4D Molecular Therapeutics, Inc. announced U.S. Food and Drug Administration (FDA) clearance of the Investigational New Drug Application (IND) for 4D-175, an R100 vector-based intravitreal genetic medicine, for the treatment of patients with GA. The Phase 1 GAZE clinical trial will assess 4D-175 in patients with GA secondary to AMD. The study design consists of an open-label, sequential cohort Dose Exploration stage, in which patients will receive a single intravitreal injection of 4D-175 at one of three dose levels.

Clinical trial objectives include safety and tolerability, definition of the Phase 2 trial dose level(s), transgene expression and biological activity. The IND clearance enables the initiation of GAZE clinical study sites, and 4DMT expects to begin enrollment in H2 2024. sCFH is an engineered and optimized version of CFH that can fit into adeno associated virus (AAV) vectors with robust expression and full functionality confirmed in human cells in vitro, as well as 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 through targeted delivery of a therapeutic sCFH transgene could restore normal complement regulation and reduce retinal injury that manifests as progressive GA.

Preclinical proof-of-concept for this approach using 1) human sCFH delivered systemically using an AAV vector in a mouse model of atypical hemolytic uremic syndrome (aHUS) and 2) a mouse version of sCFH delivered using an AAV vector in mouse models of C3 glomerulopathy and aHUS each demonstrated recovery from complement dysregulation, reduced organ damage and improved survival. Preclinical data from 4D-175 in vitro and in vivo characterization studies were presented at the 2024 ARVO Annual Scientific Meeting in May.