Fulcrum Therapeutics, Inc.

Greetings and welcome to Fulcrum Therapeutics' fourth quarter and full year 2022 earnings conference call. At this time, all participants are in a listen-only mode. A brief question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Chris Calabrese. Thank you, Chris. You may begin.

Thank you, and good morning. Welcome to the Fulcrum Therapeutics fourth quarter and full year 2022 financial results and business update conference call. Please be reminded that remarks made during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about the company's future expectations and plans including the clinical hold of FTX 6058, clinical development timelines, and financial projections. While these forward-looking statements represent Fulcrum's views as of today, they 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 filings 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 Dr. Robert J. Gould, Interim Chief Executive Officer of Fulcrum, who will provide a corporate overview and will discuss key pipeline updates. Esther Rajavulu, Chief Financial Officer, who will cover the financials before we open the call for Q&A, and Dr. Alan Ezekiewicz, member of the Fulcrum Board of Directors, who will serve as a Senior Clinical Advisor, will be able to answer questions during the Q&A portion of the call. With that, it's my pleasure to turn the call over to Robert.

Thank you, Chris. Good morning. I appreciate everyone taking the time to join us today. We provided several important business updates this morning in our press release in 10K, including additional color on the FTX 6058 full clinical hold, data from the now suspended 12 milligram cohort of the phase 1B sickle cell disease trial, updated guidance on our cash runway, and changes to our management team. Let me start by discussing our most recent updates to the FTX 6058 program, our oral HPF inducer for the potential treatment of patients with sickle cell disease. As we announced on February 24th, we received verbal notification from the FDA on February 23rd that they had placed a full clinical hold on the investigational new drug application for FTX6058, and we received the formal clinical hold letter from the FDA on February 24th. We immediately suspended dosing and paused enrollment in the Phase 1B trial. In its communication to us, the agency noted that the hold related to both preclinical data previously submitted in April, October, and December 2022, and nonclinical and clinical evidence of hematological malignancies observed as other inhibitors of the Polycoma Presa Complex 2, or PRC2. The agency specifically noted that the profile of hematologic malignancies observed in the nonclinical studies of FTX6058 is similar to that observed with other inhibitors of PRC2, and that hematologic malignancies have been reported clinically with other PRC2 inhibitors. The agency requested that Fulcrum further define the population where the potential benefit of continued treatment with FDA Act 6058 outweighs potential risk. The hold was not a result of any clinical finding in the Phase 1B trial that was ongoing at the time of the hold. Prior to the clinical hold, we had completed dosing at 6 milligram dose and were completing dosing patients in the 2 milligram cohorts And we're enrolling and dosing the 12-milligram dose cohort. In early January, we shared data from the completed 6-milligram cohort with 10 patients that demonstrated up to 9.5% absolute HPF increases from baseline and similar treatment responses to FDX6058 in subjects on and off background hydroxyurea. We also shared partial data from the ongoing two milligram cohort in January. This morning, we provided an updated data set from the two patients that completed dosing in the two milligram cohort and the now suspended 12 milligram cohort in which we enrolled three patients. The two milligram patients that completed 84 days of dosing achieved absolute HPF increases up to 4.6% through the end of treatment suggesting 2 mg is a potentially minimally efficacious dose. Data from a patient in our 12 mg cohort who completed 42 days of treatment demonstrated absolute HPF increases up to 10%, as well as improved biomarkers of hemolysis. A way of comparison, at this same early time point of 42 days, adherent patients at the 6 mg dose had an average increase in absolute HPF of 4.5%, while adhering patients at the 2-milligram dose had an average increase in absolute HBF of less than 1%. So these new data continue to support a significant reduction of HBF as well as a robust dose response effect. All three subjects at the 12-milligram dose also had an increase in hemoglobin of at least 1 gram per deciliter at the 28-day study time point, with one subject achieving a 2 gram per deciliter increase by day 42. We find these initial data to be highly encouraging and further supportive of the clinical potential of this drug. FTX6058 has generally been well tolerated to date with no drug-related treatment emergent serious adverse events or discontinuations due to treatment emergent adverse events. All adherence subjects showed clinically relevant improvement in the 6 and 12 milligram dose cohorts, consistent across subjects both on and off background hydroxyurea, which is the current standard of care. These clinical data gave us great confidence that FTX6058 has the potential to provide a differentiated therapeutic option for people living with sickle cell disease and a favorable benefit-risk profile. We remain committed to 6058's further development and look forward to working closely with the FDA to address all outstanding concerns as rapidly as possible. We will provide an update once we have more clarity on the path forward. For now, we are suspending our previous guidance to complete the Phase 1B trial and our guidance to select a registration enabling dose in the fourth quarter of 2023. Now turning to our most advanced program, losmapinib, a selective P38 alpha beta mitogen activated protein kinase inhibitor. Losmapinib is in phase three development for the treatment of FSHD. FSHD is an autosomal dominant genetic form of muscular dystrophy, which has an estimated patient population of 16,000 to 38,000 in the United States alone. It is characterized by progressive muscle death and fat infiltration, and results in the inability to perform daily life activities due to a significant impairment of upper extremity function, loss of mobility, and chronic pain. Although it's one of the most common forms of muscular dystrophy, there are currently no approved treatments. And we believe Los Matamoros has the potential to address the urgent need for a safe and effective disease-modifying treatment that can slow or stop disease progression. We initiated REACH, our double-blind placebo-controlled phase three trial of Lasnavamon in June 2022, and are currently enrolling patients in the U.S., Canada, and Europe. The trial is expected to enroll approximately 230 adults, and we are on track to complete enrollment in the second half of 2023. The primary endpoint is the absolute change from baseline in reachable workspace, or RWS, a quantitative measure of upper extremity range of motion and function that specifically evaluates shoulder and proximal arm mobility with 3D motion sensor technology. Preserving this upper extremity function is critical for maintaining the ability for self-care and other activities of daily living that directly influence quality of life and independence. In addition to safety and tolerability, secondary endpoints include muscle fat infiltration, or MFI, an important marker of disease pathology, and self-reported outcomes such as the patient global expression of change or PGIC and quality of life measures. These will include healthcare utilization questionnaires that will inform our thinking about payer strategy as we prepare for a potential commercial launch. REACH was designed as a highly efficient 48-week trial and is intended to be registration enabling both in the U.S. and in ex-U.S. geographies. We are confident that we have selected reliable measures of disease progression, and we hope to demonstrate meaningful advantages for losmapamon compared to placebo. Encouraging, our Phase IIb Redux IV trial demonstrated significant improvement in RWS relative to placebo at 48 weeks. Furthermore, top-line results from the ongoing open-label extension show that participants in the initial treatment arm who continue to receive losmapamon demonstrated durability of effect through a 96-week period. Additionally, patients who crossed over from placebo to losmapamod after the initial 48-week trial period showed improvement and slowing of disease progression as measured by RWS mean change from baseline. We believe these data support the disease-modifying potential and long-term benefit of losmapamod. To date, losmapamod has been dosed in over 3,600 patients across multiple therapeutic areas, and results from REDUX-IV and our open label extension trial provide evidence of an encouraging safety and tolerability profile. We have reached alignment as regulators in the US and Europe on the primary endpoint for REACH, and as we drive our clinical path forward for Los Matamoros, we'll continue to leverage the large safety database and build on our learnings from REDUX-IV and ongoing open label extension trial. Now turning to other corporate matters, we announced this morning that Dr. Santiago Arroyo, our chief medical officer who joined us in November 2022, resigned from the company late last week, effective March 7th, to pursue another opportunity. We are excited to appoint Dr. Ian Frazier as interim CMO effective today. Dr. Frazier brings over two decades of experience in advancing therapies through early and late stage development and possesses deep expertise in regulatory affairs. He most recently served as vice president and clinical fellow at Allovir, an Elevate Bio company. He previously held clinical development roles of increasing responsibility at Abide Therapeutics that was acquired by Lundbeck in 2019. And prior to that was part of the clinical development organization at Merck. In addition to Dr. Frazier joining us, Dr. Alan Azikowitz, member of the Fulcrum Board of Directors since February 2017, will serve as a senior clinical advisor to ensure program continuity. With that, I will turn the call over to Esther to provide an update on our financials.