FDA kicks off review of Karuna’s schizophrenia drug KarXT

Karuna Therapeutics said this morning that the FDA has formally started its review of KarXT, aiming to become the first drug to reach the market for schizophrenia with a new mechanism of action in decades.

The US regulator has set an action date of 26th September next year for a decision on KarXT, which combines muscarinic agonist xanomeline tartrate and muscarinic antagonist trospium chloride, as a treatment for adults with schizophrenia - a condition that affects around 3.9 million people in the US and 24 million worldwide.

For around 70 years, the treatment of schizophrenia has relied almost entirely on drugs that block dopamine D2 receptors, but KarXT is one of a clutch of new therapies emerging from the pharma industry pipeline that works in a different way, along with rivals like Newron Pharma’s evenamide and Sumitomo/Otsuka’s ulotaront.

Karuna’s drug is thought to exert its antipsychotic effects through muscarinic M1 and M4 receptors in the central nervous system, targeted by xanomeline, while trospium prevents side effects by blocking the drug’s effects on the peripheral nervous system.

Karuna maintains that the drug could help tackle symptoms of the disorder without causing side effects common with older drugs like olanzapine and risperidone, such as weight gain, movement disorders (tardive dyskinesia) and sedation.

A recent draft review by the influential Institute for Clinical and Economic Review (ICER) in the US concluded that in clinical trials, it had been shown to improve the proportion of hospitalised schizophrenia patients showing a 30% or greater improvement in symptoms compared to placebo over five weeks, without the weight gain that is a problem with current antipsychotic medications.

A lack of data after five weeks is a concern, according to the review, which says the drug appears to be “promising” but with an inconclusive net health benefit compared to older drugs. Karuna is currently conducting two phase 3 studies looking at the long-term safety and efficacy of the drug.

GlobalData has predicted that KarXT will launch in the US next year, and achieve sales of $1.1 billion by 2031 thanks to its safety profile and ability to broadly target symptoms of schizophrenia, i.e. both positive (delusions and hallucination) symptoms and negative (social withdrawal and apathy).

Looking at its rivals, ulotaront – an agonist of 5-HT receptor 1A and trace amine-associated 1 (TAAR-1) receptors – stumbled in phase 3, failing to meet the primary endpoints in the DIAMOND 1 and 2 trials reported earlier this year.

That makes KarXT’s closest rival evenamide, which modulates glutamate and blocks voltage-gated sodium channels and is currently in late-stage testing for patients with treatment-resistant schizophrenia as an add-on to current therapies, and as a monotherapy for those who don’t respond to current drugs.