Recent FDA approvals of siRNA drugs have revolutionized drug development for this therapeutic modality, which leverages RNA interference as a gene silencing mechanism. Advancements in drug delivery, chemistry, and manufacturing have paved the way for siRNA therapeutics as promising candidates for precision medicine. siRNA has emerged as a powerful tool for gene silencing, demonstrating potential across various therapeutic areas, including oncology, hematology, infectious diseases, ocular disorders, metabolic conditions, dermatology and rare genetic diseases. Notably, multi-targeting siRNA drugs holds immense promise for previously undruggable targets.
As the field continues to evolve rapidly, optimizing drug development with tailored approaches is essential. Several classes of siRNA drugs, incorporating diverse delivery technologies and strategies, are being developed to target extrahepatic tissues. In this dynamic landscape, identifying key challenges and enhancing siRNA efficacy while addressing safety concerns are crucial for smooth clinical transition.
This whitepaper highlights recent advancements in siRNA therapeutic development, focusing on CMC and nonclinical development strategies. Key CMC considerations focus on the specifications, starting materials, and sameness challenges. On the nonclinical side, both on-target and off-target safety assessments are pivotal. Nonclinical studies should be fit-for-purpose, taking into account the therapeutic RNA construct, the carrier or 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 and advance siRNA therapeutics toward commercialization.