Translational and clinical development of therapeutic siRNA and ASOs: current industry practices, perspectives, and recommendations

Abstract

RNA-based therapies, particularly small interfering RNA (siRNA) and antisense oligonucleotides (ASOs), represent a promising modality class with the potential to target previously "undruggable" proteins, and with potential for precision medicine approach. The successful development of these therapeutics relies on a comprehensive understanding of several key factors, including bioconjugation, bioanalytical techniques, biotransformation, tissue distribution, computational modeling and simulation, and clinical pharmacology. Bioconjugation strategies are essential for enhancing metabolic stability, facilitating cellular uptake, and targeting specific tissues, thereby improving efficacy and minimizing dosing. Tailored bioanalytical methods are crucial for assessing pharmacokinetics (PK) and pharmacodynamics, with particular emphasis on tissue PK in cases where plasma PK does not reflect therapeutic activity. Biotransformation and tissue distribution studies are essential, although a less comprehensive package may be adequate for well-established chemistry. Given the unique properties of oligonucleotides, computational modeling plays a critical role in predicting drug behavior in target tissues, supporting dose optimization. Clinical pharmacology for oligonucleotides is less complex than for small molecules, as they are less likely to interact with common drug metabolizing enzymes or transporter proteins. This white paper, developed by the Innovation and Quality (IQ) Consortium Nucleic Acids Working Group, consolidates industry insights and recommendations to inform best practices and regulatory guidelines, ensuring the safe and efficient development of siRNA and ASO therapies.

Graphical Abstract

Figure 1.

Industry recommendation on design of ASO and siRNA tissue distribution studies to support regulatory filing.

Figure 2.

Organ impairment study decision tree.