4D Molecular Therapeutics is on shaky ground as its Fabry disease gene therapy program, dubbed 4D-310, has been hit with an FDA clinical hold.
The hold, disclosed in a Feb. 3 Securities and Exchange Commission (SEC) filing, follows a voluntary enrollment hold enacted in early January after three cases of a kidney condition were reported among the first six patients enrolled across two trials.
At the time, the company proposed to withdraw its Investigational Drug Approval—an FDA approval stamp that allows companies to test an investigational drug in human trials—for the 4D-310 trials, one of which is conducted in the U.S. and the other in the Asia-Pacific region. However, the FDA recommended that 4DMT keep its Investigational New Drug Application as open and active and continue long-term follow-up for the six patients dosed. 4DMT followed the recommendation and said it would evaluate the program in the second half of 2023 after gathering 12-month clinical data, including ongoing safety and cardiac endpoints for a potential pivotal trial.
Just a few weeks later, the FDA has issued a clinical hold for the U.S. portion of the phase 1/2 trial. In its notification, the FDA acknowledged 4DMT’s paused enrollment and told the biotech to continue follow up for treated patients under the current IND, which remains open and active, according to the new SEC filing. The agency said it would provide feedback regarding the 4D-310 trials within 30 days.
“Overall, we believe this hold is an administrative step having no impact on our plans or timing for the 4D-310 program,” David Kirn, M.D., co-founder and CEO of 4DMT, told Fierce Biotech in an emailed statement. The leader also said the company believes the hold is consistent with 4DMT's Jan. 9 release announcing the decision to pause enrollment.
The program subject to the hold is an adeno-associated virus (AAV) gene therapy being assessed among patients with Fabry disease, a serious genetic neurological disorder. The studies are designed to assess the safety of the therapy and its ability to boost levels of the AGA enzyme at the root of Fabry and thereby improve cardiac function. 4DMT is using a vector designed to target organs such as the heart in hopes of maximizing the therapy’s impact.
Early data revealed three cases of atypical hemolytic uremic syndrome, a condition associated with the formation of clots in small blood vessels in the kidneys, in the six patients. One of the cases was a grade 4 dose-limiting toxicity. That patient needed temporary hemodialysis. All three cases cleared up within two to four weeks, and no other treatment-related serious adverse events occurred, but the incidents prompted 4DMT to cut enrollment short.
“We had preemptively stopped the current trial using prednisone as immune prophylaxis, with the goal to pursue the new standard rituximab/sirolimus regimen to prevent AAV-associated aHUS; therefore, the hold has no additional impact on the program/pipeline or the company’s phase 3 plans, in which we have aligned with the FDA on endpoints for,” Kirn said.
4DMT still plans to present detailed safety, cardiac biopsy and cardiac efficacy data at the WORLD Symposium on Feb. 25.
The SEC filing also comes a day after the California-based biotech published a news release about FDA approval for testing genetic medicine D-150 in patients with diabetic macular edema (DME). The asset is already being assessed in a phase 1/2 trial for patients with wet age-related macular degeneration, which just entered the phase 2 portion. Now, 4MDT plans to launch a phase 2 trial for DME patients, dubbed SPECTRA, with enrollment expected to start in the third quarter of 2023.
4DMT’s setback gives competitor Sangamo Therapeutics a boost after several rivals have stumbled. Avrobio pulled out of the race one year ago, and Amicus Therapeutics’ preclinical prospect got caught up in the biotech’s rethink of its gene therapy operations. Freeline Therapeutics continues to push a Fabry gene therapy through the clinic but may lack the investor enthusiasm needed to make it to the finish line, as seen in its $32 million market capitalization, leaving Sangamo at the front of a thinning pack for Fabry gene therapy programs.