AVR-RD-01 Gene Therapy Clears Fabry Patient of Toxic Substrate, Trial Reports

The first patient dosed with AVR-RD-01, an investigational gene therapy being tested in the ongoing Phase 2 FAB-GT clinical trial in people with Fabry disease, showed a 100% reduction, or complete clearance of toxic substrate, in a kidney biopsy one year later. 

This result, which meet the trial’s primary goal, was consistent with the first kidney biopsy from another patient, showing an 87% reduction in toxic substrate, as previously reported by Avrobio, the therapy’s developer. 

These data are being presented virtually this week at the 17th annual WORLD Symposium, along with positive data from the company’s gene therapy programs targeting Gaucher disease type 1 and cystinosis. 

“We are thrilled to begin the new year with this update, which adds to the breadth of strong clinical data we’ve reported across our leading lysosomal disorder pipeline of single-dose gene therapies,” said Geoff MacKay, president and CEO of Avrobio, in a press release. “With 13 patients dosed across three clinical programs, we have observed sustained and potentially transformative improvements in key biomarkers and functional metrics, with data from our Fabry disease program out 3 ½ years after dosing.”

Fabry is a genetic disorder caused by mutations in the GLA gene, leading to a deficiency in the protein alpha-galactosidase A. Its lack causes a toxic buildup of metabolites, particularly a fatty substrate called globotriaosylceramide (Gb3) in lysosomes, the recycling center of cells, giving rise to damage in the kidneys, heart, and the central nervous system (brain and spinal cord). 

Enzyme replacement therapy (ERT) is a standard Fabry treatment using alpha-galactosidase A to replace the missing protein. ERT must be given continuously over a lifetime to avoid symptoms returning, and patients require close monitoring for side effects. 

“Fabry disease is a serious and life-shortening condition for many patients that requires lifelong fortnightly ERT infusions, with life-limiting symptoms manifesting throughout the body and brain, and we urgently need options to halt, prevent or reverse progression of the disease,” said Mark Thomas, MD, FAB-GT lead investigator.

Use of AVR-RD-01 gene therapy starts by isolating adult stem cells from a patient’s blood, and exposing them to a modified lentivirus carrying a non-mutated copy of GLA. The cells are then returned to the patient to allow for the production of functional alpha-galactosidase A.

This investigational gene therapy is currently being tested in the open-label, FAB-GT trial (NCT03454893) in the U.S., Australia, and Canada. It is recruiting up to 12 males, ages 18 and older (in the U.S.) who have not received an approved therapy within the past three years. Four patients have been dosed in the trial so far. Contact details can be found here. 

“Additionally, enrollment activities for our Fabry disease trial are accelerating, giving us added confidence in our efforts to meet our goal of having dosed a cumulative 30 patients across all our clinical programs by the end of the year,” MacKay said. “With this strong momentum, we look forward to clarifying the regulatory pathway with regulatory agencies.”

The kidney biopsy from the trial’s first patient dosed using Avrobio’s proprietary plato gene therapy platform showed a reduction from an average of 4.0 globotriaosylceramide (Gb3) inclusions per peritubular capillary (PTC) before treatment to zero inclusions per PTC one year after dosing, representing a 100% drop. (PTCs are the small blood vessels that allow for minerals and ions to be re-absorbed into the blood when it is leaving the kidneys.)

The assessments were made independently by two pathologists who blindly examined 99 digital images of sectioned kidney tissue from the 12-month biopsy. All images scored zero inclusions of Gb3. 

“The complete clearance of Gb3 substrate in kidney tissue, coming on top of strong results from the first evaluable kidney biopsy in this trial, is very exciting,” Thomas added.

The company also reported data suggesting stable blood and leukocyte (white blood cells) alpha-galactosidase A activity in patients across the fully enrolled Phase 1 (NCT02800070) trial and the FAB-GT study of AVR-RD-01, showing treated patients were making functional protein. Continuous low levels of Fabry disease biomarker globotriaosylsphingosine (lyso-Gb3) were also reported. 

People living with Fabry often experience progressive left ventricular muscle enlargement and fibrosis, leading to poorer heart function. FAB-GT patients showed stable heart structure and function 12 months after gene therapy. 

No unexpected safety events were reported. As of the safety data cut-off date of Nov. 26 and Dec. 7, the eight serious adverse events reported in the Phase 1 and Phase 2 trials have been consistent with the stem cell protocol or pre-existing conditions, and all were resolved. 

Avrobio wants to expand the global pool of patients by leveraging existing sites, with four Fabry patients from Brazil currently undergoing screening for potential treatment in Australia.