Fulcrum Therapeutics, Inc. is a clinical-stage biopharmaceutical company focused on developing small molecules to improve the lives of patients with genetically defined rare diseases. The company's pipeline is anchored by two lead clinical-stage product candidates, losmapimod and pociredir, which are being evaluated for the treatment of facioscapulohumeral muscular dystrophy (FSHD) and sickle cell disease (SCD), respectively.
Business Overview
Fulcrum Therapeutics was incorporated in 2015 and has since been dedicated to identifying and validating cellular drug targets that can potentially modulate gene expression to address the root causes of genetically defined rare diseases. The company's lead product candidate, losmapimod, is an oral small molecule selective p38 alpha/beta MAP kinase inhibitor that has demonstrated the ability to inhibit DUX4 expression and prevent downstream muscle death in patients with FSHD. FSHD is a rare form of muscular dystrophy with an estimated U.S. prevalent patient population of 30,000. The disease is characterized by a slow but relentless loss of muscle function, resulting in significant impairment of upper extremity muscle function and mobility, with 20% of patients becoming wheelchair-bound.Losmapimod Clinical Development
Fulcrum's Phase II ReDUX4 trial of losmapimod in FSHD, recently published in Lancet Neurology, demonstrated improvements in functional outcomes, structural outcomes, and patient-reported outcomes compared to placebo. Building on these encouraging results, the company completed enrollment of 260 patients in the global Phase III REACH trial in September 2023.The REACH trial's primary endpoint is the change from baseline in the relative surface area (RSA), a quantitative assessment of reachable workspace that correlates with the ability to perform activities of daily living. In the Phase II study, losmapimod demonstrated a 10% net change in the RSA score relative to placebo at 48 weeks. Fulcrum is currently assessing the extent to which a specific change in the RSA score is meaningful to patients, in collaboration with the FDA's Clinical Outcomes Assessment Group. Key secondary endpoints include muscle fat infiltration, shoulder dynamometry, and patient-reported quality of life measures.
Pociredir Clinical Development
Fulcrum's other clinical-stage product candidate, pociredir, is an oral HbF (fetal hemoglobin) inducer being developed for the treatment of sickle cell disease (SCD). SCD is a lifelong inherited blood disorder that severely impairs quality of life for approximately 100,000 people in the U.S. and 4.4 million people worldwide. The standard of care for SCD has historically involved blood transfusions, pain medications, and hydroxyurea, all of which only provide symptom relief.In August 2023, the FDA lifted the clinical hold on Fulcrum's Phase Ib PIONEER study of pociredir in SCD. The company is now working to reinitiate the study, with Cohort 3 evaluating pociredir at a 12 mg once daily dose and Cohort 4 evaluating a 20 mg once daily dose, each for a 3-month treatment duration. Prior to the clinical hold, the PIONEER study had demonstrated that pociredir increased total HbF by up to 10 percentage points from baseline, or approximately 25% total HbF, after just 42 days of treatment.
Sanofi Collaboration for Losmapimod
In May 2024, Fulcrum announced a collaboration and license agreement with Sanofi for the development and commercialization of losmapimod outside the United States. Under the terms of the agreement, Sanofi will obtain exclusive commercialization rights for losmapimod in ex-U.S. markets, while Fulcrum will retain rights in the U.S. and focus on planning for a strong domestic launch. Fulcrum will receive an $80 million upfront payment, as well as up to $975 million in potential regulatory and sales milestones, and tiered royalties ranging from the low-teens to mid-twenties on Sanofi's annual net sales of losmapimod outside the U.S. The companies will also share global development costs for the product.This partnership allows Fulcrum to leverage Sanofi's exceptional regulatory, development, and commercial capabilities across approximately 100 countries outside the U.S., while the company concentrates its efforts on the lucrative U.S. market. Sanofi's deep expertise in the neuromuscular space, including with products like Fabrazyme and Cerezyme, is expected to be invaluable as Fulcrum navigates the regulatory and reimbursement landscape for losmapimod in ex-U.S. markets.
Financial Performance
For the full year 2023, Fulcrum reported annual net income of -$97.3 million, annual revenue of $2.8 million, annual operating cash flow of -$91.0 million, and annual free cash flow of -$91.5 million. In the first quarter of 2024, the company had no collaboration revenue, compared to $0.3 million in the prior-year period. Research and development expenses increased to $19.8 million in Q1 2024 from $16.7 million in Q1 2023, primarily due to the advancement of the REACH clinical trial for losmapimod. General and administrative expenses decreased to $10.1 million in Q1 2024 from $11.5 million in Q1 2023, driven by lower employee compensation costs.As of March 31, 2024, Fulcrum had $213.3 million in cash, cash equivalents, and marketable securities. On a pro forma basis, considering the $80 million upfront payment from the Sanofi collaboration, the company's cash position increases to $293.3 million. Fulcrum now expects its current cash resources, together with the Sanofi payment, to fund its operating requirements into 2027.
Risks and Challenges
Fulcrum faces several risks and challenges common to clinical-stage biotechnology companies, including the inherent uncertainty of drug development, the need to obtain regulatory approvals, and the ability to successfully commercialize its product candidates. The company's lead programs, losmapimod and pociredir, are still in clinical development, and there is no guarantee that they will ultimately receive marketing approval or achieve commercial success.Additionally, Fulcrum's ability to generate revenue is currently limited, as it has not yet commercialized any products. The company's future success will depend on its ability to successfully develop, obtain regulatory approval for, and commercialize its product candidates, either independently or through strategic partnerships. Failure to do so could have a material adverse effect on Fulcrum's financial condition and results of operations.
Outlook and Catalysts
Fulcrum remains on track to report topline data from the Phase III REACH trial of losmapimod in the fourth quarter of 2024, which will be a key milestone for the company. The successful completion of this trial and potential regulatory approval of losmapimod would mark a significant achievement for Fulcrum, as it would bring the first-ever FDA-approved therapy for patients with FSHD.In the meantime, the company is focused on preparing for the potential commercial launch of losmapimod in the U.S., including the hiring of a Chief Commercial Officer and other key personnel to support market access and genetic testing initiatives. The collaboration with Sanofi for ex-U.S. commercialization is expected to accelerate the global availability of losmapimod and mitigate commercial execution risk for Fulcrum.
For pociredir, Fulcrum is working to reinitiate the Phase Ib PIONEER study and plans to share data from the 12 mg and 20 mg cohorts in advance of advancing to the next stage of development. The company believes pociredir, as a first-in-class oral HbF inducer, has the potential to provide a differentiated therapeutic option for patients living with sickle cell disease.