FDA OKs First-in-Class Antipsychotic for Schizophrenia

The US Food and Drug Administration (FDA) has approved Cobenfy (Bristol Myers Squibb), a first-in-class antipsychotic approved for schizophrenia. The drug targets cholinergic receptors as opposed to dopamine receptors, which has been the standard of care for more than 30 years.
It combines xanomeline, an oral muscarinic cholinergic receptor agonist and trospium chloride, an oral pan-muscarinic receptor antagonist. It was developed by Karuna Therapeutics, now part of Bristol Myers Squibb. 
“This drug takes the first new approach to schizophrenia treatment in decades,” Tiffany Farchione, MD, director of the Division of Psychiatry, Office of Neuroscience, in the FDA’s Center for Drug Evaluation and Research, said in a news release announcing the approval. 
The combination of xanomeline and trospium introduces a “fundamentally new approach” to treating schizophrenia by selectively targeting M1 and M4 muscarinic receptors in in the brain, Ken Kramer, PhD, vice president and head of worldwide medical affairs, neuropsychiatry, at Bristol Myers Squibb, told Medscape Medical News for a recent story in the lead-up to the FDA decision.
“This activity occurs without any dopamine receptor blockade, which makes this approach distinct from the current standards of care, which rely on targeting dopamine and/or serotonin receptors,” Kramer added.
Primary Endpoints Met in Pivotal Phase 3 Trials
The FDA approval of xanomeline/trospium for schizophrenia is supported by data from the EMERGENT clinical program, which includes three placebo-controlled efficacy and safety trials and two open-label trials evaluating the long-term safety and tolerability of the drug for up to 12 months.
The EMERGENT-2 and EMERGENT-3 trials both met their primary endpoints, demonstrating statistically significant reductions of schizophrenia symptoms compared with placebo, as measured by the Positive and Negative Syndrome Scale (PANSS) total score change from baseline to week 5.
Compared with placebo, treatment with xanomeline/trospium was associated with a 9.6-point reduction and an 8.4-point reduction in PANSS total score in EMERGENT-2 and EMERGENT-3, respectively, as reported previously by Medscape Medical News. 
All secondary endpoints were also met, with active treatment demonstrating statistically significant reductions compared with placebo at week 5.
Secondary endpoints included change in PANSS positive subscale, PANSS negative subscale, PANSS Marder negative factor, Clinical Global Impression-Severity (CGI-S) score, and percentage of participants achieving at least a 30% reduction from baseline to week 5 in PANSS total score.
Better Side-Effect Profile 
The most common adverse reactions (≥ 5%) were nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease. 
Unlike other antipsychotics, xanomeline/trospium did not cause weight gain or extrapyramidal symptoms. “The drug does not have atypical antipsychotic class warnings and precautions and does not have a boxed warning,” Bristol Myers Squibb said in a press statement. 
The FDA noted in its announcement that the prescribing information includes warnings that xanomeline/trospium can cause urinary retention, increased heart rate, decreased gastric movement, or angioedema of the face and lips. 
The drug is not recommended for patients with mild hepatic impairment and should not be used in patients with known hepatic impairment. There is also a risk for liver damage. 
Patients should be advised to stop using xanomeline/trospium if they experience signs or symptoms of substantial liver disease, including yellowing of the skin or the white part of the eyes, dark urine, and unexplained itching. 
Because xanomeline/trospium is substantially excreted by the kidney, it is not recommended in patients with moderate to severe renal impairment.
Xanomeline/trospium should not be prescribed to patients with urinary retention, moderate or severe kidney or liver disease, gastric retention, untreated narrow-angle glaucoma, or a history of hypersensitivity to either Cobenfy or its components.
The medication is expected to be available in late October in 50 mg/20 mg, 100 mg/20 mg, and 125 mg/30 mg capsules.
Full prescribing information is available online.
‘Major’ Advance
Several experts weighed in on the approval of xanomeline/trospium for schizophrenia in a statement from the UK nonprofit organization, Science Media Centre.
“As a clinician and researcher, this is possibly one of the most exciting developments in our field, and I am very excited about this,” commented Sameer Jauhar, MD, PhD, consultant psychiatrist, King’s College, London.
“We have had false dawns before; despite significant efforts in the field (with significant financial investment) phase 3 trials of newer compounds have so far been disappointing.
This novel treatment is the first of its kind, which does not act directly on the dopamine system, with good phase 3 trial data,” said Jauhar.
He noted that the side-effect profile from the phase 3 trials “suggests it has less of the side effects noted with current treatments,” but acknowledged that these trials are “short in duration, and we will need longer-term trials, to inform clinical care.”
Robert McCutcheon, MRCPsych, PhD, Department of Psychiatry, University of Oxford, said the approval of xanomeline/trospium for schizophrenia is a “major advance.”
“Current treatments are ineffective for many of the symptoms of schizophrenia; we need compounds with novel mechanisms of action. This is the first treatment that has a different target. We hope this may mean it can help people who don’t respond to standard treatments and maybe help the symptoms that aren’t helped by existing treatments,” said McCutcheon.
Paul Keedwell, MBChB, PhD, consultant psychiatrist and fellow of the Royal College of Psychiatrists, took a more cautionary view.
“New candidates for the treatment of this frequently debilitating condition are always welcome. However, the clinical effectiveness needs to be tested in real clinical settings. We also need to know how well it is tolerated, given its tendency to cause gastrointestinal problems in some patients,” Keedwell said. 
The company has launched the Cobenfy Cares program to support patients who have been prescribed the drug. Patients can enroll in the program in late October, corresponding with product availability. The Cobenfy Cares phone number is 1-877-COBENFY.
 
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