Nonclinical toxicity study duration in AAV gene therapy development: Evidence from industry survey supports adequacy of short-term assessments

Adeno-associated virus (AAV)-based gene therapies are emerging as transformative treatments for serious diseases; however, determining the optimal duration of nonclinical toxicity studies remains a key regulatory and scientific question. To address this, the EFPIA Gene Therapy Working Group surveyed 24 AAV gene therapy programs across 13 companies to assess current practices and the value of long-term (≥6 months) toxicity studies. Results showed that ≤3-month studies were sufficient to characterize the toxicology profile in 87.5% of programs that completed a toxicity assessment in a ≥6-month long-term chronic studies, with only one program identifying new toxicities in longer chronic studies with impact on clinical development. Common AAV-related toxicities, such as liver and dorsal root ganglia effects, were observed within the first 6 weeks post-administration. Longer studies were often driven by sponsor's perception based on internal experience or need to assess durability, rather than regulatory requirements. These findings aligned with regulatory reviews of approved AAV products (e.g., Zolgensma, Luxturna, Roctavian) that consistently demonstrated the adequacy of ≤3-month studies for approved and marketed products. The outcome of this survey supports a risk-based, science-driven approach to <i>in vivo</i> study duration, emphasizing that shorter-term studies are generally sufficient for identifying relevant toxicities associated with AAV-based gene therapies. Embracing this approach can reduce animal use, accelerate development timelines, and support harmonized regulatory expectations for AAV gene therapy products.