Karuna Submits Highly Anticipated NDA for KarXT in Schizophrenia

 Karuna Therapeutics announced Thursday it has submitted a New Drug Application to the FDA for KarXT, which, if approved, would offer the first new mechanism of action to treat schizophrenia in more than 50 years.

The NDA submission for KarXT, an investigational agonist of muscarinic acetylcholine 1 receptors M1 and M4, is backed by three registrational trials from the EMERGENT program. The candidate hit the primary endpoint in the EMERGENT-1, EMERGENT-2 and EMERGENT-3 trials, demonstrating a “statistically significant and clinically meaningful” reduction in total score on the Positive and Negative Syndrome Scale (PANSS) compared to placebo, according to Karuna’s press release.

This effect on negative symptoms sets KarXT apart as all currently approved therapies for schizophrenia focus on the disorder’s positive symptoms, which relate to psychosis; negative symptoms of the disease include social withdrawal, lack of motivation and apathy toward normal interests. KarXT also reduced both positive and negative symptoms on the PANSS positive, PANSS negative and PANSS negative Marder factor subscales, each of which were secondary endpoints in the trials.

In an interview with BioSpace Thursday, Karuna founder and Chief Operating Officer Andrew Miller highlighted KarXT’s safety profile.

“We see some of the most substantial considerations around current antipsychotics of weight gain and metabolic dysfunction, sedation and somnolence, motor symptoms ... and we don't see those things with KarXT because of the underlying mechanism,” he said. Miller added that KarXT comes with its own safety and tolerability considerations, but said they are limited to “generally mild-to-moderate GI side effects that are transient and resolve with time.”

The NDA submission is also the first for Karuna, which was founded in 2009 and closed a $42 million Series A financing in August 2018. At the time, Robert Nelsen, co-founder and managing director of lead investor ARCH Venture Partners, said Karuna “has all of the characteristics we look for in a game-changing CNS company.”

Karuna is expecting a standard 10- to 12-month review period for KarXT, Miller said, but added, “I do think there's the possibility that we could get a priority review period based on how differentiated the product is.” 

While the schizophrenia space has seen recent disappointments, including the Phase III failure of Sumitomo Pharma and Otsuka Pharmaceutical’s ulotaront and the termination of a second Phase II trial of Roche’s ralmitaront, there are a couple of companies hot on Karuna’s trail.

Fellow Massachusetts company Cerevel Therapeutics is developing emraclidine, a positive allosteric modulator selectively targeting the M4 receptor while also minimizing the side effects associated with pan-muscarinic agonists.  Emraclidine is currently in Phase II trials. Graig Suvannavejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, told BioSpace in a previous interview that he anticipates combined peak sales for KarXT and emraclidine to be $7 billion.

Another contender, Acadia Pharmaceuticals’ pimavanserin specifically targets the negative symptoms of schizophrenia. In a Phase II trial of adults with predominantly negative symptoms, the candidate elicited significant improvements versus placebo on the 16-item Negative Symptom Assessment (NSA-16) when added to existing regimens of antipsychotics. Pimavanserin is currently being assessed in the Phase III ADVANCE 2 study, for which Acadia anticipates topline results in 2024.

https://www.biospace.com/article/karuna-submits-highly-anticipated-nda-for-karxt-in-schizophrenia-/