FDA puts clinical hold on Fabry disease gene therapy 4D-310

3 of the 6 participants in two Phase 1/2 trials developed aHUS after treatment

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The U.S. Food and Drug Administration (FDA) has placed a hold on the 4D-310 clinical program, an experimental gene therapy for Fabry disease being developed by 4D Molecular Therapeutics (4DMT).

The hold was disclosed in a filing submitted by 4DMT to the Securities and Exchange Commission earlier this month. The FDA’s decision, which comes less than a month after 4DMT announced it would stop enrolling participants in ongoing trials, is “consistent with the company’s plans” for 4D-310, according to 4DMT.

4DMT is running two Phase 1/2 trials of 4D-310 in people with Fabry disease: one in the U.S. (NCT04519749) and another in Taiwan and Australia (NCT05629559). As of January, six participants had been dosed across both.

Fabry disease is caused by mutations in the GLA gene, resulting in the toxic buildup of fatty molecules inside cells. 4D-310 is designed to deliver a healthy copy of the gene to cells to stop this process. It uses an engineered viral vector to deliver its genetic cargo to cells.

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Three of the six participants developed atypical hemolytic uremic syndrome (aHUS), a rare disorder marked by the destruction of red blood cells, low platelet counts, and kidney damage. One of the three aHUS cases was considered a dose-limiting toxicity event, meaning the tested dose was likely too toxic to be used in clinical practice. In all three cases, aHUS resolved within two to four weeks.

In the trials, the participants received immune-suppressing corticosteroids to reduce immune-related side effects. According to 4DMT, future trials are planned to use a different immune-suppressing regimen consisting of a combination of rituximab and sirolimus, which is expected to lower the risk of aHUS and toxicity-related events.

In accordance with instructions from the FDA, 4DMT is continuing to collect clinical data from the six patients treated so far. The company plans to present detailed data from the trial, including safety findings and treatment effects on heart health, at a scientific conference later this month.

The FDA is due to provide more feedback on 4D-310 trials to 4DMT by early March.