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

临床前开发一种新疗法，可以使衰老的肌肉干细胞恢复活力并增强髋部骨折后的肌肉强度和功能

• 批准号: 10768379
• 负责人: Harshini Neelakantan
• 金额: $ 24.74万
• 依托单位: RIDGELINE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10768379
• 关键词: Acetyltransferase; Administrative Supplement; Adult; Adverse effects; Aldehyde oxidase; Animals; Award; Biological Availability; Blood; Body Weight; Canis familiaris; Cardiovascular system; Chemicals; Clinical; Clinical Pathology; Clinical Trials; Complement; Data; Dose; Elderly; Elements; Enzymes; Female; Funding; Funding Mechanisms; Grant; Half-Life; Hepatocyte; Hip Fractures; Histology; Human; In Vitro; Injury; Investigational Drugs; Kilogram; Liver; Maximum Tolerated Dose; Metabolic Biotransformation; Miniature Swine; Monkeys; Mus; Muscle; Muscle function; Muscle satellite cell; National Institute on Aging; Oral; Oral Administration; Organ Weight; Outcome; Pharmaceutical Preparations; Pharmacology Study; Phase; Plasma; Process; Quality of life; Rattus; Recovery; Recovery of Function; Regimen; Rejuvenation; Research Design; Rodent; Safety; Sampling; Skeletal Muscle Satellite Cells; System; Testing; Therapeutic; Time; Toxic effect; Toxicokinetics; Toxicology; U-Series Cooperative Agreements; Vomiting; Work; aged; clinical candidate; cost; food consumption; improved; in vivo; inhibitor; inhibitor therapy; male; manufacture; meetings; metabolic abnormality assessment; muscle aging; muscle strength; novel; novel therapeutics; older patient; pharmacokinetics and pharmacodynamics; phase 1 study; phase 2 study; pre-clinical; preclinical development; preclinical safety; process optimization; scale up; small molecule therapeutics; stem cells; therapeutic development; validation studies

ABSTRACT Ridgeline’s U44 direct to Phase 2 cooperative agreement award (U44AG074107) from the National Institute on Aging has enabled rapid therapeutic development studies of RT-002, a novel oral therapeutic to promote full functional recovery and enhance the quality-of-life in elderly adults following traumatic hip fracture. Several critical studies were completed in Year 1 of the award which successfully earned the Year 2 funding for Ridgeline. Particularly, the project completed in vitro cross-species (mouse, rat, dog, mini-pig, monkey, human) metabolite identification for RT-002 using cultured hepatocytes, in vitro translational valdiations in aged human muscle- derived progenitor cells, in vivo PK/PD studies in aged mice and rats, process optimization and scale up synthesis of ~4 kilogram GMP-like batch of RT-002, non-GLP and GLP toxicity and safety pharmacology studies in rats, in vivo oral dosing tolerability and toxicokinetic assessments for RT-002 in male and female dogs, and preliminary in vivo PK/oral bioavailability and dose escalation tolerability study in male and female mini-pigs. This supplemental project will aid in the completion of the FDA-mandated safety/toxicity studies in the chosen mini-pig nonrodent species. Our pivotal cross-species metabolism studies showed that our clinical candidate NNMT inhibitor drug RT-002 was metabolized similarly in rat, mini-pig, and human hepatocytes, with comparable biotransformation rates and identical metabolites. In contrast, the turnover rates for RT-002 in mouse and monkey hepatocytes were found to be remarkably rapid but negligable in dog hepatocytes. Importantly, the primary metabolites identified for RT- 002 in human, rat, and mini-pig hepatocytes were nearly absent in dog hepatocytes due to the absence of the major RT-002 metabolizing enzymes, aldehyde oxidase (AO) and N-acetyltransferase (NAT) in dog liver. Taken together it was concluded that dogs are not the appropriate nonrodent species to characterize safety and toxicological effects of RT-002, which was further substantiated by the poor tolerability observed in dogs following RT-002 oral dosing. Given these result, mini-pigs are chosen as the non-rodent species for the necessary RT- 002 safety/toxicology studies as proposed in this award. This supplemental project will complete the necessary RT-002 safety/toxicology studies in male and female mini-pigs to establish the maximum tolerated dose of RT- 002 and evaluate safety and toxicity following repeated oral dosing of the drug. Outcomes from this de-risking study will further validate mini-pigs as an ideal choice of nonrodent species for continued regulated GLP toxicology studies and enable Ridgeline to continue developing the novel NNMT inhibitor clinical candidate RT- 002 to reach the IND-filing milestone by the end of this project period.

摘要 Ridgeline的U44直接进入第二阶段合作协议奖（U44 AG 074107），来自国家研究所， 衰老使得RT-002的快速治疗开发研究成为可能，RT-002是一种新型口服治疗剂， 功能恢复和提高老年人创伤性髋部骨折后的生活质量。几 关键的研究是在第一年完成的奖项，成功地赢得了第二年的资金山脊线。 特别是，本项目完成了体外跨物种（小鼠、大鼠、犬、小型猪、猴、人）代谢产物的研究 使用培养的肝细胞鉴定RT-002，在老年人肌肉中进行体外翻译验证- 衍生祖细胞，老年小鼠和大鼠体内PK/PD研究，工艺优化和规模扩大 RT-002 ~4千克GMP样批次合成、非GLP和GLP毒性和安全药理学研究 大鼠中，雄性和雌性犬中RT-002的体内经口给药耐受性和毒代动力学评估，以及 在雄性和雌性小型猪中进行的初步体内PK/口服生物利用度和剂量递增耐受性研究。 该补充项目将有助于完成FDA规定的所选药物的安全性/毒性研究。 小型猪非啮齿类动物。 我们的关键跨物种代谢研究表明，我们的临床候选NNMT抑制剂药物RT-002 在大鼠、小型猪和人肝细胞中代谢相似，生物转化率相当， 相同的代谢物相比之下，发现RT-002在小鼠和猴肝细胞中的转换率 在狗的肝细胞中非常迅速但可复制。重要的是，RT-1的初级代谢产物 002在人、大鼠和小型猪肝细胞中几乎不存在于狗肝细胞中，这是由于缺乏 RT-002在狗肝脏中的主要代谢酶，醛氧化酶（AO）和N-乙酰转移酶（NAT）。采取 总之，得出结论，犬不是表征安全性的适当非啮齿动物种属， RT-002的毒理学作用，这进一步通过在犬中观察到的不良耐受性得到证实， RT-002口服给药。鉴于这些结果，选择小型猪作为非啮齿类动物种属进行必要的RT- 002安全性/毒理学研究，如本奖项中提出的。该补充项目将完成必要的 在雄性和雌性小型猪中进行RT-002安全性/毒理学研究，以确定RT-002的最大耐受剂量 002，并评价重复口服给药后的安全性和毒性。降低风险的结果 本研究将进一步验证小型猪作为非啮齿类动物种属的理想选择，以继续进行GLP监管 毒理学研究，使Ridgeline能够继续开发新型NNMT抑制剂临床候选RT- 002在本项目期结束时达到IND申报里程碑。