BMS achieves FDA approval for schizophrenia drug Cobenfy

Bristol Myers Squibb (BMS) acquired Karuna Therapeutics, the developer of KarXT, in a deal worth US $14.0 billion in equity value that completed​ earlier this year. The deal has paid off as Karuna’s lead asset was approved​ last week by the US FDA.

Cobenfy is a combination of xanomeline, which acts on the muscarinic receptor system by activating it and trospium, which blocks the muscarinic receptors outside the brain. Most schizophrenia drugs act on the dopaminergic system, so this is a first in class drug.

Xanomeline is the main active ingredient helping schizophrenia symptoms and trospium is needed to reduce side effects that can occur if muscarinic receptors outside the brain are activated, as it can’t cross the blood–brain barrier. Muscarinic receptors are found in large quantities in the gut so trospium is needed to reduce the potentially debilitating gastric side effects of xanomeline.

The approval is the result of three placebo-controlled efficacy and safety trials and two open label trials. In two phase 3 trials, EMERGENT-2 AND EMERGENT-3, Cobenfy reduced schizophrenia symptoms according to the Positive and Negative Syndrome Scale (PANSS) by 9.6 and 8.4 points, respectively, versus placebo.

A key problem with older schizophrenia drugs is while they can treat the psychotic symptoms, they also have a lot of side effects including weight gain, metabolic dysfunction and motor symptoms that are a bit like those experienced by people with Parkinson’s disease.

Cobenfy is not completely side effect free, but the adverse effects experienced by patients enrolled in the trial program were mostly mild-moderate gastrointestinal symptoms such as nausea, constipation and diarrhea, as well as some cases of high blood pressure and heart rate and dizziness.

“Due to its heterogeneous nature, schizophrenia is not a one-size-fits-all condition, and people often find themselves in a cycle of discontinuing and switching therapies,” said Rishi Kakar, chief scientific officer and medical director at Segal Trials and investigator in the EMERGENT program.

“The approval of Cobenfy is a transformative moment in the treatment of schizophrenia because, historically, medicines approved to treat schizophrenia have relied on the same primary pathways in the brain. By leveraging a novel pathway, Cobenfy offers a new option to manage this challenging condition.”

A new approach to treating a difficult disease​

Although approved drugs for schizophrenia have been available for many years, they only address part of the problem, and the side effects can be very debilitating.

There are two parts or ‘domains’ of schizophrenia. Positive symptoms, namely, hallucinations and delusions, but also negative symptoms, social withdraw, flattened affect, inability to feel emotions, and cognitive dysfunction.

Positive symptoms can be treated with anti-psychotics, although not everyone responds well. Even when these symptoms are controlled, the negative symptoms are not and are more debilitating than the positive. None of the available drugs treat these symptoms.

Cobenfy may be able to treat some of the negative symptoms and showed signs of improving cognitive function in the trials, although longer studies are needed to test whether it can have an impact on symptoms such as cognitive dysfunction. It does have a strong effect on the positive symptoms and avoids some of the problems with older schizophrenia drugs caused by their mechanism of action.

For example, acting on dopamine receptors directly can produce Parkinsonian-like motor symptoms called extra pyramidal side effects. By activating muscarinic receptors, it is possible to reduce the release of dopamine, which triggers hallucinations and delusions seen in schizophrenia, but without the Parkinsonian-like effects.