- 4D-175 comprises the proprietary low-dose intravitreal R100 AAV vector and a codon-optimized transgene encoding a highly functional shortened form of human complement factor H (sCFH)
- Complement factor H (CFH) variants with reduced function are a well-validated genetic risk factor for geographic atrophy (GA), with approximately 75% of age-related macular degeneration (AMD) patients carrying a high-risk variant of CFH
- Over 150 patients have been treated with the R100 vector, including those with wet AMD and diabetic macular edema, further validating the modularity of our Therapeutic Vector Evolution platform
- Enrollment for phase 1 GAZE clinical trial is expected to begin in H2 2024
4D Molecular Therapeutics 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.
“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,” said David Kirn, MD, co-founder and CEO of 4DMT. “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.
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; the presentation can be found on the 4DMT website here.
About 4D-175 for geographic atrophy
4D-175 combines the customized and evolved intravitreal vector, R100, and a codon-optimized transgene encoding a highly functional shortened form of human complement factor H (sCFH). The genetic medicine candidate is designed to provide durable transgene expression in the retina without significant inflammation following a single, low-dose intravitreal injection. The sCFH payload is designed to restore normal complement regulation, which has the potential to slow progression of disease.