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iStock/ Jolygon With an FDA action date of Sept. 26, Bristol Myers Squibb’s KarXT could soon be the first new type of schizophrenia drug in three decades—and the company also sees potential in Alzheimer’s psychosis and bipolar disorder. Schizophrenia patients have not seen a drug with a novel mechanism of action in more than 30 years. That could change this week if the FDA signs off on Bristol Myers Squibb’s KarXT, which has an action date of Thursday, Sept. 26. If approved, KarXT would be the first muscarinic agonist for schizophrenia, tapping into a new biological pathway to quell symptoms of the psychiatric disease. “I’m very optimistic and hopeful that [KarXT] will be a breakthrough medication,” Jeffrey Conn, professor emeritus of pharmacology at Vanderbilt University, told BioSpace . Conn is the scientific co-founder of Karuna Therapeutics, which developed KarXT (xanomeline-trospium), but he stepped aside in 2016 to focus on next-generation muscarinic compounds at Vanderbilt. BMS picked up the drug in the December 2023 acquisition of Karuna. Since then, BMS has reported positive results from a third registrational study, showing that KarXT elicited significant and clinically meaningful improvement in symptom severity. Schizophrenia is a complex condition. In addition to the classic so-called positive symptoms relating to psychosis, the neuropsychiatric disorder involves negative symptoms, including social withdrawal and lack of motivation, as well as cognitive symptoms, such as poor memory and low attention span. A recent study found the incidence of schizophrenia to be 2-3 times higher than previously thought, with more than 3.5 million people in the U.S. having been personally affected by it. Since the 1960s, schizophrenia has been treated with antipsychotics, which work by blocking dopamine signaling across the brain. Dopamine is understood to play a central role in the pathophysiology of the disease. While effective in reducing hallucinations, these drugs “come with significant consequences when it comes to the safety profile,” Carlos Dortrait, SVP and general manager of U.S. immunology and neuroscience at BMS, told BioSpace , including sedation, movement disorders and hormonal changes. KarXT’s approach is two-pronged: xanomeline targets the M1 and M4 muscarinic receptors, the activation of which has been shown to reduce schizophrenia symptoms, while trospium works to reduce the side effects, such as cardiovascular issues and increased production of saliva and tears, caused by activating this pathway. In addition, because muscarinic receptors are not expressed in key brain regions, patients avoid many of the side effects associated with the classic dopamine-based drugs, Dortrait explained. “You get the high levels of efficacy that you anticipated with the [antipsychotics] . . . however, you don’t get the consequence that comes with it.” Based on the overall body of evidence backing KarXT, Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, said there is “no doubt” in his mind that it will be approved, on time. The Case for KarXT BMS is backing its new drug application for KarXT with data from three registrational and placebo-controlled trials. The EMERGENT-1 and EMERGENT-2 studies established the drug’s efficacy in treating schizophrenia on the Positive and Negative Syndrome Scale (PANSS). A third study, EMERGENT-3, showed that KarXT could significantly improve overall symptom severity . The Phase III trials were “fairly robust in terms of the size . . . and the data were equally robust in terms of the quality of its efficacy, and it was consistent pretty much across all three trials,” Suvannevejh told BioSpace . KarXT does not have a spotless profile, however. The EMERGENT-3 trial missed a key secondary endpoint and revealed potential cardiovascular risks. In addition, while Karuna had touted KarXT’s effect on negative symptoms, it failed to specifically decrease these symptoms compared to placebo at week four in EMERGENT-3. Dortrait noted that KarXT was successful in demonstrating a statistical benefit on the PANSS-negative and PANSS-Marder factor negative score in EMERGENT-1 and EMERGENT-2. BMS also recently published a post hoc analysis showing that a subset of patients in the pivotal studies with predominantly negative symptoms at baseline saw a larger effect on negative symptoms than the overall trial population. Conn said KarXT could have a significant effect on negative symptoms of the disease, but “that’ll have to be borne out over time to see if the efficacy is there and how robust it is.” As for safety, KarXT showed an increased rate of hypertension in EMERGENT-3—6% in the treatment arm versus 2% in the placebo group. This is not unusual for muscarinic agonists, according to Conn. Several companies in the 1990s abandoned muscarinic programs due to side effects including cardiovascular issues, as well as increased production of saliva and tears, Conn noted. But Conn pointed to the trospium component of KarXT as ensuring its tolerability. “[Trospium] blocks the peripheral side effects of xanomeline, which enables clinicians to give an efficacious dose while minimizing the severity of the side effects observed with xanomeline alone,” he said. Dortrait said BMS does not believe the hypertension rates observed in KarXT’s trials will be a barrier to use, “given the transient nature of the findings” and the “definitive” data showing no change in blood pressure collected in a separate study. Remaining Unmet Need A KarXT approval aside, need will remain in this space, experts agreed. Currently, 30% of patients do not respond to treatment, Dortrait said, while an additional 50% still need symptom improvement. And 75% of patients discontinue treatment. “So, there will always be a need for innovation in this space.” Suvannevejh said one of the highest unmet needs is for a drug that “truly does well on negative symptoms.” Addressing the negative symptoms of schizophrenia has proven to be a difficult task. Acadia Pharmaceuticals had hoped to break through with pimavanserin, an atypical antipsychotic drug, but the company announced in March that it missed the primary efficacy endpoint of controlling negative symptoms in a Phase III trial. As a result, Acadia has halted development of the drug in schizophrenia. “There’s no precedent for a drug that has clear efficacy on negative symptoms,” Conn said. “The clinical tools that we have for assessing effects on negative symptoms are not nearly as well established as [those for] positive symptoms, and so I think it’s going to take more studies and broader use in the clinic to see how that turns out.” Side effects are another key area with room for improvement, Conn added. KarXT was not originally optimized with a precise understanding of which receptors had which effect, he explained, so it acts on all muscarinic receptors with “weak efficacy on some and better efficacy on others.” At Vanderbilt, Conn’s lab is working on allosteric modulators that are “very specific” for individual muscarinic subtypes “and completely avoid the peripheral receptors that lead to those side effects,” he explained. “That’s, in the muscarinic field, where I think the future lies.” BMS’s Rollout Plan for KarXT If approved, Dortrait said KarXT will be available to patients in late October. “I can tell you that we are ready to launch,” he stated. “We have made significant progress building up the organization with deep neuropsych experience from a leadership perspective, as well as our field teams; they are fully hired and in place.” Dortrait added that KarXT’s attributes place it squarely within BMS’ business model. “To have the privilege and the opportunity to bring a new and first mechanism of action to the marketplace was something that lives in line with our strategy as an organization,” he said. And schizophrenia is only the beginning for KarXT, Dortrait added, highlighting the drug’s potential in treating Alzheimer’s disease psychosis and bipolar disorder. “Our expectation is that KarXT is our first foray into schizophrenia and serious mental illnesses, but we are looking at expanding and looking very broadly across many diseases.” This week, though, KarXT’s first target is in focus. “It truly has the opportunity to be a game changer, quite frankly, in the treatment of schizophrenia,” Dortrait said.