Karuna opposes the neuro tendency

The psychiatry space has had its fair share of victims of biopharmaceuticals. But Karuna made light work of this difficult field today, claiming an emphatic victory in the pivotal Emergent-2 study of its new schizophrenia project KarXT.

Karuna still needs to gather more long-term safety data, however, and doesn’t even expect to submit KarXT to the FDA until mid-2023. But approval seems likely, so attention will turn to whether the company can make a successful solo launch by Karuna still insists she can make it on her own in the US. Still, investors may have one eye on a potential payout.

These investors sent Karuna shares up 55% at the open today. Group rival Cerevel also gained 17% this morning, although that company’s selective muscarinic project is lagging somewhat behind, with Phase 2 data due in 2024.

Exceeded expectations

There should be sustained demand for a new class of antipsychotic drugs, given that existing drugs that hit dopamine and serotonin receptors leave much to be desired.

Karuna executives talked about KarXT’s universal appeal during a conference call today. “I see clinicians using and prescribing this drug everywhere, in every patient category,” said group chief executive Steve Paul. He cited untreated patients, those who responded to current antipsychotics but experienced unpleasant side effects such as weight gain, and patients who had a suboptimal response to current medications.

Before the Emergent-2 data, some analysts expected KarXT to be largely reserved for people who didn’t respond to existing therapies; the current Rate Pharma Hence, the consensus from sellers of $1.7 billion in sales by 2028 could be due for an upgrade.

The headline findings certainly look impressive. The study met its primary endpoint, change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at week five, with KarXT-treated patients showing a decrease of 21.2 points, versus a decrease of 11.6 points in the placebo group.

That 9.6-point delta wasn’t too far from the 11.6-point spread seen in the Phase 2 Emergent-1 trial and well above the seven-point spread investors wanted to see, according to Stifel analysts.

Also impressive was the fact that Emergent-2 found a statistically significant benefit on the secondary endpoint of negative symptoms of schizophrenia, which have historically been difficult to address.

Adverse events

There are still some blanks to fill in around side effects, especially cholinergic side effects like nausea and vomiting. The project is a co-formulation of the muscarinic agonist xanomeline with trospium chloride, a peripheral muscarinic receptor antagonist – the idea being that trospium reverses the peripheral side effects of xanomeline but does not prevent its effects in the brain.

All Karuna says for now is that KarXT’s safety profile is consistent with previous studies, with cholinergic side effects being mild to moderate and “mostly transient in nature.”

As for other adverse events previously flagged as ones to watch for, Caruna noted that there were increases in blood pressure in Emergent-2, but added that blood pressure measurements were similar to placebo.

And, as in phase 2, there were increases in heart rate, but they “diminished in magnitude by the end of the trial.”

Overall, the discontinuation rate related to adverse events should be reassuring, at 7% with KarXT and 6% with placebo. And KarXT is not associated with the weight gain and drowsiness seen with older antipsychotics.

The company doesn’t believe it will need more efficacy data for a U.S. filing, but investors still have nearly a year to wait for news on that front.

KarXT trials
Trial Setup Status
Emergent-1 Patients with schizophrenia, versus placebo Done, hit
Emergent-2 Patients with schizophrenia, versus placebo Done, hit
Emergent-3 Patients with schizophrenia, versus placebo Key figures are expected for the first quarter of 2023
Emergent-4 Open ambulatory extension of Emergent-2 & 3 Recording
Emergent-5 A 52-week open-label outpatient trial Recording
get up Outpatients with schizophrenia, in addition to current SOC Key figures are expected for the first half of 2024
Get up BI Outpatients with schizophrenia, an open-label extension of Arise Recording
Adept-1 Alzheimer’s disease psychosis To begin Q3 2022
Adept-2 Alzheimer’s disease psychosis To start 2023
Adept-3 Alzheimer’s disease psychosis, open extension To start 2023
All Phase 3 except Phase 2 Emergent-1. Source: Company submission, Clinicaltrials.gov.

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