FDA Blocks 4D’s Gene Therapy Program for Fabry, Clears IND for Diabetic Macular Edema


The clinical hold comes a few weeks after the company announced it was stopping enrollment in the phase 1/2 clinical trial.

The FDA has placed a clinical hold on 4D Molecular Therapeutics’ Fabry disease gene therapy program 4D-310 while also clearing the company’s investigational new drug application (IND) for its diabetic macular edema (DME) gene therapy program, 4D-150.1,2

The hold comes weeks after 4D announced it was stopping enrollment in the phase 1/2 clinical trial of 4D-310 (NCT04519749) after 3 instances of treatment-related serious adverse events of atypical hemolytic uremic syndrome (aHUS) that resolved within 2 to 4 weeks.3 In 1 participant, a 69-year-old man with underlying kidney dysfunction, the AE was classified as a grade 4 dose-limiting toxicity and required temporary hemodialysis; the other 2 patients did not receive dialysis.

“4D-310 holds promise as a potential first-in-class treatment for Fabry disease-associated cardiomyopathy, the leading cause of death in this patient population, as demonstrated by the cardiac clinical data announced today. Utilizing a novel vector invented at 4DMT with the goal of achieving increased delivery and transduction within the heart in humans, 4D-310 is designed to enable transgene expression and disease correction directly within cardiomyocytes,” principal investigator Eric Adler, MD, professor of medicine and section head for heart failure, University of California, San Diego, said in a statement at that time.3 “We look forward to working with the 4D team to design and evaluate potential treatment regimens based on rituximab and sirolimus which in our clinical experience is effective at preventing aHUS following intravenous AAV.”

The company will continue to evaluate the 6 participants with Fabry currently enrolled and will re-evaluate the trial after collecting 12-month clinical data from these participants.2 These endpoints include peak VO2 (CPET), Quality-of-life (KCCQ) and left ventricular function by global longitudinal strain (echocardiography). At this time, the company also reported improvements in cardiac endpoints for the 3 participants that had reached 12 months of follow-up as well as a cardiac biopsy positive for widespread genome delivery and transgene expression from the 1 available participant.

READ MORE: Gene Therapy Trial Doses First Patient With Wet AMD in China

In notification of the hold, the FDA directed 4D to continue long-term follow-up of these patients and will provide further feedback within 30 days.1The FDA also permitted the IND for 4D-310 to stay open and active. 4D Molecular Therapeutics will be presenting further detailed safety, cardiac biopsy and cardiac efficacy data at the WORLDSymposium conference later in February.

Concerning the company’s ophthalmologic pipeline, the FDA’s clearance of the IND for 4D-150 allows the company to initiate the phase 2 SPECTRA clinical trial for patients with DME in the third quarter of 2023. 4D-150 is being evaluated in the ongoing phase 1/2 PRISM trial (NCT05197270) for patients with wet age-related macular degeneration (AMD), the phase 2 portion of which is currently enrolling. Initial data from the first 3 cohorts in the PRISM trial, which will be presented at the 2023 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, has supported the use of the R100 intravitreal vectorfor other indications including geographic atrophy.

“This is the sixth US IND submitted by 4DMT, and all 6 have been cleared by the FDA. The robustness and efficiency of our product design and development engine are based on sustained excellence by our manufacturing, preclinical, clinical, and regulatory teams,” David Kirn, MD, cofounder and chief executive officer, 4DMT, said in a statement.1 “We are excited to have started enrolling the Phase 2 portion of our PRISM trial in wet AMD, and to evaluate the potential of 4D-150 in patients with DME who also require frequent anti-VEGF injections and have a high treatment burden.”

1. US SEC Form 8K. 4D Molecular Therapeutics. February 3, 2023. https://ir.4dmoleculartherapeutics.com/node/7801/html
2. 4D Molecular Therapeutics announces FDA Clearance of IND application for 4D-150 genetic medicine for the treatment of diabetic macular edema. February 2, 2023. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4d-molecular-therapeutics-announces-fda-clearance-ind-2
3. 4D Molecular Therapeutics announces updates on clinical pipeline and additional preclinical programs. 4D Molecular Therapeutics. January 9, 2023. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4d-molecular-therapeutics-announces-updates-clinical-pipeline
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