HOLLYWOOD, FLA. – A novel procognitive medication has entered pivotal phase III, randomized clinical trials in patients with chronic schizophrenia, with a separate phase III trial due to start later this year in Alzheimer’s disease.
The drug, known for now as EVP-6124, is an oral alpha-7 nicotinic partial agonist. The alpha-7 nicotinic receptor is an acetylcholine receptor highly localized to the cortical and hippocampal regions of the brain. EVP-6124 acts as a coagonist in combination with acetylcholine to activate the receptor and enhance cognition, Dr. Ilise Lombardo explained at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.
In a phase IIa randomized, double-blind placebo-controlled study in patients with stable chronic schizophrenia who remained on their atypical antipsychotic therapy, EVP-6124 normalized three EEG biomarkers for cognitive processing: p50, p300, and MMN, or mismatch negativity. This encouraging finding, coupled with clinical evidence of a procognitive effect on the CogState computerized test of cognition, led to a subsequent 319-patient, 12-week, double-blind phase IIb study.
Dr. Ilise Lombardo
The phase IIb trial showed that adding once-daily EVP-6124 to standard antipsychotic medication resulted in statistically significant and clinically meaningful benefits compared with placebo in terms of global cognitive function on the CogState test as well as on the Positive and Negative Syndrome Scale (PANSS) cognitive impairment domain, the PANSS negative symptoms domain, and the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB). The drug had no effect on PANSS positive symptoms.
EVP-6124 also resulted in significant improvement in clinical function as measured on the interview-based Schizophrenia Cognition Rating Scale (SCoRS). That’s a key finding, because the Food and Drug Administration now requires evidence of improved clinical function as a condition for approval of any new treatment for schizophrenia, added Dr. Lombardo, vice president for clinical research at EnVivo Pharmaceuticals, which is developing the drug.
There are currently no approved treatments for the cognitive or negative symptoms of schizophrenia, making this a major unmet need in mental health care.
EVP-6124 proved safe and well tolerated in phase II testing. There were fewer adverse events and study dropouts than with placebo.
Based on these encouraging results, two phase III studies are underway. Each of the 26-week studies will randomize roughly 700 patients with schizophrenia. The MCCB and SCoRS tests will be the coprimary endpoints.
The recently completed double-blind, placebo-controlled, 24-week phase IIb study in Alzheimer’s disease involved 409 randomized patients. A dose-response effect was seen. The 0.3-mg dose of EVP-6124 was not significantly more effective than placebo. The 1.0-mg dose showed intermediate efficacy. And the 2.0-mg dose showed statistically significant benefits across the board, compared with placebo.
Moreover, these benefits were clinically meaningful in size. For example, the effect size for EVP-6124 at 2.0 mg/day was a solid 0.39 for the primary endpoint, which was improvement on the Alzheimer’s Disease Assessment Scale, 13-item subscale (ADAS-cog-13), Dr. Lombardo observed.
The top dose also resulted in significant improvement on numerous secondary endpoints, including the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), the Controlled Oral Word Association Test (COWAT), the Mini-Mental State Examination, and the ADAS-cog-11.