Avrobio Planning Pivotal Trial of AVR-RD-01 Gene Therapy for Fabry

Avrobio is in the planning stages of a clinical trial to support a request for approval of AVR-RD-01 as a first-line gene therapy for people with  Fabry disease.

This registration trial, which the company hopes to initiate in mid-2022 with U.S. Food and Drug Administration (FDA) agreement, will test the gene therapy head-to-head against Sanofi Genzyme’s Fabrazyme (agalsidase beta), Avrobio reported in a press release.

“We look forward to working with FDA and other regulators to design a single registration trial to support full approval that we hope will advance AVR-RD-01 as quickly as possible,” said Geoff MacKay, CEO and president of Avrobio.

Fabry disease is caused by mutations in the GLA gene, leading to a deficiency in a protein called alpha-galactosidase A. As a result of this enzyme deficiency, an intermediate molecule called globotriaosylceramide (Gb3) builds inside cells, damaging organs.

AVR-RD-01 works by introducing a healthy copy of the GLA gene to cells. To do so, researchers start by isolating adult stem cells from a patient’s blood, and exposing them to a modified, harmless virus carrying a non-mutated copy of GLA. The virus inserts the gene into the stem cells, which are then returned to the patient and help to restore normal levels of alpha-galactosidase A.

An open-label Phase 2 study — called FAB-GT (NCT03454893) — is underway in the U.S., Canada, and Australia to assess the efficacy and safety of AVR-RD-01 in Fabry patients who are new to treatment.

Results reported to date show that the therapy increases alpha-galactosidase A activity in patients, and reduces blood levels of globotriaosylsphingosine (lyso-Gb3) — a biomarker of Fabry disease — and total Gb3.

Avrobio intended to request accelerated approval of AVR-RD-01, based on FAB-GT data and an additional confirmatory trial. However, this approval path is only available to therapies addressing an unmet medical need — and that unmet need ended with the FDA’s full approval of Fabrazyme in March, which followed conditional approval initially given in 2003.

As full approval was based on a surrogate endpoint — clearance of Gb3 inclusions (substrate accumulation) in samples taken from certain small blood vessels found in kidneys — Avrobio now expects to use that same endpoint to support AVR-RD-01’s approval.

“We believe we have a potential new path to pursue full approval for investigational AVR-RD-01 as a first-line therapy for Fabry disease by conducting a single, head-to-head registration trial versus Fabrazyme using a kidney biopsy surrogate endpoint similar to our FAB-GT Phase 2 trial,” MacKay said. “We plan to design a registration trial with a scope, size and duration comparable to other gene therapy trials.”

Early FAB-GT results showed “100% and 87% substrate reductions at one year post-gene therapy in the two patients with evaluable kidney biopsies,” he added.

Avrobio also announced plans to amend trial protocol for FAB-GT to support the use of AVR-RD-01 in a broader patient population.

With six patients dosed, including two in the last two months, the company expects the trial will soon also enroll female patients, eliminate its antibody-status exclusion criteria, and collect additional cardiovascular and central nervous system data. In total, the company plans to enroll up to 14 patients in FAB-GT.

“We remain fiercely committed to our purpose: to free people living with Fabry disease from a lifetime of painful symptoms, chronic treatment and the unremitting fear of disease progression,” MacKay said.

Avrobio plans to engage with the FDA to review its revised approach, and to request advice from the European Medicines Agency on its planned registration trial.