AVR-RD-01 for Fabry disease

Last updated March 27, 2024, by Lindsey Shapiro, PhD
Fact-checked by Ana de Barros, PhD

What is AVR-RD-01 for Fabry disease?

AVR-RD-01 is an investigational gene therapy that was being developed as a treatment for Fabry disease and which has since been discontinued.

Avrobio, its developer, stopped clinical trials of AVR-RD-01 in 2022, noting it was deprioritizing its Fabry disease program due to challenges in the market and the regulatory environment for Fabry treatments, along with variable findings in clinical trials.

The therapy received orphan drug designation in the U.S. and the European Union.

Therapy snapshot

How does AVR-RD-01 work?

Fabry disease is caused by mutations in the GLA gene, resulting in a deficiency in the alpha-galactosidase A (Gal A) enzyme. This enzyme is important for breaking down a fatty substance called globotriaosylceramide (Gb3) inside cells, and its lack causes Gb3 to accumulate and damage organs.

As a gene therapy, AVR-RD-01 was designed to provide patients with a healthy version of the GLA gene, thereby enabling the body to produce its own functional alpha-Gal A enzyme to break down Gb3 and ease disease symptoms. It was packaged in a viral carrier called a lentivirus, which helps genetic material be taken up by human cells.

The treatment involved collecting a person’s hematopoietic stem cells — precursors to all mature types of blood cells — and treating them in the lab with AVR-RD-01. The modified cells then would be returned to the person via a stem cell transplant, where they were expected to give rise to mature cells containing a healthy GLA gene. In theory, this would allow the sufficient production of a functional alpha-Gal A enzyme by a patient’s own body, providing a durable and lifelong therapeutic benefit.

How was AVR-RD-01 administered?

In clinical trials, AVR-RD-01 was administered to Fabry patients via a one-time stem cell transplant. A patient’s stem cells initially were isolated from the blood and treated in the lab with the gene therapy. Meanwhile, the patient underwent a round of chemotherapy to clear out unhealthy cells and make room for the modified ones, a period known as conditioning. Cells treated with AVR-RD-01, at doses ranging from 3 million to 20 million cells per kilogram, then were returned to the patient via the transplant, given as a single into-the-vein (intravenous) infusion.

AVR-RD-01 in clinical trials

AVR-RD-01 was studied in two clinical trials in men with Fabry disease. Patients enrolled in the FACTS Phase 1 study previously had been treated with enzyme replacement therapy (ERT), while those in the FAB-GT Phase 1/2 trial had no previous Fabry disease treatment.

FACTS trial

In a first Phase 1 trial (NCT02800070) in patients, AVR-RD-01 was given to five men with classic Fabry disease, ages 29-48, with safety monitored for five years. All had been using an ERT for at least six months prior to the study.

ERT was stopped at least one month before the start of treatment, then resumed one month later. However, at six months post-treatment, ERT use was discontinued if certain clinical goals were met.

Interim trial results showed that their alpha-Gal A levels rose to near normal within a week of receiving the gene therapy.

While alpha-Gal A enzyme activity levels then decreased over time, almost three years later they were still above levels generally found in Fabry patients and did not return to the low levels recorded at the study’s start.

Reductions in Gb3 levels also were observed over time in most patients, however these levels tended to increase after participants stopped ERT.

No serious adverse events were attributed to the gene therapy.

FAB-GT trial

The FAB-GT Phase 1/2 open-label trial (NCT03454893) was launched in 2018 to evaluate AVR-RD-01 in men with Fabry, ages 16 to 50, who previously had not used a disease treatment. Its main goal was to evaluate the therapy’s safety for up to a year after the infusion. Participants then could enter an extension study (NCT04999059), where they would be monitored for up to 15 years.

Early combined results from FACTS and FAB-GT indicated that the therapy was safe, increased alpha-Gal A activity, reduced blood levels of Gb3, and lowered the number of Gb3 clumps in the kidneys while maintaining stable kidney function.

However, after nine FAB-GT patients had been treated, Avrobio reported more variable findings in clinical responses. Specifically, five patients showed unexpected reductions in alpha-Gal A activity, along with evidence that the modified stem cells were not growing and multiplying in the bone marrow as expected at three to nine months after treatment.

Given these findings, the company deprioritized its Fabry disease program in early 2022 and enrollment in the FAB-GT trial was stopped.

Common side effects of AVR-RD-01

Data from clinical trials of AVR-RD-01 found that most adverse events were consistent with those due to the chemotherapy regimen or the underlying disease. These included nausea, vomiting, dehydration, fever, fever with a low white blood cell count, and mucosal inflammation.

Two side effects — nausea and cough — were considered to be possibly related to the treatment.

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