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.