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

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