AVROBIO Reports Encouraging Preliminary Data for Phase 1/2 Trial Testing Gene Therapy in Fabry Patients

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by Diogo Pinto |

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AVROBIO, a biotechnology company developing single-dose gene therapies for rare diseases, announced positive preliminary data for its Phase 1/2 clinical trial testing AVR-RD-01 gene therapy in patients with Fabry disease.

AVR-RD-01 has shown to be safe and effective in delivering a healthy GLA gene that encodes a functional α‑galactosidase A (AGA, the enzyme that is deficient in Fabry disease).

The first two patients in the Phase 1 (NCT03454893) study continue to have AGA enzyme activity above the diagnostic range for Fabry disease, and one of these patients is no longer on enzyme replacement therapy.

Preliminary data will be presented at the 1st Canadian Symposium on Lysosomal Disease (CLSD) in Sherbrooke, Quebec, Canada, Oct. 5-6, and at the 26th Annual Congress of the European Society of Cell & Gene Therapy (ESCGT), in Lausanne, Switzerland, Oct. 16-19.

AVR-RD-01 is being studied as a single-dose gene therapy. It consists of a lentiviral vector (transporter) containing a functional copy of the GLA gene, the gene mutated in Fabry disease, that is then “inserted” into patients’ hematopoietic stem cells. These cells, in turn, are infused back into patients’ blood to restore normal GLA gene expression.

The Phase 1 part of the study is assessing the safety of AVR-RD-01 in up to six Fabry patients who were treated with standard of care enzyme replacement therapy (ERT), the only approved treatment for Fabry’s, for at least six months prior to receiving AVR-RD-01 therapy.

The investigator-sponsored Phase 1 study is being conducted by a Canadian team at the Fabry disease Clinical research and Therapeutics (FACTs), led by their principal investigator Jeffrey A. Medin, PhD.

The study’s goals include AVR-RD-01 engraftment, clinical response (measured as AGA levels in patients’ blood) and safety (the incidence and severity of treatment-related adverse side effects after AVR-RD-01 administration).

Preliminary data from the Phase 1 part of the trial showed that the first two patients have continued AGA enzyme activity — 2.6 and 3.7 nanomol of AGA per hour and milliliter (nmol/h/mL) — above the diagnostic range of classic Fabry disease — 1 nmol/h/mL — 18 and 6 months after treatment, respectively. Importantly, patient 1 is no longer receiving ERT.

The average vector copy number (VCN), the average number of copies of the lentiviral-vector inserted gene that integrated into the cell DNA, was 0.1 and 0.4 for patients 1 and 2, respectively.

A third participant of the Phase 1 study received AVR-RD-01 therapy in July 2018. Preliminary safety data showed that the three patients tolerated the therapy well, with no serious side effects being observed.

“We are encouraged by the AGA enzyme activity we are seeing after treatment with AVR-RD-01 in the first two patients with Fabry disease in the Phase 1 study,” Geoff MacKay, president and CEO of AVROBIO, said in a press release.

“Both of these patients have AGA activity that remains above the diagnostic range for males with classic Fabry disease, and all patients will continue to be followed for assessment of long-term durable response. We are especially pleased that that patient 1 was taken off ERT in mid-July and remains off,” MacKay added.

The Phase 2 study (NCT03454893), named FAB-201 and sponsored by AVROBIO, is evaluating the effectiveness and safety of AVR-RD-01 in eight to 12 treatment-naïve male patients. Goals of the Phase 2 part are similar of those of the Phase 1. The study is currently recruiting.

The only patient enrolled in the Phase 2 part of the study demonstrated an AGA plasma enzyme activity of 2.74 nmol/h/mL and VCN of 0.5, three months after the treatment with AVR-RD-01. These results are again above the diagnostic range of classic Fabry disease.

The treatment was well-tolerated, and no serious side effects were reported in this patient.

“We recently achieved an important milestone in dosing the first patient in our ERT-naïve Phase 2 FAB-201 trial. This patient is now demonstrating AGA activity above the diagnostic range for males with classic Fabry disease three months after receiving our gene therapy treatment,” MacKay said.

Aneal Khan, from the FACTs team, also commented on the achievements, “We particularly highlight the 18-month data from patient 1 who maintained AGA enzyme activity above the diagnostic range for classic Fabry disease and we received approval to discontinue ERT and observe the impact of gene therapy alone. We continue to advance our efforts for a one-time gene therapy that transforms the lives of patients with this chronic, progressive disease.”

While enrollment in both parts of the study is still ongoing, the FACTs team will continue working on improving the technology.

“In parallel, we continue our move towards the implementation of a set of process optimization initiatives, including heightened vector efficiency, our fully closed, automated manufacturing system and conditioning,” MacKay added.