Comparison of short- and long-term proteomic response to the fast skeletal myosin inhibitor, EDG-5506, in Becker muscular dystrophy (BMD)


Clinical Trials

Poster Number: M145


Ben Barthel, PhD, Edgewise Therapeutics, Molly Madden, Edgewise Therapeutics, Liz Thaler, Edgewise Therapeutics, Marc Evanchik, Edgewise Therapeutics, Kevin Koch, Edgewise Therapeutics, Joanne Donovan, PhD, MD, Edgewise Therapeutics, Sam Collins, MD, Edgewise Therapeutics, Han Phan, MD, Rare Disease Research, Alan Russell, PhD, Edgewise Therapeutics

EDG-5506 is a selective inhibitor of fast skeletal muscle myosin, designed to protect skeletal muscle from contraction-induced injury in Becker and Duchenne muscular dystrophy. In a Phase I open-label extension study (ARCH, NCT05160415) adults with BMD (N=12) were administered 10-20 mg EDG-5506 daily for 12 months, which has been observed to be associated with short-term reductions in muscle injury biomarkers, including CK and TNNI2.

Here, we validate the use of SOMAscan for quantitative measurement of CK and TNNI2. Additionally, we examine changes in CK, TNNI2, and an expanded set of muscle injury biomarkers with continued treatment and characterize the plasma proteomic changes characteristic of long-term EDG-5506 administration.

A strong, non-linear correlation between ELISA TNNI2 and SOMAscan values was observed (R2=0.96, p<0.0001). A similar relationship was discovered between circulating CK activity and the CKM somamer (R2=0.90, p<0.0001). Circulating TNNI2 levels decreased significantly after short-term EDG-5506 (1 – 2 months), with continued decreases at medium-term (2 – 6 months) and long-term (6 – 12 months) treatment periods. As with TNNI2, decreases from pre-dose baseline were seen after short-term treatment and were maintained or extended with longer treatment times. These results were confirmed with an expanded set of proteins specific to contraction-induced skeletal muscle injury. Cluster analysis of circulating protein changes from pre-dose baseline revealed a large subset of proteins that did not change after short-term treatment but did change after long-term treatment. This subset of proteins was highly enriched for pathways associated with immune and inflammatory processes. Several individual proteins associated with pro- or anti-inflammatory responses were shifted towards levels seen in unaffected individuals. Conclusions We validated the use of SOMAscan aptamers to measure CK and TNNI2 and demonstrated that reductions in muscle injury after short-term EDG-5506 therapy are maintained through long-term treatment. Further, we show that long-term treatment also results in changes to inflammatory signatures towards those of healthy individuals.