Benzinga | May 3, 2021 07:07AM EDT

AVROBIO Provides Regulatory Update on Investigational AVR-RD-01 for Fabry Disease

On March 11, 2021, approximately three weeks before the company's End-of-Phase 1 meeting, FDA granted full approval of Fabrazyme(r) (agalsidase beta)1 more than 18 years after the enzyme replacement therapy (ERT) received accelerated approval on the basis of a surrogate endpoint: reduction of GL-3 (also referred to as Gb3) inclusions in biopsied renal peritubular capillaries (PTCs). The conversion of Fabrazyme to full approval opens a new pathway for full approval of ERTs based on this surrogate endpoint, which AVROBIO believes could potentially apply to investigational AVR-RD-01. In addition, the conversion of Fabrazyme to full approval limits the accelerated approval pathways available for new therapies to treat Fabry disease. As a result, AVROBIO can no longer pursue an accelerated approval pathway for AVR-RD-01 with the FAB-GT trial as currently designed, and instead intends to discuss with FDA a registration trial with a primary efficacy endpoint of clearance of GL-3/Gb3 inclusions in biopsied renal PTCs as the basis for full 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, where we have seen 100% and 87% substrate reductions at one year post-gene therapy in the two patients with evaluable kidney biopsies," said Geoff MacKay, CEO and president of AVROBIO. "We plan to design a registration trial with a scope, size and duration comparable to other gene therapy trials."

In its FDA briefing book, which was submitted to FDA prior to Fabrazyme's full approval, the company sought an accelerated approval pathway by expanding the FAB-GT Phase 2 clinical trial and conducting an additional confirmatory trial. The revised regulatory plan anticipates retaining the two-study approach with a similar overall requirement in terms of scope, size and duration.

The company plans to engage FDA to discuss and agree upon its revised approach, with the goal of initiating the registration trial in mid-2022. Although FDA guidance provides that a surrogate endpoint in a particular clinical development program should not be assumed to be appropriate for use in a different program, AVROBIO believes this recent development could potentially apply to investigational AVR-RD-01, a gene therapy designed to facilitate the production of functional enzyme by the patient's own stem cells after a one-time treatment with the therapeutic gene.

AVROBIO also remains on track to request a CMC-oriented Type C meeting in the second half of 2021. Additionally, in parallel the company intends to seek scientific advice from the European Medicines Agency on the planned registration trial.

Two additional patients dosed in two months, with plans to amend the FAB-GT trial protocol

The ongoing FAB-GT trial continues to progress, now with six patients dosed, including two in the past two months, and additional participants are enrolled in the trial.

To help support the use of AVR-RD-01 in a broad Fabry disease population, AVROBIO expects to amend the FAB-GT trial protocol in the second quarter of 2021 by enrolling female participants, eliminating antibody-status exclusions and adding the collection of data on additional parameters that are recognized to be limitations of ERT, such as endpoints to assess the gene therapy's potential ability to address cardiovascular and central nervous system manifestations. The company plans to enroll a total of up to 14 participants in the FAB-GT trial.

"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," added MacKay.