Oligonucleotide-Based Therapeutics Conference

Oligonucleotide-based therapeutics constitute a major therapeutic breakthrough, offering access to disease processes modulated by RNA unaccessible to small molecules, proteins, and antibodies. Although initially slow, progress in this field has been steady, , while the intrinsic challenges around chemistry, stability, binding affinity and nuclease resistance were addressed. The resultant improvements in efficacy were followed by a focus on mitigating off-target effects and addressing concerns of safety and tolerance. Principle among these approaches have been structural amendments such as the now-familiar use of nanoparticle formulations, followed by adding glycosylation amendments, both largely employed for liver-directed oligonucleotides, and which demonstrate significantly enhanced target cell specificity and equally significantly reduce dose and therefore systemic exposure and off-target effects. More recently, novel and emerging oligonucleotide conjugates, particularly for targeting organs and cells beyond the liver, have entered development. Such strategies employ a variety of targeting elements that are bound to the oligonucleotide components by a variety of linkers. While other fields have elicited an FDA Guidance based on antibody-drug conjugates, there are specific considerations and experiences for our field of oligonucleotide-based therapeutics that remain unaddressed. Ever-creative, the field of oligonucleotide-based therapeutics has adopted a number of approaches, some necessitated by the unique chemistry of oligonucleotide-based drugs. This session will address principles and regulatory considerations and experience in bringing forward such novel compounds from the perspective of the regulatory approach as well as from nonclinical and early clinical translational experience.