Schizophrenia Space Awaits FDA Approval for BMS' KarXT

With an FDA decision expected on September 26, Bristol Myers Squibb’s KarXT could soon become the first innovative schizophrenia medication in 30 years. Beyond schizophrenia, this drug also shows promise for treating Alzheimer’s psychosis and bipolar disorder. Schizophrenia patients have long relied on antipsychotics that mainly target dopamine signaling, but these drugs often come with severe side effects such as sedation, movement disorders, and hormonal changes. If approved, KarXT will introduce a new mechanism of action by functioning as a muscarinic agonist, targeting different biological pathways to alleviate symptoms.

Jeffrey Conn, professor emeritus of pharmacology at Vanderbilt University, expresses optimism about KarXT's potential. Conn, who co-founded Karuna Therapeutics—the developer of KarXT—stepped aside in 2016 to work on next-generation muscarinic compounds. Bristol Myers Squibb acquired Karuna in December 2023 and has since reported promising results from a third registrational study. This study indicates that KarXT significantly improves symptom severity in schizophrenia patients.

Schizophrenia is a multifaceted disorder involving positive symptoms like psychosis, negative symptoms such as social withdrawal and lack of motivation, and cognitive symptoms including poor memory and attention span. Recent research shows that the incidence of schizophrenia is 2-3 times higher than previously estimated, affecting over 3.5 million people in the U.S.

Traditional antipsychotics have targeted dopamine pathways to manage hallucinations but often lead to severe side effects. According to Carlos Dortrait, Senior Vice President and General Manager of U.S. Immunology and Neuroscience at Bristol Myers Squibb, these side effects include sedation, movement disorders, and hormonal imbalances. KarXT aims to change this paradigm with a dual approach: xanomeline targets the M1 and M4 muscarinic receptors to reduce symptoms, while trospium minimizes side effects like cardiovascular issues and increased production of saliva and tears.

Muscarinic receptors are not located in key brain regions, allowing patients to avoid many of the side effects linked to dopamine-based drugs. “You get the high levels of efficacy that you anticipated with the [antipsychotics] . . . however, you don’t get the consequence that comes with it,” Dortrait noted.

Graig Suvannevejh, a senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, is confident in KarXT’s approval, given the robust data from three key trials. The EMERGENT-1 and EMERGENT-2 studies demonstrated the drug’s effectiveness on the Positive and Negative Syndrome Scale (PANSS), and a third study, EMERGENT-3, confirmed significant overall symptom improvement.

However, KarXT is not without challenges. The EMERGENT-3 trial failed to meet a key secondary endpoint and highlighted potential cardiovascular risks. Additionally, while Karuna Therapeutics had promoted the drug’s impact on negative symptoms, it did not significantly outperform the placebo in this regard during EMERGENT-3.

Despite these concerns, Dortrait emphasized that KarXT showed a statistical benefit on the PANSS-negative and PANSS-Marder factor negative score in earlier studies. A recent post hoc analysis indicated that patients with predominantly negative symptoms at baseline saw a larger effect than the overall trial population.

KarXT also showed an increased rate of hypertension in the EMERGENT-3 trial—6% in the treatment group compared to 2% in the placebo group. Jeffrey Conn noted that this is typical for muscarinic agonists but pointed out that trospium helps mitigate these side effects, making the treatment more tolerable.

As for future plans, Dortrait stated that KarXT would be available to patients by late October if approved. He mentioned that Bristol Myers Squibb is ready for the launch, with a well-prepared organization and field teams. Dortrait also highlighted the potential for KarXT to treat other conditions like Alzheimer’s disease psychosis and bipolar disorder, indicating that schizophrenia is just the beginning for this drug.

Overall, KarXT represents a significant advancement in schizophrenia treatment, with the potential to be a "game changer," according to Dortrait. The approval of KarXT could pave the way for more innovative treatments addressing severe mental illnesses.