A new drug designed to treat acute psychosis in schizophrenic patients is reporting impressively positive results from a Phase 2 clinical trial. After several decades of challenging development, the drug is hoped to be one of the most novel schizophrenia treatments to reach the market in years.
Called KarXT, the new drug is an oral coformulation of two compounds – xanomeline and trospium. Both drugs are relatively new compounds designed to interact with muscarinic receptors across the body. The research originally emerged in the 1990s but early studies testing xanomeline revealed the adverse side effects were intolerable.
Xanomeline, a muscarinic receptor agonist, was found to be very effective at treating psychosis associated with schizophrenia, but the extreme peripheral gastrointestinal side effects of the drug put a hold on clinical investigations. The newer KarXT formulation blends an already approved drug called trospium with xanomeline.
Trospium is a muscarinic receptor antagonist, but it notably does not cross the blood-brain barrier. So the idea behind this new formulation is that trospium should help counteract the broader physiological side effects of xanomeline, without disrupting the primary drug's efficacy in the brain.
So far, KarXT’s trial results have been quite impressive. The Phase 2 randomized, placebo-controlled trial encompassed 182 schizophrenic patients experiencing acute psychosis. Efficacy in the trial was calculated using a scale called the Positive and Negative Syndrome Scale (PANSS).
Generally, a reduction on the PANSS scale of between five and ten points would be considered clinically meaningful. In the past, antipsychotic drugs have been approved with as little as a five point reduction on the scale. The Phase 2 results for KarXT report the drug delivering an 11.6 point mean reduction on PANSS scores compared to placebo.
Adverse side effects were still reported in the trial, however, overall dropout rates between active and placebo groups were similar. And, 91 percent of the KarXT group effectively escalated to the highest dose.
“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,” says Jeffrey Lieberman, from Columbia University and a member of Karuna Therapeutics’ scientific advisory board.
KarXT is currently being trailed for a number of uses, with acute psychosis in schizophrenia being the most advanced outcome to date. Phase 1 human trials are underway testing the drug for other symptoms of schizophrenia, as well as trials testing efficacy for Alzheimer’s related psychosis.
There is still plenty of work ahead for the research team before the drug can reach the market. Larger Phase 3 trials will inevitably take several years to complete, and there is not guarantee these early results will hold in larger cohorts. Still, the initial Phase 2 results are excitingly positive and if the trials continue to be successful the new drug could reach the market in as little as five years.
“We are extremely pleased with these results, as the 11.6-point PANSS score separation from placebo far exceeded the five-point minimum improvement that has historically supported approval of current antipsychotics,” say Karuna’s chief medical officer Stephen Brannan. “With this information, and following our anticipated end-of-Phase 2 meeting with the FDA in the second quarter of 2020, we will work to initiate a Phase 3 clinical trial of KarXT in patients with schizophrenia by the end of 2020. We also plan to further analyze these results to better understand the potential of KarXT in patients with schizophrenia experiencing negative and cognitive symptoms, and to explore other CNS disorders that could benefit from this approach, such as psychosis in Alzheimer’s disease as well as the management of pain.”
The Phase 2 trial results for KarXT have yet to be published in a scientific journal.
Source: Karuna Therapeutics