Dose-ranging safety and efficacy studies to advance novel mechanism-of-action drug candidates to reverse age-related muscle degeneration

在美国，65岁及以上的人口数量将在未来十年增加30%。 与此同时，医疗保险费用预计将增加一倍，以治疗慢性疾病，将困扰这一日益增加的 老年人的数量。影响老年人的最广泛的慢性疾病之一是肌肉减少症， 在60岁以上的成年人中观察到30%，在80岁以上的成年人中观察到50%[1，2]。这 疾病的特征在于进行性年龄相关的骨骼肌萎缩; 肌肉质量和组织质量导致肌肉力量、功能和再生能力显著降低， 组织的能力，大大恶化整体健康和生活质量。此外，肌肉减少症是 使人衰弱的虚弱综合征的组成部分，严重影响个人的独立性， 中心blog目前的建议，以预防和治疗肌肉减少症包括阻力运动和蛋白质- 丰富的饮食。虽然这些建议似乎合乎逻辑，但没有实质性证据表明这些建议是合理的。 治疗持续增加肌肉质量，改善老年人的身体功能和表现。 个人[3，4]。鉴于肌肉减少症的当前范围和预期影响， 有效的疗法来减缓和逆转肌肉减少症，以支持美国老年人更健康的生活。 该第一阶段项目的目标是证明新机制的原理和安全性- 在老年动物中使用预防相关肌肉生长/功能模型的有效治疗候选物 和适当的体内安全性模型。Ridgeline Therepeutics正在开发一流的口腔 选择性靶向和抑制烟酰胺N-甲基转移酶（NNMT）的药物， 老年骨骼肌和新发现的调节细胞代谢途径，特别是NAD+ 这是在老年肌肉高度妥协的生物合成。先导系列小分子NNMT抑制剂 具有优异的物理化学性质（即，高溶解性、稳定性、渗透性）和良好的口服生物利用度， 没有早期中毒症状在老年小鼠中使用我们的候选先导NNMT抑制剂的初步结果 肌肉再生和功能改善的模型[2]显示肌肉 线粒体氧化能力，增强肌纤维生长，增加肌肉干细胞 增殖/活性。这些令人鼓舞的结果表明，我们的铅系列具有改善缺陷的潜力 在老年肌肉病理生理学和反向肌肉减少症。 为了进一步降低我们的主要候选药物作为潜在疗法的风险，以大大提高肌肉生长，质量， 和功能，该I期项目将完成（1）老年人的剂量范围有效性研究 动物来证明我们的候选药物改善肌肉生长和功能的主要证据， (2)体内长期安全性/毒性研究。临床前GLP-安全性、制剂开发和IND支持 FDA提交的研究将遵循该I期项目。

In the US, the number of individuals aged 65 and older will increase by 30% over the next decade. Concurrently, Medicare costs are expected to double to treat chronic diseases that will plague this increasing number of older adults. One of the most wide-spread chronic diseases that affects older adults is sarcopenia, which is observed in 30% of adults over 60 years of age and 50% of adults over 80 years of age[1,2]. This disease is characterized by progressive age-associated skeletal muscle atrophy; the degenerative loss of muscle mass and tissue quality cause significant reductions in muscle strength, function, and regenerative capacity of the tissue, greatly deteriorating overall health and quality of life. Moreover, sarcopenia is a core component of the debilitating frailty syndrome, which severely impacts an individual's independence and longevity. Current recommendations to prevent and treat sarcopenia include resistance exercise and protein- rich diets. While these recommendations appear logical, there is no substantial evidence to suggest these treatments consistently increase muscle mass and improve physical function and performance in aged individuals[3,4]. Given the current scope and projected impact of sarcopenia, there is a clear unmet need for effective therapies to slow and reverse sarcopenia to support healthier lives for older Americans. The objective of this Phase I project is to demonstrate proof-of-principal and safety for novel mechanism- of-action therapeutic candidates using translationally-relevant muscle growth/function models in aged animals and appropriate in vivo safety models, respectively. Ridgeline Therepeutics is developing first-in-class oral drugs that selectively target and inhibit nicotinamide N-methyltransferase (NNMT), an enzyme upregulated in aged skeletal muscle and newly discovered to regulate cellular metabolic pathways, particualrly NAD+ biosynthesis that is highly compromised in aged muscle. The lead series of small molecule NNMT inhibitors have excellent physicochemical properties (i.e., highly soluble, stable, permeable) and good oral bioavailability, with no early signs of toxicity. Preliminary results using our candidate lead NNMT inhibitor in an aged-mouse model for muscle regeneration and functional improvement[2] revealed significantly improved muscle mitochondrial oxidative capacity, enhanced muscle fiber growth, and increased muscle stem cell proliferation/activity. These promising results suggest that our lead series has the potential to improve defects in aged muscle pathophysiology and reverse sarcopenia. To further derisk our lead candidates as potential therapeutics to greatly improve muscle growth, mass, and function in aged individuals, this Phase 1 project will complete (1) dose-ranging efficacy studies in aged animals to demonstrate proof-of-principal for our drug candidates to improve muscle growth and function, and (2) in vivo long-term safety/toxicity studies. Preclinical GLP-safety, formulation development, and IND-enabling studies for FDA submission will follow this Phase I project.