New drug could be "game changer" in treatment of schizophrenia

KarXT, a new investigational drug for the treatment of acute psychosis in schizophrenia patients, has met its primary endpoint in Phase 2 Clinical Trial, reports Karuna Therapeutics.

In the clinical trial, the drug demonstrated a statistically significant and clinically meaningful 11.6 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) score compared to placebo and also good overall tolerability.

"The results of the Phase 2 trial are impressive and encouraging because they indicate that KarXT, if approved, could represent a game-changing therapeutic advance in the treatment of patients with schizophrenia," said Jeffrey Lieberman, a member of Karuna's scientific advisory board, said in the company's press release.

"The effectiveness of antipsychotics has been limited by the frequent and serious side effects of first- and second-generation drugs which are difficult for many patients to tolerate, are potentially harmful, and lead to high rates of discontinuation and relapse. In addition to its novel mechanism of action, KarXT could be a new therapeutic option that has the potential to offer robust efficacy devoid of weight gain, metabolic effects, and extrapyramidal side effects," said Lieberman.

The Phase 2, randomized, double-blind, placebo-controlled, inpatient trial enrolled 182 patients aged 18 to 60 who were diagnosed with DSM-5 schizophrenia and were experiencing acute psychosis. Patients were washed-out of any antipsychotic medicines. They were then randomized in the ratio 1:1 to receive either KarXT or placebo for five weeks.

The primary outcome measure of the trial was the change from baseline on the total PANSS score on KarXT vs. placebo treatment at week five.

KarXT was dosed as xanomeline 50 mg/trospium 20 mg twice a day for two days and then increased to xanomeline 100 mg/trospium 20 mg starting on day three. Beginning on day eight, if KarXT was well tolerated, an option was given to escalate the dose of KarXT to xanomeline 125 mg/trospium 30 mg twice a day. If a patient escalated to the highest dose, the dose could be decreased back to xanomeline 100 mg/trospium 20 mg twice per day, based on tolerability, if needed. No dose changes were allowed during the last two weeks of the trial.

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Key findings of the trial include:

• KarXT demonstrated a statistically significant and clinically meaningful 11.6 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) score compared to placebo (p<0.0001) and


• The drug also demonstrated good overall tolerability.


• A statistically significant reduction in the secondary endpoints of PANSS-Positive and PANSS-Negative scores were also observed.


• KarXT was well tolerated in the Phase 2 trial, with similar discontinuation rates between KarXT (20%) and placebo (21%).


• The number of discontinuations due to treatment-emergent adverse events (AEs) were equal in the KarXT and placebo arms (N=2 in each group).


• The overall AE rate of patients on KarXT was 54% vs. 43% on placebo, with the most common AEs being constipation, nausea, dry mouth, dyspepsia, and vomiting. The tolerability of KarXT was also reflected in the trial's high rate of dose escalation.


• In the trial, 91% of KarXT treated patients escalated to the increased dose which was similar to the escalation rate with placebo.


• Occurrences of somnolence, weight gain, and extrapyramidal symptoms were also similar to placebo.


• One serious adverse event (SAE) was experienced in the drug treatment arm, in which the patient discontinued treatment and subsequently sought hospital care for worsening psychosis, meeting the regulatory definition of an SAE.

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The Phase 2 trial results for KarXT have yet to be published in a scientific journal.

"The schizophrenia treatment landscape has remained rather stagnant for decades with therapeutic options relying on discoveries dating back to the 1950s," said Steve Paul, chief executive officer, president, and chairman of Karuna. "KarXT and its novel muscarinic receptor mechanism of action represent the potential to become a true advancement in how schizophrenia is treated, allowing patients relief from their debilitating psychotic symptoms without experiencing some of the very troubling side effects associated with current treatments."

About Schizophrenia

Schizophrenia is a chronic and psychiatric disorder that affects the person's ability to think, feel and behave clearly. It is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. It is characterized by recurring episodes of psychosis requiring long-term treatment with antipsychotic drugs in most patients, it affects more than 21 million people worldwide. The treatment of choice is antipsychotic drugs, but there has been controversy on the selection of the right antipsychotic agent.

About KarXT

KarXT is an oral formulation of two compounds -- xanomeline (a novel muscarinic receptor agonist) and trospium (a muscarinic receptor antagonist) -- which is designed for the treatment of psychosis and related symptoms. It exhibits its action by preferential stimulation of muscarinic receptors in the central nervous system (CNS). This combination has the potential to be a new option for treating the difficult symptoms of debilitating CNS disorders, such as schizophrenia, without subjecting patients to the problematic side effects associated with the current antipsychotic standard of care therapies.