The U.S. Food and Drug Administration (FDA) is expected to make a decision by September 26 on approval of KarXT, a potential first-of-its-kind antipsychotic drug that would be the first drug with a new mechanism of action to treat schizophrenia in decades.
KarXT, developed by Karuna Therapeutics, now part of Bristol-Myers Squibb, has been called a potential “game changer” in the treatment of schizophrenia based on “impressive” results from a Phase 3 trial.
But what makes KarXT novel? How is it different from traditional antipsychotics? What does the data show? And does it deliver the benefits we hope?
How did we get here?
The road to developing an effective drug for schizophrenia that relieves psychotic symptoms without bothersome side effects has been a long one.
Dating back to the 1950s, the first generation of antipsychotics targeted postsynaptic dopamine 2 (D2) receptors. The first drug in this class, chlorpromazine, was approved by the FDA in 1954. Since then, numerous drugs with the same mechanism of action have been developed. However, these drugs have been associated with significant neurological side effects, especially parkinsonism.
In 1989, second-generation antipsychotics were introduced, starting with clozapine. These still targeted the D2 receptor but had fewer neurological side effects. However, these drugs had other undesirable side effects, such as increased risk of infections, weight gain, and metabolic effects such as elevated blood glucose and lipid levels. This often leads to high rates of drug switching and poor adherence to treatment.
“All antipsychotics approved to date for the treatment of schizophrenia share the same basic mechanism of action, which targets dopamine and serotonin receptors in the brain,” said Ken Kramer, M.D., vice president and worldwide medical head, Neuropsychiatry, Bristol-Myers Squibb. Medscape Medical News.
With current drug therapies, “approximately 60 percent of patients either have a partial response to treatment or experience troublesome side effects that lead to treatment discontinuation. Approximately 75 percent of patients discontinue treatment within the first 18 months, many of whom never find an effective and/or tolerable treatment,” Kramer said.
What is the difference with KarXT?
KarXT is a combination of the oral muscarinic cholinergic receptor agonist zanomeline and the oral pan-muscarinic receptor antagonist trospium chloride. Evidence suggests that the muscarinic cholinergic system is involved in the pathophysiology of schizophrenia.
“KarXT is a fundamentally new approach to treating schizophrenia that works by selectively activating M1 and M4 muscarinic receptors in areas of the brain associated with schizophrenia symptoms,” Kramer said.
“This effect occurs without blocking dopamine receptors, making this approach different from current standard therapies that target dopamine or serotonin receptors,” he added.
For people with schizophrenia, it can be difficult to manage both the symptoms of the illness and the unwanted side effects of treatment.
“There remains an unmet need for new mechanistically unique treatments with clinical efficacy and safety profiles to improve outcomes for patients with schizophrenia,” Kramer noted.
Does it work?
The safety and efficacy of KarXT was evaluated in the Phase 3 EMERGENT-2 and EMERGENT-3 trials, with both studies meeting their primary endpoints.
Emergent 2 The study enrolled 252 adults with schizophrenia whose psychotic symptoms had recently worsened enough to require hospitalization. After a two-week screening period, all were randomly assigned 1:1 to receive either xanomeline trospium or a placebo.
Xanomeline and trospium were titrated from 50 mg/20 mg twice daily to 125 mg/30 mg twice daily for a total of 5 weeks. Efficacy and safety analyses were performed in patients who received at least one dose of study drug.
Reports say Medscape Medical NewsAt the end of the treatment period, KarXT was associated with a significant reduction in the Positive and Negative Symptom Scale (PANSS) total score of 9.6 points compared with placebo. The PANSS total score decreased by 21.2 points with KarXT compared with 11.6 points with placebo (P < .0001; Cohen's d effect size, 0.61).
All secondary endpoints were also met, with active treatment demonstrating a statistically significant reduction compared to placebo at week 5 (P < .05).
Secondary outcomes included change in PANSS positive subscale, PANSS negative subscale, PANSS Marder negative factor, Clinical Global Impression score, and the proportion of participants who achieved at least a 30% reduction in PANSS total score from baseline to week 5.
The most common side effect was constipation (21%). Other side effects included dyspepsia (19%), nausea (19%), vomiting (14%), headache (14%), high blood pressure (10%), dizziness (9%), and gastroesophageal reflux disease (6%).
“What’s really exciting” is that the drug didn’t cause weight gain or extrapyramidal symptoms compared with a placebo, said Ann Shin, MD, clinical research director of the Schizophrenia and Bipolar Disorder Research Program at McLean Hospital in Belmont, Massachusetts, and assistant professor of psychiatry at Harvard Medical School in Boston. Medscape Medical News When the data was released, the results of the EMERGENT-3 trial confirmed the results of the previous trial.
“I think a lot of people with schizophrenia would be willing to take the medication, both in terms of efficacy and side effects,” Singh said.
Notes and cautions
“These findings suggest that the effects of psychiatry are more prevalent in older adults than in older adults,” said Xiaoduo Fan, MD, professor of psychiatry at the University of Massachusetts Chan Medical College in Worcester, Massachusetts, and director of the Massachusetts Mind Center. Medscape Medical News thatKarXT “is very likely to be the first of a new class of antipsychotics that targets muscarinic receptors, moving away from currently available ‘D2, me too’ antipsychotics that act primarily on dopamine receptors.”
Fan said it’s important to note that both EMERGENT-2 and EMERGENT-3 were short-term (five-week) studies in hospitalized patients with acute psychiatric illness, and participants in both studies were primarily male and African-American.
“The long-term efficacy and side effects of KarXT in clinically stable outpatient and real-world schizophrenia patient populations are unknown,” Fan said.
“Furthermore, these short-term trials seem to suggest that KarXT is more effective against positive symptoms. The clinically meaningful benefits of KarXT against negative symptoms and cognitive impairment, the other two major unmet needs in schizophrenia treatment, remain unclear,” Fan cautioned.
He noted that two yet to be published 52-week, open-label trials, EMERGENT-4 and EMERGENT-5, will provide additional information about KarXT’s long-term efficacy and safety.
“However, these trials did not include a control group. Studies with active controls are needed to directly compare KarXT with other antipsychotics,” Fan said.
He is involved in the ongoing ARISE trial investigating KarXT as an adjunct treatment for patients with schizophrenia who have had an inadequate clinical response to currently available antipsychotics.
“Until we have more data, it remains to be seen whether KarXT will be a game-changer,” Fan said.
Kramer added that KarXT’s manufacturer has not provided any pricing details at this time, but “we are working hard on pricing and contracting and look forward to working with payers to make KarXT available quickly to all appropriate patients.”
If approved, KarXT is expected to be available in late October.
Kramer is an employee of Bristol Myers Squibb. Hwang has received research support from Alkermes, Eli Lilly, Janssen, Otsuka Pharmaceutical, Roche, Lundbeck, Boehringer Ingelheim, Neurocrine Biosciences, Intracellular Therapies, Teva, and Bristol Myers Squibb, and is a member of the US Advisory Board for BMJ Best Practices and a contributor to BMJ Best Practices – Schizophrenia Topics. Singh had no relevant disclosures.
