Novel Mechanisms Beyond Incretins: RNAi, Myostatin Inhibition, and Unimolecular Agonists

New RNAi therapy OLX501A demonstrates greater visceral fat reduction in early trial, representing a novel mechanism beyond incretins. Apitegromab (myostatin inhibitor) preserved ~55% more lean mass during tirzepatide treatment in Phase 2, proof-of-concept for muscle-sparing adjunct. Preclinical GRK-biased agonists and trispecific peptibodies also show promise. New RNAi therapy WVE-007 (Wave Life Sciences) targeting INHBE enters Phase 2a with muscle preservation and infrequent dosing profile, expanding the RNAi pipeline. These developments diversify the obesity pharmacotherapy pipeline beyond GLP-1-based agents.