Nancy A. Melville

April 10, 2015

COLORADO SPRINGS, Colorado — Encenicline (Forum Pharmaceuticals), a novel α-7 nicotinic acetylcholine receptor partial agonist, shows improvement of cognitive impairment in schizophrenia in a phase 2 randomized, controlled trial, potentially ushering in a long-anticipated treatment for an aspect of the disease not addressed by antipsychotics.

"These data shows that pro-cognitive effects in schizophrenia were observed for encenicline as assessed by two independent cognitive measures and a functional measure," said Ilise Lombardo, MD, who is vice president of clinical research and medical affairs at Forum Pharmaceuticals, Watertown, Massachusetts, in presenting the findings here at the 15th International Congress on Schizophrenia Research (ICOSR).

Although cognitive impairment occurs in nearly all (98%) patients with schizophrenia, antipsychotics do not adequately offer improvement, Dr Lombardo said.

"Antipsychotics remain the mainstay of pharmacotherapy for schizophrenia with limited, if any, benefit in improving cognitive impairment. There is a clear need for pharmacological agents that target cognitive impairment."

With its unique mechanism seen as potentially helping to improve memory and cognitive function, encenicline is being studied as an adjunct to antipsychotics in treating cognitive impairment in schizophrenia as well as Alzheimer's disease.

For the phase 2, multicenter, double-blind study, 319 patients with a diagnosis of schizophrenia for 3 or more years were randomly assigned 1:1:1 to receive encenicline in doses of 0.27 mg or 0.9 mg once daily or placebo for 12 weeks.

The results showed significant cognitive improvements in the encenicline groups in both dose groups at various measures.

For the primary efficacy endpoint of Overall Cognitive Index score, as well as Trails 2 and 4 tasks from the Neuropsychological Test Battery (NTB), patients receiving the 0.27-mg dose had significant improvement over placebo (P = .03 for both).

In a subset of 154 patients only in the United States, both dose groups showed a trend toward improved cognition in the MATRICS Consensus Cognitive Battery tests, but the improvement from baseline was greater in the higher-dose 0.9-mg group (P = .06 compared with placebo) than the 0.27-mg group.

Pro-Cognitive Effect

Improvement in clinical function was further seen in the measures of the Schizophrenia Cognition Rating Scale, with the 0.9-mg group showing a significant improvement over placebo (P = .01) in terms of the mean change from baseline.

Patients in the 0.9-mg group also showed significant improvements in the Positive and Negative Syndrome Scale (PANSS) Cognition Impairment domain compared with placebo (P = .029) as well as for PANSS-negative subscale scores (P = .028).

Dr. Lombardo noted that the primary outcome data were difficult to interpret because, the higher dose has consistently shown greater improvement.

"Those data were inconsistent with the other measures of cognition and all of the measures of function and other assessments in this study, as well as, importantly, in the phase 1 data on schizophrenia," she said.

"In all of those other measures, we did see the more robust effect was in the higher dose than the lower dose."

There were no treatment-emergent adverse events in the treatment groups that were considered serious, and covariate analyses have shown no notable effects of smoking, sex, or baseline severity, Dr Lombardo said.

She noted that two 6-month, phase 3 trials are underway for encenicline, involving 700 patients each.

The approach of targeting nicotinic acetylcholine receptors for cognitive improvement in schizophrenia has attracted particular interest because of deficiencies shown in patients with the condition, according to a phase 2 study on the first drug in the class of α-7 nicotinic acetylcholine receptor partial agonists, the agent 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A).

"[Schizophrenia] patients' heavy smoking suggests attempted self-medication through this mechanism," wrote the authors, who included Robert Freedman, MD, from the University of Colorado Denver's School of Medicine in Aurora.

Dr Freedman told Medscape Medical News that the drug class has shown some promising signs in animal studies.

"A pro-cognitive effect was suggested (with the α-7 nicotinic acetylcholine receptor partial agonist) by the preclinical evidence in laboratory animals," he said. "The mechanism of action, activating a nicotinic receptor, is far different from most current antipsychotics."

"The exception is clozapine, which releases large amounts of acetylcholine from the brain's synapses as one of its many effects, and thereby indirectly activates nicotinic receptors."

While the need for a therapy to specifically address cognitive function in schizophrenia has yet to be met, it's not from a lack of trying.

A review published in Schizophrenia Bulletin in 2013 underscored the efforts, describing a multitude of shortcomings in more than 100 clinical trials examining treatment of cognitive impairment in schizophrenia.

Huge Unmet Need

"This has been an area of substantial interest but no drug to date has worked, despite multiple attempts," Philip D. Harvey, PhD, the Leonard M. Miller Professor of Psychiatry and Behavioral Sciences at the University of Miami Miller School of Medicine in Florida, told Medscape Medical News.

"Antipsychotic medications do nothing for cognition, and cognitive impairment is associated with disability," he said.

"Meanwhile, cognitive remediation interventions have shown that improving cognitive function leads to improvement in everyday activities for these patients."

Dr Harvey noted that some earlier efforts in developing a drug in the α-7 nicotinic receptor class have not successfully advanced, largely because of a very short half-life of the compounds.

"The earlier compounds did have a signal for efficacy, but due to the short half-life they had to be administered multiple times a day and that's just not practical for patients with severe mental illness."

Anticipation in psychiatry is high for a drug that successfully overcomes the challenges, he stressed.

"Everyone in the field is very excited about the idea that a drug like this would have efficacy," he said. "It really could fill a hugely unmet need."

The study was funded by Forum Pharmaceuticals. Dr Lombardo is an employee of Forum Pharmaceuticals. Dr Freedman has disclosed no relevant financial relationships. Dr Harvey is a consultant for Forum Pharmaceuticals but has no financial interests in the development of encenicline.

15th International Congress on Schizophrenia Research (ICOSR). Abstract 2207646. Presented March 30, 2015.

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