Scholar Rock announced new preclinical data showing the potential of SRK-439 topreserve lean mass and improve metabolic health as part of healthy weight loss. These data showed that SRK-439 maintained lean mass and improved fat mass loss when used in combination with a GLP-1 receptor agonist (GLP-1 RA; in separate experiments with semaglutide and liraglutide) in diet-induced obesity (DIO) mice. SRK-439 treatment also led to incremental lowering of fasting glucose beyond the levels seen with semaglutide alone.

Detailed results were presented by Melissa Fulham, PhD, of Scholar Rock, at the Keystone Symposia?sObesity: Causes and Consequences meeting in Vancouver, BC, Canada on February 5. In January, Scholar Rock announced that the U.S. Food and Drug Administration cleared the company?s Investigational New Drug (IND) application for its Phase 2 proof-of-concept trial of apitegromab to treat obesity in patients taking a GLP-1 RA. Trial initiation is on track for mid-2024, and data from the apitegromab Phase 2 trial are expected in mid-2025. In parallel, Scholar Rock is developing SRK-439, a novel investigational selective myostatin inhibitor, optimized for the treatment of obesity.

Selectivity and affinity: SRK-439 works by selectively binding to the pro- and latent forms of myostatin, as confirmed through in vitro ELISA testing that shows SRK-439 does not bind to closely related TGFß family members GDF11 and Activin A, both of which, if inhibited, have potentially detrimental effects outside of the muscle. The studies confirmed that SRK-439 binds to latent myostatin with 0.579 nM affinity. This selectivity and affinity, along with favorable developability characteristics and durable pharmacokinetics suggests that SRK-439 could be suitable for dosing in a subcutaneous formulation and in a low dose volume in a population of adults with obesity.

Changes in body weight, lean mass, and fat mass: Quantitative nuclear magnetic resonance (qNMR) was used to analyze body composition in DIO mice in two separate experiments. In the first, mice received either liraglutide, 0.06 mg/kg daily, or liraglutide, at the same dose, plus SRK-439 in either a 0.3, 1.0, or 3.0 mg/kg weekly dose. In the second experiment, DIO mice received either semaglutide, 0.04 mg/kg daily or semaglutide, at the same dose, plus SRK-439 in either a 0.1, 0.3, 1.0, or 3.0 mg/kg weekly dose.

Total body weight, lean mass, and fat mass were assessed. As expected, both liraglutide and semaglutide reduced body weight in DIO mice compared to baseline. SRK-439 diminished the GLP-1 RA-driven lean mass loss in combination with semaglutide (?7.55% to ?1.43% change from baseline in lean mass) and with liraglutide (1.98% to 5.55% from baseline).

These results were dose-dependent: lean mass was preserved more as the dose of SRK-439 increased. SRK-439 also improved fat mass loss (?36.60% to ?46.32% from baseline with semaglutide; ?17.31% to ?19.04% from baseline with liraglutide). SRK-439 is a novel, preclinical, investigational myostatin inhibitor that has high in vitro affinity for pro- and latent myostatin and maintains myostatin specificity (i.e., no GDF11 or Activin-A binding), and is initially being developed for the treatment of obesity.

Based on preclinical data, SRK-439 has the potential to support healthier weight management by preserving lean mass. The efficacy and safety of SRK-439 have not been established and SRK-439 has not been approved for any use by the FDA or any other regulatory agency.