AVROBIO, Inc. announced new interim pharmacokinetic, pharmacodynamic and clinical efficacy data, showing stabilization or reversal of multiple clinically relevant measures in five patients with Gaucher disease after they received a single dose of AVR-RD-02, an investigational hematopoietic stem cell (HSC) gene therapy. In addition, following positive discussions with regulators, AVROBIO plans to initiate a global, registrational Phase 2/3 clinical trial in Gaucher disease type 3 (GD3) in the second half of 2023. Gaucher disease is the largest, most common lysosomal disorder.

Even on enzyme replacement therapy (ERT) – the current standard of care – people with Gaucher disease type 1 (GD1) typically have a shortened life expectancy and may experience debilitating symptoms that significantly reduce their quality of life. GD3 is a more severe, progressive form of Gaucher disease, which presents with more widespread systemic manifestations, typically refractory to standard of care treatment, as well as neurological signs and symptoms. AVR-RD-02 for GD3: First pediatric patient dosed with investigational AVR-RD-02: An 11-year-old patient was dosed at the University of Manchester, U.K., on a named patient basis; Fifteen months post gene therapy, the patient has normalized peripheral glucocerebrosidase (GCase) enzyme activity and plasma chitotriosidase, a marker of activated macrophages, and remains off enzyme replacement therapy (ERT) and substrate reduction therapy (SRT); Patient's albumin levels increased 33% eight months post gene therapy, reflecting improvements in lymphadenopathy and enteropathy?. This patient was previously refractory to maximal and multimodal medical therapy, including ERT, SRT, enteral steroids, dietary restrictions and intermittent albumin infusions;?

Additionally, the patient did not develop any new lesions on MRI assessments post gene therapy, on a background of rapidly developing lesions, and had no clinically detectable change in neurological status or new neurological manifestations 15 months post gene therapy; Safety data from this patient indicate no adverse events (AEs) related to drug product. All AEs observed were related to myeloablative conditioning, stem cell mobilization, underlying disease or pre-existing conditions. AVR-RD-02 for GD1: Clinically meaningful reductions in organomegaly and improvements from baseline ERT levels in plasma lyso-Gb1 and chitotriosidase activity: All four adult GD1 patients in the Guard clinical trial who have been infused with investigational AVR-RD-02 to date saw sustained engraftment with vector copy numbers (VCN) between 0.54 to 0.86 per diploid genome 14 weeks to two years post gene therapy, and reconstitution of GCase enzyme activity both in plasma and peripheral blood leukocytes within the normal range; Glucosylsphingosine (lyso-Gb1) decreased 21% to 70% (21%, 21%, 30% and 70%, respectively) below ERT baseline levels for all four patients 12 weeks to two years post gene therapy.

A downstream metabolic product of glucocerebroside, lyso-Gb1, is considered a sensitive and specific biomarker used for disease monitoring; The metabolite chitotriosidase was reduced in the two patients with evaluable samples to date, reflecting a reduction in macrophage activation and inflammation. Patient 1's chitotriosidase level has almost completely normalized, declining from a high of 145.8 µmol/L/h prior to gene therapy treatment to 42.4 µmol/L/h (=38.1 µmol/L/h is considered normal range) two years post gene therapy. Patient 2, who was in the normal range before gene therapy treatment, still decreased from 24.3 µmol/L/h at baseline to 19.2 µmol/L/h at week 52;3 Importantly, three of the four patients dosed demonstrate a reduction in liver and spleen volume below their own ERT baseline.

Patient 4 is not yet out far enough post gene therapy to be scanned for liver or spleen volume: Patient 1 data showed a clinically significant 24% reduction in liver volume at 104 weeks post gene therapy (patient underwent a splenectomy during childhood); Patient 2 data showed a clinically significant 11% reduction in liver volume and 23% reduction in spleen volume at 52 weeks post gene therapy; Patient 3 data showed a 4% reduction in liver volume and a 19% reduction in spleen volume, at 26 weeks post gene therapy; Safety data from the four patients dosed to date indicate no AEs related to drug product. All AEs observed were related to myeloablative conditioning, stem cell mobilization, underlying disease or pre-existing conditions. The majority of AEs were mild or moderate and resolved without clinical sequelae.?

Additionally, hemoglobin and platelet levels, a core feature of successful Gaucher disease treatment, remain in normal range following gene therapy; The ongoing Guard1 clinical trial (NCT04145037) is a multinational, open-label study to assess the safety and efficacy of investigational AVR-RD-02 in approximately eight to 16 participants (male or female) who are =18 and =50 years of age with a confirmed diagnosis of GD1. Planning first ever, randomized controlled clinical trial for GD3 in 2023: The company plans to initiate a Phase 2/3 pediatric clinical trial for investigational AVR-RD-02 in GD3 in the second half of 2023, following constructive meetings with the U.S. Food and Drug Administration (FDA) and U.K. Medicines and Healthcare products Regulatory Agency (MHRA); Global, open label, parallel-arm and randomized controlled clinical trial designed to evaluate the efficacy and safety of investigational AVR-RD-02. The trial is expected to include approximately 40 GD3 participants (male or female) who will be randomized 1:1 to receive HSC gene therapy or continue to receive standard of care ERT.

Following the observation period, eligible participants who received ERT can cross over into the active arm and receive HSC gene therapy; Planned primary efficacy endpoint is a novel, multi-domain endpoint to reflect the systemic and heterogeneous nature of Gaucher disease, including ataxia (impaired coordination), breathing ability and liver and spleen volume. A key secondary efficacy measure will examine substrate levels in cerebrospinal fluid (CSF), which reflects the impact of the HSC gene therapy in the central nervous system; ? Overall, data from both the Guard1 and planned global Phase 2/3 GD3 clinical trials are expected to further development of this investigational gene therapy?, leveraging the similar underlying pathophysiology for both types of Gaucher disease.