Ridgeline Therapeutics, Inc.

Preclinical Validation of a Novel Adjunct Small Molecule Drug to Prevent Muscle Loss and Enhance Weight Loss in Older Adults - Abstract Obesity Is a Chronic Health Concern in the US1, Affecting More Than 40% of ADULTS2 and Resulting in Devastating Health COMPLICATIONS3-4. Annual Medical Costs to Treat Obesity-related Comorbidities Exceed $260B, and Medical Expenditures Are 290% Higher for Obese Versus Non-obese INDIVIDUALS5. a Variety of Obesity Treatments Have Emerged, Among Which the Newest Class of Glucagon-like PEPTIDE-1 (GLP-1) Receptor Agonist Drugs Have Become Highly Popular Given Their Potential to Achieve Substantial Weight Loss (15-21% Weight Loss Within 68-72 WEEKS6) Without Lifestyle Modification(s) or Surgery. However, Serious Concerns Surrounding GLP-1 Drug Use Have Become Prominent, Including an Excessive Proportion (>25%) of Lean Mass-to-weight LOSS7-8, Weight Loss PLATEAUS7, 9-11, Essentially Complete Weight Regain Following Treatment DISCONTINUATION12-14, and Numerous Adverse EFFECTS7, 9, 15; These Concerns Disproportionately Impact Adults ≥60 Years OLD16. Nicotinamide N-methyltransferase (NNMT) Is a Novel, Validated Target for OBESITY17-21 and Age-related Muscle DEGENERATION22-23. Inhibiting NNMT Significantly Reduces Body Weight, Adiposity, Diabetic Biomarkers, and Fatty Liver in a Diet-induced Obesity (DIO) Mouse Model Without Modifying Food INTAKE17. When an NNMT Inhibitor Is Combined With a Low-fat Normal Diet, Dio Mice Show Significant and Rapid Declines in Body Weight and Fat Composition, and Increased Lean Mass, Resulting in a Body Composition Profile Similar to Lean (non-obese) CONTROLS18. NNMT Inhibition Independently Improves Recovery of Muscle Strength (i.e., Muscle Peak Torque) and Muscle Fiber Size After Injury in Aged MICE22. Importantly, Our Clinical Candidate NNMT Inhibitor, RT-002, Has Completed Nearly All Studies Needed to Support an Investigational New Drug (IND) Submission as a Treatment to Promote Recovery From Musculoskeletal Injury in Older (≥ 55-YEAR-OLD) Adults. the Above Successes Clearly Position RT-002 as a Novel Candidate to Combine With GLP-1 Obesity Drugs (e.g., Semaglutide [wegovy®]) to Prevent and Reverse GLP-1 Treatment-associated Excessive Muscle Loss. This Project Will Use Aged Dio Mice to Test This Hypothesis and Validate RT-002 as a Viable GLP-1 Adjunct Therapy to Preserve Muscle Mass and Strength During Weight Loss. Aim 1 Will Define Efficacious Dose Combinations of RT-002 and Semaglutide That Preserve Muscle Mass and Strength While Retaining the Weight- and Fat-loss Effects of Semaglutide. Aim 2 Will Establish the Maximum Tolerated RT-002/SEMAGLUTIDE Combination-dose and Determine the No Observable Adverse Effect Levels of the Two Drugs in Combination During 28-DAY Repeat-dosing. Aim 3 Will Determine the RT-002 Dose That Increases Relative Muscle Mass After Discontinuing Semaglutide Monotherapy. Upon Project Completion, a New Ind to Use RT-002 as a GLP-1 Adjunct Therapy Will Be Submitted to the Us Fda.