Yale Daily News

On Sept. 26, for the first time in nearly 30 years, the U.S. Food and Drug Administration approved a new oral drug, Cobenfy, developed by Bristol Myers Squibb, to treat schizophrenia.

Schizophrenia is a complex and varied disorder, and for many patients, existing treatments often come with side effects like weight gain, tremors and emotional dullness. Historically, these side effects have made it difficult for patients to adhere to their prescriptions. 

Cobenfy targets a different neurotransmitter system in the brain than existing antipsychotics, making it a first-of-its-kind therapy that may not have the downsides of traditional treatments. Clinicians, therefore, are eager to explore whether Cobenfy’s new mechanism alleviates symptoms in patients who haven’t responded well to traditional treatments.

“It is exciting to have an alternative option,” said Dr. Phillip Corlett, associate professor of psychiatry at the School of Medicine. “Up to 50 percent of patients still experience delusions and hallucinations despite taking existing medications targeting dopamine receptors.”

Effectiveness of Cobenfy

Clinical trials have shown Cobenfy’s potential to alleviate a wide range of schizophrenia symptoms, including hallucinations, delusions and social withdrawal. 

In these trials, patients were given escalating doses of the drug, and results indicated significant improvement compared to a placebo group. As a result, clinicians are cautiously optimistic about the potential of this therapy in reshaping schizophrenia care.

“Cobeny is the first FDA-approved antipsychotic that does not block dopamine D2 receptors and does not produce extrapyramidal motor symptoms,” Dr. John Krystal, professor of translational research and psychiatry. “It also appears to be relatively effective for reducing negative symptoms.”

According to Krystal, the excitement around Cobenfy is also driven by its potential to address cognitive deficits and negative symptoms, areas where traditional antipsychotics often fall short. Traditional antipsychotics often worsen negative symptoms like cognitive impairment and lack of motivation, which can severely affect patients’ daily lives. In contrast, Cobenfy may avoid these issues, improving the overall quality of life for patients. 

Researchers hope the drug could also alleviate cognitive deficits, a key concern for many patients. Cognitive impairments often limit patients’ ability to maintain employment or complete daily tasks. This is a largely unmet need in schizophrenia treatment, as traditional medications provide little relief in this area.

“Cobenfy doesn’t cause the weight gain and motor side effects we often see with dopamine-based medications,” Corlett said, highlighting one of the drug’s key advantages. “That’s a clear benefit for patients who have struggled with these side effects in the past.”

Changing view of schizophrenia

According to Dr. Deepak Cyril D’Souza, professor of psychiatry, historically, schizophrenia has been viewed as a singular illness, but experts are increasingly viewing schizophrenia as an umbrella term, encompassing multiple disorders with varying causes and mechanisms. This new view is guided by research that suggests that schizophrenia consists of distinct subtypes that respond differently to treatments.

D’Souza continued, stating this understanding has important implications for the development of treatments with novel mechanisms like Cobenfy. By exploring mechanisms outside of traditional dopamine regulation, such as Cobenfy’s targeting of the cholinergic system, clinicians hope to treat these diverse underlying causes more effectively, treating patients based on their unique neurobiological profiles.

Cobenfy was first developed unintentionally. Initially, it was developed as xanomeline, a treatment for Alzheimer’s disease, since manipulating the cholinergic system appeared to reduce psychosis in some Alzheimer’s patients. During trials, however, researchers observed that it also improved symptoms of schizophrenia. 

Although promising, xanomeline caused significant side effects related to its cholinergic mechanism. To address this, scientists combined xanomeline with trospium, an anticholinergic drug that does not cross the blood-brain barrier, helping reduce the unintended side effects of xanomeline while preserving its effectiveness. This combination became Cobenfy, and researchers believe it could be particularly beneficial for a subgroup of schizophrenia patients whose psychosis is driven by the cholinergic system.

Long Term-Impact of Cobenfy

Cobenfy’s development is also part of a broader movement toward exploring alternative pathways in the treatment of schizophrenia, Krystal emphasized. The approval of a non-dopaminergic drug is creating new avenues for more research into underexplored areas of neurobiology, such as how Cobenfy could be used in combination with existing treatments to provide a more comprehensive approach to managing symptoms.

Corlett stated the road ahead for Cobenfy involves further studies, including trials to determine its long-term efficacy and safety. Bristol Myers Squibb is also investigating its use in combination with dopamine-based medications, as well as its potential applications in other psychiatric disorders, such as Alzheimer’s-related psychosis and bipolar mania.

While Cobenfy’s approval marks a significant step forward in schizophrenia treatment, questions remain about its long-term impact, particularly in addressing cognitive symptoms and its potential effectiveness for treatment-resistant patients. Early studies have focused primarily on positive and negative symptoms of schizophrenia, but some secondary outcomes related to cognitive function were also promising.

D’Souza, who has been closely following the development of Cobenfy, believes that future research will need to explore Cobenfy’s impact on cognitive functioning, an area where existing antipsychotics offer limited benefit. D’Souza has expressed both hope and caution regarding the drug’s potential cognitive benefits, stating it is still a bit early to tell. 

“Cognitive symptoms have a significant impact on the functioning of patients with schizophrenia — holding jobs, balancing a checkbook, remembering to take medications — these are the areas where improvement is needed most,” he said. “Any drug that might actually improve cognition would be great. I’d like to see further studies focused on that.”

In addition to cognitive symptoms, researchers are also interested in understanding Cobenfy’s efficacy in treatment-resistant cases of schizophrenia. For many patients, traditional dopamine-targeting medications have limited effects or intolerable side effects, but Cobenfy’s new mechanism’s different avenue for treatment may be the answer. Future studies could reveal whether Cobenfy can provide relief for this subgroup of patients.

In the longer term, D’Souza foresees this new class of antipsychotics reshaping how schizophrenia is treated.

“This is the first new mechanism that’s been approved in almost 70 years, and hopefully this will spur further research on other mechanisms. Many big pharmaceutical companies stopped developing schizophrenia drugs, but the hope is that this might bring them back.”

Cobenfy’s two active ingredients are xanomeline and trospium chloride.