Cobenfy, a recently FDA-approved schizophrenia drug developed by Bristol Myers Squibb, demonstrates cognitive benefits in patients with pre-existing cognitive impairments, according to a post-hoc analysis utilizing Cambridge Cognition's CANTAB (Cambridge Neuropsychological Test Automated Battery) assessment tool. The drug, which targets M1 and M4 muscarinic receptors, represents a novel approach to schizophrenia treatment, differing from traditional antipsychotics that primarily block dopamine receptors.
Novel Mechanism of Action
Cobenfy, a combination of xanomeline and trospium chloride, is the first approved schizophrenia medication in decades that does not target the D2 dopamine receptor. Xanomeline selectively activates M1 and M4 muscarinic acetylcholine receptors in the brain, which are key modulators of neural networks underlying cognitive function. Trospium chloride is included to minimize peripheral side effects by preventing xanomeline from affecting receptors outside the central nervous system.
Clinical Trial Results and Cognitive Impact
Two pivotal Phase 3 clinical trials, involving over 500 participants with acute schizophrenia, led to Cobenfy's approval. These trials demonstrated significant reductions in both positive (hallucinations, delusions) and negative (flat affect, reduced motivation) symptoms compared to placebo. Notably, traditional antipsychotics often fall short in addressing negative symptoms.
A post-hoc analysis of these trials, published in The American Journal of Psychiatry, focused on the cognitive performance of participants as measured by the CANTAB battery. While the overall group did not show significant cognitive improvement, a subset (approximately 38%) with moderate to severe cognitive impairment at baseline experienced notable benefits. Specifically, those receiving Cobenfy showed improvements in their composite CANTAB score, with the most significant gains observed in verbal memory (recall and recognition). The effect size was described as "moderate."
The Role of CANTAB
The CANTAB, a digital cognitive assessment tool, provided precise and objective measurements of cognitive function in the clinical trials. Rob Baker, Chief Operating Officer and Joint Managing Director at Cambridge Cognition, emphasized the importance of CANTAB in enhancing data collection, improving trial accuracy, and accelerating the development of effective treatments for schizophrenia. The tool's ability to identify cognitive improvements in specific patient subgroups highlights its value in clinical research.
Implications and Future Directions
William P. Horan, Ph.D., a lead investigator in the analysis, noted that this is "the first time a monotherapy for the treatment of schizophrenia has shown a replicable cognitive benefit." The researchers also found that the cognitive effects of Cobenfy were independent of its impact on positive and negative symptoms.
The research team suggests that future studies should focus on clinically stable patients with known cognitive impairments to further evaluate Cobenfy's cognitive benefits. This could involve a well-controlled trial specifically designed to recruit patients with pre-existing cognitive deficits, which are estimated to affect a majority of individuals with schizophrenia.
