Full Approval of Treatment Standard Forces Avrobio to Adjust Fabry Disease Therapy Plans

On May 3rd, Massachusetts-based Avrobio announced updated regulatory plans for AVR-RD-01, its investigational gene therapy candidate. The change is an outcome of the full approval received by Sanofi’s Fabrazyme, the current standard therapy for treating Fabry disease. To be in sync with the FDA’s updated requirements, Avrobio has now proposed a head-to-head clinical trial to evaluate AVR-RD-01 against Fabrazyme.

Fabry disease is a rare disease caused by mutations in the GLA gene that leads to defects in fat metabolism. Victims typically suffer from chronic pain, gastrointestinal complications, hearing loss, kidney issues, and an increased risk of stroke and heart attacks.

In 2003, Fabrazyme became the first enzyme replacement therapy to receive accelerated approval for the condition. After nearly two decades, it received the FDA’s full approval last month. This development has changed the regulatory paths available for new investigational therapies. Therefore, companies are now pivoting to meet the new requirements.


Avrobio has been testing AVR-RD-01, its ex vivo lentiviral-based gene therapy for treating Fabry disease, since 2017. Their therapy works by modifying the hematopoietic stem cells of patients to introduce a functional GLA gene. To support the use of AVR-RD-01 in a broad population, Avrobio was planning to update their ongoing Phase 2 clinical trial by including women, eliminating antibody exclusion, and collecting data on additional parameters that could influence the effectiveness of the therapy. They also planned a second confirmatory clinical trial. 

To comply with the new FDA requirements, they will modify their plans to compare AVR-RD-01 to Fabrazyme directly and include clearance of GL-3 on biopsied renal tissue as a primary endpoint. The scope, size, and duration will be maintained. After the announcement, Avrobio stock sank almost 19% and closed shy of $9.5.

Avrobio will be consulting with the FDA for the approval of its plan, and they hope to start registration in mid-2022. The full approval of Fabrazyme could also have consequences in the requirements of other regulatory bodies abroad. For this reason, Avrobio plans to discuss its upcoming trial with the European Medicines Agency.

“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.”

Other Candidates

The full approval of Fabrazyme will also affect other experimental gene replacement therapies in the fray, namely Protalix Therapeutics’ PRX-102, Freeline Therapeutics’ FLT190, and Sangamo Therapeutics’ ST-920. It will be interesting to see how these companies would adjust clinical trials of their candidates.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: FDA Rejects Protalix’s Enzyme Replacement Therapy for Rare Genetic Disease

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