APPLYING SCIENTIFIC AND OPERATIONAL INSIGHTS FROM PRIOR CLINICAL TRIALS TO OPTIMIZE EFFICACY SIGNAL DETECTION IN A PROOF OF CONCEPT TRIAL WITH KYN-5356 IN COGNITIVE IMPAIRMENT ASSOCIATED WITH SCHIZOPHRENIA

Background

Despite decades of effort since the MATRICS trial design recommendations and regulatory framework were developed, pharmacological treatment for cognitive impairment associated with schizophrenia (CIAS) remains a completely unmet medical need. Detecting pharmacological efficacy signals in CIAS remains a challenge in clinical development, with numerous trials yielding negative or inconclusive outcomes despite compelling mechanistic hypotheses. KYN-5356 is a novel first-in-class inhibitor of KAT-II (human kynurenine aminotransferase 2) in development for treatment of CIAS. The First-InHuman study in healthy participants delivered consistent evidence of target engagement across biochemical and electrophysiological biomarkers and suggestive evidence of cognitive improvement after a 6-day treatment period.

Methods

Efforts to evaluate scientific and operational factors contributing to failed and negative clinical trial outcomes have identified areas of trial design, population selection, and operational conduct with potential to decrease risk for scientific failure. We describe the integration of strategies from each of these domains into the design of a Phase 2 Proof-Of-Concept study evaluating the efficacy, safety, PK, and PD effects of KYN-5356 in CIAS.

Results

Study KYN5356-CL-002 is a Phase 2, randomized, double-blind, placebo-controlled 28 day treatment study of 3 dose levels of KYN-5356 and placebo in 150 clinically stable participants with schizophrenia age 18-55. Design elements to reduce measurement variance include using a limited number of highly experienced research sites, selecting a computerized version of the Brief Assessment of Cognition in Schizophrenia (BACS, BAC App) as the primary efficacy endpoint to standardize test administration and reduce participant/site burden, administering the BACS 3 times prior to randomization to wash out practice effects, and consistent BACS assessment timing. The negative impact of treatment non-adherence is addressed by laboratory confirmation of antipsychotic adherence and conducting the study in an inpatient setting, which also serves to minimize variability in participant background environmental factors. The study duration was supported by the rapid-onset mechanism-linked improvement in the BACS Composite T-score and PD assessments in the FIH study. Standard MATRICS entry criteria are augmented by population enrichment via a minimum deficit threshold in BACS score as well as excluding participants with substantial increases or decreases in BACS score prior to randomization. Strategies to reduce operational variance include close oversight/review of cognitive assessment quality with rater feedback and frequent Sponsor-site interaction and collaboration. A subset of approximately 75 participants will participate in a substudy with electroencephalography (EEG) measurements to assess neuromodulatory effects of KYN-5356 and relationships to baseline characteristics and change in cognition.

Discussion

This is the first study evaluating a selective KAT-II inhibitor in schizophrenia participants with CIAS. This Phase 2 study design has incorporated several design elements derived from analyses of prior CIAS clinical trials to support high-confidence assessment of the efficacy hypothesis in the service developing a treatment to address the long-unmet medical need for treatment of cognitive impairment in schizophrenia.