously in our first-in-human study in healthy volunteers. We observed as a pharmacodynamic biomarker in that study, the HBG mRNA, which is the gene that encodes HbF. We saw inductions of HBG in a dose-responsive fashion all the way from 2 milligrams up to 20 milligrams at each of those dose increments seeing an increase in HBG mRNA at the 2-week mark. As we went from 20 to 30, we did not see further induction there.

And so based on the robustness of the clinical data in the sickle cell disease patient population in PIONEER at the 12- and the 20-milligram dose, and the lack of incremental HBG1 mRNA induction earlier on, we decided not to go further on to the 30-milligram dose.

That's the first part of the question. Second part of the question relates to the individual patients who achieved a higher level of HbF earlier on. We've gone back and looked at all the individual data. This is an anomaly in terms of the overall trend of HbF across the patients across the entire PIONEER study, where we have not seen declines in HbF occurring during the treatment period. There's been no clear explanation for that, no clear lab error or mixup of the data. I think it's just likely a reflection of small numbers of patients and some variability in the assay that contributed to that. But I would remark that, that patient started out with a baseline of around 8%, ended up at 29%, which by any measure is a very robust induction of HbF. So I think that small difference to the 34% and the 29%, we don't consider that to be clinically meaningful.

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

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

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

We believe right now that conservatively, we have about a 2-year head start over the next competitor. That's probably coming from the WIZ degraders. And so we want to do everything we can to maintain that 2-year head start before other players enter into the -- enter into the market. So we will be taking the 20 milligram. We're very excited about the 20-milligram data and the 20-milligram dose is the dose that we'll be recommending that we take forward in discussions with the agency that we're planning to have sometime in the first half of this year.

Gigi, next question.

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

Hey! Thanks for taking my question and congrats on the data. I just had one on sort of safety. I know that the cutoff here is late December. So presumably, there's some additional kind of safety follow-up. And -- just curious if there's any color you can provide kind of beyond sort of what we've seen in this deck.

And then more broadly, this drug has been studied in a lot of people now and just curious sort of your comfort that this is enough of a data set you think to get the FDA comfortable with kind of expanding the study population here kind of over time. Thanks so much.

Sure. Iain, do you want to take those?

Yes, absolutely. And I think, James, even though data cutoff is 23rd of December, we do get safety information in real time. And if there were any important safety events that occurred after the data cutoff, those would be relevant and we present those. So we don't have any untoward safety events that we have become aware of through that process that need to be reported. So I think we're -- we remain comfortable that the overall generally well-tolerated profile that we've seen with pocerdir at the 20-milligram cohort, similar to that at the lower doses with no dose-related toxicities that we've seen.

So I think that, that's the key feature around updated safety, if you like. The second question relates to broadening the patient population and how comfortable do we feel about this. I think the important thing to recognize here is not only the disease severity of sickle cell disease, but also the unmet need that exists for patients. And we've seen despite what were some encouraging developments over the past several years. We've seen those being peeled back now. And so patients have fewer therapeutic options available to them now than they did just a few years ago.

So I think it's very important to contextualize moving forward with an encouraging therapy in terms of the severity of the disease and the unmet medical need and we certainly feel very comfortable about at least proposing our move forward into a registration-enabling study as part of our discussions with the agency. And naturally, that will be an important topic for our discussions upcoming with them.

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

Well, I think it's huge. We only have hydroxyurea that has shown sustained disease-modifying effects over many years and even over a lifetime in some patients. And we also know the heterogeneity of response to hydroxyurea. And as a single therapy, it's almost never good enough. There's patients who even are good responders to hydroxyurea because of the heterocellular nature of the response, continue to have severe sickle cell-related events and increased mortality.

Now the whole field of developing agents that work downstream of polymerization, and this includes [indiscernible], voxelotor, crizanlizumab, mitapivat, they've all had really unimpressive effects. It's not that there isn't -- given our current dearth of therapy, there's some role for these drugs as adjuncts to hydroxyurea. And I've written about this and discussed this in the past.

But what we really need is better ways of inducing more fetal hemoglobin and more red cells. And so that is -- obviously, the industry has taken this to heart and the most promising developments are agents like pociredir and who knows about the molecular glue degraders, but they are also show to have the potential being important agents.

So I think the unmet need is great and oral agents are the way to go if any type of therapy is going to be effective.

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

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

Great. Thanks Alex [indiscernible] congratulations on the updates as well, and I appreciate you are taking my question. Alex, as you're looking towards a potential registrational trial and certainly international implications when it comes to trialing and exploring next steps.

Just curious if you can comment perhaps on how you're thinking about just optimizing the strategic value of pociredir globally, this may be the time to think about the best way to perhaps penetrate commercially to do that work internationally. I'm just curious how you're thinking about going global, especially with markets of high unmet need ex U.S. Thanks so much.

Yes. Great. Really, really good question, Greg. And maybe just to orient folks. So what we know, and Iain talked about this at the outset, about 7.7 million patients worldwide with sickle cell disease. A lot of those patients exist in Sub-Sahara Africa. In the U.S., about 100,000, although we actually have done some research, which I think it could actually be closer to 125,000 in the U.S., about 50,000 in Europe.

We are in the process of operationalizing that Phase III study, and we're obviously doing a lot of that work right now at [risk] because we've yet to have guidance from the agency in the form of those -- in the form of those meeting minutes. And obviously, that global study will include not only sites in the U.S., but many sites in Europe, potentially some sites in Sub-Sahara Africa, like Nigeria.

And we feel that, that sort of having this to be a global study will certainly give many other physicIains besides just the physicIains in Nigeria and the U.S. that have had experience with pociredir. We really feel that that will give many more physicIains the opportunity to have experience with this drug in a clinical trial setting.

Clearly, the market opportunity very much exists, I would say, in the developed world. But that being said, I think that if we have an oral agent that can induce levels of fetal hemoglobin like what we're seeing, it really is incumbent on us as an organization to make sure that all patients around the world, regardless of whether they're in the developing world or the developed world, can have access to this drug.

And so obviously, we're thinking strategically about ways that we can maximize the uptake and the revenue of this drug, but also to make sure that we don't lose sight of the fact that there are many, many patients in the developing world that might not otherwise have access to potentially a transformative therapy like this. And so, we're clearly thinking about ways that we can ensure that all patients around the world, regardless of where they reside, can get access to a potentially transformative medication like pociredir.

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

Yes. Great. Great question. And before turning it over to Dr. Steinberg, just to remind folks, again, conservatively, we believe we have about a two-year head start over the next closest class of HbF inducers, and we believe those are the WIZ degraders. Dr. Steinberg did mention the glues and they're a little bit earlier, but -- maybe Dr. Steinberg, if you wanted just to provide a little bit more comprehensive overview of the different mechanisms of HbF induction and where they are currently in development.

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 physicIain, 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].

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

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

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

Yes. Maybe before kicking that over to Iain. So, based on the baseline VOCs that these patients were coming in with, we would have expected to see 16 VOCs in these 12 patients over that 12-week treatment period.

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

Yes. I'm happy to take that. I just want to make one clarification. So the slide that indicates the reduction of VOC, Slide #19, that is within the PD analysis set of patients. So that's in the 12 patients. And there, there were 6 VOCs observed in the 5 patients during the treatment period. And then, in addition, 3 VOCs were observed during the safety follow-up period. So that represents 9.

On the following slide, Slide #20, which is the safety slide, that includes the entire safety analysis set for the study, and that's where the 10 VOCs are reported, which includes the patient who came into the study experiencing a VOC and who ultimately experienced a Grade 5 SAE and was discontinued. So that's where the 9 and the 10 come from. I don't think that the observation of the increase from the time of the ASH presentation to this presentation, different data cut in any way changes our view of the effect on VOCs here.

Again, this is a very short study to observe that clinical endpoint. The patients are not at a steady state of maximum effect of the drug. They're increasing their HbF throughout the treatment period. And given that they are a severe patient population to start with, it's not unexpected that they would have VOCs during that early treatment period. So we do not feel in any way dissuaded or discouraged by that fact and remain, in fact, very encouraged by these trends.

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

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

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

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

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

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

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

Thank you. Bye-bye.

Bye-bye.

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

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I am one of the senior biotech analysts here at JPMorgan. I'm joined by my squad, Rati Pinge, Priyanka Grover and Joyce Zhou. Our first.

Presenting company of the day is Fulcrum Therapeutics. And presenting on behalf of the company, we have CEO, Alex Sapir. Alex?

Thank you, Anupam. Thank you, JPMorgan, and thank you for your excellent report that you issued earlier this week. If you haven't had a chance to read it. It's really, really very well done. And thank you all for joining us this morning at 7:30. As Anupam said, I'm Alex Sapir, I'm the CEO at Fulcrum Therapeutics.

I will be making several forward-looking statements throughout the next 20 or 25 minutes. So I would encourage you to please read the full listing of the risks and uncertainties in our recent filings with the Securities and Exchange Commission.

So Fulcrum's strategic focus has always been to develop oral small molecules designed to modify gene expression for rare diseases where there continues to be a very high unmet need. Our initial focus is in benign hematology and even more specifically, our focus today is in sickle cell disease. Our lead asset is a product called pociredir. It is a fetal hemoglobin inducer, and we'll talk a lot about fetal hemoglobin over the next 20 minutes or so.

It is, we believe, a best-in-class HbF inducer for the treatment of sickle cell. It does have fast track and orphan designation, composition of matter and method of use patents out until 2040. We are in the process of wrapping up a Phase Ib study in patients, but a lot of that data has been presented in 2025 in July and December, and we'll go through that data in some detail. We do have an end-of-phase meeting planned with the agency sometime scheduled in the first half of this year. And we believe that we will be kicking off our next study, which we believe has the potential to be a registrational study sometime in the second half of this year. So a lot of activity going on with Fulcrum in 2026.

Beyond that, we have a very rich discovery effort and a very deep early-stage pipeline with a very strong cash runway of $352 million at the end of last year, which takes us out into at least 2029. Here's our pipeline. You can see here, we are just wrapping up our Phase Ib study for pociredir, but we have a number of very interesting and early discovery efforts looking at other benign hematological conditions such as diamond blackfan anemia, Fanconi anemia, Shwachman-Diamond, which all fall into the bone marrow failure syndrome. You see that articulated here.

We also have a number of efforts ongoing to really develop and discover the next generation of fetal hemoglobin inducers for the treatment of sickle cell disease. We've also done a little bit of work in the field of oncology as well.

So let me spend a little bit of time and talk about sickle cell disease. Prevalence is very high. About 7.7 million people worldwide suffer from sickle cell disease. Within the more developed nations, about 100,000 people in the U.S., about half of that are 55,000 in Europe. It is a rare genetic disorder, primarily affecting black and brown population. And the disease is really caused by this sickling of the red blood cell. And when you have this sickled red blood cell, it, in essence, can -- it prevents that red blood cell and the oxygen that is associated with that red blood cell from getting to the tissues. And by not being able to get to the tissues, these patients experience not only chronic pain throughout every day of their life, but also these acute manifestations of pain, which we call vaso-occlusive crisis. And most of the time, these VOCs essentially wind people up in the hospital or the intensive care for days on end.

These VOCs contribute to about 75% of the sickle cell-related hospitalizations. In addition to that, there are many other comorbidities, stroke, leg ulcers, pulmonary hypertension, splenic sequestration. And really, the message that I want to leave you with on this slide is that these patients face a very substantial reduction in life expectancy greater than 20 years, so worse than many of some of the worst forms of cancer with a mortality rate that's 9x higher than any of us.

And the road for sickle cell has been very bumpy over the last couple of years. 2019 through 2022, there was a tremendous amount of promise in sickle cell disease. There was four products approved, Adakveo, Oxbryta and then two cell and gene therapies, Casgevy and Lyfgenia. Unfortunately, that road has not been as well paved as the patients would have hoped. In 2023, Adakveo failed in their confirmatory study to show a reduction in these vaso-occlusive crises and was subsequently withdrawn from the European market. In 2024, Oxbryta was withdrawn globally. And the cell and gene therapies as innovative and as much as a scientific breakthrough as they are, they really have not reached their potential as a commercial opportunity. About 100 patients within the U.S. of the 100,000 patients are currently receiving Casgevy or Lyfgenia. And so the conclusion here is that the unmet need remains very, very high in sickle cell.

Here's how we think. About this market along these two axes and along these four different types of products used to treat sickle cell. You have the anti-polymerization inhibitors, so that would be the PK activators, mitapivat, etavopivat, voxelotor, GBT-601, which is the follow-on product. And you also have these adhesion and inflammation modulators such as crizanlizumab. And they all act on the mature red blood cell.

Gene therapies, on the other hand, act much more upstream. So they're acting within the bone marrow as those red blood cells are being formed. And if you can get enough fetal hemoglobin in those red blood cells, they emerge from the bone marrow, very healthy, they do not sickle and you essentially, therefore, get the prevention of these vaso-occlusive crisis. The challenge with cell and gene therapy is the risks, costs and complexities of the therapy. And I think for those three reasons, that is one of the key reasons why a very, very small number of patients have received those therapies despite being on the market for more than two years. And that's really, I think, where the opportunity comes in with a novel oral once-a-day fetal hemoglobin inducer, such as pociredir.

So I want to leave you with two messages here, and I think these are really important messages to remember because as we go into the data, I want you to remember this. If you can get a patient's fetal hemoglobin levels up to 20%, you essentially are curing that patient. They have 94% of those patients are VOC free.

However, you don't need to get every patient to 20% in order to see a benefit. And that's the evidence on the right-hand side of this slide. This is data that was presented by one of our competitors in ASH of 2024 and what they demonstrated is that for every 1% increase in fetal hemoglobin or HbF, you see a 4% to 8% reduction in VOCs. So let's just imagine for a minute, if you can take a patient from an HbF level of 1 to 8, that's a delta of 7, you're going to see somewhere between a 30% or 60% reduction in VOCs during that year. That is very, very meaningful for the patient. So I want you to remember those two numbers as we get into the data in just a minute.

So when we set out on this journey in 2021, 2022, we had what we believe was the ideal product profile. We wanted a once-a-day oral that was well tolerated. Demonstrated a robust and rapid increase in HbF at a pan-cellular level. We also wanted to see reductions in the markers of hemolysis and increase in total hemoglobin and a reduction in anemia and ultimately, a reduction in VOCs. And that's exactly what we saw in these two data sets that we presented, one in July and one in December last month at the ASH conference. And there's a lot of text on here, but I'm going to walk through this data very quickly in the following slides.

So here's the study that we are in the process of wrapping up. It was a 12-week open-label study in sickle cell patients, roughly about 10 patients per arm. We tested six doses -- sorry, we tested four doses, 2 milligram, 6 milligram, 12 milligram and 20 milligram. Primary endpoint, obviously, was safety and tolerability, but we also looked at very -- at some other very important parameters such as HbF induction, hemolysis markers, anemia and so forth.

I'm going to talk now, I'm going to walk you through the data from these two cohorts, the Cohort 3b, which was 12 milligrams and Cohort 4, 20 milligrams. These two cohorts were fairly consistent, slightly more females in the 20-milligram cohort. About 60% of the patients came from the U.S. The remainders came from outside of the U.S. Baseline total hemoglobin levels were about 7% across the two arms. I'm sorry, fetal hemoglobin, I apologize. Total hemoglobin was 7.3% and 7.6% Total fetal hemoglobin was 7.1% and 7.6%. And here, you can see the number of VOCs that these patients experienced historically prior to coming into the study. So about almost 7 VOCs in the 20-milligram cohort over a 12-month period of time and about 2.5 VOCs in five of those patients over a 6-month period of time.

The 20-milligram cohort, we're going to spend most of the time on because that was the data that we just presented weeks ago at the ASH conference. It was a total of 12 patients. The data that I will show you is all patients getting through day 42, so only six weeks of treatment, six of those patients got all the way through to day 84 or 12 weeks of treatment. And we will complete the study and report out the full cohort this quarter.

So here, I think, is probably one of the most important slides of the presentation. And this is showing the induction of fetal hemoglobin over time. Each one of these slides has a similar look and feel. The blue is the 12 milligram. The green line is the 20-milligram cohort. You can see it's truncated at 42 days or six weeks. And what you're seeing here is a very, very robust and rapid increase in fetal hemoglobin from about 7% to 16.9% in the 20-milligram cohort after only six weeks.

If you just look at the data from a change from baseline, what I want to call your attention to is that the 20-milligram cohort was able to achieve a greater level of HbF induction at 6 weeks than what the 12-milligram cohort was able to achieve at 12 weeks.

So these are the individual patients. These are the 12 individual patients. The gray line is where those patients' baseline HbF levels were and the green is the increase that they saw. If the green bar is solid, that is a patient that went all the way out to day 84 or 12 weeks. If it is dash, as you see here, they had not yet completed the full day 84.

So I want to leave you with two messages on this slide. The first message, and remember that 20% that we talked about earlier, after only 6 or 12 weeks of treatment, we were able to get 7 of those 12 patients above 20% with an oral once-a-day therapy. And all patients achieved at least a 6.5% increase in their HbF or greater. So more than 50% we were able to reach that 20%. We know that 20% is transformative, but we also know that all patients were able to increase their fetal hemoglobin levels to a point where it became clinically meaningful. So like if you just look at patient #5, they were at 1.5, they got to 9 at the end of 12 weeks. That's a delta of 7.5. That's 7.5 when multiplied by those earlier numbers that I showed you a 4% to 8% reduction in VOCs, that patient over time, will see anywhere from a 30% to 60% reduction in their VOCs, clinically meaningful for those patients.

So the other thing we also wanted to look at is because this is operating in the bone marrow, while those red blood cells are being formed, as those red blood cells come out of the bone marrow, because they now have the presence of fetal hemoglobin, they should be healthier, they should not sickle. And as a result of that, you should see less hemolysis or bursting of those red blood cells. And so there's four markers that we look at: LDH, bilirubin, red cell distribution width and reticulocyte count. And you can see across both the 12 and the 20, you see LDH going down, bilirubin going down, reticulocytes going down, red cell distribution with going down. And that should all translate if you're seeing less destruction of the red blood cells because they have the presence of fetal hemoglobin, you should see an increase in total hemoglobin, which should improve factors like anemia and fatigue for these patients. And that's exactly what we saw. So an increase in total hemoglobin, patients in the 20-milligram started at about 7.3, and at the end of only 6 weeks got up to 8.1 or a delta of 0.8 grams per deciliter.

So the other thing that we wanted to look at, but I will caution you that this was -- this is a 3-month study. And I think that this relationship between increasing HbF and reduction in VOCs takes time, but we did want to look at were we seeing an impact in VOCs in this very short study.

And so if you remember the baseline VOCs that these patients had, seven of them had baseline VOCs of 6.7, almost 7 VOCs in the previous 12 months. Five of these patients had 2.5 VOCs over six months. So you would have expected to observe 16 VOCs across these 12 patients during this 12-week study had they not have received pociredir.

What we have observed as of the data cut of November 11, we've observed five VOCs across four patients or eight of these patients experienced no VOCs during the course of the study. It is early. I will caveat it that this VOCs was not an endpoint in the study. There was no adjudication committee. We probably would not have been disappointed if we did not see any reduction in VOCs given the fact that this was only a 3-month study. But the fact that we did see a very meaningful reduction from what we expected to see versus what we observed left us very, very encouraged.

And finally, safety was the primary endpoint of this study. You can see here that the 20-milligram looked very similar to the 12 milligram. We had three treatment-related AEs in the 20-milligram cohort and three treatment-related AEs in the 12-milligram cohort with the exception of one of those AEs, which we -- maybe we can talk about during the Q&A. All of those treatment-related AEs were grade 1 and resolved while on study drug. So the drug is, again, met our target product profile of an oral once a day, very well tolerated.

So, as we look forward into 2026, I mentioned that it was going to be a very important year for Fulcrum, and we've got a number of important milestones coming up over the next 12 months. We will be completing this 20-milligram cohort and we'll be reporting that out to all of you sometime in the first quarter of this year. Armed with the strength of this data, we intend to engage with the agency as part of our official end-of-phase meeting in the first half of this year, share with them the data and gain alignment on what we believe that next study should look like.

In addition to that, for these patients that have just participated in the study that I just talked through with you, these patients will have the option to go into an open-label extension study, which we expect to operationalize and begin enrolling patients in the first half of this year. We believe there's going to be very, very strong interest from many of these patients based on the anecdotal evidence that we were hearing from investigators about how well these patients were feeling while on study drug. And then in the second half of this year, we believe we have the possibility to begin enrolling in a global registrational study that will serve as the basis for an approval of pociredir.

And with that, we have a very strong cash runway of $352 million. We have cash to get us all the way through that registrational study with additional cash runway on the back end of that. So we are fully funded to support many of the anticipated regulatory milestones over the next couple of years.

And with that, I thank you, and I will turn it over to Anupam to start running through some questions.

Yes. Thanks so much, Alex. I'm going to ask the first couple of questions, but there will be an opportunity for the audience to ask a question, too. So just raise your hand.

So, Alex, just quickly, when you were at ASH when these data were presented, maybe you can just orient us to some of the KOL feedback you were getting at the conference is kind of the most derisking data that derisked the kind of program and next steps. And then I think you wanted to maybe comment on that discontinuation as well.

Sure. Absolutely. Yes. And maybe, Iain, I'll have -- you know the details of the discontinuation a bit better than I do.

Yes, I think, obviously, the physicians, as you probably have witnessed yourselves from seeing this data, some of you may be for the first time. highly, highly encouraged across the totality of the data. The robust increase in fetal hemoglobin, the reduction in all of those markers of hemolysis saying that these red blood cells are not rupturing because they're coming out of the bone marrow in a much healthier state. You're seeing then as a result, an increase in total hemoglobin. The trends toward VOCs, I think, again, physicians were saying it's interesting, but obviously, it's a hypothesis, and we need to test that in a much larger study.

But I would say the one piece of evidence of all of the totality of this data, which again was very strong. I think the one thing that the physicians are most impressed about was that very robust and rapid increase in fetal hemoglobin and the fact that we were able to get 7 of those 12 patients above 20%, again, after only 12 weeks of dosing.

So, Iain, do you want to maybe talk about the one discontinuation, the Grade 3 reticulocytopenia?

So the reticulocytopenia not the discount from the study?

Yes, yes, the Grade 3.

Yes. So there was one patient that you'll see under the list of treatment-related adverse events that includes reticulocytopenia. That patient had a year prior to enrolling in the study an experience of depressed blood counts, including neutropenia in the context of a viral infection and sinusitis that was treated with an antibiotic. When that infection resolved and the antibiotic was discontinued, those counts came back.

After enrolling in the study with pociredir at the 20-milligram dose, a few weeks into the study, experienced symptoms of a viral infection and sinusitis. They were started on amoxicillin. Their counts were noted to be depressed, including neutrophils and reticulocytes and monocytes. At that point, we discontinued the pociredir because we weren't certain about the overall clinical picture with the patient. Their viral infection got better. We did a workup there. They had a positive parvovirus IgM, although the DNA PCR on that was negative. As that infection resolved, that counts started to come back up. We clearly thought that this was -- the depression of the counts was related to that intercurrent event. And so we restarted the pociredir after a 2-week pause. And at that point, the counts continued to remain elevated and did not go down further, therefore, indicating that the drug was not related to those events. It was more the intercurrent illness.

The reticulocytopenia is listed as still related to drug. The investigator indicated that, that was because the reticulocytes did not come back to their prestudy baseline at that point. And if you recall, and Alex is projecting this now here that a reduction in reticulocytes is part of the therapeutic response to pociredir because the red cells are surviving longer and they're healthier, there's less stress on the bone marrow. And so the reticulocytes come down as a therapeutic response. And so you wouldn't expect somebody who had responded to the therapy to go back to their pretreatment baseline. But nonetheless, that's the attribution that's listed there. The overall events is clearly not related to drug. They went back on drug, counts came back, they did well, and they completed the study.

And then you have sort of updated data coming for the 20 mg cohort this quarter. What's going to be the size and scope of the data relative to what we learned at ASH? And like how are you broadly defining a win scenario for that 1Q update?

Sure, sure. Maybe I'll just -- for the people in the room, maybe I'll just go back to the presentation. So what you will see at the release of the full data on the 20-milligram cohort is each one of these green lines will go -- will extend all the way out to 12 weeks. So we'll show you the data on fetal hemoglobin induction. We'll look at individual patients. We'll look at all those markers of hemolysis. We'll look at the total hemoglobin, we'll look at VOCs. And of course, we'll look at safety as well. And the way I would answer the question in terms of a win, I would say we've already won based on the data that we've just released and that I just shared with all of you this morning.

I think if -- and we were able to achieve 16.9 in the 20 milligram after only six weeks. If we can get that to, on average across all patients of a 19% or 20% at week 12, I mean, that would be extremely, extremely powerful for these patients. So -- but that data will be imminent. That data will be coming out in the very, very near future. There is not a medical conference, so it won't be shared in the medical conference sort of ecosystem, if you will, but we will share that as part of one of our regular corporate updates.

Questions from the audience? Yes, go ahead.

Have you tried -- tested the patient with a higher dose [indiscernible]

The question is, have you tried a higher dose?

Yes, it's a great question.

[indiscernible] question. Do you have any biomarker to show the target engagement?

Sure. So let me answer the first question and then the biomarker question, I'll turn that over to Iain.

So we have tested higher doses in healthy volunteers, looking at HBG mRNA at day 14. So this is not the protein in healthy volunteers. And what we saw, we tested 2 milligrams, 6 milligram, 10 milligram, 20 milligram and 30 milligrams, so five different doses. We saw a very, very elegant dose response as patients went from 2 to 6, 6 to 10 and 10 to 20. We did not see a dose response as patients went from 20 to 30.

So I think based on what we saw in the healthy volunteers and based on the robust nature of the data that we've seen with the 20 milligram, we don't -- even though we have the option in this protocol to go higher, we don't believe that we do need to go higher. And so once we finish this cohort, we will wrap that up and get ready for an end-of-phase meeting with the agency sometime in the first half of this year.

Iain, do you want to comment on the biomarker?

Yes. So there is a biomarker of target engagement. The PRC2 complex is responsible for tri-methylation of one of the lysine residues on histone H3. And you can measure that. We did that in that first-in-human study that Alex referenced earlier, measuring it in the peripheral blood of those healthy volunteers.

The assay, unfortunately, doesn't offer a very fine level of discrimination across doses. And what that showed is you saw some inhibition of that effect. by measuring that trimethyl mark at doses as low as 2 milligrams once a day. So there was indication of target engagement at that level. At the higher doses, so the 6 and all the way to the 30, very difficult to discriminate the actual magnitude of induction. The assay maxes out at about 80% inhibition. But clearly, seeing inhibition of that over the course of the two weeks and then reversion back to baseline pretty rapidly after that ceased.

Additional questions from the audience?

On the key endpoint of vaso-occlusive crises that's commonly used in clinical trial, what gives you confidence here based on the early totality of data that you know and then put it in the context of what we're going to learn in 1Q as well?

Yes. Iain, do you want to maybe take that one?

Yes. So there really is a large body of evidence that links increased levels of fetal hemoglobin with reductions in clinical manifestations of sickle cell disease and particularly that of VOCs. And when I say a large body of evidence, it's normal human development evidence, it's genetic evidence with naturally occurring mutations that increase expression of HbF. It's pharmacological evidence, mostly with hydroxyurea and then more recently, gene therapy experience showing induction of fetal hemoglobin, essentially abolishing VOC. So there's that very tight link between increased HbF and improved clinical symptoms like VOCs.

The other piece that's very reassuring to us in the data set is that as the fetal hemoglobin goes up, you would expect to see evidence of decreased hemolysis, evidence of decreased stress on the bone marrow and evidence of increasing total hemoglobin as the red cells survive for longer. And all of those were directionally consistent across these. So we're seeing LDH bilirubins go down as a marker of less hemolysis, the reticulocytes going down. We mentioned that earlier and the total hemoglobin going up.

So, in totality, everything that you'd expect from an HbF inducer is occurring there. And then this large historical and current data set supporting that link between increased HbF and decreased VOCs.

Maybe another one for me. You've got this end of Phase I meeting coming up with the FDA. What are the key points of discussion with the agency? And in your mind, what's kind of a base case trial design for pivotal pending regulatory feedback, of course?

Yes. Great question. And maybe I'll start and then please, please add to what I'm saying.

So, I think for us, the way that we're thinking about going into this meeting with the agency is more than likely what the agency will require is a clinical endpoint in sickle cell disease. as opposed to a biomarker such as HbF for a full approval. So we believe that we will need to design a 1-year VOC study. We understand there's a lot of variability around VOCs, and we've done a lot of effort to try to reduce some of that variability, not only across centers within a geography but across geographies. So we believe that we will need to design a Phase III registrational study that has VOCs as an endpoint at 1 year, probably 2:1. Numbers of patients, we're still going through some of those powering calculations, probably a couple of hundred patients.

But based on everything that Iain said and everything that I walked through and the strength of the evidence showing this very strong relationship between HbF and VOCs. We think there is a path forward to look at fetal hemoglobin at an earlier time point, say, at 6 months in a smaller number of patients as a surrogate endpoint for the basis of an accelerated approval. So that essentially is -- we think that there is a clear path forward for that. We feel that the strength of the evidence is there to propose that, and that essentially will be kind of what we will be at a high level, taking to the agency and seeking feedback on.

Iain, anything you would add?

I think that's pretty clear.

Okay.

Any final questions from the audience, and I have one more. Maybe my final question for the session here. The gating factors to starting that OLE portion of the PIONEER and any thoughts, could we get some OLE data later in the year? And obviously, some of the key measures you're going to be monitoring?

Great question. So the only gating factor with the OLE study is getting those sites activated with that study. And so we are very active in getting those sites initiated. I believe as of last week, we had one site that had already initiated, so it was available to start enrolling patients. We are going to initially be focusing on the U.S. patients. There is a total of 17 U.S. patients that participated in either the 12-milligram cohort or the 20-milligram cohort. And so once those sites get activated, we will be enrolling those patients. We do believe, based on the anecdotal feedback that we've heard from investigators from talking with their patients of how well they felt while on therapy, we think we will have a fairly decent number of those 17 opting to go into the OLE. Some of them may be lost to follow-up or maybe on other clinical trials. So I'm sure we won't get the full 17, but we think we'll get a decent number of that 17.

And so as we start enrolling those patients on a go-forward basis, we'll provide more guidance with respect to when we'll have data to share. But we'll be looking at fetal hemoglobin. We'll be looking at VOCs. We'll probably be looking at that at a sort of monthly basis or every other month as those patients go from 3 months to 6 months to 12 months to 18 months. But that's going to be a really interesting and nice data set to see as we're enrolling in what we believe will be our registrational study, which will be our next big study.

So there'll be sort of a 2- to 2.5-year data gap there. So this OLE data that we'll have that we'll be able to present in a fairly sort of regular cadence will be really important because I think it will show a couple of things. It will show, number one, safety; and number two, the durability of effect of the drug over time because all we know now is how well the drug performs at three months. We believe that the drug could perform better after a 3-month period of time, and that's one of the things -- that's one of the hypotheses that we'll be able to test as part of the OLE study.

Iain, anything you would add there?

No, I think.

Okay.

That's it.

All right. Iain, Alex, thank you so much.

Thank you. Thanks, Anupam.

Good morning, everybody. Thank you all for joining us this morning. And I'd like to thank everybody who's online as well. We've got a fairly robust number of people online. So thank you all for joining us virtually as well.

My name is Alex Sapir, I'm the Chairman -- I'm sorry, I'm the CEO and President, not Chairman, CEO and President of Fulcrum Therapeutics.

This is a really exciting day for Fulcrum, but I think more importantly, it's an even more exciting day for patients and the sickle cell community at large, really because of the potential that this drug has to possibly truly transform patients' lives around the world. And so I think for that reason, we're so excited that you have been able to join us.

Before we get started, I just wanted to remind everybody that today's presentation will include some forward looking statements, which are based on current expectations and subject to risks and uncertainties. Actual results may differ materially, and we encourage you to review the full disclaimer on this slide together with the Risk Factors in Fulcrum's most recent filings with the SEC.

So I'd like to introduce my fellow speakers up here. Many of you know Iain Fraser. Iain and I worked together at Fulcrum. He is heading up all of development at Fulcrum. Dr. Sheinei Alan, great to have you here. Dr. Alan is Head of the Sickle Cell Center at Inova Fairfax and also the leading enroller of PIONEER. So we're absolutely delighted to have her here as well. And to my left, someone who truly doesn't need any introduction, Dr. Martin Steinberg. Dr. Steinberg is Professor of Medicine, Pediatrics and Pathology at Boston University School of Medicine. And it's really his pioneering work over the last 50 years that has really helped shape our modern understanding of sickle cell disease biology. I was talking to him earlier and was asking him how many ASH is he's actually been to. He started going to ASH, I think, in 1968. And with the exception of COVID, he's never missed one. So that's quite an impressive feat.

So here's our agenda for the day. Iain and I will just give just a couple of quick slides. I'll just give a very, very quick one slide overview on the data that Dr. Alan will go through in some detail. Iain has a couple of slides on the disease, the unmet need, and why fetal hemoglobin induction is so important in the treatment of patients with sickle cell disease. And then Dr. Alan will really spend the bulk of the time going through the data in some detail. We'll have Dr. Steinberg give his expert perspective on really what this data means for the scientific community, the clinicians and then ultimately for the patients, and then we will open it up for Q&A for all of you as well as anybody that's on the phone.

If you are online, just a quick reminder, just to submit in the written text box, which you should see on your screen right now, and we'll take those questions as they come through.

So moving on to the next slide. This is only slide before turning it over to Iain. So the first two panels here should look relatively familiar to most of you. These are panels that we presented in July when we presented the 12-milligram data. And so if you look at that middle panel, we were very excited with the 12-milligram data primarily because the drug was very well tolerated. We saw a very rapid and robust induction of fetal hemoglobin at 5.6 at week 6 and 8.6 at week 12. 44% of the patients in the 12-milligram saw a greater to or equal than 20% fetal hemoglobin at the end of the study. We saw a 2.4 fold induction in the 12-milligram really looking at dose response, all those markers of hemolysis were trending in the right direction. We were seeing trends toward pancellularity. We were seeing a really nice, impressive increase in total hemoglobin as well. And although VOCs were not an endpoint in the study, we saw very encouraging trends in terms of reduction in VOC.

So we set what we thought was a very, very high bar with that 12 milligram. I'm incredibly excited to share that we have exceeded that bar with the 20 milligram. And that's really what's reflected here on the right-hand panel that you see on this slide. The drug and Dr. Alan will go through all of these details, all of these data points in some detail.

But just to hit them at a very high level. We continue to see evidence of this drug being generally well tolerated. We saw a 9.9% mean absolute increase in HbF at week 6. As you remember, that compares to 5.6% of what we saw with the 12-milligram at week 6. And I think what's also important to note is that what the 20-milligram has been able to achieve at week 6 actually exceeds what the 12-milligram was able to show at week 12.

58% of the patients or 7 out of 12 at the time of their last study visit had seen a greater to or equal than 20% fetal hemoglobin. And as Iain will speak about, that truly does have the potential to be transformative for these patients. In the 12 milligram, we saw a 2.4-fold induction with the 20 milligram, we saw a greater than 3.75 fold induction. The drug continues to show trends towards pancellularity, improvements in anemia as because of the reduction in many of these markers of hemolysis that we've seen. And again, although not an endpoint of the study, we're continuing to see very, very encouraging trends in VOC reduction. So we could not be more delighted with the 20-milligram data that we shared in a poster form yesterday and the data that Dr. Alan will go through in just a couple of minutes.

So with that, Iain, why don't I turn it over to you, I think Iain just has a couple of slides just at a very high level, the disease, the degree of unmet need and why fetal hemoglobin is so important for this patient population. So Iain, right over to you.

Yes. Thanks, Alex. Next slide, please. Just a reminder that sickle cell disease is a debilitating disease with a very high unmet need. If we look globally, over 7 million individuals affected worldwide in the U.S., around 100,000. As you know, the disease is driven by these abnormal sickle-shaped red cells. They have a shortened lifespan because of the sickle hemoglobin that polymerizes these cells rupture, they block blood vessels, causing extreme pain for the patient. The painful VOCs are a hallmark of the disease responsible for majority of their hospitalizations, but there are a number of other acute manifestations that really have significant impact on patients' life, stroke, pulmonary hypertension, priapism, leg ulcers, splenic sequestration just to name a few. And of course, they also have chronic anemia related to the ongoing hemolysis that they experienced, and that leads to end organ dysfunction.

I think important to note that even in the 21st century, patients with sickle cell disease face a substantial reduction in their life expectancy, probably more than 20 years overall with a mortality rate that's much higher than the general population.

Next slide, please. This slide speaks to the relationship between fetal hemoglobin levels and disease symptomatology in people with sickle cell disease. There's a long history of the relationship between increased levels of fetal hemoglobin and reductions in the manifestation of sickle cell disease.

And these are just two examples that we've illustrated here. Some of you will have seen these before. On the left is some modeling data from previous trials conducted with hydroxyurea, the MSH and the CSSCD this analysis was presented last year by Novo at ASH. And for every 1 percentage point increase in HbF was an associated reduction of 4% to 8% in VOCs.

And on the right, moving to a real-world data set that we analyzed from PicnicHealth, about 700 patients in the U.S., illustrating this relationship in the patient population between increased levels of HbF. And then the percentage of patients with no VOCs in the preceding year on the y-axis.

I think one of the important points to bring out and Dr. Alan was reminding us of this yesterday, is if you look at the low end of that curve, the patients who are coming in with very low fetal hemoglobins, even small increases for those patients the curve is very, very steep and is likely to result in a clinically meaningful benefit for them.

And then, of course, on the bottom left, it's not just the VOCs, but it's also the impact on hemolysis of the cells, so reducing hemolysis, reducing anemia and reducing recurring events.

The next slide, please. So this touches on the mechanism of action of Pociredir. Again, many of you will be familiar with this. Pociredir binds to the EED subunit of PRC2. And as a result of that inhibition, there's a reduction in the methylation of histone 3 at the lysine 27 position. And the net result of that is an increase in HbF. We know that, that mechanism in part works through reductions in the activity of BCL11A, which is one of the master represses of fetal hemoglobin. There are others involved as well, including MIB but we do know that Pociredir treatment leads to a reduction in BCL11A. It binds selectively to EED. It has a clean off-target profile. And we've seen robust target engagement at doses as low as 2 milligrams once a day. The next slide, please.

And this is just a snapshot high-level overview of the development program to date progressing on the left from our in vitro work, all the way through the clinical work in sickle cell disease, patients leading into this 20-milligram cohort data. So just very briefly on the left, CD34 positive cells, whether from healthy volunteers, patients with sickle cell disease or with sickle cell trait, showing a robust induction of HbF when differentiated in vitro. In the middle panel is our early healthy volunteer data, shorter-term dosing, so 2 weeks of dosing, measuring the HbF mRNA in the peripheral blood in this case, and what you see is as you go up in the daily dose of Pociredir from 2 milligrams all the way up to 20, you get a progressive increase in that HbF mRNA between 20 and 30, it flattens out at the 2-week mark. But all the way up to 20, we've seen progressive increases, and we've measured this as a fold increase in that mRNA in the peripheral blood.

And it's been very reassuring and encouraging to see that initial mRNA translate well into the patients measuring HbF protein over the 3-month treatment period. And what we're showing here is the earlier data the study leading into the 20 mg cohort that we'll discuss today, showing the 2, 6 and 12-milligram doses, again, expressed as a percentage change from baseline in order to evaluate that dose response. As you go up on the dose, as we saw in the mRNA, you go up on the induction of HbF protein in those patients.

And the next slide.

All right. Thanks, Iain. So obviously, the moment many of you have been waiting for I'm now going to turn it over to Dr. Alan to really run through in a fair amount of detail, the data that was presented yesterday that we're going to flesh out a little bit more today. So over to you.

Thank you so much. Good morning, everybody. So I'd like to -- I'm not sitting down on a podium kind of person so I'd like to kind of walk through it with you guys. So we can all be on the same page about this.

So the data we're presenting today is the 20-milligram cohort that we're showing you. The study is still in progress, but we're showing you all the data as of the data cut from November 11. Again, this includes very sick patient population, who are not on hydroxyurea or eligible to take it. At the time of enrollment, these are patients predominantly or the more severe genotypes, ages 18 to 65. As I mentioned, hydroxyurea to be discontinued for at least 60 days. And the severity was defined either having had multiple VOCs leading to enrollment or an organ disease. The primary endpoint focused on safety and tolerability of the agent as well as the PK parameters with the secondary endpoint looking at HbF induction hemolysis and anemia. And exploratory endpoints looking at globin gene expression, the percentage of F cells as well as the incidence of VOCs. And I will point out -- talk a little bit more about that down the line that they're not adjudicated VOCs,but sort of observations in that period.

Next slide, please. So what I want to highlight for you all is the number of patients enrolled, which were 13. The patient who is included in the safety analysis, but not in the PD analysis. This was an unfortunate event in which the patient experienced a Grade 5 SAE on day 1 of treatment that was not deemed related to the study medication, but we felt -- we thought it was important to include that assessment and everybody completed to day 42. So the data we're showing you is really as of the data of the day 42 analysis of all 12 patients. And I want to highlight that also will include the -- in July when we shared this data, we didn't have all the safety analysis for the 12 milligram. Now everybody has completed the full follow-up period. So that will be included as well as for the 20 milligram.

And it's really important. I can't emphasize not the degree of adherence, 97% of the adherence rate. This was using an AI cure app, so patients were actually documented of taking the medication, but it was really impressive to see that degree of adherence.

Next slide, please. Talking a little bit about the background of patients between the 12 and what's different in the 20 milligram. Majority of females is 17% male compared to 44%, similar in age group in the early 30s. And I was really excited now to see Nigeria involved in this study. This was a slide that was activated for the 20 milligram. We're not in the 12 milligram. Again, more severe genotype HbSS, one beta 0 and beta plus. Baseline HbF, a little bit lower, 7.1%. And baseline hemoglobin, again, a little bit lower, 7.3%. And looking at VOCs for each patient enrolls to either 2.4 VOCs over 6 months or 6.71 VOCs over 12 months.

Next slide, please. What this data is showing is that as you increase in dosage of Pociredir, you see a dose-dependent increase in the Cmax, meaning that you're seeing that exposure increasing as you increase the dose, as 1 would expect.

Next slide, please. So what I want to highlight here is really looking at the HbF induction. And this is day 42, like I mentioned earlier, including all the patients in the study, and as you can see, it's always an absolute increase of 16.9% HbF, which is really impressive compared to the 16.2% that we saw at 12 weeks with a 20 milligram. So that was really phenomenal to see. And then looking at the percentage change in baseline here, again, the green going forward in the studies will be all the 20 milligrams in the blue is all the 12, so 9.9% increase compared to 8.6% at week 12. So pretty robust induction early on even doubled that of what we would see in the 12-milligram at half the time. So I think that's really interesting to see.

Next slide, please. So here, it's the individual patient breakdown. So I want to orient you, these are all the patients that were in the study, all 12. As I mentioned, they were -- had a follow-up in the study. The gray bars presents their baseline HbF and the green percent like represents their -- like increase in the HbF level with the total percentages of the top. The patients who are in solid green means they completed all 12 weeks of treatment, which is six patients. And then in the dash green are patients that were still ongoing at the time of the data cut on November 11. So we are showing all the data to the data cut in totality, where the six patients will break down a little bit further down the line.

But as you can see, what I want to highlight is that seven of those patients, of the 12 patients achieved that HbF level greater than 20%. And it's really important. I can't stress enough, as Iain mentioned earlier, that any induction of HbF is meaningful.

So I know I talked to some of you guys last night and everybody was like targeting the 20%. But for me, I won't go into it. But I really want to highlight that any improvement in HbF is really important. You can see everybody had a response to that. So that's really important. And that basically, everybody had at least greater than 6.5% increase in HbF. And as Iain mentioned earlier, even a small increment at HbF as meaningful.

Next slide, please. So this is looking at fold induction everybody who enters the study has different baselines HbF, right? So we really need to kind of harmonize what that baseline looks like to really speak to the efficacy of the agent and thinking about the dose dependent response and this is accounting for the 20-milligram patients, but the first six who completed the 12 weeks of treatment. As you can see the baseline HbF is a little bit lower 5% versus if you complete the whole 12-milligram -- 12 patients it's 7.1%. And if you compare that to the 12-milligram is 7.6%. It's a variable baseline, so we need to really harmonize for that and think about the fold induction accounting for that. And we can see there's about 3.75 fold induction in HbF in the first six patients who completed the 12 milligram.

Next slide, please. Okay. So it's really important that we're looking at how many cells or red blood cells are getting that protection they need in terms of HbF protection or using the term pancellularity. And as we're showing here, this data is not complete and more information will come out once the whole data set is complete, but really showing that there's a nice robust increase in the amount of cells who are getting HbF even at day 42 similar to the 12-milligram in terms of pancellularity, certainly 60% or more. And we will have more information on that before. But again, trending to more cells, having this HbF induction and protection.

Next slide, please. And so when you were getting an improvement in HbF, one would expect to then have more protection of the red blood cells and less cell breakdown, as measured by lactate dehydrogenase and indirect bilirubin. And as we would expect in the 20 milligram, there's a very robust nice reduction in LDH, even at week 6 or day 42, even compared to the 12-milligram cohort. And similar to the indirect bilirubin really robustly start to see these markers of hemolysis start to improve very early on in treatment.

Next slide, please. Reticulocyte and we'll talk a little bit more about this as well. It really measures the degree of erythropoiesis. And so as the hemoglobin improves and throughput is improves and erythropoiesis, we would expect to see improvement in reticulocyte counts and kind of decline of that. And so that's what we see here. There's a 33% reduction in reticulocyte head count. Thinking through as a highlight of improved stress erythropoiesis because the marrow is no longer really hyperactivated. And we see that in what we call mean red cell distribution with where the cells are more uniform .They are all being produced in a similar manner. So almost like a normalization of that and it's very robust and early in treatment that we start to see that.

Next slide, please. And so if you have improved fetal hemoglobin induction, if you have improved hemolysis, what does this mean for the total hemoglobin. And what we see early in the study is a rapid improvement in hemoglobin in patients. So 8.1 grams per deciliter day 42 as compared in this patient population. And what I want to highlight here is that in the 12-milligram cohort that we presented in July, there were two patients who had not in frequent blood transfusions because the severity of their disease whereas we didn't have anybody transfused in the 20-milligram cohort. So this data are very clean in the sense that there's no confounding effects of transfusion.

And again, this then kind of going back to the change from baseline, it really shows within 6 weeks, you're seeing a nice change in baseline of hemoglobin at 0.8 grams per deciliter compared to 0.9 grams per deciliter at week 12.

Next slide, please. This is really important, something the computer really wants. I understand that. Thanks for going backwards. We'll wait until that next slide comes up. But really that induction in hemoglobin and not having any of those very sick genotype and phenotype of patients not undergo transfusion. For me, it's really profound. And if you think about it, especially the study being conducted in resource limited areas of the world where the highest burden of disease is, I think the implications of that are something that it's really exciting to think about.

So as I mentioned earlier, patients needed to have VOCs as part of their inclusion criteria to enter the study. And so that's where we have that data. So 2.4 VOCs in some patients over 6 months or 6.71 VOCs over a 12-month period of enrollment. So based on that, statistically, then we would expect to see at least 16 VOCs to that would be expected across 12 weeks of treatment in this very sick and severe population. However, at the time of the data cut in November 11 there was only five VOCs observed in four patients, and that includes the first patient I mentioned earlier, it was not part of the overall assessment.

So basically, what I think it's also really important is to highlight that 8 of the 12 patients or 67% reported no VOCs during this treatment period, which I think is significant.

So combining the safety and tolerability of the drug, I do want to spend a little bit of time here. It was generally well tolerated. There was no discontinuation of the drug because of side effects. In terms of treatment-related adverse events, I'll walk you all through it. Overall, adverse events is what we would expect to see in this sick population and depending on the areas of where they live in terms of -- you see some VOCs, fatigue, malaria infection and arthralgias.

Treatment-related adverse events. There were three. I want to talk a little bit about this reticulocytopenia. So as I mentioned earlier, we would expect to see some relative reticulocytopenia that will occur with improved erythropoiesis. This only when a patient individual had a rapid reduction in their reticulocyte hemoglobin, white blood cell counts, everything where we would expect that there's what we call a myelosuppression. This was in the context of being acutely ill with a Parvo B19 infection presumably that does that to the bone marrow as well as antibiotic use. And this individual patient had a very similar profile going back almost a year before who got sick and had similar antibiotics and had the same profile.

There is a 2-week hiatus to allow this patient to recover and then restarted the drug, and everything continued to improve after that. They had nice robust improvement in their hemoglobin and their white counts and those other cell parameters. So it's unclear if it's truly related to the drug, but we honor with the investigators right because I think and that's why we need to kind of have highlight with the investigators deem possibly potentially related because they're on a study. And there was also a degree of insomnia iron overload that all still being reviewed, but probably less likely to be related in terms of treatment-related serious adverse events there.

Okay. And then as I mentioned, there were six VOCs that were reported at the time of the data cut. And that was one of the that occurred in the safety follow-up period.

Next slide, please. So again, this highlights the safety profile overall, the AEs are consistent with what we would expect in sickle cell disease, especially in this very severe population. These are patients who are really sick that would otherwise not be enrolled in a clinical trial. And so very site had no access to treatments before. And so it's not surprising that we would have some of these events that we observed. Overall, there is no dose limiting toxicities or dose discontinuation. And so these observations are really based on a total of 148 patients being exposed, 103 of them being voluntary. I mean, healthy volunteers and then 45 patients being with sickle cell disease of that more severe genotype and phenotype.

Next slide, please. So kind of as Alex mentioned, this study slide, it's really highlighting what was done with the 12-milligram and then going on to see a similar trend, but even more robustly with the 20 milligram. So again, generally well tolerated, no discontinuation because of adverse events or side effects, even more improvement in mean absolute HbF, 9.9% at week 6 compared to 5.6% and 58% of the patients reaching greater than 20%. HbF at the time of the data cut, so that may even look different. Once we have the full total data and then a 3.75-fold induction in HbF and week 12 of the patients. The first six patients that we analyzed. And there's this continued observation that more cells are getting HbF induction and not protection. So that pancellular distribution would that result in improvement in anemia and hemolysis. And while the study was not adjudicated for VOCs, but it was a very encouraging trend that we saw in terms of VOC reporting.

Okay. Fantastic. Dr. Alan, thank you very much, very comprehensive, very elegant, very, very well done. We covered a lot of data. I'd love to maybe hear a little bit from Dr. Steinberg having been doing sickle cell biology for more than 50 years and knowing this disease more than most. Maybe Dr. Steinberg, if you could sort of share as you see this data, let me give your perspective on what it means for the medical community, what it means for the treating physician and ultimately, in your opinion, what it means to the patient?

Sure. Thanks. Well, I'm sure many of you have heard this from me before. But at the current state-of-the-art with our inability to directly correct the sickle mutation which if it ever happens, is going to be a long time, inducing high levels of fetal hemoglobin in as many red cells as possible, is the approach to really transformative treatment. There are a lot of other treatments in development. But I think the nibbling about the edges, and we could really reverse the phenotype of the disease totally if we have enough fetal hemoglobin in enough cells. Nature has shown us that the gene therapy trials have shown us that the use of hydroxyurea has started us somewhat along the path. But what the field urgently needs is an oral fetal hemoglobin inducer, that could be used as a single agent that possibly can be used in addition to other fetal hemoglobin inducers. So I find these results which I saw yesterday and heard about before, very encouraging.

I mean in a very short period of time, this agent has achieved fetal hemoglobin levels that are about twice the level that one would expect within the average patient with hydroxyurea after all, the hydroxyurea trial showed an average fetal hemoglobin of only 9% after the trial was completed. And the hemoglobin rose about 0.5 gram, which one would expect, as Dr. Alan pointed out as you induce fetal hemoglobin. And here, we have almost twice as much fetal hemoglobin, the hemoglobin is going up more. So I think these results are really encouraging.

And if they continue along this trajectory, this will be a really valuable agent for the field and could have major effects on patient outcome. Gene therapy won't because as wonderful as it is, it's not an effective treatment to can't reach people at scale. But an oral agent has set potential. So I'm very excited about these results.

That's great. Thank you. Thank you so much. So the good news is we have a lot of time for questions. I think before we get to those questions, I know a lot of you are wondering, so what's next? And I really just want to touch on things that we're planning to do in the near future.

Obviously, as Dr. Alan mentioned, we're going to complete the 20-milligram cohort, and we do intend to share that updated data set sometime in the first quarter of next year. We are continuing to very actively prepare for an end-of-phase meeting with the FDA, which we would plan. We would submit that request to have a meeting with them sometime in the first quarter, and then have that meeting sometime in the first half of 2026.

We are moving forward with operationalizing an open-label extension study. Thanks very much to Dr. Allen's discussions that you and I had about the need or the desire for the patients to continue on therapy. So we would expect to be operationalizing that and we will actually begin enrolling patients that have been involved in PIONEER, enroll them in the open-label extension study sometime in the first half of next year.

And we are continuing, obviously, to finalize plans for a registrational study, obviously, pending regulatory feedback. We need to have that discussion with the agency, but we think in light of the data, in light of Dr. Steinberg's comments about the importance of HbF. We feel like there is a potential pathway to go directly to a registrational study, which we would plan to kick off sometime in the second half of next year.

So with that, I think we're going to go to the Q&A. We do have a microphone here. We've got a couple of hands up here in the room. So please state your name, your company affiliation. And then we'll check and see if there's any questions that are coming in online. So Yes, Sam?

Great. Matt Biegler from Oppenheimer. Not a lot to pick at here, guys, so congrats on the data. Dr. Steinberg, I -- my pointed question to you is do you think that this can be a cure for some patients? Because you've published, I think, statistical modeling in blood [ 2014 ], I think you came to the conclusion that you need maybe 30%, 35%. We're seeing that in some patients. So can this be a functional cure?

Well, sure. You noticed from the slide that patients respond differently. The fetal hemoglobin genes are poised to be reactivated. They're a peculiar gene compared to other genes in the body. And the control of them is very complex and some people have the innate ability with the proper push to express large amounts of fetal hemoglobin. And we saw that in hydroxyurea and you see it here. So there are some people who have the right genetics and the right cellular biology. That will probably -- there's the potential for inducing 20%, 30% or more fetal hemoglobin, which will be distributed fairly homogeneously among all the cells. So I mean the aspirational goal is mimicking gene therapy, and it's possible. I doubt if it's going to happen to everybody because we're all different genetically and some people just can't do it. So I think the potential is there, yes.

Maybe Kristen?

This is Kristen Kluska of Cantor. Congrats on these data, a very clear dose response that you've demonstrated. What can you tell us about what the slopes of the percent HbF data look like for those patients that did reach the 12 weeks? And do you believe that you've reached a plateau?

Yes Iain, do you want to maybe take that one?

Yes. Yes, happy to do that. So of those six that reach the full 12 weeks, remember, they all started out with a mean baseline that was somewhat lower than the overall cohort. So about 5.0. But their individual slopes are either upward sloping or flattening around the 12-week mark. We haven't seen anybody declining along the way. The one patient that we discussed earlier that had drug withheld for 2 weeks they flattened out for that 2-week period, maybe slightly down, and then they bumped up again with their HbF after that. So we haven't seen that. And our expectation is that the 9.9% that we're seeing at the 6 weeks is going to end up for the full cohort is higher than that. We don't know exactly where that will be because of the patients still in transit.

Ted Tenthoff from Piper Sandler. So really remarkable results. I guess picking up on the last question, it seems like you've gone high enough, you don't need to go any higher. Is there any reason to potentially backfill between 12 and 18? And I guess the real question is, when you go into a registrational trial, do you envision doing more than one dose for potential titration or maybe even weight or age-related differences?

Yes. Iain, maybe I'll turn that one over to you.

Yes, absolutely. So I think the most important thing is we need to wait until the end of the 20-milligram cohort because we still have to finish that out before we can make those decisions. I think we've been really very much encouraged by the magnitude of change that we've seen at 20 with a very clear dose response up from the 12-milligram dose. And to date, again, we haven't completed the cohort yet. But to date, the safety has been pretty unremarkable relative to the other cohort. So we haven't seen any clear treatment-related adverse effects emerging. So based on those considerations, I think 20 seems like a reasonable dose to take forward, but I think that discussion will be more fulsome once we have the full data set.

We haven't seen anything on -- in terms of PK-related changes relative to age and weight, for example. So I'm not sure that those factors in and of themselves will form an influence, but we'll continue to look at all of those data.

Great. A couple more questions in the room here.

Congrats on the data. This is Andres Maldonado from H.C. Wainwright. One quick one from us. How should we be thinking about the post-treatment observed HbF decay? And how does that kind of durability correlate with pancellularity achieved on treatment.

Maybe, Iain, we'll start with you, and then Dr. Steinberg, I'd love to get your perspective on the latter half of that question, and you want to start...

Yes. And I think -- so the data we showed for the 12-milligram cohort, which has the off-treatment period. We didn't have that available at the time of the July release. So that's new data for the 12 cohort. We don't have all of that for 20 yet, but we will when we complete the cohort.

And what you see, if you remember from the slide is a gradual decline in the HbF once the drug has been stopped. It's not a precipitous decline. We wouldn't expect that to be the case. So the mechanism acting in the bone marrow to generate increased feel hemoglobin, releasing those cells with increased fetal hemoglobin into the circulation. Those are then going to survive longer because they're not hemolyzing as readily.

And I'm not sure based on the trajectory that we are at a steady state at the 3-month mark. So it's reflective of where we are at that time. There'll still be some cells that don't have the benefit of the HbF and others that do. And so the decline is going to reflect essentially the half-life of the red cells in the circulation at that time.

But I think the important thing is that you don't see a precipitous drop which is different than what you see with other mechanisms like the polymerization inhibitors or the PK activators which are acting on the mature red cells, you remove the drug and then they revert back immediately or pretty shortly thereafter back to their phenotype related to their hemoglobin in the cells at that time. I'm not sure if that addresses your question, but that's certainly the observations.

Not much from me, I mean you have two populations of cells. One is long lived, the fetal hemoglobin cells. You have the intrinsic cells don't have that much fetal hemoglobin in a short lived. So it's going to stay for a while. But of course, you have to continue to take the agent to have continued fetal hemoglobin expression.

Great. Alex and team, congratulations on the data. Maybe a question for Dr. Alan. I think we sensed your appreciation for maybe some of those smaller absolute increases in hemoglobin with this cohort reaching at least 6.5% increase. Can you just talk a little bit about that appreciation, how that translates clinically even though smaller increases certainly having a wider impact?

Absolutely, this is a very sick population who otherwise has no access to treatment. So being able to induce HbF even in a small percentage of those cells or even a small degree in more cells, it's really helpful and it improves outcome. There's a data set that Iain mentioned earlier, the PicnicHealth data set that we presented at ASCO earlier this year. It's a very real-world data of consenting patients in the U.S. and Canada. And what it looked at was percentage of HbF and the degree of like occurrence of VOCs. And as Iain mentioned, even a small percentage in HbF increase going from -- so your chance of being VOC-free it, for example, 0% HbF is about 12% for the whole year. When you go to 5% HbF, that chance of VOC free goes to nearly 60%. And so that even small increment in HbF and having that protection does lead to meaningful improvement in somewhat in the reduction of hemolysis and in fetal hemoglobin in downstream vaso-occlusive events.

So for me, as a provisioner taking a very sick patient population or otherwise has no access to treatment to get or treatment. It's really exciting. And again, I think everybody has mentioned this is only a 12-week study. So long term, and the implication could be even more profound.

Tazeen has a question.

Congrats on the data. I wanted to get the thoughts maybe from Dr. Alan first and then from the rest of the team about what you think the path to widening the addressable patient population might be? You've shown convincing evidence that more severe patients are responding at least in the early stages. But what do you see as the addressable patient population ultimately? And how are you going to take that into account when you design your registrational study?

And then just a follow-up. Was there any difference in cohort 4 baseline fetal hemoglobin level versus Cohort 3B? I just wanted to clarify that.

Do you want to start? And maybe Iain, I can pass it on to you, and then Dr. Steinberg and myself. Yes, great question, Tazeen.

So in the 20-milligram cohort, they had lower baseline hemoglobin compared to the 12-milligram with the 20-milligram didn't have any transfusions for the treatments of a little bit lower baseline. As a clinician, I want to bring treatment to as many patients as I possibly can. And so for me, clinical trials, I would love to capture not only the disease severity based on genotype but also phenotypic characteristics. So it's probably beyond the scope of what I can say because I'm not the one really running the studies. But I do think based on what we see, if you have the more severe patient population responding as favorably, then it kind of you could potentially think through expanding that to capture more patients and maybe seeing even more of a robust response. But I don't know what your basis plans are for that.

Yes. I think it's a really important question. Based on the current severity criteria and also the hydroxyurea concomitant administration exclusion. We estimate it's about 20% currently of the total U.S. population and the sort of levers to push to broaden that are on the one hand, the patient severity itself, so decreased frequency of VOCs, for example, less end-organ disease.

And then the second big one is the concomitant HU. And I think we consider both of those to be important. And those will be issues that we'll be discussing with the regulators as we move forward with our plans for the next study and for studies beyond that potentially.

Yes. So those questions we're certainly going to pose in our end-of-phase meeting with the agency sometime in the first half of next year. And I think the way I think about this is I think about it sort of speed to market versus time in the clinic. And I will favor speed to market, getting this drug to the market as quickly as possible, having talk to people like Dr. Alan, having talked to patients and realizing that they really have very few treatment options today. I mean we have hydroxyurea, Voxelotor was pulled off the market. Gene therapy, as you said, is really not scalable. I think we estimate be 200 patients of the 100,000 in the U.S. have actually gone on gene therapy and crizanlizumab because of the failed confirmatory study really is not being commercially used that much in the U.S.

So to me, if it was stay in the clinic longer, say, for 1 year, 1.5 years, and broaden the patient population versus getting this drug to the market as quickly as possible and then look to expand that patient population while you're on the market, I think we would opt for speed to market as opposed to more time in -- on the development side. Any other thoughts you would add?

I think there's a general misconception of the severity of the pathophysiology of sickle cell disease. And historically, sickle cell disease has been pain. But that's not the only thing. And pain is a bad thing that is the worst thing for most patients. But even when they don't have pain, the diseases relentlessly progressing.

So the hemolytic anemia of sickle cell disease is a major cause of mortality and morbidity because it affects organs that don't necessarily immediately bring the patients to the clue, like to develop pulmonary hypertension, nephropathy, cerebrovascular disease. So expanding the treatment criteria to include patients who aren't totally crippled by pain. I think it's very important. Even when they're not having pain, have disease. I mean we implicitly recognize this because we start every newborn 9 months on hydroxyurea, right? They're not sick. But we know that they're going to be sick and they're going to be sick in many different ways. So I think that really expands the market for treatments that have the potential to really have an impact on the disease.

James has a question.

Great. James from Stifel. Congrats on the data. Maybe just one follow-up on safety. I think the color you gave around the reticulocytopenia case is really helpful and makes a lot of sense of why it's not drug related. And private cohorts you've shown individual kind of patient curve showing blood counts generally stay within the normal range. Is there any more color you can provide on some of these other patients in this cohort in terms of how their cell counts tracked and if there's any sort of outliers?

Iain, do you want to start?

Yes. So we haven't seen any treatment-related adverse events related to cytopenias. So neutropenia, lymphopenia, thrombocytopenia and so on. As we discussed earlier, the decrease in counts here, certainly, the neutropenia and the thrombocytopenia observed in this patient we're almost certainly related to that intercurrent viral infection in the treatment and/or the treatment with the antibiotics. And those accounts came back once Pociredir was reinstituted. So we don't think that those are drug-related effect.

I think you do see some movements on these accounts. We've discussed the reticulocytes in particular. Those come down as a reflection of the decreased stress on the bone marrow. And so that's a sort of therapeutic response, if you like. lot of these patients do come in with higher baseline white blood cell counts as well. And those tend to come down, but they -- we haven't seen that manifest as neutropenia AEs as such.

Great. Are there any more questions in the room okay? And I don't believe that there's any questions online.

So a couple of just follow-ups. First of all, thank you all for joining us, and thanks so much for your interest in the data. Dr. Alan will actually be doing an oral presentation on this poster today at the poster walk from 11:15 to 12:15 in Lecture Hall B3, B4. So if you all are heading over to the conference and are so inclined. There'll be another opportunity for Dr. Alan to present the data and also to take questions. And then finally, I always like to end here, which is none of this would be possible. None of this really, really provocative and potentially transformative data would be possible. It wasn't for the patients that decided to enroll in these trials. So really, our thanks go out to those patients, the caregivers and then also, most importantly, the investigators that work so closely with their patients to shepherd them through these trials. So on behalf of the entire team at Fulcrum, thank you all for joining.

Good morning, and welcome to the Fulcrum Therapeutics Third Quarter 2025 Financial Results and Business Update Conference Call [Operator Instructions] This call is being webcast live and can be accessed on the Investors 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 may include statements about the company's future expectations and plans, clinical development time lines 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. 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.

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 9x 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 12-milligram dose cohort of the Phase Ib 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 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. 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 20-milligram dose cohort with a total of 12 evaluable patients, and we 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- and 20-milligram cohorts is a testament to the enthusiasm from the physicians involved in the study. 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 at the -- 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. 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.

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 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 30, 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 and 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, cash equivalents and marketable securities of $200.6 million compared to $241 million as of December 31, 2024. The decrease of $40.4 million is primarily due to the cash used to fund our operating activities. And 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. 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 3 quarters of this year with 1 of 2 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. And with the opening remarks concluded, Shannon, let's go ahead and open up the line for questions.

[Operator Instructions] Our first question comes from the line of Kristen Kluska with Cantor Fitzgerald.

So I appreciate you disclosing the baseline characteristics for this cohort, and it looks pretty similar to what we saw for Cohort 3. 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?

Yes. Kristen, it's a great question. We're going to handle that in 2 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. 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 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 pancellularity.

We were seeing all of the markers of hemolysis going down as we would have expected and a subsequent increase in total hemoglobin nearing 1 gram per deciliter at the end of that 12 weeks. 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. So I would argue that I think we have one 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.

So 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 the -- basically the first half of patients that started on the study and what we plan to present at ASH coming up in December.

Yes, absolutely, Alex. 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 day 84 treatment visit at the time of the data cutoff that will serve the ASH meeting data presentation. And we expect that we should have 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 HbF 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 will be very important to accommodate the baseline for those 50% or so of the patients. And then obviously, when we release the full day 84 data, once everybody has completed the full treatment period, that will 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. 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.

Yes. Great question, Kristen. And you're absolutely right. I think that the timing of starting the OLE study was quite frankly, it was really borne out of discussions that I 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.

And so 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 to come off of -- once they come off of 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 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?

Yes. Happy to do that, Alex. So 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 3 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.

Our next question comes from the line of Joseph P. Schwartz with Leerink Partners.

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-milligram cohort that will get data on first and how it compares to the second half of patients who were enrolled?

Yes. 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.

Yes. 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 times of 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. But I think it is important just thinking ahead that overall, the trend there was just by chance, the initial patients enrolled in the cohort who are on average lower than the 7.1% mean.

Yes. And 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 day 84 by the time of ASH, we're looking really more like apples to oranges. And the way to account for differences in 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 6 milligram to the 12 milligram. 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 full deduction because that is one way to essentially sort of normalize for differences in the baseline. 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 7.1% and the 7.3% that we mentioned in our opening remarks.

Okay. Great. And then how are you currently thinking about the addressable market following Oxbryta withdrawal? And can you give us some insight into your assumptions that go into your current estimate?

Yes, 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 number of VOCs in the course of a given year. And our belief is that about 25% of patients have either 4 VOCs during a 12-month period of time or 2 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 hydroxyurea. 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 U.S. currently meet the inclusion/exclusion criteria as 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 costs and risks and the complexities of that therapy. So 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.

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

Maybe 2 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? And then what's included in the cash runway guidance with respect to the scope of the Phase III program? Maybe you could speak about duration and endpoints that would be included in that guidance?

Yes. 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.

Yes. Thanks, Corinne. So I think importantly, we'll be looking across the totality of the data in the 20-milligram 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-milligram dose cohort could well outperform that, which we observed at the 12-milligram cohort.

And I think one of the key learnings from the 12-milligram data readout as we compare there the 12-milligram to the previous 6-milligram 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 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 on 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've observed across both the healthy volunteers and the patients that we've treated to date.

Yes. And Corinne, 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 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. So it's sort of an all-in full success of what we have going on in the pipeline at this time.

Our next question comes from the line of Edward Tenthoff with Piper Sandler.

Thanks for all the detail that you provided. Really excited to see the results down in Orlando 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? 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 will be a poster or an oral presentation?

Yes. Two great questions, Ted. Yes. So the abstract that will be made public by ASH next Monday, November 3, does not include any of the data from the 12 -- sorry, 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.

And then in terms of whether it's a poster or an oral, 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 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 pociredir? Is it the percent 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?

Yes, it's a great question. And I'll start, but Iain will probably have a better answer than I will. In the -- and 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.

And when I sort of pressure tested your very -- your question with them, which is if you look across these 5 parameters, right, increasing levels of fetal hemoglobin, the pancellularity, the decrease in markers of hemolysis, the subsequent increase, number 4, 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 has shown to be very well tolerated.

I've asked that question, which of those sort of 5 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 pancellular 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 product. Iain, anything to add?

Yes. Sorry, go ahead, go ahead, please.

No, 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-milligram dose where about half of the patients were able to achieve that, I think, is particularly encouraging. 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 HbFs in the 2%, 3%, 4% range, often associated with very severe disease.

And for those patients to get right up into the 20s 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 there are 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 transformative 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?

Yes. 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.

Our next question comes from the line of Matthew Biegler with OPCO.

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 2 cohorts are largely similar in terms of baseline severity and like maybe the heterogeneity in baseline hemoglobin is just random variation.

Yes, it's a great question.

Yes, Matt, thanks. Yes, 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 -- the patients enrolling earlier just happened to have those lower baseline. I don't think it's a geographic aspect related to that you may want to mention...

Okay. Got you. Maybe a bigger picture question for me is then 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?

Yes. Iain, do you want to take that?

Yes. 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 milligram. 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 14-day mark when we escalated there from 20 milligram to 30 milligram. So based on that, along with the promising data that we've already seen at the 12-milligram cohort, in our expectations around the 20-milligram cohort. We're not planning to proceed with that 30-milligram dose.

Our next question comes from the line of Andres Maldonado with H.C. Wainwright.

Congrats on the progress. One quick one for me. So I guess when you have the 20-milligram data in hand, the question becomes, how do you feel how generalizable procedure's efficacy will be in the less severe patients? And can you maybe walk us through the mechanistic argument for why that will be?

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

Yes. And I think -- thanks, Andres. I think 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 12 and the 20-milligram 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 scale, so 6 milligrams and 2 milligrams and a few at 12 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 pociredir to induce HbF based on the patient's disease severity. And 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 trait. So they heterozygous 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 pociredir to induce HbF.

[Operator Instructions] Our next question comes from the line of Luca Issi with RBC.

Congrats on all the progress. Maybe Iain, a quick one actually on safety. Obviously, we appreciate that it's 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.

And then maybe just a quick one on the plan going forward here. Can you just talk about the clinical plan beyond this Phase Ib? Like 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? Again, any color there, much appreciated.

That's great. Yes, Luca, 2 great questions. Great to have you on the call as well. Iain, maybe I'll turn that one over to you.

Yes. Thanks, Luca. 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 I program back to the agency to discuss next steps with them. There was 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 benefit 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 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.

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 HbF 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.

Our next question comes from the line of Tazeen Ahmad with Bank of America.

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 though, 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 3.

Yes. Two great questions, Tazeen. I'll start and then I'll turn it over to Iain for maybe additional color. Yes. So as I mentioned in the question that Ted asked, the abstracts when they get released by ASH on -- 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. And we'll find out on Monday, whether that data has been accepted 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 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 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 like 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. So 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. If it's all the patients, we'll share that. So 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 in the 12 milligram, Iain, do you want to take that one?

Yes, sure. Happy to do that. Thanks, Tazeen. So as you will recall, for the 16 patients in the 12-milligram cohort we previously presented in the end -- at the end of July, the data for the full day 84 treatment period, we did not have the follow-up data. So there's a 4-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-milligram cohort.

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.

Good morning, everyone. Thanks for joining us here on day 3 of the Goldman Sachs Global Healthcare Conference. I'm thrilled to be joined this morning with the team from Fulcrum Therapeutics. Maybe I'll let you guys introduce yourself first and then provide a brief overview of the company.

Sure. I'm Alex, thank you all for joining. I'm Alex Sapir, I'm the President and CEO of Fulcrum. I've been there for about 2 years and have a long history of leading previous biotech company focused on rare disease.

Yes. My name is Iain Fraser. I head up early clinical development at Fulcrum and I've been there just a little over 2 years.

And Fulcrum, just by way of background, Fulcrum is a biotech company that is using small molecule technology to modify gene expression for rare diseases. And we've really decided to focus very much on non-malignant hematology. So we have a Phase Ib, very interesting Phase Ib asset in sickle cell disease, which I'm sure we'll talk a little bit about over the next half hour or so. By the way, the clock is not winding down.

And then in addition to that, we also have some other -- there we go. And then we also have some really earlier-stage assets, but for some other very, very interesting benign hematological conditions such as Diamond Blackfan anemia, Schwachman-Diamond syndrome, I'm sure we'll talk a little bit about that after we talk about our lead asset.

Absolutely. Okay. So maybe let's start with pociredir, the lead asset, as you said, in sickle cell disease. And let's start with like a brief refresher. What is the mechanistic rationale that underpins pociredir in sickle cell?

Sure. Iain, do you want to take that?

Yes. So pociredir fundamentally is an inducer of fetal hemoglobin. And that is a key mechanism in sickle cell disease that over many years now with genetic and pharmacological evidence has been shown to be protective in sickle cell disease and reducing the severity of the disease.

How it does that, it inhibits an enzyme called PRC2, which is responsible for regulating gene expression because of methylate histone and compacts the DNA in the nucleus and by inhibiting that PRC2 complex, you get less methylation of the histones, alterations in gene expression, and it turns out that one of the most highest up-regulated genes under those circumstances is the gene that encodes fetal hemoglobin to get a robust induction of fetal hemoglobin.

Great. So maybe talk to us about the role of fetal hemoglobin in sickle cell disease. And then what do we know about kind of the thresholds at which patients with sickle cell have fetal hemoglobin? At what point do they kind of reach normal activity and sort of the clinical manifestations of that?

Yes. It's long been known now that increased fetal hemoglobin decreases the severity of sickle cell disease. Initially, genetic evidence, patients who co-inherit sickle cell disease gene along with the gene for hereditary persistence of fetal hemoglobin, which is normally switched off after birth. Some individuals have continued expression of that. They have a fundamentally much milder course of their sickle cell disease.

We then move into the pharmacology, drugs that induce fetal hemoglobin and hydroxyurea is the main example of that. Induced fetal hemoglobin reduce the severity of the disease, not only the severity of the disease, but also the mortality associated with sickle cell disease. And then more recently, genetic evidence where interfering with the mechanisms that suppress fetal hemoglobin with gene therapy and stem cell transplantation, you can induce very high levels of fetal hemoglobin and essentially abolish the manifestations of the disease.

In terms of what the actual threshold numbers are, we know that for any individual patient, any increase in fetal hemoglobin is beneficial to them. It makes their disease less severe. We also know that once you get into the range of about 25%, so that's of all the total hemoglobin, 25% is fetal hemoglobin. That's when it becomes significantly transformative for these patients. Going above that doesn't hurt, but it doesn't incrementally change it. Things flatten out there. So small increases for individual patients are still clinically meaningful at around the mid-20s transformation.

So you mentioned pociredir as a fetal hemoglobin inducer, but what have you shown in preclinical or clinical settings in terms of that increase in fetal hemoglobin?

Yes. So preclinically, we've been able to show using CD34 positive cells that we differentiate, that you get a dose or an exposure-related increase in fetal hemoglobin as you increase the concentration of pociredir. That was reaffirmed in our first-in-human study. So not sickle cell disease patients, but healthy volunteers where you can look at the gene expression in the peripheral blood that HBG gene and we showed a dose response in that gene as we went up from placebo, which is flat. 2 milligrams gives you a little bump. And then as you go up from 2 to 6, 6 to 10, 10 to 20 at each of those doses, incremental bumps in the HBG mRNA, so the mRNA encoding fetal hemoglobin. 20 to 30 in that 2-week dosing period didn't show an incremental bump but between 2 and 20, clear dose response.

Moving to the patients where we now measure the protein in the cells in sickle cell disease patients. To date, we've dosed 2 milligrams, 6 milligrams and a few patients at 12. We have a cohort of 12 milligrams that's fully enrolled, a new cohort that is 16 patients, and that readout will be in the third quarter of this year. We had a few patients before that were dosed with 12 and in those patients, we were able to show 2 to 6, 6 to 12 dose responsive increases in fetal hemoglobin measured at the protein level.

Okay. So obviously, you had a couple of patients treated to 6, you said a couple of 12, but then there was a clinical hold that was put on the program. So can you talk to us about the history of that clinical hold and sort of what then had to happen in order to resolve it?

Yes, absolutely. So the clinical hold was instituted by the agency in February of 2023, was not based on any clinical data from the program. And at that point, we had about 100 healthy volunteers in our initial study and we've had 16 patients in the sickle cell disease study. So no clinical findings that were of concern.

The concern from the agency was that in the preclinical toxicology studies or in a subset of those preclinical toxicology studies, there was an observation of hematological malignancies in some of those animals. And that information, coupled with what the agency knew about an approved drug that is also a PRC2 inhibitor called tazemetostat or TAZVERIK, It's approved synovial sarcoma and lymphoma. And in their preclinical studies, they had had some hematological malignancies in their preclinical animals. And then in the pivotal clinical trial in patients treated for malignancy, they had a 0.7% rate of secondary malignancies. So these are patients who already had chemotherapy and/or radiation for their primary malignancy and then developed it during the exposure to tazemetostat, not a controlled study and in a patient population that's predisposed to those particular hematological secondary malignancies.

Nonetheless, FDA attributed those to drug. Because of that said, we, FDA believe that there's a risk associated with this mechanism, even though the exact molecular mechanisms are different. Tazemetostat inhibits a catalytic subunit, EZH2, pociredir inhibits an accessory or guide subunit called EED, but they both inhibit PRC2. Because of that, FDA said, we believe that early on in your development program, you should confine your studies to those patients that are most severely impacted by sickle cell disease and who don't have a lot of therapeutic options.

It was not a request to do additional studies in order to get back into the patient population. It was largely or exclusively a matter of redefining the patient population from what had been an all-comer sickle cell patient population to one with more severe disease with no therapeutic options.

And then so where we are now is, as Iain mentioned, in early '23, clinical hold was put in place 6 months after that, because the FDA was not requiring us to do any additional studies, we were off clinical hold 6 months into 2023, so third, fourth quarter of 2023. Spent a lot of time in 2024, identifying new sites that met this new, more severe inclusion/exclusion criteria for patients. So it really wasn't until, I would say, the fourth quarter of 2024, where we were able to really start actively enrolling in, as Iain mentioned, this new 12-milligram cohort followed by a 20-milligram cohort, which we're currently enrolling in.

Okay. Great. So you have mentioned now a couple of times is ongoing 12-mg cohort. There's a 20-mg cohort as well. Maybe you could just provide an outline of the current trial protocol and what you guys are evaluating in those studies?

Sure. I can take that one. Yes. So the study that we keep referring to is the PIONEER trial. It is a Phase Ib study, open-label, 4 cohorts in increasing dosages. So as Iain mentioned, we started with a 2-milligram cohort escalated to a 6, escalated to a 12, and we're currently enrolling in a 20-milligram cohort.

The third cohort, the 12-milligram cohort recently completed enrollment. We had a total of 16 patients in that cohort. And we will be sharing the results of that data, and we'll talk maybe in a little bit about what data we're planning to show. We should have that data to share with everybody in early in the third quarter of this year.

And then that 20-milligram cohort, Cohort 4, which is currently screening and actively enrolling patients, we should have that data by the end of the year. So really important year for Fulcrum and that we will have not 1, but 2 very important clinical readouts in patients during the next -- really during the next 6 months.

Okay. Great. And then maybe you can talk a little bit about the patient. Obviously, you've narrowed the patient population down. What are some of the other key inclusion, exclusion criteria in the patient population that you're enrolling?

Yes. So in the bucket of disease severity, the most common and frequent requirement for disease severity is based on counting acute events, these vaso-occlusive crises. And in order to get into the study, patients need to have experienced at least 4 of those episodes over the preceding 12 months or 2 over the preceding 6 months in order to get into the study. There are some variances on that. So there's an acute crisis called an acute chest that's more severe than a VOC so that gets counted as 2 VOCs essentially. But basically, it's those 4 VOCs.

There's also disease severity based on end organ disease. So there are some patients who have severe sickle cell disease may not be having frequent acute events, but they do have manifestations of the chronic hemolytic anemia. So they have renal insufficiency, right-sided heart disease, pulmonary hypertension. So -- are also permitted.

And then in addition to the disease severity, there's therapy-related criteria in order to get into the study. And these patients need to have at least tried hydroxyurea in the past. So that's the current standard of care and has been for over 30 years now. And they might have tried it and failed because they didn't get increases in fetal hemoglobin or an improvement in their clinical disease. They may have had adverse events to hydroxyurea and been intolerant to it. They need to have tried and failed in some respect. They also may not be on concurrent HU during the study. So those are the main inclusion/exclusion criteria.

Can you explain why people who are on concurrent HU are not included? And what the impacts might be in terms of the patient outcome?

Yes, absolutely. So this was something that came out of the clinical hold from the agency. It was not based on any experimental preclinical or clinical data. It was really governed by concern from FDA that HU itself is labeled as a carcinogen and has a black box warning for malignancy. And so what the agency said is given that there are potential concerns about PRC2 mechanism, and I think they're concerned about other epigenetic mechanisms as well because as we see other compounds that induce fetal hemoglobin by that mechanism coming into the clinic, they too seem to have this restriction on concomitant HU. So it's a theoretical concern around the mechanism of action.

There's no reason that patients who are on HU or cells that are exposed to HU would not also still respond to pociredir. On top of that, we have both preclinical and some early clinical data to support that because in the initial cohorts of patients that we studied, there were some of those on concomitant HU because the restriction was not in place at that time and those patients responded to pociredir pretty much as well as those that were not.

kay. You mentioned they had to activate new sites. Enrollment is now complete in the 12 mg ongoing in the 20. I guess could you talk about like the pace of enrollment into this study and sort of what you've seen, what you're seeing today and let us know if you feel confident in the 20 mg kind of time lines as you've laid them out?

Sure, sure. Yes. I think what we experienced, Corinne, was a very sort of typical type of enrollment curve for a study of this type. So you start off, very sort of like, I would say, the enrollment curve is very flat initially as physicians start to get experience with the trial and putting patients on drug and then getting feedback from those patients, again, this is an open-label study where all patients are receiving drug. And then I think because of that sort of positive feedback that some of those physicians may be getting from their patients, they start to get more excited about the study. They start to understand the operational nuances of the study and they start to enroll patients.

So what we saw end of last year, beginning of this year was a very much of a change in the slope of the enrollment rate that we've been seeing. And so in terms of your question about level of confidence of the 20-milligram cohort readout by year-end, we feel very confident based on where we are with that 20 milligram that we will be able to hit that previous guidance that we provided.

Great. I think you have shared some things around the baseline patient characteristics in the 12 mg cohort. Maybe you can remind us what that is and just how you -- should we expect something similar in the 20 or what should we be paying attention to there?

Yes. Yes. So the -- what we did disclose in our most recent earnings call was that those 16 patients had a baseline fetal hemoglobin level of 7.6. And that was the average. The median was 7.7, so very, very similar.

In terms of what to expect at the end of that study, I think as Iain mentioned, any increase in fetal hemoglobin is beneficial to patients. There's been some recent data that came out at ASH last year that essentially concluded by looking retrospectively at previous studies that had shown that for every 1% increase in fetal hemoglobin, you see about a 4% to 8% reduction in VOCs that if you can essentially increase that baseline fetal hemoglobin level from where it is today at sort of 7.6 to an absolute increase in what I would call the mid- to high single digits. So essentially, call it, a doubling of where they are today, that could be very sort of meaningful for the patients.

And the way that we think about that is, let's just take an average patient that has a 7.5. If you can double that from 7.5 to 15, call that 7x an 8% reduction in VOCs in that 4% to 8%, that sort of gets you that 50% reduction in vaso-occlusive crises which, again, many of the other drugs that have been approved for the treatment of sickle cell, looking at reduction in VOCs were right around that 50% reduction in vaso-occlusive crises at the 1 year part -- at the 1-year mark.

Okay. It's my understanding that there's also like just a function of time on therapy that drives the absolute change that you see in fetal hemoglobin. So with that in mind and considering the dose that you guys are doing with baseline hemoglobin, what would be a reasonable outcome for the 12 mg data? And then what would be reasonable at 20?

You want to take that?

Yes. So we see at the earlier doses, we see that the fetal hemoglobin seem to be plateauing around the 3-month mark. We haven't dosed longer than that, so we haven't defined that completely, but it seems to rise fairly steadily during that period. And I think that, that's a reflection of the turnover of the red cells. It's not a pharmacological parameter. It's just that the drug needs to act in the red cells and they need to undergo several cycles.

So during that 3-month period, you're seeing an increase in the fetal hemoglobin. And that seems true irrespective of the dose. What I think is different between the doses is the magnitude of change where you net out at the end of that period. And that seems to be what's different across the cohorts. And as I said earlier, from the healthy volunteers, we've previously seen that dose response from 2 to 6 to 10 to 20. And so we'd expect to see that as we get the protein data from the patients.

Okay. And in terms of -- like, obviously, the primary endpoint or the thing we're trying to understand is the change in fetal hemoglobin. Will vaso-occlusive crisis be counted in the study? Is there any reason to expect you'd see a benefit? Or is that -- is it too early for that?

Yes. So just as a quick reminder, so this is a Phase Ib study, open-label 4 cohorts, as I mentioned. So the primary endpoint of the study is obviously safety. So we will be -- that will be the one thing that we will really be focusing on to make sure that the drug is safe for patients. But then in addition to that, we will also be showing changes in fetal hemoglobin, as you mentioned. We'll also be looking at some other really important markers of hemolysis such as red cell distribution with bilirubin, total hemoglobin. So we've been looking at those as well.

In terms of your question about will we be showing VOC data. The simple answer to that is we will be. It is an important baseline characteristic, as Iain mentioned earlier. So these patients will have had to have had a minimum of 12 VOCs -- sorry 4 VOCs during a 12-month -- during the previous 12 months prior to enrolling in the study. So we will share those baseline characteristics. And then obviously, if the VOC happens during the 3 months that they are on study drug, that will obviously be reported in the AE table.

I would caution people not to read too much into the VOC data because, again, it's not an endpoint in the study. We don't have an adjudication committee. The way in which we were defining the VOC using medical records prior to initiation of the study is different than the how we're using -- than the criteria that we're using to define VOCs during the study. But the simple fact of the matter is -- data in early Q3 when we read out the 12 milligram and then at the end of the year with the 20.

Sorry, maybe just one additional point. Traditional VOC study is usually a 1-year study. We are looking at a 3-month endpoint. And so essentially during the entire 3 months, the hemoglobin is going to be going up. So we're not seeing a maximal effect until at least the end of that time. But as we said earlier, even small increases are expected to have some benefit. So just to bear that in mind as that data come out.

Okay. So with that in mind, you see 12, you see 20, let's assume for the case of the question that they show what you are hoping to see. What comes next from there in terms of the next kind of study that you would be running?

Yes. And this goes back to coming off the clinical hold and the discussions with the agency where the focus was on generating additional data to indicate whether or not this mechanism provides benefit to patients because I think that it's a question of what is the risk and benefit for patients who have this disease that's really still pretty significant in terms of not only morbidity but also mortality where the lifespan reduction is still about 20 years even in the U.S. So it's understanding the risk-benefit potential.

And what the agency discussed with us at that time was let's complete the study, let's finish the 12 milligram, let's finish the 20-milligram cohort, go back and discuss then what the next steps will be. And those next steps include can we lessen the inclusion/exclusion criteria to broaden it to less severely impacted patients that will be based on the data from the study? Is there potential evidence of benefit to allow that to occur? Let's increase the duration of the study. And potentially, that study could be a pivotal study. So it will be discussions around can we do that.

In addition, there's also the potential, we believe, for fetal hemoglobin in and of itself to act as a surrogate endpoint potentially for an accelerated approval. There's no precedent for fetal hemoglobin playing that role in sickle cell disease as yet from an approval standpoint, but there is really abundant evidence that links fetal hemoglobin to reductions in disease severity in sickle cell disease. And so that's another strand of the conversation that we'll be having with the agency.

Okay. So I want to clarify on both of those points separately. You mentioned that based on your conversation with the agency previously, you think it's possible that these studies, the Phase Ib that's ongoing would be sufficient to expand the patient population. Do you have any sense for kind of like what level of benefit or what they're going to be paying attention to? You can go...

Yes. So there are no pre-established or predefined bars and the response as you might expect, was bring us the data, we'll look at the data and make a decision there. So that's where it is.

I think based on what we know about fetal hemoglobin induction and its benefits in sickle cell disease that the data might be sufficient to drive that decision. And obviously, it depends on there being adequate acute safety and tolerability, which is what we've observed to date. And so it will be viewed both as the fetal hemoglobin induction, but also the overall safety of it.

Okay. And then I guess the other question from there is just like how quickly can you kind of meet with regulators and get some of these answers. When should we expect an update?

Yes. So as I said, it will be driven by the data coming out of the study if we need to complete the 20-milligram data. We said that 20-milligram data, we will release publicly around the end of the year. And so that gives a rough timing for when we expect to have that. And then that will trigger an end of Phase I meeting with the agency. So that will likely be early in 2026 based on the conduct of the study.

Okay. You mentioned that another key question is whether change in fetal hemoglobin is a good surrogate endpoint for a registrational study. Talk to us about like what a pivotal design would look like in the case they do agree to a surrogate versus what it would look like if you are to run sort of a full outcome study?

Yes. And I think those possibilities are still there. They haven't been decided yet. If you do, just in general, use a surrogate endpoint for a conditional approval, the rules are that you need to also conduct a confirmatory study. And so whatever your design is, it can either be a separate study with the accelerated approval in one study or it can, in fact, be part of the same study where you do an initial data cut around the surrogate endpoint and then continue the study in order to get the support of evidence, the support of clinical evidence to do that.

So how might that look for sickle cell disease, so HbF as a surrogate endpoint you might expect that at the 6-month mark, you could potentially get a read on that, that would be sufficient as a surrogate endpoint. We know that traditionally, historically, the 1-year mark has been used for clinical readouts like VOCs. And so base case without an accelerated approval, it would be a 1-year study with a VOC-like primary endpoint for an accelerated approval could be a 6-month readout on that and then either a separate study or the same study continued in order to derive the 1-year data.

In terms of like roughly the number of patients that you think there will be both an efficacy component and a safety component, what do you understand in terms of maybe both?

Yes. So a little early to say without the fine details of the design. But from an efficacy standpoint, a few hundred patients typically would be required to drive that. So 200, 300 patients in that sort of broad range.

From a safety point of view, that's something, again, that we'll be discussing further with the agency. Base case in these types of diseases is agency typically looking for 100 patients exposed for a year on treatment, but they've shown some variability around that. So that's a key topic that we'll be discussing.

Okay. Maybe we could spend some time on the market size. First, you could talk about like kind of the overall sickle cell population? And then can you help us understand the carve-out that you're currently limited to versus what sort of unlocks if you're able to go into a broader patient population?

Sure. I'm happy to take that. Yes. So I think just in terms of the prevalence of the population. In the U.S., there's approximately 100,000 patients that suffer from sickle cell disease. Globally, the estimates are anywhere from 4 million. I've actually seen all the way up to 8 million. A large percentage of the non-U.S. prevalent population obviously resides in sub-Sahara Africa. About 95% of all sickle cell patients are black.

I will say before I talk in more detail about some of the other questions that you asked about, I think that the other thing that's also really important to mention is the unmet need is extremely high in this patient population. There was about a year ago, there was a recent withdrawal, a product called voxelotor, which was a product that was being marketed by Pfizer. Unfortunately, that got withdrawn from the market. The cell and gene therapies really have not seen the uptake that people would have expected. And I think that obviously has to do with the complexity of the treatment, the cost of the treatment, the risk associated with myeloablation. So this market is really one in which I think there's a very, very high unmet need.

As Iain mentioned earlier, there's a lot of interest in fetal hemoglobin induction. There's a number of other companies that are also approaching this from a fetal hemoglobin induction perspective, albeit with different mechanisms of action. So I think over the next couple of years, what you will probably see is continued sort of interest and investment around the fetal hemoglobin sort of mechanism as opposed to the anti-polymerization mechanism, which others are studying such as the voxelotor drug that I mentioned have been withdrawn and probably the next latest stage asset is mitapivat by Agios.

Okay. Maybe then you could talk a little bit about the competitive landscape as you see it. Maybe let's talk about like how do you see the sickle cell market evolving with the advent of potentially new therapies? Is this going to be polypharmacy, sequential use? And where would an HbF inducer fit in that context?

Do you want to start and then I can jump in?

Yes, sure. I think there's certainly a recognition that HbF induction really is a key mechanism in the disease. I think there are gene therapy, particularly the CRISPR Vertex therapy, which specifically induces fetal hemoglobin has really confirmed that. So I think there's a lot of interest in that as being a holistic treatment, if you like, for sickle cell disease.

I think there's likely a place for drugs like the PK activators that do not induce fetal hemoglobin. They bind directly to the hemoglobin or they alter the environment within the red cells to change the affinity of the hemoglobin for oxygen. And those PK activators have clearly been shown to decrease hemolysis and also to increase total hemoglobin. And so that's clearly the mechanism of action there.

The impact on the other manifestations of the disease, particularly the acute events associated with sickle cell disease are a little more questionable and I think that's a key focus for what will be coming out there. So those compounds might be particularly efficacious for patients whose total hemoglobin doesn't seem to be rising. So that might be the niche for that, and we'll have to see. But I think the fetal hemoglobin mechanism really offers the potential to really reduce the hemolysis as well as have an impact on these acute events.

Yes. And I think ultimately, in answer to your question about polypharmacy, I think ultimately, it will come down to how strong the data is with the oral HbF inducers, as Iain mentioned at the outset. If some of these oral HbF inducers, such as pociredir at the 20-milligram can get those patients to a sort of mid-20%. And as Iain mentioned, that's essentially transformative for patients. Monotherapy may be adequate. If they're not able to do that, it could be a combination of multiple HbF inducers, targeting different pathways.

So I think ultimately, I think we'll learn a lot over the next couple of years based on the data that's going to be generated by us this year and by others in subsequent years.

Okay. I know we only have a few minutes left. So maybe you can briefly do the pipeline?

Sure. Sure. Do you want to talk a little bit about some of the year-to-date aplastic anemia we're looking at?

So what we've disclosed is that by the end of the year, we expect to be submitting an IND for a compound that is targeted at a disease called Diamond Blackfan anemia. That's a genetically inherited aplastic anemia. It affects about 2,500 to 3,000 individuals in the U.S. and is very underserved in terms of what therapies are available.

So they typically treat it with transfusion, so red cell transfusions, which have all the complications associated with repeated transfusions, including iron overload and corticosteroids, some of which -- some of the patients respond to and then lose responsiveness, and then, of course, that's associated with its own complications over time. So this would be targeting the mechanism of action of that disease.

We haven't yet disclosed the molecular basis of that mechanism, but we believe that, that is also likely to be applicable in some of the other inherited genetic aplastic anemia such as Schwachman-Diamond syndrome, Fanconi anemia, 5q minus. So there's a number of these rare genetically inherited conditions that all end up with affecting the bone marrow and its ability to produce red cells, and this mechanism might be applicable there. So that's the next step in terms of getting into the clinic. We also have a robust discovery effort looking at other end users of fetal hemoglobin, and that continues to be a focus in the lab.

Maybe a final question here. Just remind us the cash balances and the runway. In particular, what activities are embedded in that runway?

What?

What activities.

Yes, yes. Okay. Yes, I think in today's market, we're in a very enviable position in terms of our balance sheet. At the end of Q1, we had a balance sheet of $226 million of cash. We've guided that this year, we will burn somewhere between $55 million and $65 million. So take the sort of midpoint of that of, call it, $60 million. First quarter, we burned slightly under $15 million. So we have a balance sheet -- or sorry, a cash runway that takes us out into at least 2027, and that is assuming success on the pociredir program in terms of advancing to the next clinical trial in 2026 as well as bringing some of the other products that are currently in discovery for which we're going to be filing our first IND at the end of this year, bringing those into the clinic as well.

So essentially assume success of the entire pipeline that we're currently working on.

Beautiful. Well, thank you guys for the time this morning. I appreciate it. Thanks everyone joining us here and online.

Yes. Thank you all. Thanks so much.