Long-Term Data Support Efficacy, Safety of New Schizophrenia Drug

Recently approved xanomeline and trospium chloride (Cobenfy) demonstrated long-term efficacy and safety in patients with schizophrenia, long-term results from the phase III EMERGENT-4 trial showed.

Participants who continued taking the drug after the initial 5-week treatment period of two prior trials had a durable improvement in their Positive and Negative Syndrome Scale (PANSS) total score, with a 33.8-point drop at the end of the 52-week open-label period.

Meanwhile, participants who switched to xanomeline and trospium chloride after receiving placebo during the prior trials also had a significant improvement in PANSS total score, with a 31.3-point improvement from baseline, reported Inder Kaul, MD, MPH, of maker Bristol Myers Squibb in Princeton, New Jersey, at the Psych Congress in Boston.

Of the 35 participants who completed the 52-week trial, 68.6% had a 30% or more reduction from acute trial baseline in floor-adjusted PANSS total score.

Similar improvement patterns were noted for the PANSS positive subscale, PANSS negative subscale, and Clinical Global Impression-Severity (CGI-S) scores. By week 4 of the open-label period, there were no differences between the two groups for any efficacy measures.

In addition, the open-label EMERGENT-5 trial, which included adults with schizophrenia who had stable symptoms on a prior antipsychotic and no prior exposure to xanomeline and trospium, showed positive results with the combination. By week 52 of treatment, participants had the following mean changes from baseline:

• PANSS total score: -5.5 points
• CGI-S score: -0.4 point
• PANSS positive subscale score: -1.9 points
• PANSS negative subscale score: -0.8 point

Of the 283 participants who completed this trial, 30% had a 30% or greater reduction from baseline in floor-adjusted PANSS total score.

“The long-term findings should provide additional confidence to healthcare providers when deciding to prescribe Cobenfy, as this data reinforces the efficacy and tolerability seen in previous short-term trials,” EMERGENT program investigator Rishi Kakar, MD, chief scientific officer and medical director of Segal Trials in Miami Lakes, Florida, told MedPage Today.

“As Cobenfy is the first new differentiated, mechanistically unique treatment, the consistent data seen over 52 weeks should be especially compelling and reassuring to providers and their patients,” he said. “Due to the chronic nature of illness, most patients with schizotypal personality disorder often need to take medication for years. Thus, it becomes important to know if medication has a potential to show continued symptom improvement if taken over the long term. This is what makes the long-term data very compelling.”

In EMERGENT-4, safety with xanomeline and trospium chloride was similar to what has been previously reported, with 35.5% of participants experiencing at least one treatment-related adverse event. Most were mild or moderate gastrointestinal events and didn’t lead to discontinuation.

As seen in prior trials, there was also a small drop in body weight by week 52 (-1.9 kg), and a small increase in blood pressure and heart rate, which peaked at week 2 of the open-label phase:

• Systolic blood pressure: mean change of +1.9 mm Hg from acute trial baseline
• Diastolic blood pressure: mean change of +0.7 mm Hg from acute trial baseline
• Heart rate: mean change of +3.9 bpm from acute trial baseline

There were no clinically meaningful changes in prolactin levels, the Simpson-Angus Scale, the Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale. There were also no reports of akathisia or tardive dyskinesia.

“Schizophrenia is a highly heterogeneous disease which continues to create immense burden to both patients and their caregiver. Patients often must make a tradeoff between drugs’ effectiveness and side effect profile,” said Kakar. “The robust efficacy seen in research patients in both short- and long-term trials, combined with a compelling tolerability profile without weight gain, movement disorders, or metabolic changes, makes Cobenfy a highly welcomed addition for patients and providers.”

Approved in September, the drug was the first new class of drug for schizophrenia in over 30 years, with approval based on results from the 5-week EMERGENT-2 and EMERGENT-3 trials. Instead of working on dopaminergic and serotonergic receptors in the brain, this drug targets the M1 and M4 muscarinic receptors. This different mechanism of action may help patients who don’t respond to or tolerate dopamine-blocking agents.

Both trials met their primary endpoint, demonstrating significantly greater reductions in the PANSS total score compared with placebo (P

• EMERGENT-2: -21.2 vs -11.6, respectively
• EMERGENT-3: -20.6 vs -12.2

When the 152 participants from EMERGENT-4 were enrolled in EMERGENT-2 and -3, all had a primary schizophrenia diagnosis with an acute exacerbation of psychosis warranting hospitalization. Mean age was 44.9, 75% were men, 61.2% were Black or African American, and 36.8% were white. All had a baseline PANSS total score of 80-120 (ranges 30-210), and a CGI-S score of 4 or higher (ranges 1-7).

Participants were started on twice-daily oral doses of xanomeline 50 mg/trospium 20 mg and were titrated up to a maximum dose of 125 mg/30 mg for 52 weeks.

In a qualitative interview-based survey that was administered to participants at month 6 of treatment, the average satisfaction score for xanomeline and trospium was an 8.1 out of 10 versus a score of 5.7 for past treatment. If given the option, 78.3% said they would continue taking the drug after the trial.

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