Optimizing siRNA Therapeutics: Addressing Nonclinical And Manufacturing Complexities

The recent FDA approvals of siRNA drugs have revolutionized drug development, harnessing RNA interference as a powerful gene-silencing mechanism. Breakthroughs in drug delivery, chemistry, and manufacturing have propelled siRNA therapeutics to the forefront of precision medicine, unlocking new possibilities across diverse therapeutic areas, including oncology, hematology, infectious diseases, ocular disorders, metabolic conditions, dermatology, and rare genetic diseases. Notably, multi-targeting siRNA therapies offer a groundbreaking approach to previously undruggable targets, expanding the potential impact of this modality.

As the field rapidly evolves, optimizing siRNA drug development through tailored, innovative strategies is essential. Various classes of siRNA therapeutics, incorporating diverse delivery technologies, are being developed to reach extrahepatic tissues, pushing the boundaries of targeted gene silencing. However, enhancing efficacy while addressing key safety and regulatory challenges remains critical for ensuring a smooth clinical transition.

This whitepaper explores recent advancements in siRNA therapeutic development, with a particular focus on Chemistry, Manufacturing, and Controls (CMC) and nonclinical development strategies. Key CMC considerations include defining robust specifications, managing starting material complexities, and addressing challenges related to product sameness. On the nonclinical front, comprehensive safety assessments — both on-target and off-target — are crucial. Nonclinical studies must be fit-for-purpose, accounting for the therapeutic RNA construct, the delivery system, individual carrier components, and the final combined product.

By adopting a strategic, risk-based approach to both CMC and nonclinical studies, companies can navigate regulatory uncertainties, mitigate development risks, and accelerate the path of siRNA therapeutics toward commercialization — unlocking their full potential in precision medicine.