No new treatments for schizophrenia have been approved in nearly three decades, but last week, the US Food and Drug Administration (FDA) approved Cobenfy for the psychiatric disorder, a decision welcomed by both doctors and patients alike.
Developed by Karuna Therapeutics, which was subsequently acquired by Bristol Myers Squibb, the drug works in an entirely different way from existing medications for schizophrenia, reports TIME Magazine.
How scientists developed it
While schizophrenia treatments primarily target the dopamine neurotransmitter system in the brain, Cobenfy goes after a different one, the cholinergic system, through muscarinic receptors.
Decades ago, scientists at Eli Lilly had studied the muscarinic system as a possible treatment for Alzheimer’s disease, since manipulating it seemed to reduce some of the symptoms of Alzheimer’s-related psychosis that some patients develop.
The company’s researchers also serendipitously learned that a compound they developed to activate the system also improved symptoms of schizophrenia. But cells in many parts of the body, like the brain, but also the bladder, gut, salivary glands, eyes and heart, contain receptors for the muscarinic system, which meant it was challenging to selectively target just those in the brain and not elsewhere.
Because the compound, called xanomeline, caused wide-ranging side effects, Lilly’s researchers shelved further study on it.
Andrew Miller, co-founder of Karuna, became intrigued by this research and tried to figure out how to activate the muscarinic system in the brain while tamping it down elsewhere in the body. He and his team tested 7 000 compounds and eventually combined xanomeline with a drug that had been approved by the FDA in the 1970s for treating overactive bladder, to suppress muscarinic activity elsewhere in the body.
“It’s a pretty out-of-the-box approach,” said Miller. “The overactive bladder drug has nothing to do with psychiatry.”
Combining it with a serendipitous discovery of xanomeline “didn’t fit the traditional model of innovative drug discovery”. But it worked.
What studies have found
In a study the company published last December in The Lancet, the researchers reported that the combination – now called Cobenfy but then called KarXT – helped to significantly reduce symptoms of schizophrenia such as hallucinations, delusions, paranoia, social withdrawal, and a loss of motivation, compared with a placebo.
Those data were part of the application that the company submitted to the FDA for approval.
Bristol Myers Squibb acquired Karuna in 2023 largely based on these encouraging results.
“When we looked at the available neuroscience and neuropsychiatric assets out there, we didn’t want the next dopamine agonist or antagonist in the marketplace, which all of the physicians have (already) seen,” said Adam Lenkowsky, chief commercialisation officer for Bristol Myers Squibb.
“We wanted a truly revolutionary asset, one with a different mechanism: a first-in-class, best-in-category asset we think could transform the space.”
Samit Hirawat, chief medical officer at Bristol Myers Squibb, said that not only does Cobenfy address schizophrenia in an entirely new way, but its approach could be used for other neurological conditions as well. “The breadth of applicability of this medicine is what attracted us.”
Dr Rishi Kakar, chief scientific officer at Segal Trials who led several studies on Cobenfy, said that the uniqueness of the mechanism of action differentiated this medication “from everything else we had so far, and truly caught my eye right off the bat”.
Kakar, a psychiatrist who treats patients as well as conducts research, added that historically, only about 40% of people with schizophrenia respond to dopamine-based treatments, and the other 60% who may respond often stop taking their medications because of intolerable side effects, which can include uncontrolled muscle movements, dizziness, fainting, and weight gain.
The trials included patients who were hospitalised for acute schizophrenia and randomly assigned to receive Cobenfy as a pill taken twice a day or a placebo for five weeks. To reflect the real-world population of patients, some had been taking existing medications but stopped because of the side effects, or weren’t compliant.
All patients went through a wash-out period of up to two weeks to ensure any measurements of their outcomes during the study were due solely to Cobenfy or placebo.
Patients received escalating doses of the drug, and prescribing doctors were able to adjust dosages for their patients depending on their symptoms.
The studies documented a significant reduction in overall symptoms of schizophrenia in the patients receiving Cobenfy compared with placebo. “My viewpoint is that (this difference) can mean someone can potentially carry on a better life by having symptom control,” said Kakar.
What else to know about Cobenfy
The FDA approved Cobenfy as a monotherapy, meaning it is meant to be taken alone, without other medications, but more studies will be needed to see how the medication works in combination with existing treatments, and what the benefits and risks are of combining them.
“I think many clinicians are going to try this as a first-time pharmacological option, because they will find that the reduction in symptoms is fairly robust,” said Kakar. “From what I saw, it has true value for the unmet need we have.”
Lenkowsky said Bristol Myers Squibb is conducting a trial studying Cobenfy in combination with dopamine-based medications that will yield results in about a year.
In contrast to the existing dopamine-based treatments, the side effects of Cobenfy reported by the volunteers in the studies were mostly mild to moderate, involving nausea and gastrointestinal distress, and tended to lessen with time. The label also alerts patients that the drug is associated with urinary retention, increased heart rate and swelling in the face in rare cases; the medication is not recommended for people with a history of liver or kidney disorders.
Bristol Myers Squibb is continuing to study the drug for its longer term effects, as well as to understand and potentially guide doctors on how to adjust doses for patients as their symptoms change over time.
The success in schizophrenia patients may lead to other uses of the drug in other conditions as well.
“Neuropsychiatry is at the cusp of bringing an explosion of new medicines, and Cobenfy is the start of a pipeline of potential products,” said Hirawat.
The company is currently studying the drug in Alzheimer’s-related psychosis, and next year plans to start late-stage trials investigating whether it can improve bipolar mania, Alzheimer’s-associated agitation, and Alzheimer’s-associated cognitive impairment.
In 2027, the company hopes to begin trials in people with autism.
Study details
Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial
Inder Kaul, Sharon Sawchak, Christoph Correll, Rishi Kakar, Alan Breier, Haiyuan Zhu et al.
Published in The Lancet on 13 January 2024
Summary
Background
New treatments with new mechanisms are urgently needed for people with schizophrenia. Xanomeline is a dual M1 and M4-preferring muscarinic receptor agonist that does not block D2 dopamine receptors, unlike all currently approved treatments for schizophrenia. Xanomeline–trospium (KarXT) combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride with the goal of ameliorating xanomeline-related adverse events associated with peripheral muscarinic receptors. The EMERGENT-2 trial aimed to assess the efficacy and safety of KarXT in people with schizophrenia experiencing acute psychosis.
Methods
EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3 trial in people with schizophrenia. Participants were adults aged 18–65 years with a diagnosis of schizophrenia who had a recent worsening of psychosis warranting hospital admission, a Positive and Negative Syndrome Scale (PANSS) score of 80 or higher, and a Clinical Global Impression-Severity score of 4 or higher. The participants were recruited from 22 inpatient sites in the USA, and were randomly assigned (1:1) to KarXT or placebo twice per day. Participants randomly assigned to KarXT received 50 mg xanomeline and 20 mg trospium twice per day for the first 2 days and then 100 mg xanomeline and 20 mg trospium twice per day for days 3–7. Beginning on day 8, KarXT dosing was flexible with an optional increase to 125 mg xanomeline and 30 mg trospium twice per day and the option to return to 100 mg xanomeline and 20 mg trospium based on tolerability. The primary endpoint was change from baseline to week 5 in PANSS total score. Efficacy analyses used the modified intention-to-treat population (all randomly assigned participants who received at least one trial medication dose and had at least one post-baseline PANSS assessment). Least squares mean change from baseline, SE, and least squares mean difference between the KarXT and placebo groups at week 5, along with the 95% CI and two-sided p values were calculated for the primary and secondary continuous efficacy endpoints. Safety analyses included all participants receiving at least one trial medication dose and used descriptive statistics.
Findings
From Dec 16, 2020, to April 13, 2022, of 407 people who were screened, 252 participants meeting enrolment criteria were randomly assigned to the KarXT (n=126) or placebo (n=126). Baseline PANSS total scores were 98·3 (KarXT; n=126) and 97·9 (placebo; n=125). The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favoured KarXT (–21·2 points, SE 1·7) versus placebo (–11·6 points, 1·6; least squares mean difference –9·6; 95% CI –13·9 to –5·2; p<0·0001, Cohen's d effect size=0·61). All secondary endpoints were also met, and favoured KarXT versus placebo (p<0·05). The most common adverse events with KarXT versus placebo were constipation (27 [21%] vs 13 [10%]), dyspepsia (24 [19%] vs 10 [8%]), headache (17 [14%] vs 15 [12%]), nausea (24 [19%] vs seven [6%]), vomiting (18 [14%] vs one [1%]), hypertension (12 [10%] vs one [1%]), dizziness (11 [9%] vs four [3%]), gastro-oesophageal reflux disease (eight [6%] vs zero [0%]), and diarrhoea (seven [6%] vs four [3%]). Treatment-emergent adverse event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]), weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%]).
Interpretation
In the EMERGENT-2 trial, KarXT was effective in reducing positive and negative symptoms and was generally well tolerated. These results support the potential for KarXT to represent a new class of effective and well tolerated antipsychotic medicines based on activating muscarinic receptors, not the D2 dopamine receptor-blocking mechanism of all current antipsychotic medications. Results from additional trials, including the identical EMERGENT-3 trial and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional information on the efficacy and safety of KarXT in people with schizophrenia.
TIME Magazine article – FDA approves first new schizophrenia drug in decades (Open access)
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