AVROBIO Inc. (AVRO) Reports New Interim Safety Data Across Investigational Gene Therapies for Fabry and Gaucher Disease Type 1

October 19, 2021 7:11 AM EDT

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AVROBIO, Inc. (Nasdaq: AVRO), a leading clinical-stage gene therapy company with a mission to free people from a lifetime of genetic disease, today reported new safety data from the first lentiviral gene therapy clinical trials for Fabry disease and Gaucher disease, as well as new high-resolution cellular data providing insights into the mechanisms of action of its gene therapies. The data are being presented at the virtual 28th Annual Congress of the European Society of Gene & Cell Therapy (ESGCT), Oct. 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,” said AVROBIO President and CEO Geoff MacKay. “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.”

Fabry disease clinical trial safety data reinforce predictable and generally consistent safety profile

New safety data from the first eight adult patients dosed in the Phase 2 FAB-GT trial and the five adult patients dosed in the investigator-sponsored Phase 1 trial show no adverse events (AEs) or serious adverse events (SAEs) related to drug product AVR-RD-01. The AEs and SAEs experienced by trial participants to date in the two trials have been generally consistent with myeloablative conditioning, protocol-mandated drugs, underlying disease or pre-existing conditions. Of all safety events reported to date, 4% were classified as SAEs (n=11), consisting of nausea, vomiting, dehydration, fever, febrile neutropenia and mucosal inflammation, all of which resolved without clinical sequelae.

These safety data are from patients in the FAB-GT study with a mean post-gene therapy follow up of 16 months (range: 2-38 months) and the Phase 1 study with a mean post-gene therapy follow-up of 39 months (range: 29-54 months). Safety data from the ninth patient recently dosed in the FAB-GT study are still being analyzed, but preliminary data are consistent with the overall safety profile.

“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,” said Mark Thomas, M.D., principal investigator of the AVROBIO-sponsored FAB-GT Phase 2 trial of AVR-RD-01, an investigational gene therapy for Fabry disease, nephrologist at the Department of Nephrology, Royal Perth Hospital and clinical professor at the University of Western Australia Medical School. “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.”

With AVROBIO’s Bu90-Target Concentration Intervention (TCI) conditioning regimen, patients receive four daily doses of the conditioning agent busulfan, each adjusted to target a cumulative area under the curve of 90 mg x hr/L. This targeted dosing is intended to maximize busulfan’s ability to make space in the bone marrow for the genetically modified stem cells to engraft, while minimizing the risk of out-of-range toxicity. AVROBIO is also working with clinicians to develop comprehensive care guidelines designed to help gene therapy care teams further proactively mitigate or prevent potential side effects.

Six of the 14 Fabry disease patients in the trials have been treated using AVROBIO’s proprietary plato® gene therapy platform, which includes a state-of-the-art optimized lentiviral vector, proprietary tag technologies, proprietary analytical techniques and Bu90-TCI. The platform’s industry-leading closed, automated manufacturing platform is designed to bring gene therapy to patients worldwide.

The safety data cut-off date for the Phase 1 trial was July 26, 2021, and for the FAB-GT trial was Aug. 20, 2021.

Previously reported efficacy data from the two trials have documented stable and sustained enzyme activity and reductions of 87% and 100% in kidney Gb3 inclusions for the evaluable kidney biopsies of two Fabry disease patients. AVROBIO is planning to share updated efficacy data from both trials during the first quarter of 2022. Enrollment in the FAB-GT trial (NCT03454893) is ongoing, and further details are available on clinicaltrials.gov.

Gaucher disease type 1 clinical data at 12+ months show no unexpected safety events

New safety data from the first patient dosed in the Phase 1/2 Guard1 trial of AVR-RD-02 show no SAEs and no AEs to date related to drug product more than 14 months post-treatment. Reported AEs for this patient, who was treated with investigational AVR-RD-02 incorporating key elements of AVROBIO’s proprietary plato® gene therapy platform, have been consistent with myeloablative conditioning, protocol-mandated drugs, underlying disease and pre-existing conditions. The safety data cut-off date was Aug. 31, 2021.

A second patient has now been dosed in the trial.

Previously reported efficacy data from the Guard1 clinical trial has shown improvement across biomarkers for the first-treated Gaucher disease patient, as well as platelet and hemoglobin levels maintained in the normal range. Enrollment in the Guard1 trial (NCT04145037) is ongoing, and further details are available on clinicaltrials.gov.

Novel techniques provide insight on safety at DNA level of bone marrow and blood cell types

Standard safety follow-up for ex vivo lentiviral gene therapy patients includes looking at the number and location of transgene insertions broadly across nucleated blood cell populations. AVROBIO has developed a new approach involving high-resolution molecular biology follow-up that enables the collection and monitoring of integration sites for individual cell types and at different stages of cell maturation. Additionally, using single-cell transcriptional profiling, AVROBIO has traced stem/progenitor cell states from their initial source, through transduction, to multiple years after infusion in patients.

All samples analyzed to date show a stable composition of genetically engineered cell populations in the blood starting six months after gene therapy. The company has seen no evidence of persistent dominant clonal expansion across all patients studied. In addition, when combining this information with data derived from the patients’ own bone marrow, the company detected identical insertion sites between blood cell progenitors and their mature cell progeny.

“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,” adds MacKay.

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