Animal models have limitations for safety assessment of gene therapies: FDA adcomm

Regulatory NewsRegulatory News | 02 September 2021 |  By 

An advisory committee to the US Food and Drug Administration (FDA) has said animal models are “problematic” in assessing the safety risks of gene therapies derived from adeno-associated virus (AAV) vectors.
FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) held a virtual meeting on 2 September to discuss the best animal models to study to assess safety of these products.
“AAV are a popular type of gene therapy, yet we are seeing a variety of safety issues with them” said Wilson Bryan, the director of the Center for Biologics Evaluation and Research’s Offices of Tissues and Advanced Therapies (CBER’s OTAT).
FDA has thus far approved two marketing applications for AAV-based gene therapy (GT) products, both to Novartis. The firm received approval for Luxturna (voretigene neparvovec) in 2017 and Zolgensma (onasemnogene abeparvovec-xioi) in 2019.  Yet these drugs are not without safety risks.
FDA’s Rosa Sherafat-Kazemzadeh, an official in OTAT’s division of clinical evaluation and pharmacology/toxicology, reports there have been “severe” adverse events in AAV vector clinical trials, including instances of acute liver and kidney failure in children. She said that about one third of the 500 children under the age of 2 treated with Zolgensma had at least once adverse event of hepatoxicity.
In its briefing materials,  FDA said it is “seeking the committee’s insights into strategies to evaluate and mitigate risks in the context of AAV vector-based product design and quality, preclinical studies, and clinical trials.”
Animal models are problematic  
FDA asked the committee to discuss the “merits and the limitations of animal studies to characterize the risk of AAV-vector mediated oncogenicity, and provide recommendations on specific preclinical study design elements.”
The chair of the committee, Lisa Butterfield, an expert in tumor immunology and vice-president of the PICI Research Center at the University of California at San Francisco, summarized the consensus of the committee.
“In terms of the merits and the limitations of animal studies, I heard agreement that in general, the animal studies are problematic with respect to humans,” said Butterfield. “Sometimes they show us what is possible and other times they are not sufficiently representative of the human situation.”
Butterfield added that a neonatal mouse can show what is possible in assessing safety risks in humans but "may not be a good model for newborns."
One committee member pointed out that it may be too early to make a recommendation on the design of preclinical animal studies.
Taby Ahsan, a biomedical engineer and head of analytical development and characterization for therapeutic discovery at the MD Anderson Cancer Center in Houston TX, said that “it may be premature to provide you with general recommendations on preclinical study requirements when there are questions about species relevance and how to tease that apart.”
Ahsan added that there are also needs to be a move to standardize preclinical study designs. She said that “standardization will help drive forward the preclinical recommendations.”
Another member recommended a more coordinated effort to standardize dose considerations in preclinical studies to characterize the risk of AAV vector mediated oncogenicity.
“These are complex biologics and there needs to be a more centralized and coordinated effort to standardize dose considerations, and that is something that the field can work towards,” said Barry Byrne, professor and associate chair of pediatrics, molecular genetics and microbiology, and director of the Powell Center School of Medicine at the University of Florida in Gainesville.
FDA CTGTAG meeting on toxicity risks of AAV vectors for gene therapies


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