Gaucher Disease HSC Gene Therapy Demonstrates Efficacy and Safety in Phase 1/2 Trial

Two patients treated with AVR-RD-02 showed clinically meaningful reductions in liver size.

AVROBIO’s AVR-RD-02, an investigational hematopoietic stem cell (HSC) gene therapy being evaluated for the treatment of Gaucher disease type 1 (GD1), has demonstrated efficacy and safety in interim data from the phase 1/2 Guard1 clinical trial (NCT04145037).1 The data was presented in a poster at the WORLDSymposium 2023, held February 22-26, in Orlando, Florida.

AVR-RD-02 consists of autologous CD34+ cells that have been modified ex-vivo to express functional glucocerebrosidase (GCase), the disease-targeted enzyme. Among 6 patients that have been enrolled in Guard1, 4 patients had been dosed and were evaluable as of the November 22, 2022, data cutoff. These patients included Patient 1, a 31-year-old white female patient; Patient 2, a 44-year-old white female patient; Patient 3, a 24-year-old white male patient; and Patient 4, a 34-year-old white male patient. 

Patient 1 received a dose of 3x106 CD34+ cells/kg. Her prior treatment included 23 years of imiglucerase and 5 months of velaglucerase. Patients 2 received a dose of 6.6x106 CD34+ cells/kg ; her prior treatments included 15 years of imiglucerase, 2 years of eliglustat, and 4 years of velaglucerase. Patient 3 received a dose of 7x106 CD34+ cells/kg. Prior treatment for this patient included 25 years of unspecified enzyme replacement therapy (ERT), 2 years of eliglustat, and approximately 2.5 years of imiglucerase. Patient 4 received a 4.1x106 dose of CD34+ cells/kg; his prior treatment included 19 years of imiglucerase, 9.5 years of velaglucerase, and an additional 2 years of imiglucerase.

Vector copy number (VCN) trends following AVR-RD-02 infusion implied sustained engraftment, with VCNs between 0.54 and 0.86 observed at the points of latest follow-up for each patient. Normalized GCase activity in the plasma and in peripheral blood leukocytes following treatment with AVR-RD-02 and cessation of treatment with ERT was observed in the 4 patients. It was also observed that levels of Lyso-Gb1, a marker of substrate accumulation, decreased from ERT baseline levels by 70%, 30%, 21%, and 21% for patients 1 through 4, respectively. Levels of chitotriosidase, a marker of Gaucher cells, were evaluable in 2 patients. Patient 1 showed almost normalized levels of chitotriosidase 2 years after treatment with AVR-RD-02 and Patient 2 maintained stable levels in the normal range for nearly 1 year following treatment. All 4 patients showed evidence of hematological reconstitution following an expected transient decline in hemoglobin and platelet levels after treatment with AVR-RD-02.

In addition to the biomarker data, several patients also showed significant improvements in organomegaly. Patient 1 showed a 24% reduction in liver volume at 104 weeks and Patient 2 showed an 11% reduction in liver volume at 52 weeks; both of these changes were considered clinically meaningful. In addition, Patient 3 showed a 4% reduction at 24 weeks, though this was below the 10% threshold required to be considered clinically meaningful. Patient 4’s data is not yet available. Patient 2 also showed a clinically meaningful (20% or greater) reduction in spleen size of 23%. Patient 3 showed a 19% reduction in spleen size. Patient 1 had undergone a splenectomy and Patient 4’s data is not yet available.

In terms of safety, there were no adverse events (AEs) deemed related to AVR-RD-02 in the 4 treated patients. All AEs and serious AEs were deemed related to myeloablative conditioning, drugs mandated by the protocol or study procedures, underlying disease, or pre-existing conditions. Among these AEs were anemia, leukopenia, neutropenia, thrombocytopenia, eye pain, decreased appetite, dehydration, headache, hypophosphatemia, amenorrhea. There were 71 AEs in total and 2 serious AEs.

Ultimately, the investigators concluded that all 4 patients experienced improvements over baseline ERT measures after receiving AVR-RD-02. AVROBIO has announced that a phase 2/3 clinical trial for patients with type 3 GD is anticipated in the second half of 2023.2

Click here to read more coverage of WORLDSymposium 2023.

1. Adera M, Veselinovic M, Treohan A, Golipour A, Ridha E. The Guard1 clinical trial - A first in-human, phase 1/2 study evaluating AVR-RD-02, a hematopoietic stem cell (HSC) gene therapy for Gaucher disease: Preliminary safety, pharmacodynamic and clinical efficacy results from the subjects observed for up to 24 months post-infusion. Presented atWORLDSymposium 2023, held February 22-26, in Orlando, Florida. Abstract #8
2. AVROBIO announces new positive clinical data and outlines clinical development plan following regulatory discussions for its Gaucher disease gene therapy. News release. AVROBIO. December 7, 2022.

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