Gene Therapy AVR-RD-01 Effectively Prevents Buildup of Toxic Gb3 in Fabry Patients, Interim Data Show

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by Alice Melao |

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PRX-102 and BRIGHT trial data

Avrobio’s investigational gene therapy AVR-RD-01 shows potential in promoting durable beneficial effects to treat Fabry disease, with enhanced therapeutic activity compared with the standard-of-care enzyme replacement therapy, according to preliminary clinical data.

These findings were reported after the evaluation of the first eight patients with Fabry disease who received treatment with AVR‑RD‑01 in the ongoing Phase 2 FAB-201 trial (NCT03454893) and the investigator-sponsored FACTs Phase 1 trial (NCT02800070).

“We are extremely pleased with the emerging data set and its support for AVR-RD-01 to potentially address the genetic basis of Fabry disease,” Geoff MacKay, president and CEO of Avrobio, said in a press release. “As these clinical trials progress, we aim to position AVR-RD-01 as a first-line therapy.”

Fabry disease is a rare genetic disorder that occurs due to mutations in the GLA gene, which is responsible for the production of an enzyme called alpha-galactosidase A (AGA). This enzyme is responsible for breaking down a type of fat called globotriaosylceramide (Gb3 or GL-3) into building blocks that the body’s cells can use.

AVR-RD-01 is a cell-based therapy that uses the patient’s modified hematopoietic stem cells — which generate other blood and immune cells — to produce a functional alpha-galactosidase A enzyme.

Researchers use an engineered, harmless viral vector to carry a functional version of the GLA gene and introduce it into a patient’s stem cells before these cells are reinserted back into the patient.

The safety and efficacy of AVR-RD-01 is being explored in the FAB-201 trial, which is currently recruiting in Australia. To date, three patients with genetically confirmed Fabry disease have been dosed with AVR-RD-01.

The first analysis of a kidney tissue biopsy showed substantial reduction of Gb3 substrate. The biopsy was collected from a patient who had not been previously treated with enzyme replacement therapy (ERT).

Two independent reviewers reported an average reduction in the number of Gb3 inclusions from about 3.55 to 0.47 after one year of receiving AVR-RD-01. This represents a reduction of 87% in the amount of accumulated substrate in the kidneys. In addition, an 87% reduction in plasma levels of lyso-Gb3 — the toxic metabolite of Gb3 — was observed one year after treatment.

“We believe the 87% Gb3 clearance in the kidney biopsy may be considered clinically relevant since Gb3 accumulation in organs of Fabry patients is associated with significant morbidity and early mortality,” said Birgitte Volck, MD, PhD, president of research and development at Avrobio.

“We are excited by the magnitude of the Gb3 reduction observed in the first patient’s kidney biopsy at 12 months. This is the primary efficacy endpoint in FAB-201 and an efficacy endpoint that has previously been utilized by the [U.S. Food and Drug Administration] in evaluating and approving treatment for Fabry disease,” she added.

Additional data collected from five Fabry patients enrolled in the ongoing investigator-sponsored Phase 1 FACTs trial further demonstrate the efficacy and durability of the treatment.

The first four treated patients experienced a 33% to 41% reduction of lyso-Gb3 levels compared to the levels observed while taking ERT. In particular, these values were maintained for more than two years in the one patient who experienced a 41% reduction.

In general, AVR-RD-01 produced a durable effect, sustained for six months or longer, with enhanced AGA enzyme activity.

After AVR-RD-01 administration, patients showed stable kidney and cardiac functions, and two patients who discontinued ERT have remained off ERT for over at least nine months.

“I believe today’s data indicate that AVR-RD-01 is substantially reducing the build-up of Gb3 substrate in kidney tissue to potentially effective clearance levels,” said Mark Thomas, MD, lead investigator of the FAB-201 trial, nephrologist at Royal Perth Hospital, and clinical professor at the University of Western Australia Medical School.

“This, along with the sustained reduction in Gb3 and lyso-Gb3 in plasma observed to date, could translate into substantially improved patient outcomes over the current standard of care,” he added.

So far, no unexpected trends or safety issues have been reported, with adverse events being consistent with the required pre-conditioning protocol, underlying Fabry disease, or pre-existing conditions.