A comprehensive overview of programs surfaced by Sleuth from patents, company websites, news / press releases, conference abstracts, publications and more.

While today GLP1s dominate, numerous companies are working on next-gen approaches that promise better muscle preservation, infrequent dosing and more favorable side effects. Among these are Alnylam, targeting upstream pathways including INHBE and ACVR1C, Wave Life Sciences, targeting INHBE inhibition and Arrowhead Pharma advancing both INHBE and ALK7 targeting programs.

While the space is very early, there are a few signals that are getting investors excited:

• Some MoAs target fat exclusively, leading to muscle mass preservation, which is particularly critical for geriatric patients
• Weight loss kinetics thus far have been comparable to leading marketed GLP1s, such as semaglutide
• Less frequent dosing (semi-annual or annual shots) offers a significant QoL benefit
• Potentially better tolerability profile, particularly due to limited GI side effects, which is the leading cause of GLP1 discontinuations today
• Flexibility to compete as a monotherapy, add-on to GLP1s or a post-GLP1 maintenance / off-ramp that blocks weight rebound

In the wake of renewed gene editing safety concerns, RNA editing offers a safe alternative - these approaches are being compared to base editing (i.e. BEAM-302), with bulls pointing to a potentially larger therapeutic index with fewer liabilities

One concern with any of these modalities is the cost comparison versus oral, small molecule GLP1s, which will be extremely COGS efficient and thus potentially introduce downstream market access / pricing risk.

With that said, investors are more focused on near-term readouts, with both Wave and Arrowhead presenting data in late 2025. Sentiment is generally positive, with enrollment for both completing ahead of schedule.