Researchers have published evidence indicating that Cobenfy, a new drug for schizophrenia approved by the FDA in September 2024, may help reduce cognitive impairments in some patients, in addition to its previously documented effect of reducing both positive and negative symptoms of the illness.

Cobenfy, developed under the name KarXT, combines two compounds called xanomeline and trospium chloride. It is the first-ever drug approved for schizophrenia that does not target the D2 dopamine receptor in brain cells. Xanomeline targets two specific receptors in brain cells, called M1 and M4, that are part of the muscarinic acetylcholine system. Trospium chloride prevents xanomeline from affecting receptors in the body’s peripheral nervous system, i.e., outside the central nervous system, in order to minimize side effects that could arise if peripheral receptors were activated.

The drug was approved for the treatment of schizophrenia in adults after two pivotal phase 3 clinical trials reported in 2024. Both trials were 5 weeks in duration, and tested the new drug in a combined sample of over 500 participants with acute schizophrenia (the subjects had been hospitalized). Those who received the drug had significant reductions in both positive and negative symptoms, compared with those receiving placebo. Neither first- nor second-generation antipsychotics, while often very effective in reducing positive symptoms such as hallucinations and delusions, have appreciable therapeutic impact on negative symptoms, which include flat affect, reduced motivation, and social withdrawal.

A team of investigators led by William P. Horan, Ph.D., wanted to follow up on preliminary evidence from a phase 2 trial of the new drug suggesting that it might also improve cognitive performance in at least some patients. Dr. Horan is a 2016 BBRF Maltz Prize winner and 2008 and 2004 BBRF Young Investigator. The team also included Steven M. Paul, M.D., an emeritus member of the BBRF Scientific Council, who played an important role in the drug’s development; Richard S.E. Keefe, Ph.D., 2003 BBRF independent Investigator and 1995 and 1991 Young Investigator; and Philip D. Harvey, Ph.D., BBRF Scientific Council member and 2023 BBRF Lieber Prize winner.

As the team noted in their paper appearing in the American Journal of Psychiatry, considerable pharmacologic and genetic evidence from non-human studies indicates that the M1 and M4 muscarinic receptors “are key modulators of neural networks underlying cognitive function.” These receptors are concentrated in brain regions crucial for cognition, including the hippocampus and prefrontal cortex. Xanomeline, which activates these two receptors, has shown promising effects on cognitive functioning in animal models. It has also been explored as a potential therapeutic in Alzheimer’s disease, based on findings that it may improve memory impairments. However, these earlier studies did not involve the recently approved version of the new drug which combines xanomeline with trospium chloride.

The phase 3 clinical trials for Cobenfy included baseline cognitive assessments of participants before the trial began, with most also undergoing additional assessments after 3 and 5 weeks, the latter marking the conclusion of each trial. This cognitive data was not a factor in the drug’s approval, but is of great interest since no existing “monotherapy” for schizophrenia, i.e., no single-drug treatment such as antipsychotics, effectively addresses the cognitive impairments associated with the illness. These include deficits (relative to unaffected individuals) in executive function, visual and spatial memory, the ability to pay attention in a sustained manner, and verbal recall and recognition. During the phase 3 trials, these cognitive domains were evaluated using the Cambridge Neuropsychological Test Automated Battery (CANTAB), a brief assessment delivered via a tablet device.

The new study of the phase 3 results was sponsored by Karuna Therapeutics, the company that developed Cobenfy, which has been acquired by Bristol Myers Squibb.

The new study retrospectively analyzed the phase 3 trial results, building on observations from the earlier phase 2 trial. It found that participants who took Cobenfy (rather than placebo) performed better on the CANTAB battery—but this benefit applied only to those who had moderate or more severe cognitive impairment prior to the beginning of the trial.

In the overall group that combined the participants in the two phase 3 trials who received Cobenfy for 5 weeks, the drug was not associated with cognitive improvement in any of the domains tested. But a subset of the whole had significant preexisting (“baseline”) cognitive issues (about 38% of the total group of 357); of these 71 received Cobenfy and 66 received placebo. Those who received Cobenfy had improvements in their composite CANTAB score, with the largest improvements seen in verbal memory, involving both recall and recognition. The size of the effect is described by the team as “moderate.”

Such benefits are deemed significant by the researchers, since, as Dr. Horan points out, it was “the first time a monotherapy for the treatment of schizophrenia has shown a replicable cognitive benefit.”

The team also found that cognitive effects of Cobenfy had no correlation with the drug’s therapeutic impact on schizophrenia’s positive and negative symptoms. Participants receiving the drug had improvements in those symptoms compared with those receiving placebo, whether or not they also had cognitive improvement.

As a next step, the team suggested the current results warrant “a well-controlled trial in clinically stable patients,” i.e., unlike those in the phase 3 trials, who were experiencing acute episodes. The new trial might specifically seek to recruit patients known to have cognitive impairments, they suggested. It has been estimated that a majority of schizophrenia patients have such impairments, although the impacts of these impairments on function vary widely, from case to case.