With the failure of AbbVie’s emraclidine in two mid-stage trials, Bristol Myers Squibb’s Cobenfy is ‘sole muscarinic winner.’
When the FDA signed off on Bristol Myers Squibb’s Cobenfy this September, it was considered a landmark approval for a schizophrenia space that hadn’t seen a novel drug in 30 years and spurred momentum for a therapeutic class targeting the muscarinic pathway. That momentum took a hit last week when AbbVie’s muscarinic candidate emraclidine failed a pair of highly watched mid-stage trials. The announcement also positioned BMS as the clear winner of last year’s schizophrenia sweepstakes.
In December 2023, BMS acquired Karuna Therapeutics and its lead asset KarXT (now Cobenfy) for $14 billion just a couple weeks after AbbVie picked up Cerevel Therapeutics and its lead program emraclidine for $8.7 billion.
Muscarinics have generated excitement, partly due to their ability to avoid some of the side effects that come along with antipsychotics, which have been the standard of care for the psychiatric disorder since the 1960s. While effective in reducing hallucinations, these drugs come with a host of significant adverse effects including sedation, movement disorders and hormonal changes, Carlos Dortrait, SVP and general manager of U.S. immunology and neuroscience at BMS, previously told BioSpace. Because muscarinic receptors are not expressed in key brain regions, they are able to sidestep many of these side effects, Dortrait said.
While Cobenfy excelled, establishing its efficacy in treating schizophrenia in three registrational trials, emraclidine failed to show a statistically significant improvement in symptoms compared to placebo during the two Phase II trials, EMPOWER-1 and EMPOWER-2, AbbVie reported Monday. While the studies were only mid-stage, Mizuho Americas analyst Graig Suvannevejh previously told BioSpace that they were designed as “potentially registrational” as they were much larger than average Phase II trials.
AbbVie’s stock fell by 12% at market open Monday in response to the news. Meanwhile, BMS’ shares were trading up roughly 11% Monday “on perceptions of reduced competition for Cobenfy,” William Blair analysts wrote in an investor note.
BMO Capital Markets Evan David Seigerman put BMS’ victory more directly: “AbbVie’s trial failure positions Bristol as the sole muscarinic winner.”
AbbVie’s miss following the approval of Cobenfy was a bit of a shock to those closely tracking this space. “[W]hile we always thought the prior [Phase Ib] . . . plausibly overestimated the effect size of [emraclidine], it’s outright surprising to see it flat out fail in both pivotal [Phase IIbs],” Stifel analysts wrote in a note to investors on Monday.
Suvannevejh agreed, telling BioSpace in an email Friday, “The negative results for emraclidine . . . came as a surprise to many, mainly due to the very positive Phase 1b data seen previously from Cerevel Therapeutics, and to a degree, the very positive sets of data for . . . KarXT.”
No one—including BMS—is 100% sure how, or how well, Cobenfy works. “Exactly how KarXT works is an open question (it’s a bit of a promiscuous drug),” the Stifel analysts wrote. However, it targets both the M1 and M4 receptors, while emraclidine only targets M4. “There’s been a longstanding thesis that M1 may contribute to efficacy on cognition,” Stifel said.
William Blair analysts concurred, writing that “while additional details are necessary to fully understand the EMPOWER study outcomes, the results may suggest M1 and M4 agonism are needed to drive maximum benefit for patients, expanding Cobenfy’s first-mover advantage and ultimate market opportunity.”
AbbVie did not rule out further development of emraclidine. “While we are disappointed with the results, we are continuing to analyze the data to determine next steps,” Roopal Thakkar, executive vice president of research and development and chief scientific officer, said in the company’s Monday press release.
A Robust Schizophrenia Pipeline
BMS and AbbVie are not the only companies in the muscarinic space for schizophrenia. In August, Neurocrine Biosciences reported positive topline data from a Phase II trial of NBI-1117568, an oral muscarinic M4 selective agonist. A 20-mg dose of the candidate met the trial’s primary endpoint, improving positive and negative symptoms of schizophrenia with a statistically significant result at week six. On the Positive and Negative Syndrome Scale (PANSS), the therapy achieved a placebo-adjusted mean reduction of 7.5 points. All other doses of NBI-1117568 failed to meet the primary endpoint.
Analysts also noted at the time that NBI-1117568 underperformed KarXT, which achieved an 11.6-point placebo-adjusted PANSS reduction in the Phase II EMERGENT-1 trial. This measurement may not necessarily foretell success, however, as a 30-mg dose of emraclidine improved the PANSS total score at six weeks by 12.7 points compared with placebo in its Phase Ib trial. Still, BMO Capital Markets analyst Evan David Seigerman said in August that “a path forward in schizophrenia may still exist” for NBI-1117568, which has shown a better safety profile including gastrointestinal tolerability and weight gain symptoms. Neurocrine plans to move forward with a Phase III trial in early 2025, according to a press release announcing the Phase II results.
Suvannevejh also highlighted earlier stage Neumora Therapeutics, which in its 3Q results and business update this week reaffirmed its interest in and efforts toward advancing a new M4 positive allosteric modulator candidate for schizophrenia. This program is expected to enter the clinic in 2025, he said.
Moreover, while muscarinics are front and center in the schizophrenia space right now, they’re not the only mechanism of action being pursued for the intractable neuropsychiatric disorder. Reviva Pharmaceuticals is developing brilaroxazine, a serotonin-dopamine signaling modulator, while Boehringer Ingelheim and Alto Neuroscience are targeting the cognitive symptoms of the disease.
However this treatment area develops, it is clear that at this time BMS has a comfortable lead in the schizophrenia space. At the time of its approval, Truist Securities analysts wrote that “KarXT has first mover advantage and is at least 2-3 years ahead of the competition.” Now, that runway could be longer.
