Fulcrum Therapeutics, Inc.

Good morning, and welcome to the Fulcrum Therapeutics Third Quarter 2025 Financial Results and Business Update Conference Call. Currently, all participants are in a listen-only mode. This call is being webcast live and can be accessed on the Investors section of Fulcrum's website at www.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 any obligation to do so. Please refer to Fulcrum's most recent followings 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. 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, 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, POSIRDIR, for the treatment of sickle cell disease, which is an inherited blood disorder with a high unmet need, afflicting approximately 100,000 people in the U.S. and approximately 7.7 million people worldwide. There is an ever-increasing need for better treatment options for sickle cell disease patients who face not only an impaired quality of life due to chronic pain, fatigue, and acute complications like vaso-occlusive crises, but also very high rates of mortality. Patients with sickle cell disease face a greater than 20-year reduction in life expectancy with a mortality rate that is nine times higher than the general population. 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 1b pioneer trial, which demonstrated a potential for POSIRIDER to meaningfully improve outcomes for people with sickle cell disease. Digging into that data a little bit more at a high level, Poseradir 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, POSIRADIR continued to be well tolerated with all treatment AEs being grade one in severity and all resolving during the treatment period without any disruption in study drug. These encouraging results achieved our target product profile criteria and position POSIRADIR 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 Posiridine 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'll 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 in time to participate in the 12 milligram cohort. The mean and median HPF 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 POSIRADIR has the potential to provide a differentiated therapeutic option for people living with sickle cell disease. We look forward to sharing additional results from the Pioneer Trial at the upcoming ASH conference in December, and we plan to engage with the FDA for an end of phase one meeting in Q1 of 2026 to align on the next stage of our clinical development for Pociridae. Now, outside of Pociridae, we continue to advance our program for the potential treatment of bone marrow failure syndromes, such as diamond black fan anemia, 5Q deletion syndrome, Schwachmann-Diamond syndrome, and Fanconi anemia. And we plan to submit an IND for these benign hematological conditions in the fourth quarter of 2025. Additionally, we recently presented preclinical data at ESMO this month for FTX6274, an oral EED inhibitor, which demonstrated robust efficacy in castration-resistant prostate cancer models. We are encouraged by these findings, which highlight the potential of EED inhibition beyond our current hematology programs. 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 Los Mapamad program, partially offset by increased costs relating to advancing our posterior program. The general administrative expenses were $7.6 million for the third quarter of 2025, compared to $8.4 million for the third quarter of 2024. The decrease of $0.8 million was primarily associated with decreased professional services costs. The net loss was $19.6 million for the third quarter of 2025 compared to a net loss of $21.7 million in the third quarter of 2024. Now, turning to the balance sheet, we ended the third quarter of 2025 with cash, 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 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 Beceradier. And with that, Alex, let me turn the call back over to you.