Good morning, and welcome to Fulcrum Therapeutics' first quarter 2026 financial results and business update conference call. Currently, all participants are in a listening mode. 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 timelines, and financial projections. While these forward-looking statements represent Fulcrum's views as of today, this should not be relied upon as representing the company's views in the future. Fulcrum may update these statements in the future, but is not taking on an obligation to do so. Please refer to Fulcrum's most recent files 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 Sapier, CEO and President of Fulcrum. Joining Alex on the call are Alan Musso, Chief Financial Officer, and Dr. Ian Frazier, 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, 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 I-B Pioneer trial of Posteriodere 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, 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 posiridere taken once daily demonstrated a robust and clinically meaningful increase in HBF from 7.1 percent at baseline to 19.3 percent 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 seven of the 12 patients experiencing no VOCs during the 12-week treatment period. And importantly, Poseradir 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 Poseridere's potential to address the underlying biology of sickle cell disease and support our belief that Poseridere 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 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 posterity. We also continue to support initiatives aimed at improving the care journey for people living with sickle cell disease, including our recent collaboration with MedicAlert 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 Pocere Deer, 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 posterior deer through the next phase of clinical development. Now, before turning it over to Alan, I want to cover two other important corporate updates. First, I want to welcome Josh Lurer 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 Oxbrita. We are honored to have Josh join 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, I'll turn it over to Alan to review our financial results, and again, Alan, thanks for all you've done for Fulcrum. 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'll now go our results for the first quarter ended March 31st 2126 the research and development expenses were 14.1 million for the first quarter of 2026 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 of marketable securities of 333.3 million compared to 352.3 million as of December 31st, 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 Posteriodeer through the next phase of clinical development. And with that, I'll turn it back over to you all. 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 Posteriodeer'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 POSIRDIR 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?

Thank you. As a reminder, to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compel the Q&A roster. Our first question comes from the line of Joe Schwartz with Lee Rink Partners. Your line is now open.

Hi. Thanks for taking my questions. 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 lessons shape your Phase III design and execution?

Yeah, it's a great question, Joe, and I may start, and I'll also turn it over to Ian to see if he wants to add anything. I mean, I think the one 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, population, especially in the severe patient population that we studied in the Pioneer trial and the severe patient population that we would expect to continue in our next phase of clinical development. I would say that's learning number one. I would say learning number two is that there is such a strong connection between fetal hemoglobin and reduction in VOCs. And, you know, we've known this for a long time, but, you know, spending time as much as I have with people like Marty Steinberg, who has spent decades researching the underlying biology of fetal hemoglobin, you know, he says it 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 two things taken together, one 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, you know, that's really, I think, what continues to, you know, motivate me and make me excited for the next, you know, for the next phase of this ACID's journey along the clinical development timeline. Ian, 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. Thanks. 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 Poseridae so far in terms of that clinical profile to support your case?

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

Yeah, thanks, Alex. Thanks, Joe. You know, 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 one 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

Thank you. Yeah. Thanks, Joe. Next question, Shannon?

Our next question comes from the line of Anupam Rama with J.P. Morgan. Your line is now open. Anupam Rama, your line is open. Please check the mute button.

Oh, yeah. Thanks, guys, so much for taking the question. And Alan, best wishes on the retirement, ma'am. So at the Sickle Cell Disease Research Symposium, will there be any new analyses that will be 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 1B. What portion of the patient from Pioneer went to the OLE, and could we see that update maybe around ASH?

Yeah, maybe, let me, I'll answer the second question, and then, Ian, I can turn it over to you to answer the first question. Yeah, so we have enrolled our first patient in this open-label long-term dosing for post-SERIDER. Right now, ONAPOM, 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 posiridere. We don't think we'll get all of them. Some may be lost to follow-ups. Some may be in other clinical trials. But I think given what we've heard from investigators in terms of the interest level in going back on therapy, we should expect to see a decent number of that 17. You know, if you ask me to, you know, try to predict is ASH 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, you know, 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 are dosed for longer, 24 weeks or six 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 as 2026.

Thanks so much for taking me. Thanks for taking the second question.

Yes. Yeah, this is Ian. I can handle that one. So we've indicated that we expect to provide a fulsome reporting 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. Thanks so much for taking our

questions. Yeah, thanks, Anna Pom. Shannon, next question? Our next question comes from the line of Kristen Klasko with Cantor. Your line is now open. Hi, good morning, everybody, 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? Yeah, 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 break the question up into two 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 FDA? I think what we've, 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 a standing room only, and towards certain parts of the meeting, there were very few dry eyes in the house. And so I think that, you know, 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, end organ damage, leg ulcers, I could go on and on. And so I think that it's important that, you know, the senators and congressmen on the sickle cell disease caucus, on the rare disease caucus, on the doc caucus, they understand that and can help sort of lend their support in terms of how high the unmet need is in this patient population. So I'd say that's, I would say, more on the Hill side. I think on the FDA side, you know, I would point you to Agios' recent press release that showed that they will be moving forward with filing an SNDA in the coming months for sickle cell disease with metipivet. And we think that what that shows is, you know, 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.

Ian, anything you would want to add to that?

No, I think you covered the key points really well, Alex. You know, 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 post-Syrodeer.

Thank you. 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 endpoints 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? Thank you again, everyone.

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

Yeah, thanks, Alex, and thanks, Kristen. So as we've indicated before, at the 12-week treatment duration with posiridia, the HBF levels are starting to flatten out, but we don't believe they've reached their peak level at that point. And so one 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 markers, markers 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 markers. 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 post-siridia for some time, so it's not the traditional open-label extension where they roll over immediately into that. So they'll be starting from a new baseline, but it's the extended dosing duration in particular that we're interested in tracking.

Thank you. Yeah, thanks, Kristen.

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

Thanks, and congratulations to Alan as well from all of us in terms of the retirement. Maybe a question for us in 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 PASER to play, particularly if there's more kind of oral medications that come to market over the next

couple of years? Thanks. Sure, absolutely. I'll start and then Ian, you may want to add some additional points that I maybe leave off. So yeah, I think the way we think about this, Kristen, is there's sort of oral and it's interesting. This market is one that I think will grow exponentially over the next five 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 toward the oral treatment options. And there's really, to us, we think about this as sort of two different approaches. One is sort of operating downstream on the mature red blood cells like the PK activators do. 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 fetal hemoglobin and are formed and 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 the upstream underlying cause of the disease as we're doing with posterior deer, we believe that that will ultimately be the treatment of choice as we look over the next five 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 closest oral HBF inducer would be BMS's product, BMS 986, which is a dual degrader, WIS and ZBTB 7A or LRF for short. So they're currently in the clinic in a phase one study, and they expect to announce the results of that phase one 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 three study, while the next closest competitor, BMS, is reporting out their phase one study results in 2027. And so, you know, maintaining that two-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. Ian, 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 points, 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 induces. Thank you. Thanks, Corinne.

Shannon, next question. Our next question comes from the line of James Condolas with Stifo.

Yolan is now open. Hey, thanks for taking my question. And I'll add my congrats as well, Alan. Maybe just one sort of kind of on the competitive landscape and all these regulatory dynamics. You know, 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, you know, if a drug were to be approved on VOCs, does that sort of change what the FDA may be open to approving, you know, as it relates to endpoints that are not a VOC endpoint? Just curious your

perspectives there. Thanks. Yeah, James, great question. Maybe just to orient everybody, they did have a co-primary total hemoglobin and VOCs, and they hit on that. It was a 27% reduction in vaso-occlusive crises, so very similar to the percent reduction in VOCs that we saw with another product that's currently approved, and generally not widely used, a product called L-glutamine that's all a 25% reduction in VOC. So I wanted just to make sure that everybody on the call was oriented to specifically what James was talking about. Ian, maybe I'll have you sort of take the heart of James's question, which is really around if there's any potential sort of read-through with Pasir-Dir and our path

forward. Ian? Yeah, 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 endpoint. Great. Thanks, James, for the

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

is not open. Great. Thanks so much. Thanks and 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 know, you mentioned PKR activators and some of the other quote-unquote 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? Thanks. Yeah, it's a really

good question, Matt. And 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, you know, 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-to-phase meeting with them. But we do see that as an important part of the ongoing clinical development program for post-siradir. Yeah, I think, Ian, maybe if you want to take kind of maybe just beyond HU, is there, you know, the idea of possibly combining an HBF inducer with potentially a PK activator and potentially, you know, operating on different mechanisms and potentially seeing greater efficacy than either one could achieve on their own?

Yeah, yeah, 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. You know, I think as we think of those, however, our primary objective at the moment really is to generate an interpretable data set with posterior 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.

yeah i think that's well said ian thanks again thanks man our next question comes from the line of gregory rinza with truest securities your line is now open great good morning everyone and

thanks for taking my question and also let me add my congratulations to alan on his service at fulcrum and in the in the industry alex i know of course that the focus is on on posterior 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 HPF 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? Thanks so much.

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

Yeah, 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.

Yeah, it's great. And then, yeah, I think, Greg, in terms of your first question, you know, our discovery efforts, so 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 of 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 posiridira once it eventually hits the market. I think at this point, it's a little bit premature, Greg, to kind of estimate when we would start seeing things coming out of our discovery efforts and conducting those IND enabling studies. But I will say that, you know, 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 Pocera Deer, given how we see this market evolving over the next five to 10 years. That's really helpful. I appreciate

all the callers. Yeah, thanks, Greg. Thank you. 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.