PROJECT SUMMARY Heart failure caused by progressive dilated cardiomyopathy is the primary cause of death in patients with Duchenne muscular dystrophy (DMD), a fatal inherited muscle wasting disorder defined by the FDA as an orphan disease. Cardiomyopathy is detectable in children as young as 10 years old and is present in most patients by their late teens. Most DMD patients die in their late 20s from heart failure. There are no approved medications for DMD cardiomyopathy. Little effort has been devoted to cardiomyopathy therapeutic development despite it being the main cause of DMD patient mortality. The vast majority of DMD therapies in development focus on treating skeletal muscle degeneration. Current standard of cardiac care for DMD patients utilizes steroids and off-label anti-hypertensive and heart failure drugs to reduce heart inflammatory damage, workload, and tissue remodeling. Revidia Therapeutics, Inc. is a cardiac regenerative medicine company developing small molecules that reactivate endogenous cardiac repair and regenerative processes. We are advancing a novel subcutaneous formulation of our lead small molecule MSI-1436 into clinical trials as a treatment for DMD cardiomyopathy. MSI-1436 has already proven human safety. It functions by inhibiting the tyrosine phosphatase PTP1B via a novel allosteric mechanism. PTP1B normally inactivates endogenous tissue repair and regeneration processes. MSI-1436-induced inhibition of PTP1B reactivates these processes, which in turn reverses tissue damage. Using blinded and randomized experimental and data analysis protocols, we have shown that MSI-1436 stimulates heart muscle regeneration, improves heart function, and reduces infarct size in wild type adult mice following myocardial infarction; improves left ventricle ejection fraction in a mouse pressure overload dilated cardiomyopathy model; slows cardiac degenerative changes in young D2.B10- Dmdmdx/J DMD mice; and improves left ventricle ejection fraction in aged DMD animals. Doses of MSI-1436 that reverse cardiac injury are up to 50-times lower than the maximum well tolerated human dose. Revidia has completed multiple IND-enabling workstreams including 1) FDA pre-IND meetings, 2) efficacy testing in multiple animal models, 3) in vitro safety pharmacology, 4) ADME studies, 5) dose-range finding, 6) CMC development and 7) Good Laboratory Practice (GLP) manufacturing. The final IND-enabling workstream that must be completed is FDA-required GLP-compliant safety and toxicity testing of subcutaneously administered MSI-1436. Proposed studies will validate subcutaneous MSI-1436 dose formulations and bioanalytical methods and perform repeat dose toxicology and genotoxicity testing and CNS, respiratory and cardiovascular safety pharmacology testing. Completion of these studies will allow IND application submission in early 2025 and initiation of clinical trials later that year. Treatment of DMD cardiomyopathy with MSI-1436 has significant potentia...