A FIRST-IN-HUMAN STUDY TO EVALUATE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF KYN-5356, A FIRST-IN-CLASS INHIBITOR OF KYNURENINE AMINOTRANSFERASE II (KAT-II)

Background

Dysregulation of the kynurenine pathway has been implicated in a number of psychiatric and neurological disorders. In the brain, KAT-II catalyzes the conversion of kynurenine to kynurenic acid (KYNA), a neuroactive metabolite. KYNA acts as an endogenous inhibitor of the nicotinergic alpha-7 and NMDA receptors, both of which are relevant for cognition. In the cerebrospinal fluid (CSF) of people with schizophrenia, KYNA levels are consistently elevated, suggesting a potential mechanism for cognitive impairment associated with schizophrenia (CIAS). Preclinical data show that KYNA directionally modulates cognition with increased KYNA impairing cognition whereas lowering KYNA improves cognition. Thus, reduction of KYNA via targeted inhibition of KAT-II may have beneficial effects on cognitive function. KYN-5356 is a novel, potent, brain-penetrant, reversible, and selective KAT-II inhibitor that is being developed for CIAS.

Methods

We conducted a first-in-human study of KYN-5356 in adult, healthy subjects (clinicaltrials.gov: NCT06225115) at a single site in the United States. The study was comprised of three parts: Part 1, a single ascending dose study; Part 2, a multiple ascending dose study with 7 days of dosing; and Part 3, a food effect study. The primary objective of Parts 1 and 2, which were randomized, double-blind, and placebo-controlled, was to assess the safety and tolerability of KYN-5356 following single and multiple oral doses. The secondary objective was to evaluate the plasma pharmacokinetics of escalating single and multiple doses of KYN-5356. In Part 2, several pharmacodynamic biomarkers were assessed at baseline and on treatment to determine central target engagement of KYN-5356: CSF was collected to quantitate KYNA levels, electroencephalography (EEG) measurements were obtained to assess neuromodulatory effects, and a computerized version of the Brief Assessment of Cognition in Schizophrenia (BACS, BAC App) was used as a standardized test battery to measure cognitive performance.

Results

For Part 1, a total of 40 male and female participants with a mean age of 32.8 years were randomized to receive a single dose of KYN-5356 or placebo across five single-dose KYN5356 dosing cohorts. For Part 2, a total of 24 male and female participants with a mean age of 33.2 years were randomized to receive multiple doses of KYN-5356 or placebo across 3 cohorts. For Part 3, a total of eight male and female participants received two single doses of KYN-5356, once after a fasting period, and once after a standardized meal. Overall, KYN-5356 was safe and well-tolerated. In both plasma and CSF, KYN-5356 displayed excellent pharmacokinetic properties, suggesting adequate exposure in the CNS. There was clear evidence of target engagement across several central biomarkers: (1) KYN-5356 led to a dose-dependent reduction of KYNA levels in the CSF; (2) KYN-5356 demonstrated statistically significant effects on EEG activity linked to improved function of cognitive pathways; and (3) KYN-5356 showed suggestive evidence of cognitive improvement.

Discussion

To our knowledge, this is the first study that evaluated a selective KAT-II inhibitor in humans. The favorable safety and tolerability profile, the evidence of target engagement across biochemical and electrophysiological biomarkers, as well as the suggestive evidence of cognitive improvement warrant continued clinical development in CIAS. Expansion into additional indications will also be discussed.