Despite the recent emergence of a new drug class, schizophrenia remains one of the most challenging neuropsychiatric diseases to treat—and Cobenfy’s first steps into the market indicate there is still room to grow.
When the FDA greenlit Bristol Myers Squibb’s Cobenfy in 2024 as the first novel drug for schizophrenia in 35 years, it was widely seen as a turning point in treating the intractable neuropsychiatric disease. But with the drug struggling out of the gate and a still imperfect side effect profile, there is plenty of room for improvement—and competitors.
“The magnitude of our effect is deep,” Laura Gault, senior vice president and head of neuroscience development at BMS, told BioSpace in an interview. “Cobenfy is a novel [mechanism of action] with a very different side effect profile compared to what people have been using for the last 75 years.”
Cobenfy—formerly KarXT—is a combination of xanomeline, a muscarinic agonist, and trospium chloride, also a muscarinic antagonist, that came to BMS in the $14 billion acquisition of Karuna Therapeutics in 2023.
However, side effects are still a part of the Cobenfy story, particularly with regard to pro-cholinergic symptoms that impact the gastrointestinal system, according to Christopher Kroeger, CEO of MapLight Therapeutics, which is also developing a muscarinic receptor agonist and hopes to compete with BMS’s first-to-market entry.
“The challenge with Cobenfy has been that it is not proven to be particularly tolerable,” Kroeger told BioSpace. Because the components of the drug “have to be in exquisite balance, you can have high interpatient variability.”
Two years in, however, BMS has already heard a lot of success stories, Gault said, where even after a short time on treatment, patients are seeing “very meaningful changes in terms of a reduction in symptoms, but also their ability to engage in life in a way that they had been unable to do.”
Sales numbers, however, reflect a smaller splash.
Cobenfy brought in $155 million in sales for BMS in 2025, well below some analysts’ predictions during the drug’s late phase development at Karuna. Early sales forecasts for Cobenfy were more than double this number, Mizuho analyst Graig Suvannavejh told BioSpace.
Still, Gault said BMS isn’t concerned with the slow start. Since re-entering the neuroscience space with its $74 billion mega-merger with Celgene in 2019, the company has built up its acumen in the arena, which has enjoyed something of a Big Pharma renaissance over the past few years.
“Anytime you bring a new drug, especially a drug with a new [mechanism of action], into the field … [doctors] need to take some time to get to know it,” Gault said.“They need to see those first few experiences with their own eyes before they feel confident to prescribe it regularly.”
Suvannavejh agreed that with schizophrenia in particular, requiring a “Goldilocks approach” to balance side effects and efficacy, Cobenfy has strong potential. “I do think Cobenfy can be a good drug,” he said.
A balancing act
In schizophrenia, decades of treatment have laid bare the challenges inherent in the disease—and the tightrope drug developers must walk between efficacy and tolerability.
Older drugs that primarily affect the brain’s dopamine receptor leave patients with “very potent, very harsh side effects,” Suvannavejh said.
From earlier medicines like Eli Lilly’s Zyprexa to Johnson & Johnson’s Risperdal to next generation antipsychotics such as BMS’ Abilify and more recently, AbbVie’s Vraylar and J&J’s Caplyta, the mechanism of action remained the same despite differences in potency.
“These are just different mousetraps with the same biology, trying to optimize efficacy and safety tolerability,” Suvannavejh said.
Enter muscarinics. Marked by sizable acquisitions, including BMS’s purchase of Karuna and AbbVie’s $8.7 billion pick-up of Cerevel Therapeutics in 2023 and emraclidine—which ultimately led to a high-profile clinical failure in schizophrenia—muscarinic receptor inhibitors gained a good deal of attention for their potential to avoid some of the worst side effects of drugs targeting the dopamine receptors.
In addition to MapLight, AbbVie continues to progress emraclidine in Phase 2, while smaller biotechs like Neurocrine BioSciences and Neumora Therapeutics are also hoping to challenge BMS in the muscarinic space.
Because muscarinic receptors are not expressed in key brain regions, patients avoid many of the side effects associated with the classic dopamine-based drugs, Carlos Dortrait, senior vice president of neuroscience commercialization and global commercial strategy, told BioSpace prior to Cobenfy’s approval.
But Cobenfy’s main muscarinic agonist xanomeline comes with other adverse effects, primarily gastrointestinal, which require an additional ingredient to balance them out and avoid conditions that can lead to poor patient compliance—already a challenge among those with schizophrenia or Alzheimer’s disease psychosis, Suvannavejh said.
MapLight hopes to differentiate and challenge Cobenfy on a couple of fronts.
MapLight posted mixed trial results from a Phase 2 trial of its candidate earlier this month, garnering significant scrutiny from analysts. The results for ML-007-MA “muted” the competitive threat to Cobenfy, BMO Capital Markets said in a note to investors on July 27.
A twice-daily formulation of MapLight’s ML-007C-MA met the Phase 2 ZEPHYR trial’s primary endpoint, reducing symptoms of schizophrenia on the Positive and Negative Syndrome Scale (PANSS) at five weeks, with patients seeing a 4.5-point improvement. However, a once-a-day version of the pill that the company hoped would rival Cobenfy’s twice-daily regimen failed to meet the same expectation.
Cobenfy demonstrated an 8-to-10-point reduction in a pair of Phase 3 trials dubbed EMERGENT, according to BMO.
Still, Kroeger believes MapLight showed what it needed to earn a place next to Cobenfy on the market. He additionally argued that the results have been “misinterpreted” in the public sphere.
The misinterpretation, he said, stems from trying to compare specific PANSS scores across trials and ignoring aspects that are important in the real world, such as cognition and a secondary endpoint measuring clinicians’ global impression of disease severity.
MapLight’s drug also demonstrated important signals in cognition, according to Kroeger. While PANSS measures alleviation of so-called positive symptoms such as hallucination, delusion and disordered thinking and negative symptoms including apathy, withdrawal and lack of engagement with the world, 80% of patients with schizophrenia also suffer from cognitive challenges that have a meaningful impact on quality of life, the CEO noted.
Unlike Cobenfy—whose cognitive signal data were drawn from post-hoc pooled analyses, according to a MapLight spokesperson—ML-007C-MA hit a prespecified secondary endpoint in the ZEPHYR trial, which looked at cognitive performance.
Cobenfy’s market challenges are an opportunity for MapLight to showcase “significant differences in safety we’ve seen in the clinic [that are] going to be even larger when we get to real-world experience,” Kroeger said.
“The whole idea was to develop a drug that can give you the same kind of efficacy that Cobenfy delivered in a way that patients can tolerate,” Kroeger said. “And that’s what we showed in the study.”
Rates of discontinuation in MapLight’s program were lower than with Cobenfy, Kroeger said, attributing this result to fewer moderate and severe adverse events despite instances of mild side effects such as nausea and vomiting.
BMO in its note conceded this point, writing that MapLight’s pill could be more impactful in older adults with schizophrenia alongside Alzheimer’s disease due to lower rates of symptoms such as dry mouth, blurry vision and constipation. MapLight saw a GI discontinuation rate of just 2% in ZEPHYR, the biotech reported. However, BMO said the effect will likely not be enough to derail Cobenfy’s leadership from a market share perspective.
Comparing across clinical trials from different drugmakers is messy at best, Suvannavejh said. While acknowledging that MapLight’s “efficacy seemed to fall short of what was shown in the Karuna clinical trials,” the analyst said that given the high unmet need in schizophrenia, there’s room for more than just one or two of the same kind of drug.
“Just because we have one muscarinic right now in Cobenfy doesn’t mean there can’t be another five more,” Suvannavejh said.
