'Landmark' Schizophrenia Drug in the Wings? 

Pauline Anderson

March 02, 2021

A novel therapy that combines a muscarinic receptor agonist with an anticholinergic agent is associated with a greater reduction in psychosis symptoms compared with placebo, new research shows.

In a randomized phase 2 trial comprised of nearly 200 participants, xanomeline-trospium (KarXT) was generally well tolerated and had none of the common side effects linked to current antipsychotics, including weight gain and extrapyramidal symptoms such as dystonia, parkinsonism, and tardive dyskinesia.

"The results showing robust therapeutic efficacy of a nondopamine targeting antipsychotic drug is an important milestone in the advance of the therapeutics of schizophrenia and other psychotic disorders," co-investigator Jeffrey A. Lieberman, MD, professor and chairman in the Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York City, told Medscape Medical News.

If approved, the new agent will be a "landmark" drug, Lieberman added.

The study was published in the February 25 issue of the New England Journal of Medicine.

Long Journey

The journey to develop an effective schizophrenia drug that reduces psychosis symptoms without onerous side effects has been a long one full of  of excitement and disappointment.

First-generation antipsychotics, dating back to the 1950s, targeted the postsynaptic dopamine 2 (D2) receptor. At the time, it was a "breakthrough" similar in scope to insulin for diabetes or antibiotics for infections, said Lieberman.

That was followed by development of numerous "me too" drugs with the same mechanism of action. However, these drugs had significant side effects, especially neurologic adverse events such as parkinsonism.

In 1989, second-generation antipsychotics were introduced, beginning with clozapine. They still targeted the D2 receptor but were "kinder and gentler," Lieberman noted. "They didn't bind to [the receptor] with such affinity that it shut things down completely, so had fewer neurologic side effects."

However, these agents had other adverse consequences, such as weight gain and other metabolic effects including hyperglycemia and hyperlipidemia.

Today, about 20% to 33% of patients with schizophrenia still do not respond to conventional treatments. Many have poor functional status and quality of life despite lifelong treatment with current antipsychotic agents.

"The pharmaceutical industry, biotech industry, and academic psychiatric community have been desperately trying to find novel strategies for antipsychotic drug development and asking, 'Is D2 the only Holy Grail or are there other ways of treating psychotic symptoms of schizophrenia?' " Lieberman said.

Enter KarXT— a novel combination of xanomeline with trospium.

An "Ingenious" Combination

Xanomeline, an oral muscarinic cholinergic receptor agonist, does not have direct effects on the dopamine receptor. Evidence suggests the muscarinic cholinergic system is involved in the pathophysiology of schizophrenia.

However, there may be dose-dependent adverse events with the medication, such as nausea, vomiting, diarrhea, sweating, and hypersalivation from stimulation of peripheral muscarinic cholinergic receptors.

That's where trospium chloride, an oral pan-muscarinic receptor antagonist approved for treating overactive bladder, comes in. It does not reach detectable levels in the cerebrospinal fluid and should avoid adverse central nervous system effects.

Lieberman said the idea of the drug combination is "ingenious."

The new phase 2 multisite study included adult patients with a validated diagnosis of schizophrenia who were hospitalized with an acute exacerbation of psychosis, and who were free of antipsychotic medication for at least 2 weeks.

Participants were required to have a baseline Positive and Negative Syndrome Scale (PANSS) total score of 80 points or more.

In addition to seven positive symptom items, including delusions, hallucinations, and conceptual disorganization, the PANSS has seven negative symptom items. These include restricted emotional expression, paucity of speech, and diminished interest, social drive, and activity. Each item is scored from 1 to 7, with higher scores indicating more severe symptoms.

Patients also had to have a score on the Clinical Global Impression-Severity (CGI-S) scale of 4 or higher. Scores on the CGI-S range from 1 to 7, with higher scores indicating greater severity of illness.

The modified intention-to-treat analysis included patients randomly assigned to receive oral xanomeline-trospium (n = 83) or placebo (n = 87).

The dosing schedule was flexible, starting with 50 mg of xanomeline and 20 mg of trospium twice daily. The schedule increased to a maximum of 125 mg of xanomeline and 30 mg of trospium twice daily, with the option of lowering the dose if there were unacceptable side effects.

Mean scores at baseline for the treatment and placebo groups were 97.7 vs 96.6 for the PANSS total score, 26.4 vs 26.3 for the positive subscore, 22.6 vs 22.8 for the negative subscore, and 5.0 vs 4.9 in the CGI-S scale.

"Impressively Robust" Effect Size

The primary endpoint was change in the PANSS total score at 5 weeks. Results showed a change of -17.4 points in the treatment group and -5.9 points in the placebo group (least-squares mean difference, -11.6 points; 95% CI, -16.1 to -7.1; P < .001).

The effect size, which was almost 0.8 (0.75), was "impressively robust," said Lieberman, adding that a moderate effect size in this patient population might be in the order of 0.4 or 0.5.

"That gives hope that this drug may not just be as effective as other antipsychotics, albeit acting in a novel way and in a way that has a less of side effect burden, but that it may actually have some elements of superior efficacy," he said.

There were significant benefits on some secondary outcomes, including change in the PANSS positive symptom subscore (-5.6 points in the treatment group vs -2.4 points in the placebo group; least-squares mean difference, -3.2 points; 95% CI, -4.8 to -1.7; P <  .001).

The active treatment also came out on top for CGI-S scores (P < .001), and PANSS negative symptom subscore (P < .001).

Because participants were hospitalized with an acute exacerbation of positive symptoms at time of study, it is difficult to determine "definitive efficacy" for negative symptoms, Lieberman noted. Negative symptoms may have improved simply because positive symptoms got better, he said.

Although the study included adults only, "there is nothing in the KarXT clinical profile that suggests it would be problematic for younger people," Lieberman noted. This could include teenagers with first-episode psychosis, he added.

Safety Profile

Adverse events were reported in 54% of the treatment group and 43% of the placebo group. AEs that were more common in the active treatment group included constipation (17% vs 3%), nausea (17% vs 4%), dry mouth (9% vs 1%), dyspepsia (9% vs 4%), and vomiting (9% vs 4%). All AEs were rated as mild or moderate in severity and none resulted in discontinuation of treatment.

Rates of nausea, vomiting, and dry mouth were highest early in the trial and lower at the end, whereas constipation remained constant throughout the study.

Persistent constipation could affect the drug's "utility" in elderly patients with cognitive issues but may be more of a "minor nuisance" compared with other antipsychotics for those with schizophrenia, said Lieberman. He added that constipation might be mitigated with an over-the-counter treatment such as Metamucil. Importantly, there was no difference between groups in extrapyramidal symptoms.

In addition, participants receiving the active treatment did not have greater weight gain, which was about 3% vs 4% in the placebo group. The mean change in weight was 1.5 kg (3.3 lb) and 1.1 kg (2.4 lb), respectively.

Lieberman praised the manufacturer for undertaking the study.

"In an era when Big Pharma has retreated to a considerable degree from psychotropic drug development, it's commendable that some companies have stayed the course and are succeeding in drug development," he said.

Exciting Mechanism

Commenting on the findings for Medscape Medical News, Thomas Sedlak, MD, PhD, director of the Schizophrenia and Psychosis Consult Clinic and assistant professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine, Baltimore, Maryland, called some aspects of the study "exciting."

What's especially important is that the novel agent "acts by a different mechanism than what we have been using for maybe 60 years," said Sedlak, who was not involved with the research.

"There has been a lot of research in the last few decades into drugs that might act by alternate mechanisms of action, but nothing's really gotten to market for schizophrenia," he noted.

Another interesting aspect of the study is that it examined a combination drug that aims to maximize effects on the brain while minimizing periphery effects, Sedlak said.

In addition, he called the PANSS results "respectable."

"It's interesting that you get a big change in PANSS total score, but it's not as big in the positive symptom score as you might have expected; and it's not a huge drop in negative symptoms either," said Sedlak.

It's possible, he said, that the drug is targeting PANSS elements not captured in the main positive or negative symptom items; for example, anxiety, depression, guilt, attention, impulse control, disorientation, and judgment.

Sedlak noted that while the new results are exciting, the enthusiasm may not be long-lasting. "When a new drug comes out, there's often a lot of excitement about it, but once you start using it, expectations may deflate," he said.

"More flexible ratios" of the two components of the drug might be useful to treat individual patients, he added.

In addition, using the components by themselves might be preferable for some clinicians.

"I think a lot of physicians prefer using two separate drugs so they can alter the dose of each one independently and not be stuck with the ratio the manufacturer is providing," Sedlak said.

However, he acknowledged that studying different choices of ratios would require much larger trials.

The study was supported by Karuna Therapeutics and the Wellcome Trust. Lieberman reports having served on an advisory board for Karuna Therapeutics and Intra-Cellular Therapies. Sedlak has disclosed no relevant financial relationships.

N Engl J Med. Published online February 25, 2021. Full text

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