Stem Cell Gene Therapy Show Clinical Improvements in Gaucher Type 1 and 3


AVROBIO plans to initiate a global phase 2/3 trial of AVR-RD-02 in GD3 in the second half of 2023.

AVROBIO’s hematopoietic stem cell (HSC) gene therapy AVR-RD-02 has demonstrated clinically meaningful improvements in patients with type 1 Gaucher disease (GD1) as well as in the first patient with type 3 Gaucher disease (GD3) dosed in the Gaurd1 phase 1/2 trial (NCT04145037).

“We are thrilled to share new, compelling data from patients impacted across the spectrum of Gaucher disease, the most common lysosomal disorder. This includes what we believe to be transformational data from the first pediatric GD3 patient treated with an HSC gene therapy, showing complete biochemical correction, which means both enzyme activity and substrate levels have normalized post gene therapy. This pharmacodynamic efficacy equates with improvements in major refractory elements of disease for this patient, something the child has never experienced on current standard of care,” Essra Ridha, MD, MRCP, FFPM, chief medical officer, AVROBIO, said in a statement. “Following constructive regulatory conversations, including with FDA, we are now focused on initiating a randomized controlled, Phase 2/3 clinical trial for GD3 next year, the first such trial for a gene therapy, to further evaluate the benefit-risk profile of AVR-RD-02 in a clinical trial setting.”

AVR-RD-02 was well-tolerated in the patient with GD3, aged 11 years, with no adverse events (AE) related to the therapy and only to myeloablative conditioning, underlying disease or conditions, and stem cell mobilization. At 15 months post-treatment, the patient remains off enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) and has normalized peripheral glucocerebrosidase (GCase) enzyme activity, and plasma chitotriosidase and albumin levels increased 33% eight months post gene therapy. This patient was previously refractory to maximal and multimodal medical therapy, including ERT, SRT, enteral steroids, dietary restrictions and intermittent albumin infusions. With a background of rapidly developing lesions, no new ones developed post gene therapy and there were no clinically detectable changes in neurological status or new neurological manifestations.

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“Following gene therapy, we have seen real changes in our life and our son's life. The first few weeks were a bit rough in terms of mucosal inflammation, hair loss and skin changes, but overall, he appeared to respond to the treatment very well. He is off ERT, steroids and SRT completely, with no return of PLE symptoms, such as edema and GI distress. He still has seizures but no further change in cognitive abilities. My son now is sleeping throughout the night, while he used to wake up often. Our family gained freedom as we are no longer tied to a challenging medication schedule and many hospital visits,” the parent of the patient shared during a webcast presentation of the data.

The 4 adult patients with GD1 treated have had sustained engraftment with vector copy numbers (VCN) between 0.54 to 0.86 per diploid genome 14 weeks to 2 years post gene therapy, as well as restored plasma and peripheral blood leukocyte GCase enzyme activitywithin the normal range. Glucosylsphingosine decreased below ERT baseline levels for all 4 patients (range, 21-70%) and the metabolite chitotriosidase significantly reduced in 2 evaluable patients, 1 to within normal range. All 3 evaluable patients had reductions in liver volume (range, 11-24%); these patients, excepting 1 that underwent a splenectomy during childhood, also had reductions in spleen volume (range, 19-23%; follow-up range, 26-104 weeks). Similarly to the patient with GD3, no AEs were related to the therapy, and most were mild or moderate and resolved without clinical sequelae. Hemoglobin and platelet levels, also remained in normal range following gene therapy

“Additionally, today’s interim data from the ongoing Guard1 clinical trial, our Phase 1/2 trial for GD1, reinforce the potential clinical impact of HSC gene therapy in this subset of Gaucher disease, with the first patient dosed now two years post gene therapy. In our previous update, we shared favorable data across clinical biomarkers – today, we’re pleased to share new interim data showing not only sustained pharmacodynamic efficacy, but also some clinically significant reductions in liver and spleen volume, demonstrating that our gene therapy is having an impact above and beyond the standard of care baseline measures,” Ridha added. “We believe our current GD1 and planned GD3 clinical trials combined will create a robust data set that will further the development of this investigational gene therapy and move us ever closer to bringing a potential one-time treatment option to people living with Gaucher disease.”

AVROBIO plans to initiate an open-label, randomized, controlled, parallel-arm, global, registrational phase 2/3 clinical trial evaluating AVR-RD-02 in GD3 in the second half of 2023.The trial has a target enrollment of 40 male or female participants with GD3 who will be randomized 1:1 to receive AVR-RD-02 or continue to receive standard of care ERT and later receive the therapy during the crossover period. The trial will primarily assess a novel, multi-domain endpoint that takes into account many systemic and heterogeneous features of GD, including ataxia, breathing, and liver and spleen volume. A key secondary endpoint will be examining cerebrospinal fluid substrate levels.

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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