FDA approves first novel schizophrenia drug in 35 years

In one of the most anticipated decisions of the year, the FDA made Thursday approved BMS's Cobenfy for the treatment of schizophrenia – a new era in the treatment of the neuropsychiatric disease. Cobenfy is the first muscarinic agonist for schizophrenia, and its approval comes 35 years to the day after the FDA approved Clozaril (clozapine) as the last new class of treatment for this indication.

BMS demonstrated the effectiveness of Cobenfy, formerly known as KarXT, using data from three pivotal trials in which the drug showed benefit in treating schizophrenia on the positive and negative syndrome scale.

“This approval provides a new alternative to the antipsychotic medications previously prescribed for people with schizophrenia,” Tiffany Farchione, director of the Division of Psychiatry, Office of Neurosciences in the FDA's Center for Drug Evaluation and Research, said in a statement.

Original article published September 23rd

Schizophrenia Space awaits first-in-class FDA approval for KarXT from BMS

Schizophrenia patients have not seen a drug with a novel mechanism of action in more than 30 years. That could change this week when the FDA approves Bristol Myers Squibb's KarXT, which is scheduled to be effective on Thursday, September 26. If approved, KarXT would be the first muscarinic agonist for schizophrenia and would open up a new biological route to alleviating symptoms of the psychiatric disease.

“I am very optimistic and hopeful [KarXT] will be a breakthrough drug,” said Jeffrey Conn, professor emeritus of pharmacology at Vanderbilt University BioSpace.

Conn is the scientific co-founder of Karuna Therapeutics, which developed KarXT (xanomeline trospium). However, he resigned in 2016 to focus on next-generation muscarinic compounds at Vanderbilt. BMS acquired the drug in December 2023 acquisition from Karuna. BMS has since reported positive results from a third pivotal study showing that KarXT produced a significant and clinically meaningful improvement in symptom severity.

Schizophrenia is a complex illness. In addition to the classic so-called positive symptoms of psychosis, the neuropsychiatric disorder also has negative symptoms such as social withdrawal and lack of motivation, as well as cognitive symptoms such as poor memory and low attention span. A current one study found that the incidence of schizophrenia is two to three times higher than previously thought, with more than 3.5 million people personally affected by it in the United States.

Since the 1960s, schizophrenia has been treated with antipsychotics, which work by blocking dopamine signaling in the brain. Dopamine is understood play a central role in the pathophysiology of the disease. While these drugs are effective in reducing hallucinations, they have a “significant impact on the safety profile,” said Carlos Dortrait, SVP and general manager of US immunology and neurosciences at BMS BioSpaceincluding sedation, movement disorders and hormonal changes.

KarXT's approach is two-pronged: Xanomeline targets muscarinic receptors M1 and M4 activation Trospium has been shown to reduce the symptoms of schizophrenia, while trospium has been shown to reduce side effects such as cardiovascular problems and increased saliva and tear production caused by activation of this pathway. Additionally, because muscarinic receptors are not expressed in key brain regions, patients avoid many of the side effects associated with classic dopamine-based medications, Dortrait explained. “You get the high level of effectiveness you expected [antipsychotics] . . . However, you don’t get the consequence that comes with it.”

Based on the totality of evidence supporting KarXT, Graig Suvannevejh, senior equity analyst for biopharmaceuticals and biotechnology at Mizuho Americas, said there is “no doubt” it will be approved in a timely manner.

The case for KarXT

BMS is Backing its new drug application for KarXT with data from three regulatory and placebo-controlled studies. The EMERGENT-1 And EMERGENT-2 Studies demonstrated the drug's effectiveness in treating schizophrenia on the Positive and Negative Syndrome Scale (PANSS). A third study, EMERGENT-3, showed that KarXT could do this significantly improve the overall severity of symptoms.

The phase III studies were “quite robust in scope”. . . and the data were equally robust in terms of the quality of their effectiveness and broadly consistent across all three studies,” said Suvannevejh BioSpace.

However, KarXT does not have a flawless profile. The EMERGENT-3 study missed an important secondary endpoint and possible cardiovascular risks revealed.

In addition, Karuna had although touted Due to KarXT's effect on negative symptoms, it failed to specifically reduce these symptoms compared to placebo at week four in EMERGENT-3.

Dortrait noted that KarXT managed to demonstrate a statistical advantage in PANSS-negative and PANSS-Marder factor-negative scores in EMERGENT-1 and EMERGENT-2. BMS also recently published one Post hoc analysis This shows that a subgroup of patients in the key studies with predominantly negative symptoms at baseline found a greater effect on negative symptoms than the entire study population.

Conn said KarXT could have a significant impact on the disease's negative symptoms, but “that needs to be demonstrated over time to see if the efficacy is there and how robust it is.”

In terms of safety, KarXT showed increased rates of hypertension in EMERGENT-3 – 6% in the treatment arm versus 2% in the placebo group. According to Conn, this is not uncommon for muscarinic agonists.

Conn noted that several companies abandoned muscarinic programs in the 1990s due to side effects such as cardiovascular problems and increased saliva and tear production. However, Conn pointed out that the trospium component of KarXT ensures its tolerability.

“[Trospium] “blocks the peripheral side effects of xanomeline, allowing physicians to deliver an effective dose while minimizing the severity of side effects seen with xanomeline alone,” he said.

Dortrait said BMS does not believe the high blood pressure rates seen in the KarXT trials will be a barrier to use, “given the temporary nature of the results” and the “final” data showing no change in blood pressure, which will be presented in a separate study were collected.

Remaining unmet needs

Apart from KarXT approval, there will still be a need in this area, experts agree.

Currently, 30% of patients are not responding to treatment, Dortrait said, while another 50% still need improvement in symptoms. And 75% of patients stop treatment. “So there will always be a need for innovation in this area.”

Suvannevejh said one of the biggest unmet needs is a drug that “works really well against negative symptoms.”

Combating the negative symptoms of schizophrenia has proven to be a difficult task. Acadia Pharmaceuticals had hoped to make a breakthrough with pimavanserin, an atypical antipsychotic, but the company announced in March that it missed the primary efficacy endpoint of control of negative symptoms in a Phase III trial. As a result, Acadia halted development of the schizophrenia drug.

“There is no precedent for a drug showing clear effectiveness for negative symptoms,” Conn said. “The clinical tools we have available to assess the impact on negative symptoms are not nearly as well established as [those for] positive symptoms, and so I think there needs to be further study and wider clinical application to see how this plays out.”

Side effects are another important area for improvement, Conn added. KarXT wasn't originally optimized with a precise understanding of which receptors had what effect, he explained, so it works on all muscarinic receptors with “weak potency in some and better potency in others.” At Vanderbilt, Conn's lab is working on allosteric modulators that are “very specific” to individual muscarinic subtypes “and completely bypass the peripheral receptors that lead to these side effects,” he explained. “That’s in the muscarin space where I think the future lies.”

BMS' rollout plan for KarXT

If approved, KarXT will be available to patients in late October, Dortrait said. “I can tell you we are ready to launch,” he said. “We have made significant progress in building the organization with extensive neuropsych experience from a leadership perspective as well as our field teams; They are fully set and operational.”

Dortrait added that KarXT's features make it a perfect fit for BMS's business model. “Having the privilege and opportunity to bring a new and first mechanism of action to market is consistent with our strategy as an organization,” he said.

And schizophrenia is just the beginning for KarXT, Dortrait added, emphasizing the drug's potential in treating Alzheimer's psychosis and bipolar disorder. “We expect KarXT to be our first foray into the world of schizophrenia and serious mental illness, but we plan to expand and take a very comprehensive look at many diseases.”

This week, however, the focus is on KarXT's first goal. “Frankly, it has the opportunity to fundamentally change the treatment of schizophrenia,” Dortrait said.