4D Molecular Therapeutics announced updated interim safety and efficacy data from the two 4D-310 INGLAXA Phase 1/2 clinical trials for Fabry disease cardiomyopathy. All three patients with 12 months of follow-up demonstrated improvement on cardiac contractility, exercise capacity and quality of life endpoints. Treatment was generally well tolerated, with transient acute aHUS being the only significant adverse event.

Following a detailed investigation into the etiology of aHUS, 4DMT is engaging with the FDA to resume enrollment based on updated exclusion criteria and the highly effective rituximab/sirolimus immunosuppressive regimen. Data will also be presented at the WORLDSymposium™ 2023 in Orlando, Florida on February 25th, 2023. INGLAXA Phase 1/2 Clinical Trials Design: Dose-escalation and dose-expansion trial assessing a single intravenous infusion of 4D-310 in a broad and diverse Fabry disease patient population.

Treated patients in three geographies: INGLAXA-1 (U.S.) and INGLAXA-2 (Taiwan and Australia). Enrolled six patients, each treated with 1E13 vg/kg of 4D-310 and a prophylactic corticosteroid immunosuppressive regimen. Assessed FDA-recommended pivotal trial cardiac endpoints in three patients who completed 12 months of follow-up (cut-off date of December 5, 2022) including: Left ventricular contractility – Change from baseline at 12 months in global longitudinal strain on echocardiography (GLS on ECHO).

Exercise capacity – Change from baseline at 12 months in cardiopulmonary exercise testing (peak VO2 by CPET). Quality of life status – Change from baseline at 12 months in Kansas City Cardiomyopathy Questionnaire (KCCQ). Cardiac biopsy available from one patient in the INGLAXA-2 trial.

Cardiac Outcomes: Cardiac contractility (GLS) assessed on ECHO: meaningful improvement in 3 of 3 patients (GLS worsened on ERT natural history study). Exercise capacity (peak VO2) assessed by CPET: meaningful improvement in 2 of 3 patients (worsened on ERT natural history study). Cardiac quality of life (physical limitations, symptoms) assessed with KCCQ: clinically meaningful improvement in 2 of 2 patients, and the third remained stable at 100% (no possibility for improvement from baseline).

Cardiac biopsy: healthy tissue, no inflammation, and widespread transgene expression in 50% of cardiomyocytes; transgene expression was highly selective for cardiomyocytes: 4.4 genomes/cardiomyocyte (qPCR) and 16.2 RNA transcripts/cardiomyocyte (RT-qPCR). Safety and Tolerability: Treatment was generally well-tolerated except as noted below – no liver, heart, or DRG toxicity observed. Transient acute aHUS (n=3): Day 3-7 onset; resolution started within 1-4 days.

Known class effect of IV administered AAV due to rapid anti-AAV capsid IgM antibody rise, capsid binding and complement pathway activation. Investigation of single grade 4 DLT aHUS patient indicated that complement pathway activation, which drives aHUS, was present before 4D-310 dosing. Investigation of IV administered AAV associated aHUS and development of mitigation strategies were conducted in close collaboration with world experts in immunology and gene therapy including Paul J. Utz, M.D., Professor of Medicine, Immunology and Rheumatology Stanford University; Dimitris Mastellos, PhD, National Center for Research, Greece; and Barry Byrne, MD, PhD, University of Florida.

Next Steps for Development of 4D-310: Align with FDA on plan to remove clinical hold and resume enrollment following protocol amendment including the following: Implement highly effective rituximab/sirolimus immunosuppressive regimen. Exclude patients with pre-dosing complement activation. Continue current protocol follow-up for all six patients enrolled to date, including cardiac efficacy assessments supportive of regulatory approval: peak VO2 (CPET), quality of life (KCCQ), and left ventricular function (GLS on ECHO).

Phase 3 CMC plans, assays & trial design aligned with FDA. Provide program update in the second half of 2023.