4D Molecular Therapeutics has become the latest developer of a Fabry disease gene therapy to run into difficulties. After seeing three cases of a kidney condition in the first six patients, the biotech has decided to stop enrollment and collect more follow-up data before deciding on the next steps.
California-based 4D is studying 4D-310, an adeno-associated virus (AAV) gene therapy, in two clinical trials. The studies are designed to assess the safety of the therapy plus its ability to boost levels of the AGA enzyme at the root of Fabry and thereby improve cardiac function. 4D is using a vector designed to target organs such as the heart to maximize the impact of the drug.
Early data suggest safety could be a stumbling block for the program. In six patients treated across the two trials, 4D saw three cases of atypical hemolytic uremic syndrome (aHUS), a condition associated with the formation of clots in small blood vessels in the kidneys.
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 have prompted 4D to rethink its plans. With enrollment stopped, the biotech is waiting on 12-month data on the six current patients before deciding the fate of the program.
4D expects to have the data in the second half of the year. If the company keeps developing 4D-310, it plans to change its immune inhibition regimen, dropping the corticosteroid used in the existing trials in favor of rituximab and sirolimus. 4D called rituximab and sirolimus “an established clinical regimen to prevent AAV-associated aHUS.” The biotech has reached alignment with the FDA on phase 3 endpoints, but, with the adverse events overshadowing the cardiac data, it is unclear whether it will get that far.
The setback to 4D gives another boost to Sangamo Therapeutics, which could end up winning the Fabry gene therapy race by default if its rivals keep stumbling into pitfalls. Avrobio pulled out the race one year ago, eliminating one clinical-phase contender, and Amicus Therapeutics’ preclinical prospect got caught up in the biotech’s rethink of its gene therapy operation the following month.
Freeline Therapeutics continues to push a Fabry gene therapy through the clinic, but investor enthusiasm for its early clinical data is summed up by the biotech’s $32 million market capitalization. With 4D hitting turbulence, Sangamo sits at the front of a thinning pack of Fabry gene therapy candidates.