Karuna Therapeutics, a biopharmaceutical company dedicated to uncovering, advancing and providing groundbreaking medicines for individuals facing psychiatric and neurological conditions, has recently disclosed encouraging outcomes from the Phase III EMERGENT-2 trial of KarXT (xanomeline-trospium) in adults diagnosed with schizophrenia.
“New treatments and novel mechanisms are urgently needed for people with schizophrenia because many don’t respond to their therapy and others only have a partial improvement in symptoms or intolerable side effects,” said Rishi Kakar, MD, chief scientific officer and medical director of Segal Trials and lead investigator of the Phase III EMERGENT-2 trial, in the company’s press release.
If approved, KarXT would represent the first major innovative pharmacological approach in decades for treating schizophrenia.
Schizophrenia is a complex mental disorder characterized by disrupted thought processes, perception, emotional responsiveness and social behavior. Its course varies among individuals but often is chronic and significantly debilitating. The disorder stems from a combination of chemical imbalances and other changes in the brain, with a tendency to run in families and environmental factors contributing as well.
Active phases of schizophrenia can include symptoms such as delusions, hallucinations, incoherent speech, cognitive difficulties and diminished motivation. However, with appropriate treatment, most symptoms can improve substantially, and the likelihood of recurrence can be minimized.
Schizophrenia impacts nearly 24 million people globally, with approximately 2.8 million individuals affected in the US.
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How Does KarXT Work?
KarXT is an investigational muscarinic antipsychotic in development for treating schizophrenia and Alzheimer’s-related psychosis. It stands out for its novel approach, acting as a dual M1/M4 muscarinic acetylcholine receptor agonist in the central nervous system. This mechanism is designed to improve the positive, negative and cognitive symptoms associated with schizophrenia.
Unlike traditional therapies that typically target dopamine receptors, KarXT takes a unique path by not directly antagonizing these receptors, offering a potentially groundbreaking alternative for managing schizophrenia.
Published in The Lancet, data from the randomized, double-blind, placebo-controlled Phase III EMERGENT-2 trial highlights the effectiveness and tolerability of KarXT in individuals with schizophrenia. The trial revealed a statistically significant and clinically meaningful reduction of 9.6 points in the Positive and Negative Syndrome Scale (PANSS) total score for KarXT compared to placebo (-21.2 for KarXT vs. -11.6 for placebo, p<0.0001) at Week 5. Across all pre-specified secondary outcome measures, including changes in PANSS positive subscale, PANSS negative subscale, PANSS Marder negative factor, Clinical Global Impression-Severity score and the percentage of participants achieving a ≥30 percent reduction from baseline to Week 5 in PANSS total score, KarXT demonstrated statistically significant reductions compared to placebo at Week 5 (p<0.05) for each endpoint.
The clinical study further underscored the favorable tolerability profile of KarXT. The most common adverse events were constipation, dyspepsia, nausea, vomiting, hypertension, dizziness, gastro-oesophageal reflux disease and diarrhea.
“The antipsychotic activity and differentiated safety and tolerability profile demonstrated in EMERGENT-2, and the other completed EMERGENT trials, provide hope to the healthcare community and patients that KarXT may provide a much-needed new way to treat those living with schizophrenia,” added Dr. Kakar.
Data from KarXT demonstrates a clinically meaningful and statistically significant reduction in positive and negative symptoms of schizophrenia in adult patients undergoing acute psychosis, coupled with a distinctive tolerability profile. The New Drug Application (NDA) for KarXT in the treatment of schizophrenia in adults has recently been accepted, with a Prescription Drug User Fee Act (PDUFA) action date set for September 26, 2024.
New Treatments for Schizophrenia
In 2023, Teva Pharmaceuticals and MedinCell announced the US Food and Drug Administration (FDA) approval of Uzedy (risperidone) extended-release injectable suspension for treating schizophrenia in adults. Uzedy’s therapeutic impact on schizophrenia may involve a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism. Administered through injections every one or two months, Uzedy represents a long-acting schizophrenia treatment that eliminates the need for daily pills.
This year, Otsuka America Pharmaceutical, Inc., and Lundbeck have also revealed FDA approval for Abilify Asimtufii (aripiprazole) for intramuscular use — a once-every-two-months injection designed for the treatment of schizophrenia in adults. The efficacy of aripiprazole may stem from a combination of partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors, along with antagonist activity at 5-HT2A receptors. Clinical data indicates that 90 percent of individuals treated with Abilify Asimtufii experienced significantly longer relapse-free periods compared to those on placebo.
More Notable Candidates Are on the Way
In November 2023, Neumora Therapeutics, Inc., a pioneering clinical-stage biopharmaceutical company dedicated to redefining neuroscience drug development, announced the start of a Phase I study to assess its innovative candidate, NMRA-266, in a cohort of healthy adult participants. NMRA-266, a highly selective positive allosteric modulator of the M4 muscarinic receptor, represents Neumora’s promising venture in addressing schizophrenia and other neuropsychiatric disorders. The unique pharmacological profile of NMRA-266, functioning as a selective M4 receptor-positive allosteric modulator, suggests its potential to deliver antipsychotic efficacy while minimizing the adverse effects commonly associated with existing antipsychotics and non-selective muscarinic agonists.
Simultaneously, BioXcel Therapeutics, Inc., a biopharmaceutical company employing AI methodologies to revolutionize drug development in neuroscience and immuno-oncology, announced its alignment with the FDA’s recommendation for a Phase III study. This study aims to evaluate the feasibility of at-home use of BXCL501, an investigational therapeutic, for managing agitation associated with bipolar disorders or schizophrenia.