A new treatment for schizophrenia – backed by Wellcome-funded research – has been approved by the FDA and has the potential to change the lives of millions of people living with the condition globally.
Schizophrenia is a severe, long-term mental health condition that affects around 1 in 300 people worldwide. Symptoms include hallucinations, delusions, muddled thoughts, loss of interest in everyday activities and social withdrawal.
While there are different treatment options available, antipsychotic drugs are commonly used to treat the condition, however they don’t work for everyone.
Now, a new combination drug called Cobenfy has been approved by the US Food and Drug Administration (FDA). It is the first new pharmacological approach for treating schizophrenia in over 50 years and may provide an alternative option for people living with the condition. Cobenfy was developed by Karuna Therapeutics Inc. which was acquired by Bristol Myers Squibb in March 2024.
Cobenfy is a combination therapy meaning it combines two different drugs, xanomeline and trospium chloride, into one treatment.
These drugs target receptors in the brain and body associated with the cholinergic neurotransmitter system – which has a key role in learning and memory, digestion, control of heartbeat, blood pressure, movement and many other functions. There are two types of cholinergic receptors, nicotinic and muscarinic. In Cobenfy, xanomeline activates muscarinic receptors in the brain, whereas trospium chloride blocks activation of muscarinic receptors in the body.
Xanomeline was originally developed to treat Alzheimer’s disease by US pharmaceutical company, Eli Lilly and Company. While it was shown to improve cognition and some of the behavioural symptoms of Alzheimer’s in trials, including reducing delusions, agitation, and hallucinations, its development was stopped as some people experienced problematic side effects. These side effects were caused by muscarinic receptor activation in the body.
Karuna’s founder, Andrew Miller, anticipated that combining trospium chloride with xanomeline would reduce these side effects and hypothesised this new therapy would reduce psychosis in people living with schizophrenia.
And it worked.
Wellcome funded the Phase 1 and then Phase 2 trial of Cobenfy in 2015 and 2018.
Drug development is a lengthy, expensive and risky process. On average, 73.2% of psychiatric drug candidates fail to make it through Phase 2, the stage of clinical development that involves definitive testing of how well the drug works in people with that mental health problem.
We loaned approximately US $11.7 million to Karuna through two awards. We converted our loans to equity in the company as it progressed through fundraising rounds. Due to the success of Karuna’s work, the value of that company increased significantly, and therefore so did the value of Wellcome’s equity.
Our early high financial-risk investment has the potential impact of a new class of medicine for the 24 million people living with schizophrenia worldwide and the income we received from the shares can be reinvested in new research.
In March 2024, Karuna was acquired by Bristol Myers Squibb.
In the Phase 1 trial, Cobenfy was shown to be safe and well tolerated with a 50% reduction in side effects compared to xanomeline alone in healthy adults. Results from the Phase 2 trial in people with schizophrenia were also positive, and in 2019, it was announced that Cobenfy led to a statistically significant reduction in schizophrenia symptoms in adults living with schizophrenia compared to placebo. Results from Phase 3 trials of Cobenfy in schizophrenia found the treatment to:
- result in clinically meaningful and statistically significant improvements in symptoms of psychosis, such as delusions and hallucinations, compared to placebo
- improve negative symptoms of schizophrenia, including lack of motivation, social withdrawal, and cognitive impairment, often not impacted by current drugs, and
- cause low incidence of common side effects of current antipsychotics, such as sleepiness, weight gain and abnormal motor movements
Historically, antipsychotic drug treatments have focused on the neurotransmitter dopamine. They work to block some of the dopamine receptors in the brain, which can lead to problematic side effects. These side effects mean that some people stop taking the medication, causing them to relapse. Moreover, between 20% and 33% of patients don’t respond to dopamine-targeting drugs at all.
The Cobenfy trial was the first positive Phase 3 trial for an investigational medicine that does not directly rely on dopaminergic or serotonergic pathways in the brain in approximately 70 years. Cobenfy works in a completely new way and was found to be well tolerated and relieve symptoms of schizophrenia, providing a potential treatment option for people with psychosis – a key priority for our Mental Health team.
While current therapies for schizophrenia can be effective in managing select positive symptoms, like hallucinations and delusions – they do not address other life-limiting symptom areas. For example, negative symptoms like social withdrawal and cognitive symptoms like memory problems. Cobenfy has the potential to address all three symptom areas associated with schizophrenia (positive, negative and cognitive).
Following trials evaluating the short and long-term effectiveness of Cobenfy in treating schizophrenia, the developers filed a New Drug Application with the FDA in mid-2023. Cobenfy was approved by the FDA for the treatment of schizophrenia in September 2024.
Bristol Myers Squibb is also evaluating Cobenfy as an adjunctive therapy, which means it could be used in combination with other treatments for schizophrenia, and evaluating the drug for the treatment of Alzheimer’s-related psychosis. Phase 3 trial results are expected in 2025 and 2026, respectively.
It’s really exciting to see what the potential lasting impact of this new breakthrough treatment option will be for schizophrenia, especially for those for whom current drug treatments don’t work. It’s wonderful to be part of the Cobenfy success story and to have funded research that may change the lives of millions of people.
We’re funding research to help create transformative change in early intervention for anxiety, depression and psychosis.
There are currently no open funding opportunities for Mental Health. Learn more about the funding we provide.
This article was first published 19 October 2022.
A new treatment for schizophrenia – backed by Wellcome-funded research – has been approved by the FDA and has the potential to change the lives of millions of people living with the condition globally.