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.

抽象的 Ridgeline的U44 Direct至2阶段合作协议奖（U44AG074107） 衰老已使RT-002的快速治疗开发研究是一种新型的口服疗法，以促进完整 创伤性髋部骨折后，功能恢复并增强了老年人的生活质量。一些 批判性研究在奖项的第一年完成，该奖项成功地为Ridgeline赢得了2年级的资金。 特别是，该项目完成了体外跨物种（小鼠，大鼠，狗，迷你猪，猴子，人类）代谢物 使用培养的肝细胞鉴定RT-002的体外翻译瓣膜 衍生的祖细胞，体内PK/PD在老年小鼠和大鼠中的研究，过程优化和扩展 RT-002，非GLP和GLP毒性和安全药理学研究的〜4千​​克GMP样批次的合成 在大鼠中，男性和雌性犬的RT-002的体内口服剂量耐受性和有毒动力学评估，以及 在男性和女性迷你小狗中，初步的体内PK/口服生物利用度和剂量升级可耐受性研究。 这个补充项目将有助于完成FDA规定的安全/毒性研究 迷你鸽非生产物种。 我们关键的跨物种代谢研究表明，我们的临床候选NNMT抑制剂RT-002 在大鼠，迷你猪和人肝细胞中类似地代谢，具有可比的生物转化率和 相同的代谢产物。相反，发现RT-002在小鼠和猴子肝细胞中的周转率 在狗肝细胞中非常迅速，但可以忽略不足。重要的是，针对RT-确定的主要代谢产物 002在狗肝细胞中几乎没有人，大鼠和迷你猪肝细胞，因为没有 狗肝脏中主要的RT-002代谢酶，醛氧化酶（AO）和N-乙酰基转移酶（NAT）。拍摄 结论是，狗不是适当的非生产物种来表征安全性和 RT-002的毒理学作用，这进一步证实 RT-002口服给药。鉴于这些结果，为必要的RT-选择微杆作为非腐蚀物种 002该奖项提出的安全/毒理学研究。这个补充项目将完成必要的 RT-002在男性和女性迷你小狗中的安全/毒理学研究以建立最大耐受剂量的RT- 002并评估药物口服反复给药后的安全性和毒性。这种脱离风险的结果 研究将进一步验证迷你猪作为持续调节GLP的非生产物种的理想选择 毒理学研究并使Ridgeline能够继续开发新型的NNMT抑制剂临床候选RT- 002到本项目期末到达IND-FIRE里程碑。