One-time AVR-RD-01 Gene Therapy Safe Up to 4.5 Years, Trials Report

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by Marta Figueiredo PhD |

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AVR-RD-01 gene therapy | Fabry Disease News | illustration of genes

A single dose of Avrobio’s investigational gene therapy AVR-RD-01 continues to show a favorable safety and tolerability profile for up to 4.5 years in adolescents and adults with Fabry disease, according to latest data from Phase 1 and Phase 2 clinical trials.

Notably, up to 3.5-year data previously showed the therapy was also effective at increasing the levels of alpha-galactosidase A (Gal A), the faulty enzyme in Fabry patients, and in reducing the levels of disease biomarkers. Updated efficacy data from both trials are expected in the first months of 2022.

Together, the results support AVR-RD-01 as a safe and effective one-time treatment for people with Fabry disease, and Avrobio earlier announced plans to launch a pivotal trial in mid-2022 to support future regulatory requests for its approval.

The new safety findings were presented at the virtual 28th Annual Congress of the European Society of Gene & Cell Therapy, held virtually Oct. 19–22.

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“We believe that these data further support the risk-benefit profile of AVROBIO’s investigational gene therapy for Fabry disease,” Mark Thomas, MD, the principal investigator of the FAB-GT Phase 2 trial of AVR-RD-01 at its Australian site, Royal Perth Hospital, said in a press release.

“With previously reported durability data out more than three and a half years for the first patient, these new data strengthen the safety profile of this gene therapy,” added Thomas, who is also a clinical professor at the University of Western Australia Medical School.

AVR-RD-01 is a gene therapy that uses a modified and harmless virus to deliver and insert a healthy copy of the GLA gene into the DNA of a patient’s blood progenitor cells, or hematopoietic stem cells. This gene provides the instructions to produce Gal A and is mutated in Fabry patients.

Hematopoietic stem cells are first collected from a patient’s bone marrow, genetically modified in the lab, and then infused back to the patient after receiving Avrobio’s Bu90-target concentration intervention conditioning regimen.

This regimen — based on busulfan, a chemotherapy agent — was designed to maximize busulfan’s ability to kill cells in the bone marrow and make space for the genetically modified stem cells to grow, while minimizing its toxicity risk.

Because other cells in the vicinity take up the working Gal A produced by the modified stem cells, AVR-RD-01 has the potential to restore the enzyme’s levels and activity throughout the body.

Two ongoing clinical trials are testing the single-dose gene therapy in people with Fabry disease. A Phase 1 investigator-sponsored trial, called FACTs (NCT02800070), is assessing the therapy’s safety and biological activity in five men over five years.

The Avrobio-sponsored FAB-GT Phase 2 trial (NCT03454893), also called FAB-201, is evaluating the one-year safety and effectiveness of AVR-RD-01 in up to 12 patients, ages 16 to 50 (18 to 50 in the U.S.), who have not received prior treatment within three years.

The U.S., Canada, and Australia have recruiting sites involved in this trial. Since August, eligible patients also include females — whose symptoms are usually milder than those of male patients — and those with antibodies against agalsidase, the Gal A-mimicking enzyme delivered through enzyme replacement therapy (ERT).

Patients completing FAB-GT have the choice to enter an extension study (NCT04999059) that will assess the therapy’s long-term safety and effects for up to 15 years.

Previous interim results from both trials showed that AVR-RD-01 increased Gal A activity, reduced blood levels of Gb3 and lyso-Gb3, and led to 87% and 100% drops in kidney toxic Gb3 deposits after one year in the two patients with evaluable samples. Gb3 and lyso-Gb3 are fatty molecules that build-up to toxic levels without Gal A and are used as disease biomarkers.

These effects, including a generally stable kidney function that contrasts with the natural course of the disease, were sustained for at least 3.5 years post-dosing.

Newly announced, updated safety data concerned the five men treated in FACTs, with a mean follow-up of about 3.5 years (range: 2.4–4.5 years), and the first eight men dosed in FAB-GT, with a mean follow-up of 16 months (range, two–38 months, or a little over three years).

Results found no adverse events or serious adverse events related to AVR-RD-01 for up to 4.5 years post-treatment, with events reported to date being generally consistent with those linked to the chemotherapy regimen, underlying disease, or other pre-existing conditions.

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There were 11 serious adverse events, representing 4% of all adverse events, and consisted of nausea, vomiting, dehydration, fever, low levels of white blood cells with fever, and mucosal inflammation. The mucosa is a membrane that lines several body cavities and covers the surface of internal organs. All serious adverse events were resolved without clinical consequences.

Safety data from the ninth patient recently dosed in the FAB-GT trial are still being analyzed, but preliminary results were consistent with the therapy’s overall safety profile.

Avrobio is working with clinicians to develop guidelines designed to help gene therapy care teams further proactively reduce or prevent potential side effects of the chemotherapy regimen.

In addition, the company developed new approaches to better assess the safety profile of its investigational gene therapies at the cellular level. Particularly, the monitoring of gene insertion sites in the DNA of individual blood cell types and at different stages of maturation.

Genetic integration potentially can be associated with a risk of cancer-promoting mutations or can affect the activity/sequence of other genes.

Nonetheless, “all samples analyzed to date show a stable composition of genetically engineered cell populations in the blood starting six months after gene therapy,” Avrobio stated in the release, suggesting the absence of insertion-related problems.

In addition, analysis showed that the inserted gene was located at the same DNA region between blood cell progenitors and their resulting mature blood cells, further supporting the stability and rigidity of the integration.

“Patient safety is at the core of our plato gene therapy platform and we have developed industry-leading techniques, including being able to monitor at the cellular level the integration site and transcription profiles of our investigational therapies,” said Geoff MacKay, Avrobio’s president and CEO.

“We believe these data provide a valuable and unique tool to monitor at the DNA level the safety of our investigational therapies within the different bone marrow and blood cell types,” MacKay concluded.