As the FDA prepares to render a verdict on BMS’ closely watched schizophrenia drug, BioSpace takes a closer look at the late-stage pipeline for this neuropsychiatric disorder.
A new era of schizophrenia treatment could be on the horizon as Bristol Myers Squibb awaits the FDA’s decision on the company’s recently acquired drug KarXT. If approved, KarXT would represent the first novel approach for schizophrenia in several decades.
“What we’re on the cusp of is the first approval for a brand new, novel mechanism of action,” Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, told BioSpace.
Schizophrenia is a neuropsychiatric disorder comprising positive symptoms relating to psychosis as well as negative symptoms such as social withdrawal and lack of motivation, in addition to cognitive symptoms. It affects more than 3.5 million people across the U.S., with the treatment market expected to top $7 billion by 2028, according to The Business Research Company.
First-generation antipsychotics made their debut in the 1960s and 1970s, Suvannevejh said. They were then followed by second-generation antipsychotics. Both work by targeting the dopamine and serotonin receptors, he explained.
KarXT, which came into BMS’ possession with the $14 billion acquisition of Karuna Therapeutics in December 2023, belongs to a class called muscarinic receptor acting modulators. Unlike existing schizophrenia treatments, KarXT does not directly block dopamine receptors. Instead, it works through the dual activation of the M1 and M4 muscarinic acetylcholine receptors in the central nervous system, a mechanism shown to improve positive, negative and cognitive symptoms in schizophrenia without the side effects associated with antipsychotics.
Antipsychotics can induce excessive sleepiness and weight gain, among other adverse effects, which can lead to discontinuation, Suvannevejh said. The muscarinic class, on the other hand, has shown “best in class efficacy” and “potentially best in class safety and tolerability. . . . That’s why we think there is a lot of pent-up demand for this new class of drugs.”
Following behind KarXT in the schizophrenia pipeline are several drugs targeting the positive, negative and cognitive symptoms of the disease via the muscarinic pathway and others. BioSpace takes a closer look at five of these investigational therapies.
Neurocrine Biosciences
NBI-1117568
A recent readout from a Phase II trial of Neurocrine’s NBI-1117568, an oral muscarinic M4 selective agonist, sparked further interest in the schizophrenia space—though few accolades from investors.
While the candidate improved symptoms of schizophrenia, it did so only at the lowest dose tested, Neurocrine reported. Specifically, NBI-1117568 met the trial’s primary endpoint, improving the positive and negative symptoms of the psychiatric disease, at the 20-mg dose after six weeks. The severity of the disorder was also improved at this dose level. All other doses—30 mg, 40 mg and 60 mg—failed to meet the trial’s primary endpoint.
Investors were unimpressed, and the company’s shares dropped 20% following the results, due partly to a lower Positive and Negative Syndrome Scale (PANSS) score than its competitors.
Neurocrine plans to move forward with a Phase III trial in early 2025, according to a press release announcing the results.
AbbVie
Emraclidine
Like KarXT and NBI-1117568, emraclidine targets the M4 receptor. AbbVie came into possession of emraclidine when it acquired Cerevel in December 2023 for $8.7 billion in a deal that closed Aug. 1.
Emraclidine is currently in Phase II development. However, Suvannevejh said the studies have been designed as “potentially registrational” as they are much larger than average Phase II trials.
“Because of the strong data we’ve seen with drugs like KarXT . . . I think the expectation [for emraclidine] is you should also expect to see very good efficacy and equally, if not more importantly, very good safety and tolerability,” he added.
A Phase Ib trial of emraclidine in adults with schizophrenia demonstrated a “clinically meaningful and statistically significant improvement” in PANSS total score at six weeks, according to a press release announcing the trial’s publication in The Lancet.
Reviva Pharmaceuticals
Brilaroxazine
Taking a different tack, Reviva Pharmaceuticals is developing brilaroxazine, a serotonin-dopamine signaling modulator, for schizophrenia.
“Schizophrenia is primarily caused by imbalance of [the] serotonin and dopamine signaling cascade,” Laxminarayan Bhat, founder, president and CEO of Reviva, told BioSpace. An effective treatment is expected to balance the levels of these neurochemicals by directly or indirectly modulating both dopamine and serotonin signaling cascades, he explained. “The difference with our drug with respect to dopamine signaling cascade is we have more potent activity for D4, [which is] highly expressed in the frontal cortex” and implicated in the negative and cognitive symptoms of schizophrenia, Bhat said.
Reviva announced topline results from the pivotal Phase III RECOVER trial of brilaroxazine in October 2023. The treatment met the trial’s primary endpoint, showing a “statistically significant and clinically meaningful” 10.1-point reduction in PANSS total score vs. placebo after four weeks when dosed at 50 mg. Brilaroxazine at this dose also elicited reductions in all major symptom domains and secondary endpoints, according to Reviva. The drug was “generally well-tolerated” with a side effect profile comparable to placebo at both the 50 mg and 15 mg doses.
In April, the company announced it had reached alignment with the FDA on a registrational Phase III program for brilaroxazine where two positive four-week studies plus a year-long safety study could support a new drug application. Topline data from a one-year open-label extension are expected in the fourth quarter of this year.
Boehringer Ingelheim
Iclepertin
Boehringer Ingelheim is developing iclepertin, a glycine transporter 1 (GlyT1) inhibitor, to treat the cognitive symptoms associated with schizophrenia. GlyT1 is thought to play an important role in regulating both inhibitory and excitatory neurotransmission.
Iclepertin is Boehringer’s lead small molecule candidate for schizophrenia—the company is also working on a digital therapeutic for negative symptoms—and is currently being studied in three large, randomized, controlled studies, which are expected to read out in 2025, according to Mike Jablonski, vice president of clinical development and medical affairs at Boehringer.
The cognitive symptoms of schizophrenia, which include poor memory, low attention span and forgetfulness, are “often overlooked,” Jablonski told BioSpace. “Even if [the] positive symptoms are controlled through antipsychotic utilization, that doesn’t address the cognitive symptoms,” he said, calling this a real unmet need.
Boehringer delved deeper into the schizophrenia space in March, inking a deal worth up to $732 million with Sosei Heptares (now Nxera Pharma) to address the positive, negative and cognitive symptoms of the disease. Under this deal, the German multinational has the exclusive option to license Sosei Heptares’ portfolio of GPR52 agonists.
Alto Neuroscience
ALTO-101
Alto Neuroscience is also targeting cognitive symptoms with ALTO-101, a novel inhibitor of phosphodiesterase 4 (PDE4) enzymes, disruptions in which potentially play a role in schizophrenia.
“PDE4 is an enzyme that breaks down cAMP, an intracellular signaling molecule important for cognition and neuroplasticity, which has long been of interest for its putative pro-cognitive and antidepressant effects,” Amit Etkin, founder and CEO of Alto, told BioSpace in an email.
Alto kicked off a Phase II study of ALTO-101 in June 2024, intending to enroll approximately 70 individuals between 21 and 55 years of age with schizophrenia and “a demonstrable level of cognitive impairment.” Topline data are expected in the second half of 2025.
In a Phase I study, the candidate demonstrated positive effects on cognition and electroencephalography (EEG) measures relevant to cognitive function, according to Alto. A transdermal formulation of ALTO-101 achieved greater systemic drug exposure than an oral version of the drug, the company reported. Transdermal ALTO-101 will be tested in the Phase II trial.
