Karuna’s Phase III data could lead to new class of drug for schizophrenia

Published: Aug 08, 2022

By Tristan Manalac

BioSpace

On Monday, Boston biopharma Karuna Therapeutics released results from the Phase III EMERGENT-2 trial showing that KarXT (xanomeline-trospium), its lead candidate, can strongly reduce symptom severity in schizophrenia patients.

EMERGENT-2 is a randomized and double-blinded trial that compared KarXT, given at flexible dosing regimens, against placebo. The trial lasted for five weeks and enrolled more than 250 adults with schizophrenia who were also experiencing psychosis symptoms. Both active and placebo arms were given twice-daily treatments and the trial was held in an inpatient setting.

In a conference call this morning, Karuna representatives said that KarXT was able to meet EMERGENT-2’s primary endpoint, which was a significant decrease in symptom severity as measured by the Positive and Negative Symptom Scale (PANSS). In particular, patients receiving Karuna’s candidate improved by nearly 10 PANSS points more than placebo comparators, an effect that was both statistically and clinically meaningful.

Afflicting more than 20 million people across the globe, schizophrenia is a psychological condition that compromises how a person perceives reality. It typically first arises during the late teenage years or in early adulthood and is one of the leading causes of disability worldwide. People with schizophrenia experience two broad classes of symptoms: positive symptoms, such as hallucinations or delusions, and negative symptoms, including withdrawal, strongly suppressed emotions, or limited speech.

All approved treatments for schizophrenia fall under a class of drugs called antipsychotics. While generally effective, these drugs trigger a host of side effects like excessive sleepiness and weight gain, which lead to high levels of discontinuation. Antipsychotics can currently only address positive symptoms of schizophrenia, and there are no treatments for the condition’s negative symptoms.

KarXT sets itself apart from existing schizophrenia treatments in the market by acting along a different pathway. Whereas antipsychotics typically target D2 dopamine and 5HT-52A serotonin receptors, KarXT is a muscarinic receptor agonist that strongly prefers the M1 and M4 receptors. The candidate is comprised of xanomeline, a muscarinic agonist, and trospium, a muscarinic antagonist—this combination maximizes KarXT’s therapeutic potential while minimizing its side effects.

This unique mechanism of action has given KarXT a unique efficacy and safety profile. Looking at key secondary efficacy indicators, Karuna found that its candidate elicited improvements not only in terms of positive symptoms but also in negative symptoms.

Treatment was also generally well-tolerated and adverse events were mostly in line with what had been reported in previous KarXT trials. Importantly, treatment did not lead to the common side effects of antipsychotics.

“The field has not seen true innovation in decades,” Steve Paul, M.D., chairman of the board, president and chief executive officer of Karina, said during the call. In this vein, the team finds the EMERGENT-2 findings very exciting, with potentially transformative ramifications for the field.  

“We are another step closer to potentially providing the first new class of medicine in more than 50 years to the millions of people worldwide living with schizophrenia,” Paul said in a statement.

Based on their candidate’s promising Phase III performance, Karuna is looking at filing a New Drug Application for Karuna by mid-2023. Company representatives during the call said that at the moment, the lack of long-term safety data is the only roadblock left for the NDA, and studies are already underway to address this.

Further ahead, the company is planning trials to test KarXT as a combo schizophrenia treatment with other approved drugs and to assess its potential in treating Alzheimer’s disease.

Source: BioSpace