Pairing the in-licensed muscarinic acetylcholine receptor agonist xanomeline with the well-known muscarinic antagonist trospium chloride in the single drug called Karxt gave Karuna Therapeutics Inc. the required phase II efficacy against acute psychosis in schizophrenia, while keeping a quite satisfactory safety and side-effect profile.

The pioneering mechanism of action's success also gave Boston-based Karuna a whopping stock raise, letting shares close (NASDAQ:KRTX) up 443%, or $78.32, at $96. Karuna plans an end-of-phase II meeting in the second quarter of next year, and – if all goes well – a phase III study with the same fundamental design will start before the end of next year. Regulators will determine "whether we will need two phase IIIs in addition to what we believe is a very compelling phase II study," CEO Steve Paul said during a conference call with investors.

Karxt turned up 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 showed good overall tolerability. Researchers also found a statistically significant reduction in the secondary endpoints of PANSS-Positive and PANSS-Negative scores (p<0.001).

Therapy was well-tolerated, with similar discontinuation rates between drug (20%) and placebo (21%) arms. The number of quits due to treatment-emergent adverse events (AEs) was equal in the Karxt and placebo arms: two in each group. The idea with the treatment is to fight debilitating central nervous system (CNS) disorders such as schizophrenia without the odious problems that dog antipsychotic therapies typically used, such as weight gain, metabolic effects and extrapyramidal (motor) dysfunction. Placebo response was "about what we hoped for, really," Paul said.

Overall, the AE rate of patients on Karxt was 54% vs. 43% for placebo, with the most common being constipation, nausea, dry mouth, dyspepsia and vomiting. Karxt's tolerability was also reflected in the trial's high rate of dose escalation, Karuna noted. Ninety-one percent of Karxt-treated patients escalated to the increased dose, which was similar to the escalation rate with placebo. Cases of somnolence, weight gain and extrapyramidal effects also proved similar.

One serious AE (SAE) cropped up in the drug treatment arm. Chief Medical Officer Stephen Brannan said that "in these types of trials it's not uncommon to see folks leaving because they are not responding or have worsening symptoms," which also happened in the placebo arm. "This particular patient had been involved for a couple of weeks and decided to leave. The reason it became an SAE is because, shortly thereafter, they ended up being hospitalized," which made the case fit the FDA's definition of an SAE.

The magnitude of the improvement with Karxt stacks up nicely against the meta-analyses of published trials with approved antipsychotics, which reported an average difference of nine to 10 points in PANSS scores vs. placebo. Changes as small as five points have served as enough for FDA clearance in the past.

Synergy with other antipsychotics?

Muscarinic acetylcholine receptors came on the scene decades ago as an alternative target to dopamine receptor-based treatments for treating psychosis, but unwanted effects kept them on the back burner. Researchers theorized that such effects were caused by stimulating muscarinic receptors in peripheral tissues. This is why Karuna tried xanomeline, an agonist that preferentially stimulates M1 and M4 muscarinic receptors, alongside trospium, an approved muscarinic receptor antagonist that does not measurably cross the blood-brain barrier, confining its effects to peripheral tissues. (Approved in 2007 as Sanctura in the hands of Lexington, Mass.-based Indevus Pharmaceuticals Inc., trospium has since become available in generic form.) Thus was born Karxt, designed to activate muscarinic receptors in the CNS while avoiding the side effects associated with agitating those outside.

Xanomeline, for its part, was in-licensed from Eli Lilly and Co., of Indianapolis. Lilly conducted a small (20 patients) placebo-controlled, double-blind, randomized trial in schizophrenia, collaborating with the Indiana University School of Medicine. A much larger phase II experiment (343 patients) was done in Alzheimer's disease (AD). Karuna is investigating its combo in AD, too. "With respect to the read-through [from Karuna's schizophrenia study to AD], we are impressed with the safety profile here," Paul said, though the patients in the schizophrenia trial were younger. "We have every expectation of getting back to AD and the psychosis that occurs there in about 40 to 50 percent of advanced patients. There's really nothing to treat that." Karuna will conduct a phase Ib trial in healthy elderly subjects. "We will do it a little differently, in terms of dose titration," he said. "Now we have the trospium combination, so we're cautiously optimistic that the drug will be reasonably well-tolerated." (See BioWorld, Aug. 3, 2018.)

Paul said Karuna "wanted to first and foremost demonstrate that our drug worked well as a monotherapy," but Karxt might also work well as an augmentation to current antipsychotics, and researchers at the company "have preclinical data that suggest we'll see actually some synergy" with them. The lack of the usual side effects is a strong selling point, with "most likely no risk of tardive dyskinesia, [although] we're going to have to demonstrate that for sure," he said.

Another closely watched player in the space is San Diego-based Acadia Pharmaceuticals Inc., which in September said that its phase III trial testing Nuplazid (pimavanserin) in dementia-related psychosis met its primary endpoint, demonstrating a highly statistically significant longer time to relapse compared to placebo in a planned interim efficacy analysis. The study's independent data monitoring committee recommended the study stop early, based on halt criteria requiring a one-sided "p" value of less than 0.0033 on the study's primary endpoint. Fuller data from the experiment are due at the Clinical Trials on Alzheimer's Disease annual meeting early next month in San Diego. Nuplazid was approved by the FDA for Parkinson's disease psychosis in late April 2016. It's a selective serotonin inverse agonist and antagonist that preferentially targets the 5-HT2A receptor. (See BioWorld, Sept. 10, 2019.)

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