Neurocrine Biosciences’ effort to chase down Bristol Myers Squibb and Karuna Therapeutics in schizophrenia just got more complicated.
In a Phase 2 readout Wednesday morning, Neurocrine reported that its drug NBI-’568 improved patients’ schizophrenia. The data appear good enough to move the candidate into Phase 3 — and potentially win an approval if it continues to hold up — but the biotech would likely face questions over whether it can compete on the market.
The results, while positive, were weaker than the company was hoping for, and fell short of Karuna’s drug KarXT, which faces an FDA decision date next month.
Eiry RobertsNeurocrine’s topline data showed the low dose of NBI-’568 induced an average 18.2-point reduction from baseline in the Positive and Negative Syndrome Scale (PANSS) after six weeks, compared with 10.8 points in the placebo group. That 7.5-point difference reached statistical significance (p=0.011), but was short of the eight-point difference that CMO Eiry Roberts said was the goal earlier this month.
While there are limits to comparing across trials, that was also a smaller difference than KarXT has shown in earlier studies. In two Phase 3 studies last year, KarXT demonstrated 8.4-point and 9.6-point differences between the active and placebo arms. A Phase 2 study from 2021 also showed an 11.6-point difference.
Investors were disappointed with the results, and Neurocrine’s stock $NBIX fell about 20% in trading Wednesday. William Blair analyst Myles Minter said that while the data weren’t a “home run,” the program warrants further development in Phase 3 studies.
Roberts told Endpoints News in an interview Wednesday that when looking at past antipsychotic and psychiatric drug classes, there has been room for multiple approved drugs. Roberts highlighted how this was the case for D2 antagonists, a class of older schizophrenia drugs.
“The differentiation that happened over time for that class was focused not necessarily on improving efficacy, but in improving benefit-risk and also improving the tolerability,” Roberts said.
Compared to KarXT, the two most important differences for NBI-’568 are the ability to take it with or without food and the smaller likelihood for off-target effects, Roberts argued.
Neurocrine’s drug is a muscarinic 4 agonist, a similar mechanism of action to KarXT, which is an M1/M4-preferring muscarinic agonist. Bristol Myers completed its $14 billion acquisition of Karuna in March, and the FDA is expected to make a decision by Sept. 26.
The dose response factor
During a call that Neurocrine held Wednesday with investors, several analysts asked about the apparent lack of a dose response across the trial arms testing four doses. None of the other three dosing groups reached statistical significance, Neurocrine said Wednesday.
But Roberts said that it’s not uncommon to see the lack of a “traditional” dose response in these kinds of psychiatric trials. CEO Kevin Gorman also acknowledged that the non-linear dose response from the Phase 2 study wasn’t that common for this class before KarXT came along, and said Neurocrine may never know why it happens.
Kevin Gorman“Will we, or any others, ever have satisfying answers to these kinds of dose response curves in psychiatry? Maybe, maybe not,” Gorman said. “It’s going to be from drug to drug, but it’s certainly been seen.”
Even though the data for KarXT appear stronger at this point, Roberts and Gorman both pointed to how in the schizophrenia setting, different “audiences” may look at different data, saying the average change on their drug’s PANSS score is still competitive for the class.
There was also a slight difference in the length of the two trials: Karuna also studied its drug’s effect out to five weeks, compared to six weeks for NBI-’568. A graph in Neurocrine’s presentation appeared to show a bigger difference between the active and placebo arms at five weeks — of 10 points — and Roberts told Endpoints that Neurocrine designed its study as a six-week trial because patients at higher doses needed a one-week titration period.
Neurocrine said its Phase 3 program is expected to begin in early 2025. In addition to Bristol Myers and Karuna, AbbVie and Cerevel are also studying an M4 muscarinic receptor agonist in schizophrenia called emraclidine, with Phase 2 results expected later this year. MapLight Therapeutics snagged a $225 million Series C late last year to run a Phase 2 trial for ML-007C-MA, its M1/M4 agonist, as well. As of March, the trial was planned to start in “late” 2024.
Editor’s note: This article has been updated to include information from Neurocrine’s investor call Wednesday morning.