RARE Daily

Avrobio Reports Positive Results of Its Gene Therapy for Fabry Disease

February 8, 2021

Rare Daily Staff

Avrobio reported that one year after dosing, the first patient given its experimental ex vivo lentiviral gene therapy in the ongoing phase 2 FABGTi trial in patients with Fabry disease had complete clearance of toxic substrate in a kidney biopsy, the trial’s primary efficacy endpoint.

Fabry disease is an X-linked inherited disease that results from deficient activity of the lysosomal α-Galactosidase-A enzyme resulting in progressive accumulation of abnormal deposits of a fatty substance called globotriaosylceramide (Gb3) in blood vessel walls throughout a person’s body. Fabry patients inherit a deficiency of the α-Galactosidase-A enzyme, which is normally responsible for the breakdown of Gb3. The abnormal storage of Gb3 increases with time and, accordingly, Gb3 accumulates, primarily in the blood and in the blood vessel walls. The ultimate consequences of Gb3 deposition range from episodes of pain and impaired peripheral sensation to end-organ failure—particularly of the kidneys, but also of the heart and the cerebrovascular system.

The kidney biopsy for Patient 4 in the phase 2 trial showed a reduction from an average of 4.0 globotriaosylceramide (Gb3) inclusions per peritubular capillary (PTC) at baseline to zero inclusions per PTC one year after dosing, a 100 percent reduction. Two blinded pathologists, who independently scored 99 digital images of the sectioned kidney from the 12-month biopsy, made the assessment. Every image scored zero inclusions.

Patient 4 is the first in the trial treated using AVR-RD-01, Avrobio’s proprietary plato gene therapy platform, which includes a state-of-the-art lentiviral vector, a personalized conditioning regimen with precision dosing and an automated, closed manufacturing process intended to deliver potent and consistent drug product from manufacturing sites worldwide at commercial scale.

“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,” said Mark Thomas, the lead investigator in the FAB-GT trial, a clinician in the department of nephrology at Royal Perth Hospital and a clinical professor at the University of Western Australia Medical School.

Two of four FAB-GT trial participants had evaluable kidney biopsies. Patient 1 showed an 87 percent reduction, and effective clearance of Gb3 inclusions per PTC compared to baseline.

In addition to the kidney biopsy, Avrobio reported updated data suggesting generally stable and sustained plasma and leukocyte alpha-galactosidase A (AGA) enzyme activity and a corresponding reduction in toxic plasma lyso-Gb3 in patients across the phase 1 and FAB-GT trials of AVR-RD-01. To date, four patients have been dosed in the phase 2 FAB-GT trial and five patients have been dosed in the fully enrolled phase 1 trial.

New aggregated data across all cardiac measures for the FAB-GT patients show patients continue to exhibit stable cardiac structure and function at 12 months post-gene therapy, which is notable given that people living with Fabry disease often experience progressive left ventricular hypertrophy and fibrosis, leading to reduced cardiac function.

Additionally, the company is leveraging existing trial sites to potentially expand the pool of patients globally, with four Fabry disease patients from Brazil currently moving through the travel, screening, consent and enrollment process for potential treatment at Avrobio’s global center of excellence in Australia.

No unexpected safety events have been identified in the AVR-RD-01 phase 1 and phase 2 trials as of the safety data cut-off date of November 26, 2020 and December 7, 2020, respectively. Eight serious adverse events (SAEs) reported in the two Fabry disease trials have been consistent with the conditioning regimen, stem cell mobilization, underlying disease or pre-existing conditions. All SAEs have been resolved without clinical sequelae.

“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,” said Geoff MacKay, president and CEO of Avrobio. “With this strong momentum, we look forward to clarifying the regulatory pathway with regulatory agencies.”

Photo: Geoff MacKay, president and CEO of Avrobio

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