The FDA placed 4D Molecular Therapeutics’ gene therapy program, 4D-310, on clinical hold, the company announced Thursday.
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The FDA put 4D Molecular Therapeutics’ gene therapy program, 4D-310, on clinical hold, the company announced Thursday.
4D had already paused enrollment into the 4D-310 program after detecting three cases of atypical hemolytic uremic syndrome (aHUS), a kidney condition characterized by an increased risk of blood clots in the organ, among the first six patients enrolled across two trials.
Though all aHUS episodes were resolved in two to four weeks, one instance qualified as a grade 4 dose-limiting toxicity. It necessitated temporary hemodialysis in a 69-year-old man with underlying kidney dysfunction.
4D will reassess its Fabry program in the second half of this year after long-term clinical data from all six patients are available.
4D-310 is an investigational gene therapy that uses a proprietary vector to deliver a functional copy of the GLA gene, which encodes for the enzyme alpha-galactosidase A.
In Fabry disease, mutations in GLA produce altered forms of the enzyme, leading to the intracellular accumulation of toxic substances throughout the body and, eventually, progressive organ dysfunction.
4D’s gene therapy candidate is being trialed in two Phase I/II studies: one conducted in the U.S. and another in Taiwan and Australia.
In its clinical hold notice to 4D, the FDA acknowledged the company’s preemptive program pause but instructed it to continue long-term follow-up of all patients dosed with 4D-310. The regulatory body also opted to keep the program’s current Investigational New Drug application open and active.
4D will present more detailed safety, efficacy and cardiac biopsy data for 4D-310 at the upcoming WORLD Symposium later in February.
Another Gene Therapy Put on Hold
California-based 4D is only the latest to encounter a stumbling block in the gene therapy space.
Earlier this month, the FDA also tempered Texas-based Taysha Gene Therapies’ gene therapy development when it asked the company to dose more patients in a double-blinded, placebo-controlled trial for TSHA-120, its candidate for giant axonal neuropathy.
In December 2022, the Agency also placed Entrada Therapeutics’ Investigational New Drug application for Duchenne muscular dystrophy hopeful ENTR-601-44 under a clinical hold. No reason for the delay had been given at the time.
The FDA is taking a cautious approach to gene therapies and pauses them for safety concerns.
In June 2022, Astellas temporarily suspended its Phase I/II FORTIS trial in late-onset Pompe disease after one patient developed a serious adverse event, even though the episode was classified as mild. The regulatory agency lifted the clinical hold in January.
Massachusetts-based bluebird bio also received a partial suspension in December 2021 for its sickle cell disease gene therapy candidate (lovotibeglogene autotemcel) after an adolescent patient developed persistent non-transfusion-dependent anemia. The FDA released the candidate from the hold a year later.
