P31-02 Summary of nonclinical toxicity evaluation of SJP-0132, a TRPV1 antagonist

SJP-0132 is a selective antagonist of transient receptor potential cation channel subfamily V member 1 (TRPV1) that has been developed as an eye drop drug for treatment of dry eye disease. Several other TRPV1 antagonists have been discontinued in development as therapeutic drugs due to emerging adverse effects (e.g. induction hyperthermia). To assess the safety of SJP-0132, nonclinical toxicity studies were conducted in accordance with established guidelines for toxicity testing. For evaluation by a clinical dosing route, SJP-0132 eye drops were instilled into the eyes of rabbits and dogs at concentrations from 0.3% to 3% for 4 or 39 weeks. For evaluation of systemic toxicity, SJP-0132 was administered by oral gavage to rats and dogs for 2 to 26 weeks at doses from 0.5 to 400 mg/kg/day. In vitro and in vivo genotoxicity were assessed using Ames test, mouse lymphoma thymidine kinase assay, and rat micronucleus test. Carcinogenicity was evaluated by oral gavage to Tg-rasH2 mice and rats for 6 or 24 months, respectively, at doses from 0.5 to 100 mg/kg/day. Reproductive and developmental toxicity studies, including fertility and early embryonic development, embryofetal development, and pre- and post-natal development studies, were performed by oral gavage to rats and rabbits at doses from 0.5 to 100 mg/kg/day. The potential of skin sensitivity/photosensitivity of SJP-0132 eye drops was assessed by local lymph node assay and Harber method using mice and guinea pigs, respectively. Oral administration of SJP-0132 in dogs resulted in an elevation of body temperature, a class effect of TRPV1 antagonists, at 4 mg/kg/day and above. However, the ocular instillation of SJP-0132 eye drops did not show any toxicologically significant findings in rabbits and dogs including body temperature and the eyes. In the carcinogenicity study in rats, age-related skeletal muscle atrophy, as a non-neoplastic change, progressed in male rats at 5 mg/kg/day and above. SJP-0132 did not show carcinogenic potential in Tg-rasH2 mice and rats. Moreover, no genotoxicity and skin sensitivity/photosensitivity potentials were detected. No toxicological finding was noted in the reproductive and developmental toxicity studies. We conducted a series of nonclinical toxicity studies of SJP-0132 and summarized the results. The elevation of body temperature and progression of age-related skeletal muscle atrophy appeared only at doses much higher than those used clinically. The margin of exposure between animals and humans was more than 80-fold. These results suggest that SJP-0132 is a promising therapy option for dry eye disease with a tolerable safety profile.