4D Molecular pauses enrollment in Fabry trials after kidney problems in three patients
4D Molecular Therapeutics said it has stopped enrolling patients in its two clinical trials of a gene therapy being investigated for Fabry disease.
The biotech will wait until the second half to evaluate 12-month clinical data on the six patients enrolled on 4D-310. The two trials, one in the US and the other in Taiwan and Australia, were each estimated to enroll 18 adults with the disease, in which the body lacks the enzymes needed to break down fats. For those with the inherited lipid storage disorder, fats build up in blood vessels and tissue, which leads to difficulties in the kidneys, heart and nervous system.
The California gene therapy developer said it found three cases of atypical hemolytic uremic syndrome (aHUS) in the two trials. One was considered a grade 4 dose-limiting toxicity and the 69-year-old patient, with an underlying kidney dysfunction, required temporary hemodialysis. The other two patients did not receive dialysis, 4DMT said, noting the aHUS process, in which abnormal blood clots form in blood vessels in the kidneys, was resolved in all three patients within two to four weeks.
4DMT said three patients were evaluable for 12-month cardiac data, all in the US study, at the Dec. 5 cut-off. Improvements in multiple cardiac endpoints were seen in all three patients, the biotech said.
Despite the enrollment pause on the Phase I/II studies, 4DMT said it has aligned with the FDA on endpoints for a potential pivotal trial, including two primary endpoints testing changes in cardiopulmonary exercise at months 12 and 24 and a quality of life questionnaire.
Going forward, the drug developer said it does not plan to incorporate the corticosteroid regimen that it has been using.
“In parallel with patient followup, 4DMT will evaluate its preferred approach of utilizing the rituximab-sirolimus immune inhibition regimen with 4D-310; the rituximab and sirolimus combination is an established clinical regimen to prevent AAV-associated aHUS,” the company said, noting that would likely require new clinical protocol and amended or new INDs.
More safety data will come out at the WORLDSymposium on Feb. 25, 4DMT said.
4DMT’s enrollment pause represents the latest setback in the field for Fabry gene therapy R&D. Around this time last year, Avrobio axed its candidate, AVR-RD-01, after reviewing Phase II data. The biotech had previously eyed an accelerated approval but changed those plans after Sanofi got FDA approval for its enzyme replacement therapy Fabrazyme.
Others in the Fabry gene therapy space include Freeline Therapeutics, Sangamo, Amicus Therapeutics and CANbridge Pharmaceuticals, which has a worldwide license on a capsid from AstraZeneca-acquired LogicBio. Amicus already markets an oral therapy for Fabry, sold under the brand name Galafold.
Sangamo had a few data drops last August and October, showing its gene therapy appeared to be working. London-based Freeline expects to report initial safety and efficacy data from a second cohort of its Fabry gene therapy in the first half of this year.
In the broader Fabry disease space, Chiesi and Protalix Biosciences received an FDA no-go in April 2021, but they sent their experimental drug back to the agency and now have a May 9 PDUFA date.
Editor’s note: This story has been updated to note AstraZeneca-acquired LogicBio’s capsid has been licensed to CANbridge Pharmaceuticals.