Model-Informed Approaches and Innovative Clinical Trial Design for Adeno-Associated Viral Vector-Based Gene Therapy...

Area of Science:

• Gene therapy
• Viral vector technology
• Drug development

Background:

• Gene therapy (GT) using viral vectors shows promise for severe diseases, with recent product approvals.
• Adeno-associated virus (AAV) vector-based gene therapies are complex, requiring specialized expertise.
• Irreversible treatment effects and limited understanding of rare diseases necessitate careful benefit-risk assessment.

Purpose of the Study:

• To explore the application of model-informed drug development (MIDD) in AAV-based gene therapy.
• To identify challenges and suggest improvements for developing AAV gene therapies.
• To highlight the role of quantitative tools in optimizing clinical development.

Main Methods:

• Review of collective experiences in AAV gene therapy development.
• Identification of challenges in dose selection, exposure-response relationships, and study design.
• Application of model-informed drug development (MIDD) principles.

Main Results:

• MIDD provides a framework to utilize the totality of data for decision-making.
• Quantitative tools can support dose selection and optimize clinical trial designs.
• MIDD aids in endpoint selection and patient enrichment strategies for rare diseases.

Conclusions:

• MIDD is well-suited for the rational development of novel AAV-based gene therapies.
• Addressing challenges in dose selection and study design is crucial for AAV GT.
• Further incorporation of MIDD tools can enhance the development of these transformative therapies.