Fabry and Gaucher Gene Therapies Well-Tolerated

AVROBIO’s gene therapies for Fabry and Gaucher disease seem to be well-tolerated, according to interim safety data from multiple trials the company recently announced.

The data, from the open-label, phase 1/2 FAB-GT trial (NCT03454893) of AVR-RD-01 in classic Fabry disease and the open-label, phase 1/2 Guard1 trial (NCT04145037) of AVR-RD-02 in type 1 Gaucher disease, were presented at the European Society of Gene & Cell Therapy, October 19-22, 2021.

“We have worked from the very beginning and at every turn to incorporate a strong safety focus in our proprietary plato® gene therapy platform, by having carefully selected clinical indications; an optimized, state-of-the-art vector; closed and automated manufacturing; use of innovative analytics; and a personalized conditioning regimen, to bring lentiviral gene therapies to patients with lysosomal disorders,” Geoff MacKay, president and chief executive officer, AVROBIO, said in a statement. “We believe the data shared this week continue to support the predictable safety profile of our investigational gene therapies targeting lysosomal disorders. Additionally, we’re particularly proud to unveil new industry-leading techniques that are designed to provide additional insight throughout the process, including safety monitoring at the DNA level within different bone marrow and blood cell types.”

AVR-RD-01 for Classic Fabry Disease

Data were reported from 8 patients in the FAB-GT trial and 5 patients in an investigator-sponsored phase 1 trial. Data from a ninth patient is still being analyzed but seems consistent with other safety patients. Phase 2 patients had a mean follow up of 16 months (range, 2–38) and phase 1 patients had a mean follow up of 39 months (range, 29–54). Data cut off dates were July 26, 2021 for the phase 1 and August 20, 2021 for the phase 2 trials. Six patients were treated using the plato® gene therapy platform, which consists of an optimized lentiviral vector, proprietary tag technology, analytical techniques and Bu90-TCI.

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These patients have experienced no adverse events (AEs) or serious AEs related to ACR-RD-01 treatment. Most AEs were due to myeloablative conditioning, protocol-mandated drugs, or underlying conditions or diseases. Serious AEs, which made up 4% of reported AEs, included nausea, dehydration, fever, febrile neutropenia and mucosal inflammation, all of which resolved without clinical sequelae.

AVROBIO previously reported efficacy data from the phase 1 and 2 trials that demonstrated stable and sustained enzyme activity and reductions of 87% and 100% in kidney Gb3 inclusions in 2 patients with Fabry disease. The 2 trials continue to enroll and updated efficacy data will be announced in the first quarter of 2022. 

“Overall, we believe that these data further support the risk-benefit profile of AVROBIO’s investigational gene therapy for Fabry disease. 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,” principal investigator Mark Thomas, MD, nephrologist, Royal Perth Hospital, and clinical professor, University of Western Australia Medical School, added to the statement. “In my team’s experience, target concentration intervention delivers an individualized busulfan dose to patients, which results in anticipated reduced blood cell counts and other common adverse events associated with the routine practice of stem cell transplantation and minimizes risk of out-of-range toxicity.”

AVR-RD-02 for Type 1 Gaucher Disease

AVROBIO announced new safety data from the first patient dosed in the Guard1 trial treated with AVR-RD-02 using the plato® gene therapy platform. The patient has had no serious AEs or AEs related to treatment as of 14 months post-treatment, with a safety date cutoff date of August 31, 2021. Again, AEs were consistent with trial drug protocols or underlying conditions. Previously reported efficacy data from the Guard1 trial demonstrated improvements in biomarkers and maintained, normal levels of platelets and hemoglobin in the first treated patient. A second patient, for which data is not yet available, has been dosed in the trial. The trial continues to enroll participants.

Using their high-resolution molecular biology follow-up and single-cell transcriptional profiling, AVROBIO has analyzed samples from participants and found that, 6 months after gene therapy, all samples analyzed showed a stable composition of engineered cell populations in the blood. No persistent dominant clonal expansion has been observed. Additionally, AVROBIO has detected identical insertion sites between blood cell progenitors and their mature cell progeny in analyzing patients’ bone marrow.

“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. 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 added to the statement.

REFERENCE

AVROBIO reports new interim safety data across investigational gene therapies for Fabry and Gaucher disease Type 1. News release. AVROBIO. https://www.biospace.com/article/releases/avrobio-reports-new-interim-safety-data-across-investigational-gene-therapies-for-fabry-and-gaucher-disease-type-1/