Anticipation Grows for BMS’ KarXT as Schizophrenia Space Awaits Groundbreaking FDA Approval
Patients with schizophrenia have not experienced a new class of medication for over three decades. This may change soon, as the FDA is expected to review Bristol Myers Squibb’s KarXT, with a decision date set for Thursday, September 26. If it gains approval, KarXT could become the first muscarinic agonist for schizophrenia, utilizing a fresh biological pathway to alleviate symptoms associated with the mental health disorder.
“I’m very optimistic and hopeful that [KarXT] will be a breakthrough medication,” noted Jeffrey Conn, a pharmacology professor emeritus at Vanderbilt University.
Conn, one of the scientific co-founders of Karuna Therapeutics, which created KarXT (xanomeline-trospium), stepped back in 2016 to concentrate on advanced muscarinic therapies. Bristol Myers Squibb acquired the drug in December 2023 along with the announcement of favorable outcomes from a pivotal study, demonstrating significant improvement in symptom severity linked to the treatment.
Schizophrenia presents a multifaceted challenge. Beyond the classic positive symptoms associated with psychosis, this complex condition also includes negative symptoms like social withdrawal and cognitive deficiencies, such as poor attention span and memory. A recent investigation revealed that the prevalence of schizophrenia is 2-3 times greater than previously estimated, impacting over 3.5 million individuals in the U.S.
Since the 1960s, the condition has largely been managed with antipsychotics, which inhibit dopamine signaling throughout the brain—an important factor in the disease’s pathophysiology. While these medications can lessen hallucinations, they may also lead to substantial side effects, including sedation and movement disorders, as highlighted by Carlos Dortrait, SVP and general manager at BMS.
KarXT operates on a two-pronged strategy: xanomeline engages the M1 and M4 muscarinic receptors—proven to alleviate schizophrenia symptoms—while trospium mitigates adverse effects like cardiovascular problems. Because these receptors are minimally active in primary brain regions, patients experience fewer side effects usually associated with dopamine-based treatments.
Graig Suvannevejh, a biotechnology equity analyst at Mizuho Americas, believes there’s a strong case for KarXT’s approval given the compelling evidence presented.
The Case for KarXT
BMS supports its KarXT application with data from three critical and placebo-controlled trials. The EMERGENT-1 and EMERGENT-2 studies confirmed the drug’s effectiveness while the EMERGENT-3 trial revealed appreciable improvement in overall symptom severity.
Although not without flaws, the Phase III trials were robust in sample size and data quality, a sentiment shared by Suvannevejh.
However, the EMERGENT-3 trial did encounter issues, including the failure to meet a significant secondary endpoint and hints at potential cardiovascular risks.
Despite earlier claims about KarXT’s impact on negative symptoms, the drug didn’t significantly reduce this type of symptom compared to placebo in EMERGENT-3. Nonetheless, Dortrait indicated that KarXT demonstrated statistically significant benefits in some forms of negative symptoms in earlier studies.
Conn expressed optimism about KarXT’s potential to address negative symptoms, though ongoing evaluation is essential.
Concerning safety, the EMERGENT-3 trial also reported a higher incidence of hypertension — 6% for the treatment group compared to 2% for the control. Such outcomes are typical for agents similar to muscarinic agonists, according to Conn.
Companies in the 90s withdrew from muscarinic drug development due to adverse effects, but Conn believes trospium’s addition bolsters KarXT’s tolerability.
“[Trospium] counteracts the peripheral impacts of xanomeline, allowing clinicians to prescribe effective doses while curtailing side effects,” he noted.
Dortrait reassured that the hypertension cases seen in trials would not hinder adoption, suggesting that findings were transient and backed by separate studies showing no marked alterations in blood pressure.
Remaining Unmet Need
Despite the anticipated approval of KarXT, significant gaps remain in treatment options for schizophrenia. As Dortrait highlighted, 30% of patients fail to respond to current therapies while 50% require better symptom management, with a staggering 75% discontinuing treatment, indicating a constant demand for innovation.
According to Suvannevejh, finding an effective drug for negative symptoms is a crucial area for advancement; addressing these difficulties has continuously challenged researchers.
Acadia Pharmaceuticals once aimed to tackle these issues with an atypical antipsychotic, maar, like many addressed before it, fell short during trials.
Conn stated there is no existing precedent for a medication demonstrating clear success with negative symptoms, and emphasized the need for further extensive studies.
Additionally, he noted that KarXT was not optimized for specific receptor interactions, impacting its side effect profile. His ongoing research at Vanderbilt aims to create allosteric modulators that selectively target certain muscarinic receptors, circumventing peripheral receptor interactions.
BMS’s Rollout Plan for KarXT
Upon approval, Dortrait confirmed that KarXT should be accessible to patients by late October. “We are fully prepared to launch,” he confirmed, highlighting that the necessary infrastructure and experienced teams are already established.
This drug aligns well with BMS’s overall strategy, offering a new mechanism to the market, which fits within their ongoing business model.
Moreover, Dortrait mentioned that the potential for KarXT extends beyond schizophrenia, indicating interest in its applications in Alzheimer’s-related psychosis and bipolar disorder as well. “KarXT opens doors for treating serious mental health challenges,” he concluded.