A new approach for treating schizophrenia

A potential new treatment for schizophrenia – backed by Wellcome-funded research – may change the lives of millions of people living with the condition globally.

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Lynsey Bilsland

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A new approach for treating schizophrenia
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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 United States-based biotech organisation called Karuna Therapeutics Inc. has developed a new combination drug called KarXT. It is the first potential new pharmacological approach for treating schizophrenia in over 50 years and may provide an alternative option for people living with the condition.

The science behind the new schizophrenia treatment 

KarXT 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 KarXT, 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.

We funded Karuna in 2015 and 2018 to undertake a Phase 1 and then Phase 2 trial of KarXT.

In the Phase 1 trial, KarXT 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, Karuna announced that KarXT led to a statistically significant reduction in psychotic symptoms in people living with schizophrenia. Seven years after our initial investment, results from a Phase 3 trial of KarXT in schizophrenia have 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
  • not be associated with common problematic side effects of current antipsychotics, such as sleepiness, weight gain and abnormal motor movements.

The difference it will make 

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 KarXT trial is 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. KarXT 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. KarXT has the potential to address all three symptom areas associated with schizophrenia (positive, negative and cognitive).

What’s next for KarXT? 

There are three ongoing trials evaluating the short and long-term effectiveness of KarXT in treating schizophrenia and how safe it is to use over a long period. Following their completion, Karuna aims to file a New Drug Application with the Food and Drug Administration (FDA) for KarXT in schizophrenia in mid-2023.

Karuna is also evaluating KarXT for the treatment of dementia-related psychosis in Alzheimer’s disease and a Phase 3 trial was initiated in August 2022.

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 Karuna’s success story and to have funded research that may change the lives of millions of people.

  • Lynsey Bilsland

    Head of Mental Health Translation


    Lynsey is Head of the Mental Health Translation team at Wellcome, which aims to develop a portfolio of funded projects that enable identification, prediction and intervention early in mental health problems.

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