32.2 TWO GLOBAL PHASE III TRIALS OF ENCENICLINE FOR COGNITIVE IMPAIRMENT IN CHRONIC SCHIZOPHRENIA PATIENTS: RED FLAGS AND LESSONS LEARNED

Abstract

Multiple lines of evidence indicate that alterations of the α7 nicotinic acetylcholine receptor (nAChR) may play a role in the pathophysiology of several neuropsychiatric disorders that manifest with cognitive impairment, including schizophrenia. Encenicline (EVP-6124), a selective α7 nAChR showed promising biomarker and clinical evidence for cognitive improvement as well as functional co-primaries in Phase II trials. Positive results led to the launch of two global Phase III trials (EVP-6124-015/016) aimed at assessing the efficacy and safety of once-daily encenicline tablets as a pro-cognitive treatment in stable patients with schizophrenia. Our primary hypothesis was that encenicline would demonstrate efficacy for the improvement of performance on the MATRICS Consensus Cognitive Battery (MCCB) and for ratings on the Schizophrenia Cognition Rating Scale (SCoRS). A detailed examination of factors with the potential to impact the trial results are ongoing (e.g., background antipsychotic medication, treatment adherence, and demographic variables) for purposes of evaluating concluding results and to inform later clinical development programs of any ‘red flags’ and key lessons learned.Two 6-month, randomized, double-blind, placebo-controlled, parallel-dosing, Phase III studies evaluated EVP-6124 versus placebo, as a pro-cognitive treatment in individuals withschizophrenia on chronic, stable, atypical antipsychotic therapy. Study methodologies wereidentical with the exception of geographical participation. A screening period of up to 28 daysoccurred as placebo run-in were individuals were assessed for their eligibility based upon pill count compliance over a 14-day period and ability to complete the MCCB cognitive battery. Eligible subjects (total n = 1,520, across both trials) continued their usual antipsychotic regimen and were randomly assigned 1:1:1 on Study Day 1 to receive 1 of 3 double-blind treatments: once-daily EVP-6124 HCl tablets (1 or 2 mg) or placebo for 26 weeks (Study Days 1 to 182). The MCCB battery was completed once during placebo run-in, at baseline, 4, 8, 12, and 26-week study visits.Robust improvements were observed in both trials on the NeuroCognitive CompositeScore (NCC; all MCCB tests except the MCEIT) and the SCoRS across all treatment groups, from screening through to baseline visit and from baseline through to week 26. However no statistically significant difference between encenicline and placebo emerged using a Mixed Model Repeated Measures change from baseline to week 26 analysis, for either NCC or SCoRS. Although in study EVP-6124-016 there was a small trend for both the 1 and 2mg groups to be greater than placebo for NCC. Encenicline was generally safe and well tolerated with adverse events reported by approximately 50% of the patients; mild constipation was most frequent. Post-hoc analyses (on-going) on pooled data from both trials are examining the effects of adherence on treatment efficacy, site effects (including experience on the part of both assessors and patients), and the impact of various demographic variables (race and geographic location) and treatment (type of anti-psychotic medication).The results from these two large Phase III studies, showed limited benefit ofencenicline for the treatment of cognitive impairment and related functional deficits in people with schizophrenia. However, a number of valuable observations were obtained from these trials which question whether the Phase III results are less reflective of the true efficacy of encenicline than the phase II studies previously indicated. These include: 1) the importance of accounting for/mitigating non-adherence to treatment, 2) multiple repeated MCCB testing sessions did not plateau learning effects and 3) subjects with greater change in Outcome scores from screening to baseline also showed aberrant changes from baseline to week 26 compared to subjects with smaller changes prior to baseline, inherently reducing signal:noise ratio. Results of additional post-hoc analyses will be discussed to guide and inform the future development of CIAS clinical trials.