Will ‘Game-Changer’ Antipsychotic Live Up to the Hype?

The US Food and Drug Administration (FDA) is due to issue a decision by September 26 on the approval of KarXT, a potential first-in-class antipsychotic. If approved, it would be the first drug with a novel mechanism to treat schizophrenia in decades.

Developed by Karuna Therapeutics, now part of Bristol Myers Squibb, KarXT has been called a potential “game-changer” for treatment of schizophrenia, based on “impressive” results of phase 3 testing.

But what makes KarXT novel? How does it differ from traditional antipsychotics? What do the data show? And will it live up to the hype?

How Did We Get Here?

The road to develop an effective drug for schizophrenia that reduces psychosis symptoms without onerous side effects has been a long one.

First-generation antipsychotics, dating back to the 1950s, targeted the postsynaptic dopamine 2 (D2) receptor. Chlorpromazine, the first of that class, was approved by the FDA in 1954. That was followed by the development of numerous drugs with the same mechanism of action. However, the medications had significant side effects, especially neurologic ones such as parkinsonism.

In 1989, second-generation antipsychotics were introduced, beginning with clozapine. They still targeted the D2 receptor, but they had fewer neurologic side effects. However, these agents had other unwanted effects, such as increased risk for infection, weight gain, and other metabolic effects including elevated blood sugar and lipid levels. This often leads to high rates of switching medications and poor adherence to treatment.

“To date, all antipsychotic medicines approved to treat schizophrenia have shared the same fundamental mechanism of action, which targets dopaminergic and serotonergic receptors in the brain,” Ken Kramer, PhD, vice president and head of worldwide medical affairs, neuropsychiatry at Bristol Myers Squibb, told Medscape Medical News.

With the current medications, “nearly 60% of patients experience a partial response to therapy or experience burdensome side effects that can lead to discontinuation of therapy. Approximately 75% of patients discontinue treatment within the first 18 months, with many failing to find an effective and/or tolerable therapy,” Kramer said.

How Is KarXT Different?

KarXT is a coformulation of xanomeline — an oral muscarinic cholinergic receptor agonist — and trospium chloride — an oral pan-muscarinic receptor antagonist. Evidence suggests 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 the areas of the brain associated with the symptoms of schizophrenia,” Kramer said.

“This activity occurs without any dopamine receptor blockade, which makes this approach distinct from the current standard of care, which rely on targeting dopamine and/or serotonin receptors,” he added.

For individuals living with schizophrenia, it can be tough to manage both the symptoms of the illness and potential unwanted side effects of treatment.

“There remains an unmet need for novel, mechanistically unique treatments that have a clinical efficacy and safety profile to help improve patient outcomes in those living with schizophrenia,” Kramer noted.

Does It Work?

The safety and efficacy of KarXT were assessed in the phase 3 EMERGENT-2 and EMERGENT-3 trials — both studies met their primary endpoints.

EMERGENT-2 enrolled 252 adults with schizophrenia who recently experienced a worsening of psychotic symptoms warranting hospitalization. All were randomly assigned in a 1:1 ratio to receive either xanomeline-trospium or placebo following a 2-week screening period.

Xanomeline and trospium were titrated from 50 mg/20 mg twice daily to 125 mg/30 mg twice daily, and patients were treated for a total of 5 weeks. Efficacy and safety analyses were conducted in those who had received at least one dose of the study drug.

As reported by Medscape Medical News, at the end of the treatment period, KarXT was associated with a significant 9.6-point reduction in Positive and Negative Syndrome Scale (PANSS) total scores relative to placebo. PANSS total scores fell by 21.2 points with KarXT vs 11.6 points with placebo (P < .0001; Cohen's d effect size, 0.61).

All secondary endpoints were also met, with active treatment demonstrating statistically significant reductions compared with placebo at week 5 (P < .05).

Secondary endpoints included change in PANSS positive subscale, PANSS negative subscale, PANSS Marder negative factor, Clinical Global Impression-Severity score, and percentage of participants achieving at least a 30% reduction from baseline to week 5 in PANSS total score.

The most common side effect was constipation (21%). Other side effects included dyspepsia (19%), nausea (19%), vomiting (14%), headache (14%), hypertension (10%), dizziness (9%), and gastroesophageal reflux disease (6%).

“What’s really exciting” is that the drug did not cause weight gain or extrapyramidal symptoms compared with placebo, Ann Shinn, MD, MPH, director of Clinical Research, Schizophrenia and Bipolar Disorder Research Program, McLean Hospital, Belmont, Massachusetts, and assistant professor of psychiatry, Harvard Medical School, Boston, told Medscape Medical News when the data were released. Results of the EMERGENT-3 trial confirmed the findings from the earlier trial.

“Both from an efficacy and side-effect perspective, I think more patients with schizophrenia are going to be willing to take medication,” Shinn said.

Caveats and Cautionary Notes

Xiaoduo Fan, MD, MPH, professor of psychiatry, UMass Chan Medical School, Worcester, Massachusetts, and director of UMass MIND, told Medscape Medical News thatKarXT holds “great promise to be the first in a new class of antipsychotic drugs targeting muscarinic receptors, which shift away from the currently available ‘D2, me too’ antipsychotics that primarily act on dopaminergic receptors.”

Fan said it’s important to note that both EMERGENT-2 and EMERGENT-3 were short-term (5-week) trials in inpatients with acute psychosis, and in both trials, participants were predominantly male and African American.

“The long-term efficacy and side effects of KarXT in more clinically stable outpatients or in the real-world schizophrenia patient population are unclear,” Fan said.

“In addition, these short-term trials seem to suggest that KarXT is more helpful for positive symptoms; clinically meaningful benefits of KarXT for negative symptoms and cognitive impairments, which are two other major unmet needs in schizophrenia treatment, are unclear,” Fan cautioned.

He noted that the two 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, which have not been published yet, will provide additional information on the longer-term efficacy and safety of KarXT.

“However, these trials do not include a control group. Studies with active control groups are needed to allow direct comparison of KarXT with other antipsychotics,” Fan said.

He is involved in an ongoing ARISE trial looking at KarXT as adjunctive treatment in schizophrenia patients with insufficient clinical response to currently available antipsychotics.

“Until more data become available, it remains to be seen whether KarXT will be a game-changer,” Fan said.

KarXT’s manufacturer is not sharing details around pricing at this time, Kramer said, adding “we have done significant work around pricing and contracting and look forward to working with payers to make KarXT available quickly for all appropriate patients.”

If approved, KarXT will be available in late October.

Kramer is an employee of Bristol Myers Squibb. Fan has received research support from Alkermes, Eli Lilly, Janssen, Otsuka Pharmaceutical Co., Ltd., Roche, Lundbeck, Boehringer Ingelheim, Neurocrine Biosciences, Intra-Cellular Therapies, Teva, and Bristol Myers Squibb; and serves on the BMJ Best Practice’s US Advisory Panel and as the contributor for the BMJ Best Practice — Schizophrenia Topic. Shinn had no relevant disclosures.