Background 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 (BMD). In a Phase I open-label extension study (ARCH, NCT05160415) adults with BMD (N=12) were administered 10-15 mg EDG-5506 daily for 12 months. Objectives We have previously measured short-term decreases in muscle injury biomarkers CK and TNNI2 with EDG-5506. Her, we examined changes in CK/TNNI2 with continued treatment and relationship to measures from plasma proteomics (SOMAscan).
Results A strong, non-linear correlation between ELISA TNNI2 and SOMAscan values (R2=0.96, p<0.0001). SOMAscan analysis returned a relative level for each protein with a 10-log range, allowing projection of TNNI2 values that were below the LLOQ of the TNNI2 ELISA (<0.2 ng/ml). Projection with SOMAscan revealed an 84% decrease from baseline in TNNI2 at 6 months (p=0.013), with 5/12 returning to TNNI2 values seen in healthy volunteers. CK revealed a similar non-linear correlation between CK activity and SOMAscan values (CKM; R2=0.90, p<0.0001) and a projected 38% decrease in mean CK vs baseline (p<0.01). A second SOMAscan analysis focused on long-term changes in proteomic signatures with EDG-5506. A set of 660 increased and 337 decreased proteins displayed progressive changes after 1-6 months dosing. Analysis of average signals revealed a reversion of each signature towards those in healthy individuals. Cluster analysis of these signatures was highly enriched for inflammatory pathways.
Conclusions We validated iSOMAscan aptamers for CK and TNNI2, which enabled more accurate determination of low-level TNNI2. In adults with BMD, EDG-5506 lowered TNNI2 and CK and showed proteomic changes in inflammatory signatures towards those of healthy individuals with longer-term dosing.