4D Molecular acquires rights for sCFH from Aevitas Therapeutics

4D Molecular Therapeutics acquired the rights and know-how for short-form human complement factor H from Aevitas Therapeutics, Inc. The transgene encoding sCFH, a shortened and optimized form of a natural inhibitor of the inflammatory complement pathway invented at the University of Pennsylvania, will be combined with 4DMT’s proprietary retinotropic R100 vector to engineer the product candidate 4D-175 for treatment of GA secondary to AMD. Geographic atrophy is a highly prevalent disease with a significant unmet medical need. According to published estimates, there are over one million individuals with GA in the U.S. alone as of 2022. The first treatment for GA, complement inhibitor pegcetacoplan injection, was approved in the U.S. in February 2023 and is administered by intravitreal injection once every 25 to 60 days. Similar treatment regimens with anti-VEGF agents for neovascular AMD have proven difficult to maintain. Challenges in adhering to monthly or every-other-month treatment for wet AMD can lead to suboptimal clinical outcomes, suggesting the same may be encountered in the treatment of GA. Thus, a treatment that achieves consistent expression of a therapeutic could lead to more optimal clinical outcomes. 4D-175 is designed to achieve continuous expression of sCFH in the retina from a single injection in order to inhibit the inflammatory complement pathway in patients with GA without requiring repeated injections. Complement Factor H is a master regulator of the complement system, functioning as a natural inhibitor of the alternative complement pathway. Dysregulation of the complement system can lead to autoimmune and inflammatory diseases, including GA. Mutations in the gene encoding CFH are among the strongest genetic risk factors for AMD including GA, with approximately 75% of patients carrying a high-risk variant of CFH with reduced complement inhibitory function, leading to complement pathway hyperactivity. sCFH is an engineered and optimized version of CFH that can fit into AAV vectors with robust expression and full functionality confirmed in human cells in vitro, and in multiple preclinical animal models and species in vivo. The construct was co-invented by Wenchao Song, Ph.D., Professor of Pharmacology at the Perelman School of Medicine at the University of Pennsylvania. Dr. Song has extensive experience researching complement-mediated inflammatory, autoimmune, and thrombotic vasculopathy disorders. Restoring CFH function using sCFH protein could restore normal complement regulation and reduce retinal injury that manifests as progressive GA. Preclinical proof-of-concept for this approach using human sCFH delivered systemically using an adeno associated virus (AAV) in a mouse model of atypical hemolytic uremic syndrome and a mouse version of sCFH delivered using an AAV in mouse models of C3 glomerulopathy and aHUS each demonstrated recovery from complement dysregulation, reduced organ damage, and improved survival.