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

ABSTRACT Ridgeline’s U44 award (U44AG074107) from the National Institute on Aging has supported critical therapeutic development studies of RT-002, a novel oral therapeutic to accelerate full functional recovery and enhance quality-of-life after traumatic hip injuries in adults ≥65 years of age. The majority of the proposed milestones for our clinical candidate drug RT-002 were completed in the past 2.5 years (award start: 09/01/21), including (i) essential studies that identified the necessary rodent and nonrodent species for human-predictive toxicology assessments, (ii) translational mechanistic and target-engagement validations in aged human muscle-derived progenitor cells and aged mice and rat preclinical models, (iii) process optimization and scale-up synthesis of ~4-kilogram GMP-like batch of drug substance, (iv) non-GLP and GLP toxicity and safety pharmacology studies in rats, (v) oral dosing tolerability and toxicokinetic (TK) assessments in male and female dogs that justified dogs as a non-ideal toxicology species, and (vi) non-GLP in vivo PK, dose escalation, and repeated-oral dosing tolerability studies in male and female minipigs that fully justified minipigs as the ideal nonrodent toxicology species. The latter study was funded by an administrative supplement award (No. U44AG074107-02S1), with the results described in this proposal. This administrative supplement project will enable us to complete FDA-mandated GLP toxicity/TK study in minipigs, the appropriate nonrodent species, and related bionalytical activities. Our pivotal cross-species metabolism studies demonstrated that RT-002 was metabolized similarly in rat, minipig, and human hepatocytes, with consistent in vivo results showing substantial systemic exposures of RT-002’s primary metabolites in rats and minipigs following oral dosing. Recently completed non-GLP dose-range finder and 14-day repeated-oral dosing toxicity/TK studies in male and female minipigs validated a maximum tolerated single dose (MTD) of at least 500 mg/kg RT-002 and an MTD of 100 mg/kg/day over 14 days (once-daily [q.d.] dosing regimen as intended in the clinical program). The steady-state RT-002 exposures were similar between sexes after 14 days of daily dosing (AUClast males = 15,000 ng*h/mL; AUClast females = 12,400 ng*h/mL), with unremarkable cardiac toxicity findings. These results support the planned pivotal GLP toxicity/TK studies in male and female minipigs to establish the no observable adverse effect level (NOAEL) and MTD of RT-002 and evaluate dose-limiting toxicities following q.d. oral dosing of RT-002 over 28 days. Outcomes from these final GLP studies will be compiled into an investigational new drug (IND) briefing package and submitted to the U.S. FDA, enabling Ridgeline to reach a crucial value-inflection point and begin clinical trials at the end of this project