Avrobio retools Fabry gene therapy plans after competing drug's full approval shuts pathway to an accelerated nod
It’s been a long road for lentiviral gene therapy player Avrobio in the rare lysosomal disorder Fabry disease after early data sent investors running for the hills back in 2018. Right on the heels of a promising readout, Avrobio will now tinker with its regulatory plans for that therapy after the FDA flipped the script and handed a competing drug an unlikely full approval.
The biotech will rejigger its development plans for AVR-RD-01, an investigational gene therapy for Fabry disease, after the FDA granted a full approval to Sanofi’s enzyme replacement therapy Fabrazyme back in March, validating a new kidney biopsy surrogate endpoint Avrobio now hopes to pursue, the company said Monday.
Avrobio was in talks with the FDA to pursue an accelerated approval for AVR-RD-01 based on kidney substrate reduction with a confirmatory study to follow. After it submitted its briefing book to the FDA, the agency handed Fabrazyme a full approval — 18 years after it first received an accelerated nod based on the reduction of the lipid Gb3.
That approval marked a new path forward for ERTs, which are used as the standard of care in Fabry disease, to receive full nods, but forced Avrobio to focus on a head-to-head registrational study against Fabrazyme, and shut off its hopes for an accelerated OK. Avrobio will still go ahead on expanding its Phase II study, which has dosed six patients so far and has seen improvement on endpoints “similar” to Gb3 reduction, with hopes of convincing the FDA to move ahead on a Phase III registrational study pegged for the middle of next year.
But nothing’s certain for Avrobio, and it warned that one therapy’s accepted surrogate endpoint doesn’t necessarily translate to another. The ex vivo therapy uses patient’s engineered hematopoietic stem cells to replace patients’ functional enzymes used to break down Gb3.
Starting this quarter, Avrobio intends to expand enrollment in its Phase II FAB-GT study to include female participants and patients regardless of antibody-status exclusions with the goal of hitting 14 patients total. Meanwhile, investigators will also monitor a new set of biomarker endpoints intended to highlight ERTs’ shortcomings, including potential for AVR-RD-01 “to address cardiovascular and central nervous system manifestations,” the company said.
It’s an unwelcome turn of events for Avrobio after it revealed triumphant Phase II follow-up data in February showing a 100% reduction in kidney substrate levels after one year in a single patient dosed with the commercial form of AVR-RD-01. It was a small but promising window into the possibility of a relatively quick path to market, which could now be pushed back considerably.
Early data for AVR-RD-01 left a bad taste in investors’ mouths after the therapy showed efficacy in Fabry in late 2018 but also posted low vector copy numbers, an indicator of how long the therapy hangs around in the body. CEO Geoff MacKay at the time argued those data were in line with expectations for how the ex vivo therapy was designed to work, but investors fled in droves all the same. Meanwhile, the company touted data showing three of five patients in a Phase I test had moved off ERTs for their disease.
Editor’s Note: This story has been updated to clarify the primary endpoint in Avrobio’s Phase II study for AVR-RD-01.