Gene therapy candidate clears FDA hurdle

4D Molecular Therapeutics, a clinical-stage gene therapy company, announced that the FDA has cleared the Investigational New Drug Application (IND) for 4D-150 for wet age-related macular degeneration (wet AMD).

The active IND enables the initiation of 4D-150 Phase 1/2 clinical trial sites, which is expected before year-end.

According to David Kirn, MD, co-founder and CEO of 4DMT, explained that 4D-150 is a dual-transgene intravitreal gene therapy encompassing the R100 capsid which was invented through Therapeutic Vector Evolution with the goal of robust and safe delivery to all regions and major cell types within the retina at relatively low doses.

“We believe that 4D-150’s design, which targets four distinct angiogenic factors with dual transgenes, has the potential for broad, robust and durable efficacy after a single low dose intravitreal administration in patients with wet AMD,’ he said. “4D-150 has the potential to be administered at significantly lower doses compared to other intravitreal AAV gene therapy approaches, and 4D-150 clinical development builds on the favorable tolerability profile to date with the same R100 capsid utilized in our 4D-125 X-linked retinitis pigmentosa (XLRP) program at significantly higher doses.”

While 4D-125 has been well-tolerated at 1E12 vg/eye, Kirn said the company believe 4D-150 has the potential for clinical activity at substantially lower doses.

According to Peter Francis, MD, PhD, CSO for the company, 4D-150 represents numerous firsts in the AAV gene therapy space and underscores 4DMT’s commitment to innovation.

“4D-150 is the first R100-based product candidate to enter clinical development in a large market disease,” he said in a statement. “In addition, it is not only the first clinical-stage dual-transgene AAV gene therapy utilizing an evolved vector, but also the first vectorized RNAi AAV gene therapy product candidate utilizing an evolved vector to enter clinical development.”

The Phase 1/2 clinical trial is a dose-escalation and randomized, controlled, masked expansion trial of intravitreal 4D-150 and is expected to enroll approximately 60 adults with wet AMD.

In the dose-escalation phase, multiple dose levels of 4D-150 will be examined in an open-label, 3+3 design with an initial dose of 3E10 vg/eye.

In dose expansion, patients (n = 50) will be randomly assigned 2:2:1 to receive one of 2 dose levels of 4D-150 (n = 20 for each dose level) or aflibercept (n = 10).

The primary endpoints of the study are safety and tolerability. Secondary endpoints include the number of supplemental aflibercept injections received, and change from baseline in best corrected visual acuity (BCVA) over time.

About 4D-150 and wet AMD
4D-150 is a dual-transgene, intravitreal gene therapy designed to inhibit four distinct VEGF factors and prevent angiogenesis and vascular permeability for the treatment of wet AMD.

We believe that targeting four distinct angiogenic factors with dual transgenes in patients with these retinal diseases has the potential for greater efficacy and/or lower required doses versus therapies that target a single VEGF factor, including in patients refractory to currently approved anti-VEGF therapies.

Intravitreal delivery of biologics to the eye is routine, and a single dose intravitreal gene therapy that could provide long-term efficacy in patients would be an advantage for patients who struggle with treatment burden and/or treatment resistance.

4D-150 builds on the tolerability to date of the R100 capsid in the 4D-125 XLRP clinical program at doses up to 1E12 vg/eye.

In the non-human primate retinal laser-induced CNV model data presented in May 2021 at the annual conference of the American Society of Gene and Cell Therapy, at doses ranging from 1E11 to 1E12 vg/eye, 4D-150 intravitreal injection resulted in 100% suppression of grade 4 angiogenic lesions.