Preclinical Development of a Novel Therapeutic to Rejuvenate Aging Muscle Stem Cells and Enhance Muscle Strength and Function Post Hip Fracture

肌肉老化的定义是质量和力量的逐渐下降，这对美国老年人（60岁以上）的福尔斯、致命伤害和创伤相关骨折构成了高风险。每年有超过30%的老年人跌倒，导致约280万例创伤性骨折，显著降低了老年人的活动性、独立性、整体健康和生活质量。在跌倒相关的损伤中，髋部骨折是最普遍和最严重的;每年有30万美国老年人因髋部骨折住院治疗，面临长期的术后康复，恢复独立生活的可能性很低，1年死亡率徘徊在10- 30%左右。 老年人髋部骨折后肌肉力量减弱易导致和预测恢复不良。包括抗阻运动和富含蛋白质的饮食在内的标准治疗只能轻微改善髋部骨折后的肌肉力量和功能结局。迄今为止，使用药物治疗来改善老年人肌肉力量的尝试还没有成功。为了应对这一挑战，Ridgeline Therapeutics开发了一流的小分子烟酰胺N-甲基转移酶抑制剂（NNMTis），可以重新激活老化的肌肉干细胞（muSC）。随着骨骼肌和muSC老化，它们越来越多地表达干扰NAD生物合成的NNMT和控制muSC再生功能和细胞能量代谢的下游事件。因此，NNMT是衰老muSC功能障碍和肌肉力量相关下降的重要促成因素。由于muSC是再生和修复的基础，因此老化muSC的复壮（包括使用NNMTi）已被证明可用于增强肌肉再生能力并改善老年小鼠的肌肉力量和功能。 Ridgeline的治疗开发工作已经从发现迅速发展到在临床相关的老年肌肉损伤模型中进行领先的优化、机制和临床前概念验证。用NNMTi RT-001铅治疗老年损伤小鼠显示muSC活性和肌纤维融合指数增加2倍，肌肉生长增加35-80%，肌肉力量增加70%。RT-001的稳健疗效和早期安全性指数证明降低了风险，并将其定位于后期临床前和IND使能研究。Ridgeline正在推进RT-001作为一种安全有效的小分子治疗药物，用于临床改善髋部骨折手术修复后老年人的肌肉力量和功能。本项目的目的与该目标直接一致，重点是完成必要的体内PK/PD研究，以优化口服给药方案，扩大合成2 kg批次RT-001，以及非GLP和GLP毒性研究;将完成辅助代谢和临床相关生物标志物评估，以补充和支持IND申报和首次人体临床试验。

Muscle-aging is defined by progressive declines in mass and strength that poses a high risk for falls, fatal injury, and trauma-related fractures among older Americans (age 60+). Each year, >30% of older adults suffer a fall, resulting in ~2.8 million traumatic fractures that significantly reduce mobility, independence, overall health, and quality of life for the elderly. Among fall-related injuries, hip fractures are the most prevalent and serious; the 300,000 elderly Americans hospitalized each year with hip fracture repairs face long-term post-surgery rehabilitation with a low probability of returning to independent living and a 1-year mortality rate that staggers around 10-30%. Dampened muscle strength predisposes to and predicts poor recovery among the elderly following hip fracture. Standard-of-care including resistance exercise and protein-rich diets only marginally improve muscle strength and functional outcomes post hip fracture. Attempts to improve muscle strength in elderly individuals using pharmacotherapies have not succeeded to date. To address this challenge, Ridgeline Therapeutics has developed first-in-class small molecule nicotinamide N-methyltransferase inhibitors (NNMTis) that reactivate aged muscle stem cells (muSCs). As skeletal muscle and muSCs age, they increasingly express NNMT that interferes with NAD biosynthesis and the downstream events that control muSC regenerative function and cellular energy metabolism. Thus, NNMT is a vital contributing factor to aging muSC dysfunction and associated declines in muscle strength. Since muSCs are fundamental to regeneration and repair, rejuvenation of aged muSCs (including using NNMTi) has proven useful to boost muscle regenerative capacity and improve muscle strength and function in aged mice. Ridgeline’s therapeutic development efforts have swiftly progressed from discovery, to lead optimization, mechanistic and preclinical proof-of-concept validations in clinically relevant aged muscle injury models. Treatment of aged, injured mice with the lead NNMTi RT-001 showed 2-fold increase in muSC activity and myofiber fusion index, 35-80% increase in muscle growth, and 70% increase in muscle strength. Robust efficacy and early safety index demonstration for RT-001 have de-risked and positioned it for late-stage preclinical and IND-enabling studies. Ridgeline is advancing RT-001 as a safe and effective small molecule therapeutic for clinical use in improving muscle strength and function among older adults following hip fracture surgical repairs. The objectives of this project directly aligns with this goal and focuses on completing necessary in vivo PK/PD studies to optimize oral dosing regimens, scale up synthesis of a 2 kilogram batch of RT-001, and non-GLP and GLP toxicity studies; accessory metabolism and clinically relevant biomarker assessments will be completed to complement and support IND filing and first-in-human clinical trials.