Regulatory 4D Molecular Therapeutics’ Fabry gene therapy put on hold...

4D Molecular Therapeutics’ Fabry gene therapy put on hold by FDA

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4D Molecular Therapeutic’s (4DMT) 4D-310 is one of the three presently available therapies for Fabry disease in the pipeline apart from Sangamo’s ST-920 and Freeline’s FLT190.

Fabry disease is a severe genetic neurological disorder characterized by the faulty GLA gene. 4DMT’s clinical trial, which has been put on hold by the FDA in a recent Security and Exchange Commission filing, is one that is focused on the impact of adeno-associated virus (AAV) gene therapy among patients with Fabry disease.

The phase ½ clinical trial for INGLAXA study had already stopped recruitment in January and instead, the biotech had opted to follow up with the six recipients of the one-shot therapy. The recent FDA hold-up comes after 3 of the 6 candidates enrolled in the therapy contracted a kidney condition by the name of the atypical haemolytic uraemic syndrome (aHUS) which is associated with the formation of clots in small blood vessels in the kidneys. Although all cases cleared within up to 4 weeks of identification, and no other treatment-related serious adverse events occurred, one participant developed a grade 4 dose-limiting toxicity. Consequently, 4DMT cut enrollment short.

Given the circumstances, the biotech had also offered to withdraw its Investigational Drug Approval, which would mean that the company could no longer test an investigational drug in human trials. This would mean that 4DMT would have to stop the usage of its 4D-310 in its 2 trials being conducted in Asia Pacific and the U.S.

The FDA instead allowed the company to keep its Investigational New Drug Application open and active on the condition that it would evaluate the program in the second half of 2023, after gathering 12-month clinical data.

This data demanded by the agency includes cardiac endpoints for a potential pivotal trial as well as data on safety. Only a few weeks later, however, the agency called for the company to hold the clinical portion of the U.S.-based trial. The agency acknowledged the firm’s present efforts in complying with directives and added that it would provide further comments on the 4D-310 trials within the next month.

David Kirn, CEO of 4DMT has shared in a statement that he does not feel that this holdup will impact the timings or plans for the program, instead, he believes that the company is still in line with its realize sent out in early January, despite the fact that enrollment for the trial is on hold.

In order to maximize the impact of its therapy, 4DMT has been using a vector designed to target organs such as the heart when assessing the safety of the therapy and its ability to boost levels of the AGA enzyme which is at the root of Fabry and thereby improve cardiac function. In order to prevent aHUS, the biotech is hoping to switch to an alternative regimen based on rituximab and sirolimus. The company was previously using a corticosteroid-based immunosuppressive regimen to allow gene therapy to take hold.

“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 further shared.

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