Gene Therapy AVR-RD-01 Shows Sustained Efficacy in Early Trial Data

Treatment with the gene therapy candidate AVR-RD-01 showed sustained efficacy and was well-tolerated in Fabry disease patients regardless of prior enzyme replacement therapy (ERT), according to preliminary results of a Phase 1 and a Phase 1/2 trial.

Avrobio’s AVR-RD-01 is a gene therapy that uses hematopoietic stem cells — stem cells that generate other blood and immune cells — to produce a functional alpha-galactosidase A (AGA) enzyme, which is deficient in patients with Fabry disease. A modified, harmless viral vector carrying a functional version of the GLA gene — which encodes the key enzyme — is introduced into the stem cells before they are reinserted into the patient.

The investigator-sponsored Phase 1 trial (NCT02800070) is testing the safety of AVR-RD-01 in up to six patients who have been treated with standard ERT for a minimum of six months. In turn, the Avrobio-sponsored Phase 1/2 study (NCT03454893), also known as the FAB-201 study, is evaluating the potential therapy’s efficacy and safety in eight to 12 previously untreated patients.

Both studies are enrolling participants — the Phase 1 trial in Canada and the Phase 1/2 in Australia. (For more information on contacts and study locations, click on the country’s name.)

To date, six patients have been treated with AVR-RD-01 — four in the Phase 1 study and two in the Phase 1/2 trial. All four patients who reached three months or longer after receiving AVR-RD-01 – three of whom are in the Phase 1 study — showed higher plasma activity of AGA at all time points compared to males with classic Fabry disease, defined at less than 1 nmol/hr/ml. 

Plasma levels of lyso-Gb3, the byproduct of globotriaosylceramide, or Gb3 — the lipid (fat) that accumulates in cells of people with Fabry disease — were decreased in three patients assessed. One of these patients is in the Phase 1/2 study and the other two are in the Phase 1 trial, but have discontinued ERT treatment.

Specifically, the patient in the Phase 1/2 trial experienced an 85% reduction in lyso-Gb3 at six months, from 202 nmol/hr/ml to 31 nmol/hr/ml. The patient’s endothelial cells of the skin showed a similar decrease after six months of treatment with AVR-RD-01.

One of the patients in the Phase 1 study showed sustained decreases in plasma lyso-Gb3 levels from month 3 and up to 22 months of treatment, after discontinuation of ERT at month 18. The other patient, who chose not to resume ERT after starting treatment with AVR-RD-01, demonstrated a reduction in plasma lyso-Gb3 from 52 nmol/hr/ml to 33 nmol/hr/ml at three months.

According to the company, meaningful changes in lyso-Gb3 levels could reflect the efficacy of AVR-RD-01 as these patients did not have potential confounding effects from ERT.

Safety results suggest that AVR-RD-01 is well-tolerated. No serious adverse events related to AVR-RD-01 were reported as of the safety data cutoff dates – Jan. 1, 2019 in Phase 1/2 and Nov. 26, 2018 in Phase 1. Adverse events were in line with those expected in patients undergoing conditioning treatment for stem cell transplants with Alkeran (melphalan).

The data further revealed the overall vector copy number — the average number of gene copies integrated into the genome of a cell — was as expected.

“Taken together, these clinical data represent a growing body of evidence of the therapeutic potential of AVR-RD-01 as a gene therapy for patients with Fabry disease,” Birgitte Volck, MD, PhD, Avrobio’s president of research and development, said in a press release. Positive preliminary results had already been reported in October 2018.

Volck said that the combination of sustained AGA enzyme levels with associated reductions in Lyso-Gb3 levels makes the results significant. “This suggests that our gene therapy exerts its effects as intended in patients previously treated with ERT, as well as in treatment-naive patients,” Volck said.

AVR-RD-01 was recently granted orphan drug status by the U.S. Food and Drug Administration.

Besides these results, Avrobio is also introducing plato, the company’s vector system and automated cell manufacturing solution. Plato is intended to enable global marketing of Avrobio’s gene therapies. According to the company, the system’s components were designed to safely improve long-term gene therapy efficacy and may be able to address manifestations in the central nervous system (brain and spinal cord).

The company is planning to use this new platform in its gene therapy programs, starting in the ongoing Phase 1/2 trial of AVR-RD-01 and its planned AVR-RD-02 clinical program in Gaucher disease.

“We are extremely pleased with today’s AVR-RD-01 data and look forward to presenting additional data from our Fabry studies over the course of the year” Geoff MacKay, Avrobio’s CEO, said. “Today’s news, along with the promise of our product pipeline and plato platform, give us great confidence for the year ahead.”