RARE Daily

With Accelerated Approval Off the Table, Avrobio Seeks Registration Trial for Fabry Disease Gene Therapy

May 3, 2021

Avrobio said following a recent meeting with the U.S. Food and Drug Administration it cannot pursue accelerated approval for its experimental gene therapy AVR-RD-01 for the lysosomal storage disorder Fabry disease because of the full approval granted to the enzyme replacement therapy Fabrazyme.

Photo: Geoff MacKay, CEO and president of Avrobio

The FDA granted full approval to Fabryzyme in February, 18 years after it was granted accelerated approval on the basis of a surrogate endpoint—reduction of GL-3 (also referred to as Gb3) inclusions in biopsied renal peritubular capillaries.

The company said it 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 percent and 87 percent 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.”

Fabry disease is a rare, inherited lysosomal disorder characterized by the accumulation of globotriaosylceramide (Gb3 or GL-3) in the body’s cells. The build-up of Gb3 is due to variations in the GLA gene, which is responsible for the production of alpha-galactosidase A, the enzyme that breaks down Gb3. When Gb3 accumulates in cells and tissues, damage may occur and result in the progressive signs and symptoms of Fabry disease, including chronic pain, gastrointestinal issues such as nausea, vomiting and diarrhea, hearing loss, heart disease, progressive kidney disease and an increased risk of stroke. Even with enzyme replacement therapy, the current standard of care for people with Fabry disease, patients typically have a shortened life expectancy and may experience debilitating symptoms that significantly reduce their quality of life. 

AVR-RD-01 is an investigational ex vivo lentiviral gene therapy designed to provide a durable therapeutic benefit for people living with Fabry disease. The therapy starts with the patient’s own hematopoietic stem cells, which are genetically modified to express functional alpha-galactosidase A (AGA). Functional AGA reduces levels of globotriaosylceramide (Gb3 or GL-3), a toxic substrate, which together with its metabolite globotriaosylsphingosine (lyso-Gb3 or lyso-GL1), are associated with the signs and symptoms of Fabry disease. AVR-RD-01 has received orphan drug designations from FDA and the European Commission.

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 said it hopes to begin a 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.

To help support the use of AVR-RD-01 in a broad Fabry disease population, Avrobio expects to amend the current phase 2 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 enzyme replacement therapies, 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.

Author: Rare Daily Staff

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