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

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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.