Evaluating Pooled Data from the EMERGENT Study Programs

Findings From the 2024 Annual Congress of the Schizophrenia International Research Society

On Sept. 26, the U.S. Food and Drug Administration (FDA) approved Bristol Myers Squibb’s schizophrenia drug, KarXT. Marketed under the brand name Cobenfy, this marks the approval of the first new schizophrenia drug in more than 50 years – and the first ever non-dopaminergic treatment option.

“Today’s approval is a significant milestone for the schizophrenia community,” Bristol Myers Squibb CEO Chris Boerner, PhD, said in a press release. “For the first time in more than 30 years, we have a new pharmacological approach with the potential to change the treatment landscape.”

Encouraging Evidence

The approval follows the pharmaceutical giant’s report on the encouraging long-term effectiveness, safety, tolerability, and metabolic data for KarXT (xanomeline-trospium). Company officials announced the results at the Annual Congress of the Schizophrenia and International Research Society (SIRS) in April in Florence, Italy.

The latest data stems from EMERGENT-4 and EMERGENT-5, the most recent phase 3, multicenter, outpatient, open-label studies of the drug. Researchers administered KarXT at 50 mg/20 mg twice daily to adult schizophrenia patients. They later bumped up the dosage to a maximum of 125 mg/30 mg twice daily.

Researchers explained that both studies primarily aimed to assess the long-term safety and tolerability of KarXT in patients diagnosed with schizophrenia. They determined efficacy as the change from baseline in the Positive and Negative Syndrome Scale (PANSS). 

Additionally, EMERGENT-4 study participants must have completed one of the two earlier phase 3 double-blind, placebo-controlled studies (EMERGENT-2 or EMERGENT-3). These previous clinical trials evaluated the efficacy of KarXT in patients with schizophrenia experiencing an episode of acute psychosis.

This differs from EMERGENT-5, a stand-alone trial, which included patients with a new schizophrenia diagnosis. The interim EMERGENT-4 efficacy data included 110 patients, including 48 with previous KarXT treatment.

The pooled safety and metabolic analysis evaluated 718 patients who received at least one dose of KarXT, including 134 patients who had completed one year of treatment. 

Pooled EMERGENT Interim Metabolic Outcomes 

Over the 52 weeks of treatment, nearly two-thirds of the participants – 65 percent – experienced weight loss, with an average total loss of 2.6 kg. Clinically obese patients with a BMI higher than 30 kg/m experienced a greater average weight loss of 4.07 kg.

During the treatment period, clinicians noted that 17.6 percent of patients showed a potentially clinically significant weight decrease, defined as more than a 7 percent drop from baseline. Conversely, 4.1 percent of patients experienced a potentially clinically significant weight increase, defined as a greater than 7 percent jump.

The researchers noted no clinically meaningful changes in total cholesterol, triglyceride, or A1C levels after one year of treatment.

Pooled EMERGENT Interim Safety Outcomes

Participants tolerated KarXT well through the most recent 52-week studies, with a cholinergic side effect profile consistent with earlier trials. Across the EMERGENT trials, 62 percent of patients reported at least one treatment-related adverse event. The most common side effects – appearing in more than 5 percent of cases – included mild and transient nausea, vomiting, constipation, dry mouth, dyspepsia, dizziness, hypertension, and diarrhea.

Prolactin and movement disorder scale scores showed no clinical or significant impact. And even though 53 percent of patients dropped out of the trial, only 15 percent of those who walked away only 15 percent did so because of treatment-emergent adverse events.

“It is promising to see that, over one year of treatment, KarXT was not associated with burdensome side effects, specifically weight gain and metabolic dysfunction, as well as extrapyramidal symptoms, which underscores its potential to provide a meaningful and differentiated option for people living with schizophrenia,” Bristol Myers Squibb Senior Vice President Roland Chen, MD shared in a press release.

EMERGENT-4 Efficacy Outcomes

In the open-label extension EMERGENT-4 trial, KarXT significantly improved symptoms of schizophrenia across all efficacy measures at 52 weeks. Researchers also noticed improvements with or without KarXT treatment during earlier trials.

“People living with schizophrenia and their care partners have long carried the burden of the condition, with a lack of treatment options that adequately treat the symptoms of schizophrenia without common debilitating side effects,” Rishi Kakar, MD, Chief Scientific Officer and Medical Director of Segal Trials and investigator in the EMERGENT program, added. “To see that the long-term tolerability profile of KarXT remains consistent with earlier studies, where the cholinergic side effects of KarXT remained mainly mild or moderate in severity, and were transient and resolving with continued treatment is very encouraging.

“These results are extremely promising and add to the growing body of data which suggest that, if approved, KarXT could provide a long-desired, differentiated treatment option for people living with schizophrenia.”