A Novel Small Molecule Oral Therapeutic to Prevent and Reverse Skeletal Muscle Atrophy in Aging Adults

Limited muscle use is widespread in older adults (e.g., post-injury immobilization, bed rest) and typically leads to disuse-induced muscular atrophy defined by substantial loss of muscle mass, strength, and function [1- 3]. The overall health and functional independence of aging adults can rapidly and progressively deteriorate as muscle disuse causes atrophy and promotes a vicious cycle of further muscle disuse and subsequent exacerbated atrophy. Standard-of-care treatments to counter skeletal muscle atrophy include physical therapy and exercise [4], but these approaches have limited success in elderly populations [5]. Although pharmaceutical interventions to treat muscle loss are in development, many have unfavorable side effects. The only approved intervention in the United States is for subtypes of atrophy related to HIV/AIDS and cachexia [6]. Thus, there is a critical need for novel treatments that prevent and reverse disuse-induced muscular atrophy in aging adults.Ridgeline Therapeutics is developing transformative small-molecule oral drugs to accelerate skeletal muscle regeneration and repair in aging adults. Ridgeline’s clinical candidate RT-002 is completing preclinical studies, with first-in-human Phase 1 clinical trials scheduled for Q4’23. RT-002’s mechanism-of-action is to inhibit nicotinamide N-methyltransferase (NNMT), an enzyme critical for maintaining cellular energy metabolism and homeostasis [7]. Inhibition of NNMT activates quiescent, dysfunctional muscle stem cells, promoting enhanced muscle fiber growth and improved muscle mass and strength in aged mice [8]. This SBIR Phase 1 project will extend these findings and test the hypothesis that RT-002 can prevent disuse-induced muscle atrophy and promote faster recovery following muscle disuse. Aim 1 will determine if RT-002 treatment can mitigate the loss of muscle mass and strength that occurs during muscle disuse. Aim 2 will determine if RT-002 treatment can improve the rate of recovery from cast immobilization-induced muscle atrophy, as measured by muscle mass, strength, and function gained over a 21-day limb remobilization (i.e., post-uncasting) period compared to the baseline measures taken on the first day of limb uncasting.The efficacy studies proposed herein will utilize a translationally-relevant unilateral hindlimb casting model of muscle atrophy in rats [9]. Casting immobilizes the hindlimb, prevents localized muscle use, and results in significant atrophy, evidenced in aged rats by substantial muscle loss and severe deficits in hindlimb muscle strength that last for several days even after cast removal [10, 11]. Furthermore, hindlimb casting is a widely- accepted model for disuse-induced muscular atrophy with translational relevance to human muscle atrophy pathologies [9, 12]. Preclinical validation of RT-002’s efficacy using this model will lay the foundation to rapidly advance its development into the clinic as a novel drug to accelerate recovery of muscle function following disuse in aging adults.