IND-enabling studies of KTX-1161, a novel NRF2 activator for corneal endothelial disease

ABSTRACT This proposal by Kuria Therapeutics seeks to conduct IND-enabling studies of KTX-1161, a topical eye drop intended to protect corneal endothelial cells (CECs) during cataract surgery and to treat Fuchs’ endothelial corneal dystrophy. KTX-1161 contains the active ingredient SCO-116 which is a proprietary small molecule that activates NRF2. NRF2 is a transcription factor that initiates protective cellular defense systems against oxidative stress, mitochondrial dysfunction, and inflammation. The KTX-1161 eye drop should act to protect against the oxidative insult from phacoemulsification and the chronic oxidative stress inherent to Fuchs’ dystrophy. Three Specific Aims in this proposal will achieve the overall goal of completing the IND-enabling nonclinical requirements in preparation for first clinical studies of KTX-1161. In Phase I, Aim 1 is to conduct the GLP genotoxicity study package typically required by FDA for small molecules. Studies include the Ames test, in vitro chromosome aberration assay, and an in vivo micronucleus test in rats to determine the genetic toxicity potential of SCO-116. In Phase II, Aim 2 includes conduct of the FDA-required GLP safety pharmacology program, an ocular pharmacokinetic study, and the typical GLP oral and ocular toxicology studies. For safety pharmacology, a rat respiratory study and hERG test will be performed. A rabbit ocular PK study was specifically requested by FDA and will be done. The rat oral and dog ocular toxicology studies will be the normal 28-day toxicology designs with the addition of detailed observations to the rat oral study as requested by FDA during a 2023 pre-IND meeting. Aim 3 comprises the writing of the nonclinical section of the IND which will include the nonclinical study reports supporting SCO-116 safety and efficacy and the written and tabulated summaries. CEC loss occurs in virtually all of the ~4 million cataract surgeries done each year in the US, with about half a million patients experiencing excessive CEC loss. With KTX-1161, Kuria aspires to reduce the number of excessive CEC losses and reduce the magnitude of average CEC loss, protecting the future vision of all patients.