4DMT Receives FDA Clearance of IND Application for 4D-175 Genetic Medicine for the Treatment of GA
4D Molecular Therapeutics announced FDA clearance of its investigational new drug application (IND) for 4D-175, an R100 vector-based intravitreal genetic medicine for the treatment of patients with geographic atrophy (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.
“GA is a leading cause of irreversible vision loss for over 5 million people globally and while current bolus complement inhibitor treatments reduce the rate of growth in GA lesions, they require burdensome monthly or bimonthly intravitreal injections and do not demonstrate functional vision benefit,” David Kirn, MD, Co-founder and Chief Executive Officer of 4DMT, said in a company news release. “4D-175 has the potential for durable clinical benefit with a single intravitreal injection, greatly reducing the current treatment burden for patients, which may lead to better long-term vision outcomes. In phase 1, we aim to explore safety and transgene expression levels to select doses for phase 2. We look forward to beginning enrollment in the phase 1 GAZE clinical trial in the second half of 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, PhD, Professor of Pharmacology at the Perelman School of Medicine at the University of Pennsylvania.
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, according to 4DMT. 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; the presentation can be found on the 4DMT website here.