Neurocrine’s schizophrenia drug succeeds at phase 2, but dosing questions remain

Results from a phase 2 trial of the candidate schizophrenia drug, currently known as NBI-1117568, show that it met the primary trial endpoint of a significant improvement in the Positive and Negative Syndrome Scale (PANSS) total score.

The San Diego-based biotech Neurocrine Biosciences licensed the muscarinic M4 selective agonist from Nxera Pharma (then Sosei Heptares) as part of a 2021 collaboration agreement​ that allowed Neurocine to develop a number of different muscarinic receptor agonists from Nxera’s portfolio.

NBI-1117568 performed well​ in the phase 2 trial, reducing the PANSS score by a statistically significant 7.5 points more than placebo over a 6-week period. However, this achievement was only in the group receiving the lowest dose of the drug (20 mg/day). Three higher dosage groups, ranging from 40-60 mg/day in total, did not achieve significantly better results than placebo.

In the 20 mg/day group, the patients also achieved secondary endpoints of improvements in the Clinical Global Impression of Severity (CGI-S) scale, Marder Factor Score – Positive Symptom Change, and Marder Factor Score – Negative Symptom Change.

The side effect profile of NBI-1117568 appeared to be good at all doses. Gastrointestinal effects were similar in frequency to placebo, cardiovascular events were also low in frequency and were “not deemed to have clinical relevance at any dose,” according to the company. Weight gain with NBI-1117568 was also similar to placebo.

"NBI-1117568 demonstrated a clinically meaningful and statistically significant reduction in PANSS scores and was well tolerated, importantly with minimal gastrointestinal effects and no weight gain relative to placebo," said Maurizio Fava, Psychiatrist-in-Chief at Massachusetts General Hospital of Harvard University, in a press statement about the trial

"As a selective M4 orthosteric agonist, the potential of NBI-1117568 as an option that could reduce symptoms of schizophrenia with fewer side effects would be a welcome alternative to current treatments for patients and caregivers."

A possible competitor for Bristol Myers Squibb’s KarXT?​

KarXT was originally developed by Karuna Therapeutics, which is now a subsidiary of Bristol Myers Squibb. It is a combination of the M1 and M4 muscarinic receptor agonist xanomeline and a non-selective muscarinic antagonist trospium.

While not on the market yet, it is currently being evaluated for approval by the US FDA following significant success in schizophrenia patients in several phase 3 trials with a decision expected in September.

NBI-1117568 is not as advanced as KarXT but could have some advantages. For example, current findings suggest it may have a better side effect profile than KarXT, although this is hard to confirm without a head-to-head comparison.

It may not be as effective, though. An earlier phase 2 study of KarXT showed a placebo adjusted reduction in the PANSS score of 11.6 points and phase 3 trials of KarXT reduced PANSS by 8–10 points.

Another potential problem for Neurocrine, which seems to have already scared investors is the apparent lack of efficacy of NBI-1117568 at higher doses. Despite an approximate 20% drop in share price after the announcement, the company has decided to continue with developing the drug and hopes to move into phase 3 trials in 2025.