The first new schizophrenia drug in decades

The Food and Drug Administration (FDA) last week approved Bristol Myers Squibb's antipsychotic drug, the first new treatment for schizophrenia in more than three decades.

Current antipsychotics block dopamine receptors to relieve hallucinations, delusions, and other symptoms of schizophrenia. However, these medications can cause serious motor and metabolic side effects such as involuntary movements and weight gain, which can lead to heart disease and diabetes.

The new drug, called Cobenfy (xanomeline and trospium chloride), targets a different neurotransmitter to indirectly affect dopamine levels. Cobenfy, formerly called KarXT, is taken as a pill twice daily.

In the United States, approximately 3 million people are treated for schizophrenia, typically with cognitive behavioral therapy (CBT), community support, and antipsychotic medications. However, about 75% of patients eventually discontinue treatment and a third are resistant to conventional antipsychotics.

“Schizophrenia is not a one-size-fits-all disease, and people often find themselves in a cycle of stopping and switching treatments,” Rishi Kakar, MD, chief scientific officer and medical director at Segal Trials and an investigator for the Cobenfy clinical trials, said in a statement. “In the past, drugs approved to treat schizophrenia relied on the same primary signaling pathways in the brain. By leveraging a novel pathway, Cobenfy offers a new option to treat this challenging disease.”

How does Cobenfy work?

Cobenfy combines Xanomeline, an experimental drug for Alzheimer's disease, with trospium, which helps suppress side effects.

Unlike current antipsychotics, xanomeline does not bind directly to dopamine receptors. Instead, it targets the M1 and M4 muscarinic receptors in the central nervous system.

When Xanomeline was first developed, it showed antipsychotic effects but also caused “unbearable side effects,” said Xiaoduo Fan, MD, MPH, professor of psychiatry and psychopharmacology at the University of Massachusetts Chan School of Medicine.

The addition of trospium prevents xanomeline from crossing the blood-brain barrier and activating receptors that can cause nausea, constipation and other gastrointestinal problems in people.

“Overall, these side effects are much milder than they were many years ago when we used Xanomeline alone. It is bearable for a patient now,” Fan said.

Existing antipsychotics can generally reduce “positive” symptoms of schizophrenia, such as depression, hallucinations, and delusions, but are far less effective at reducing “negative” symptoms, such as social withdrawal and disinterest in life. In clinical studies, Cobenfy has been shown to minimize both positive and negative symptoms. According to Fan, it also appeared to improve cognitive outcomes.

There was no difference in weight gain or treatment discontinuation between Cobenfy and a placebo.

Currently, the drug clozapine is the only option for treatment-resistant schizophrenia. However, up to 60% of patients do not respond to it and it is associated with metabolic problems.

Fan said Cobenfy could be considered before using clozapine in treatment-resistant patients. It could also benefit patients who have developed significant side effects associated with long-term use of other antipsychotic medications, such as: B. involuntary movements, uncontrollable diabetes or cardiovascular diseases.

The FDA approved Cobenfy without a boxed warning — the agency's strongest warning for serious adverse events that typically accompanies antipsychotics. However, the agency noted that Cobenfy should not be prescribed to patients with urinary retention, moderate or severe kidney or liver disease, gastric retention, or untreated angle-closure glaucoma.

How well does Cobenfy work in the long term?

There are only three published placebo-controlled studies, each lasting only five weeks. Some analysts say the short duration of clinical trials raises questions about the drug's long-term effectiveness.

In a report earlier this year, the Institute for Clinical and Economic Review wrote: “The main source of uncertainty is the lack of data on the effectiveness of.” [Cobenfy] longer than five weeks.” The authors said that given the lack of long-term data and the fact that Cobenfy is a new type of antipsychotic, it is difficult to assess whether the drug is superior to other available options.

In April, BMS released key results from two open-label studies that lasted up to a year. The company said participants in these studies did not experience serious metabolic side effects or develop motor problems.

“This is a promising drug in many ways,” Fan said. “Whether or not this will be a game-changer, meaning that it will be significantly better than currently available drugs, I think we need a lot more data to to see how it works in the real world.”

According to BMS, Cobenfy will be available in October at a list price of $1,850 per month without insurance and discounts. The company said the price was comparable to other schizophrenia antipsychotics.

The company is studying whether Cobenfy could be used to treat Alzheimer's psychosis, a condition for which there are no treatment options. It said the drug could also be useful for treating bipolar I disorder and Alzheimer's disease.