Accelerated Approval Path Blocked for AVR-RD-01 in Fabry Disease

Geoff MacKay

The full regulatory approval of agalsidase beta (Fabrazyme) has blocked the current accelerated approval pathway for AVR-RD-01 as a treatment for patients with Fabry disease, unless the company developing the lentiviral gene therapy, AVROBIO, completes a new study comparing the investigational therapy with the now fully approved enzyme replacement therapy (ERT). This update was announced by AVROBIO, following a Type B regulatory meeting between the FDA and the company in the March.

The company was engaged in conversations with the FDA to pursue a potential path to accelerated approval, based on findings from the phase 2 FAB-GT study. In early results from this study, AVR-RD-01, dosed with AVROBIO's plato platform, demonstrated a 100% clearance in the number of Gb3 inclusions per peritubular capitulary (PTC) on kidney biopsy at 1 year compared with baseline. In another evaluable patient treated prior to the development of the plato platform, there was an 87% decline in the kidney substrate Gb3 inclusions per PTC.

The current co-primary endpoints of the phase 2 FAB-GT trial are adverse events and Gb3 inclusions per PTC (NCT03454893). Under its new path toward approval of AVR-RD-01, AVROBIO plans to submit findings from the FAB-GT study, which seeks to enroll 12 participants, plus findings from an additional study that has yet to be launched. The currently all-male FAB-GT study will also be amended to include female patients with Fabry disease, those with positive and negative anti-alpha-galactosidase A (AGA) antibody status, and will also include additional end points focused on cardiovascular and central nervous system outcomes.

AVROBIO plans to develop the secondary study with FDA guidance and anticipates beginning enrollment in the study in mid-2022. The company tentatively expects Gb3 per PTC on kidney biopsy to be the primary end point. The study, and hopeful indication, will be as a first-line treatment for Fabry disease.

“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 end point similar to our FAB-GT phase 2 trial, where we have seen 100% and 87% substrate reductions at 1-year post-gene therapy in the 2 patients with evaluable kidney biopsies,” Geoff MacKay, CEO and president of AVROBIO, said in a statement. “We plan to design a registration trial with a scope, size, and duration comparable to other gene therapy trials.”

AVR-RD-01 consists of autologous CD34+ cells transduced with a lentiviral vector to encode a functional AGA gene. The plato platform, which is being used in the phase 2 study, is a closed system designed to automate the manufacturing process. At the site of care, the patient's cells are collected by apheresis and enter the plato platform, where the cells are separated, cultured, and undergo transduction with the lentiviral vector. After production, the cells are harvested and cryopreserved for administration. Prior to treatment, patients undergo myeloablative conditioning.

Early findings from the first 4 patients dosed with AVR-RD-01 in the phase 2 FAB-GT trial were presented at the WORLDSymposium in February 2021. The first 3 patients were not treated using the plato system for manufacturing. The study enrolled males exclusively and all patients were treatment-naive at study entry. The drug product vector copy number ranged from 0.5 to 1.4 (mean, 0.87) in the first 3 patients and was 1.6 in patient 4, which received AVR-RD-01 manufactured by plato.

Overall, the mean plasma AGA enzyme activity in the first 3 patients was 1.4 nmol/hr/ml. In the patient who received AVR-RD-01 manufactured using plato, it was 5.9 nmol/hr/ml. The leukocyte AGA enzyme activity showed similar findings, at a mean of 14.6 nmol/hr/mg protein in the 3 patients treated with AVR-RD-01 manufactured using traditional methods and 92.0 nmol/hr/mg protein for patient 4.

In patient 4, kidney substrate was 4.02 Gb3 per PTC a baseline, which declined to 0.0 at week 48 following treatment (P <.0001). There were 103 PTC readings at baseline and 99 at week 48, which were each scored by 2 independent blinded pathologists. Findings at 48 weeks from PTC were available from 1 patient treated with AVR-RD-01 that was manufactured before plato. In this patient, Gb3 inclusions dropped from 3.55 at baseline to 0.47 at 48 weeks (P <.0001). Across all 4 patients, there was a plasma lyso-Gb3 reduction of 70% on average. This was 86% in patients 1, 55% in patient 3, 69% in patient 4, and not available in patient 2.

In findings from both the phase 1 and phase 2 studies, durability of the treatment effect was seen up to 42 months, which was the longest follow up. In the phase 1 study, all patients who discontinued ERT remained off the therapy. Overall, across both studies, kidney function, as measured by eGFR, also remained stable for 8 of 9 patients, except for 1 patient who entered the study with advanced kidney disease. Across both studies, there were no unexpected adverse events and no serious adverse events.

“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. 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.