A New Schizophrenia Treatment: What the Approval of Cobenfy Could Mean for Handling Mental Health Disorders

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On September 26, 2024, the FDA approved Bristol Myers Squibb’s (BMS) Cobenfy (xanomeline and trospium chloride) capsules for oral use for the treatment of schizophrenia in adults. According to the government agency, it is the first approved schizophrenia treatment to target cholinergic receptors as opposed to dopamine receptors, making it the first notable breakthrough treatment for the mental health disorder in over 30 years.^1,2

“Schizophrenia is a leading cause of disability worldwide. It is a severe, chronic mental illness that is often damaging to a person’s quality of life,” said Tiffany Farchione, MD, director, division of psychiatry, office of neuroscience, center for drug evaluation and research, FDA, in a press release. “This drug takes the first new approach to schizophrenia treatment in decades. This approval offers a new alternative to the antipsychotic medications people with schizophrenia have previously been prescribed.”

Amid the FDA approval of Cobenfy, Pharmaceutical Executive sat down with Sam Clark, MD, PhD, CEO, Terran Biosciences to discuss how the approval could impact new innovations in treating mental health disorders.

“This is a big breakthrough,” said Clark. “You have the first new mechanism to treat schizophrenia in at least 50 years which involves the muscarinic receptor system. Previously, all antipsychotics were targeting the dopamine type two receptor. So, in essence, it sets the stage by now opening the door for further drugs with this mechanism to also go for an approval. This is the first time the FDA has ever approved a novel mechanism to treat schizophrenia that has differed significantly from the original antipsychotic.

“In one way, it is a green light for other 505B1 drug applications, and it also starts he clock ticking for the five-year countdown of marketing exclusivity. This means that improved versions of KarXT or Cobenfy could use the accelerated 505B2 pathway to bring improved versions to patients five years after this approval.”

Despite this big breakthrough, there are some who remain skeptical. According to a 2012 study on schizophrenia medication adherence, it is estimated that nearly half of patients who have been prescribed a medication refrain from taking it. Results from a 2020 research review found that many patients remain skeptical of the healthcare industry, disengaging as a result.^3,4

In an article on Stat News, Sally Littlefield reported thatadverse events (AEs) associated with schizophrenia medications, such as rapid weight gain, have historically ruined the quality of life for patients with the condition. As a result, Littlefield explained that she would hesitate to try Cobenfy if it was recommended to her.⁵

Despite the skepticism, Clark noted that there are several differences with Cobenfy compared to traditional schizophrenia treatments, which targets dopamine signaling.

“Current medications all go back to chlorpromazine, which was Thorazine, one of the first antipsychotics that targeted the dopamine type two receptor,” he explained. “It would block dopamine signaling. Now, we know that it can help reduce hallucinations and schizophrenia, but it also comes at the cost of causing Parkinsonian-like symptoms. Similar to the way Parkinsonism has a reduction in dopamine signaling and problems, and a lot of movement disorders result from dopamine signaling. When you block the dopamine type two receptor, you can cause movement disorders in patients, one of which is called tardive dyskinesia. This dyskinesia, it can be permanent and it's induced by antipsychotics.”

On the other hand, Clark explained that these AEs aren’t the same for patients treated with Cobenfy.

“There's also other issues, such as metabolic dysfunction, hormonal changes with the endocrine system, and the weight gain caused by traditional antipsychotics,” he said. “This is the first time you have an antipsychotic that does not target the dopamine type two receptor at all. It targets the muscarinic M1 and M4 receptors in the brain. They’re both thought to be very important, with M4 underlying what's thought to be the antipsychotic effect, and M1 underlying what's thought to be a potential cognitive boosting effect. As we know, schizophrenia is not only comprised of hallucinatory symptoms, such as psychosis, but also of social withdrawal and cognitive impairment, lack of working memory, and other things of that nature. There’s a hope that over time, Cobenfy can improve that as well by targeting these receptors.”

In an article by Boston University’s The Brink, Kim Mueser and Daniel Fulford, both professors of occupational therapy, said that Cobenfy still needs to prove its benefits in the real world compared with other schizophrenia treatments.⁶

“Until clinical trials are conducted comparing Cobenfy with other antipsychotics, it is unknown how Cobenfy might benefit patients with schizophrenia,” Mueser told The Brink. “Clearly, if it is found, and replicated, to be more effective than other antipsychotics on any of the primary outcomes of schizophrenia—psychotic symptoms, negative symptoms, cognition—many patients stand to benefit from it.”

In an exclusive interview with Pharmaceutical Executive, Dan Troy, former chief counsel of the FDA and current managing director of BRG, offered his thoughts on how the approval could impact the landscape of pharma dealmaking.

“So, I’m a sports fan, and they say the NFL is a copycat league,” said Troy. “I think the same thing goes for pharma. People like to follow a path that has already been laid out. I think that the approval of Cobenfy is going to give people hope. They’ll hopefully take a second look at schizophrenia, neuroscience, and mental health; particularly the fact that this is combining an old medicine with a new medicine to alleviate the side effects. I think that approach will intrigue a number of people.”

Troy then stressed the importance of the approval given the challenges with the development of treatments for mental health conditions.

“Neuroscience and mental health are hard because there are no animal models,” he explained. “You’re measuring things that are kind of subjective in a way that’s different then measuring tumor size or cholesterol numbers.”

References

1. FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia. FDA. September 26, 2024. Accessed November 12, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia

2. U.S. Food and Drug Administration Approves Bristol Myers Squibb’s COBENFY™ (xanomeline and trospium chloride), a First-In-Class Muscarinic Agonist for the Treatment of Schizophrenia in Adults. BMS. September 26, 2024. Accessed November 12, 2024. https://news.bms.com/news/details/2024/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibbs-COBENFY-xanomeline-and-trospium-chloride-a-First-In-Class-Muscarinic-Agonist-for-the-Treatment-of-Schizophrenia-in-Adults/default.aspx

3. Medication adherence in schizophrenia. NIH. Accessed November 12, 2024. https://pmc.ncbi.nlm.nih.gov/articles/PMC3782179/

4. Resisting governance and the production of trust in early psychosis intervention. ScienceDirect. Accessed November 12, 2024. https://www.sciencedirect.com/science/article/abs/pii/S0277953620301672

5. Why I’m wary of the new schizophrenia miracle drug. Stat News. October 15, 2024. Accessed November 12, 2024. https://www.statnews.com/2024/10/15/cobenfy-schizophrenia-schizoaffective-bristol-myers-squibb/

6. A “Game-Changing” New Drug for Schizophrenia? The Brink. October 3, 2024. Accessed November 12, 2024. https://www.bu.edu/articles/2024/a-game-changing-new-drug-for-schizophrenia/