How-To Guides

In this 5-week phase 2 inpatient study, KarXT was associated with greater improvement than placebo in acute psychosis in adults with schizophrenia. The primary result reported for the parent trial was a change in PANSS total score from baseline to week 5 of −17.4 points with KarXT versus −5.9 points with placebo (95% CI for the between-group difference, −16.1 to −7.1; P<.001). In this post hoc analysis, KarXT also showed higher categorical PANSS response rates than placebo across all 4 thresholds evaluated, with nominal P<.05 for each response criterion.

At week 5, response rates with KarXT ranged from 59.0% (n=49) at the ≥20% PANSS improvement threshold to 15.7% (n=13) at the ≥50% threshold. The proportion of KarXT-treated patients was higher than the proportion of placebo-treated patients at all 4 thresholds evaluated: ≥20%, ≥30%, ≥40%, and ≥50% improvement in PANSS total score. The article does not report the exact placebo percentages in the text, but it states that all between-group comparisons were nominally significant at P<.05.

The week 5 number needed to treat depended on the PANSS response threshold used. The reported NNTs (95% CI) were 3 (3–5) for ≥20% improvement, 4 (3–7) for ≥30% improvement, 7 (4–20) for ≥40% improvement, and 11 (6–145) for ≥50% improvement in PANSS total score. Lower NNTs indicate a larger treatment impact relative to placebo.

KarXT separated from placebo by week 2 for the lower PANSS response thresholds and by week 4 for the higher thresholds. Specifically, the ≥20% and ≥30% PANSS response criteria showed significant differences favoring KarXT by week 2, whereas the ≥40% and ≥50% thresholds did not reach P<.05 until week 4.

Yes. In the PANSS 5-factor Marder analysis, KarXT improved all 5 symptom domains versus placebo by week 5. These domains were positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility, and anxiety/depression, and the reported effect sizes at week 5 ranged from 0.48 to 0.66.

Between-group differences on all 5 PANSS Marder factors were significant starting at week 2. That means the first postbaseline assessment already showed statistically significant improvement with KarXT versus placebo across positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility, and anxiety/depression.

This was a post hoc analysis of EMERGENT-1, a phase 2, randomized, double-blind, placebo-controlled trial in acutely psychotic adults with schizophrenia. After a 7-day screening period, participants were randomized 1:1 to oral KarXT or matched placebo twice daily for 5 weeks of inpatient treatment. The modified intent-to-treat population included 83 patients in the KarXT group and 87 in the placebo group.

The trial enrolled adults aged 18–60 years with a primary DSM-5 diagnosis of schizophrenia and recent worsening of positive symptoms that warranted hospitalization. Key entry criteria included a PANSS total score greater than 80 and a CGI-S score of 4 or higher at baseline. Patients with a primary disorder other than schizophrenia in the prior 12 months, a history of treatment resistance to antipsychotics, or a ≥20% decrease in PANSS total score between screening and baseline were excluded.

KarXT differs from currently marketed antipsychotics because it is based on muscarinic receptor agonism rather than direct dopamine D2-receptor blockade. It combines xanomeline, an M1/M4-preferring muscarinic receptor agonist, with trospium, a peripheral muscarinic receptor antagonist that does not cross the blood-brain barrier. According to the article, trospium was included to reduce xanomeline's unwanted peripheral muscarinic effects while preserving central nervous system activity.

The article states that the adverse event profile was consistent with the expected effects of its components: procholinergic effects associated with muscarinic agonism and peripheral anticholinergic effects associated with trospium. Examples included nausea, vomiting, and diarrhea for procholinergic effects and constipation and dry mouth for peripheral anticholinergic effects. All procholinergic and anticholinergic adverse events were rated as mild or moderate, and none led to early discontinuation in the phase 2 trial.

No. The authors state that these findings are preliminary and based on a single 5-week, placebo-controlled phase 2 study, so they require replication. The trial had no active comparator, KarXT has not been studied head-to-head against other antipsychotics, and the 5-week duration limits conclusions about longer-term response or durability.