15 October 2018 - - US-based drug development company Karuna Pharmaceuticals, Inc, which is focused on targeting muscarinic cholinergic receptors for the treatment of neuropsychiatric disorders marked by psychosis and cognitive impairment, has initiated a Phase 2 study evaluating the efficacy and safety of its lead product candidate, KarXT (Karuna-Xanomeline-Trospium), for the treatment of psychosis in schizophrenia, the company said.

The study will use a co-formulation of KarXT, which was well-tolerated at dose levels exceeding those shown to be efficacious in previous xanomeline studies.

Top-line data results from the Phase 2 study are expected at the end of 2019.

Karuna's KarXT was evaluated in a Phase 1 dose-ranging study that enrolled 70 healthy volunteers and successfully demonstrated tolerability at dose levels exceeding those shown to be efficacious in previous studies of xanomeline alone.

The co-formulation also achieved exposure levels equivalent to or higher than the separate dosage forms used previously, and the results supported dose selection to be carried forward into Phase 2.

There were no severe or serious adverse events reported in the co-formulation study.

Side effects associated with KarXT were mild-to-moderate and transient in nature, often only lasting a few hours, and they were consistent with the previous KarXT study that used separate dosage forms for xanomeline and trospium.

The Phase 2 study is a double-blind, placebo-controlled study designed to evaluate the efficacy and safety of KarXT in approximately 160 patients with schizophrenia.

The primary endpoint is total change from baseline Positive and Negative Syndrome Scale (PANSS) score compared to placebo.

Additional endpoints will assess cognitive and negative symptoms in addition to general symptomology.

The study employs a flexible dose design where patients are randomized in a 1: 1 ratio to receive either KarXT or placebo for five weeks.

Patients assigned to the KarXT arm will be treated with 100/20 mg xanomeline/trospium with the option to increase the dose to 125 mg/30mg xanomeline/trospium after the first week of the study.

Schizophrenia affects more than 20 m people worldwide and is characterized by profound disruptions to daily life.

Symptoms are grouped within three domains: positive, negative, and cognitive. Positive symptoms are generally associated with psychotic behaviours, including hallucinations and delusions.

Negative symptoms refer to disruptions in behavior and emotions and can manifest as reduced social engagement and motivation.

Cognitive symptoms are marked by changes in memory and attention. The prognosis for schizophrenia remains poor as only 30% of patients live independently and only 10 to 20% maintain full-time employment.

There is a desperate need for new treatments in schizophrenia that not only address positive, negative, and cognitive symptoms of the disease, but are also safer than existing medicines.

KarXT (Karuna-Xanomeline-Trospium) is Karuna's lead investigational product candidate for the treatment of psychosis in schizophrenia.

It consists of xanomeline, a novel muscarinic acetylcholine receptor agonist that has demonstrated efficacy in placebo-controlled human trials in schizophrenia and Alzheimer's disease, and trospium chloride, an FDA-approved and well-established muscarinic receptor antagonist that has been shown not to enter the central nervous system.

KarXT is designed to selectively target M1/M4 muscarinic receptors in the brain while blocking their activation in peripheral tissues to significantly improve tolerability.

Results from a Phase 1 study demonstrating the improved tolerability of KarXT vs. xanomeline alone were announced in 2016, and a more recent Phase 1 study completed in 2018 supported the development of a co-formulation of KarXT that is now being evaluated in a Phase 2 study.

Karuna is a clinical-stage drug development company targeting muscarinic cholinergic receptors for the treatment of psychosis and cognitive impairment across central nervous system disorders, including schizophrenia and Alzheimer's disease, as well as pain.

The company's lead product candidate, KarXT (Karuna-Xanomeline-Trospium), is being evaluated in a Phase 2 study in people with schizophrenia, with top-line results anticipated at the end of 2019. 

Karuna, which was founded by PureTech Health (LSE: PRTC), has a worldwide exclusive license for xanomeline and has an intellectual property portfolio more broadly covering selective muscarinic targeting enabled by the KarXT approach.