Neurocrine's schizophrenia drug passes phase 2; dosing still uncertain

Results from a phase 2 trial of Neurocrine Biosciences' candidate schizophrenia drug, NBI-1117568, indicate that it met the primary trial endpoint by significantly improving the Positive and Negative Syndrome Scale (PANSS) total score. Neurocrine, based in San Diego, had licensed this muscarinic M4 selective agonist from Nxera Pharma (formerly known as Sosei Heptares) under a 2021 collaboration agreement, which grants Neurocrine the rights to develop various muscarinic receptor agonists from Nxera's portfolio.

In the phase 2 trial, NBI-1117568 successfully reduced the PANSS score by a statistically significant 7.5 points more than placebo over a 6-week period. Notably, this success was observed only in the group receiving the lowest dose of 20 mg/day. In contrast, three higher dosage groups, ranging from 40-60 mg/day, did not show significantly better results than placebo.

Patients in the 20 mg/day group also reached secondary endpoints, demonstrating 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 favorable across all dosages, with gastrointestinal effects similar in frequency to placebo and low incidence of cardiovascular events, which were deemed not clinically relevant. Additionally, weight gain associated with NBI-1117568 was comparable to that of placebo.

Dr. Maurizio Fava, Psychiatrist-in-Chief at Massachusetts General Hospital of Harvard University, commented on the trial results, stating, "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. 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."

NBI-1117568 could potentially compete with KarXT, a drug developed by Karuna Therapeutics, now a subsidiary of Bristol Myers Squibb. KarXT combines the M1 and M4 muscarinic receptor agonist xanomeline with the non-selective muscarinic antagonist trospium. Currently, KarXT is under evaluation for approval by the US FDA following positive outcomes in several phase 3 trials, with a decision expected in September.

Though NBI-1117568 is not as advanced in its development as KarXT, it may offer some advantages, such as a potentially better side effect profile. However, this remains uncertain without direct comparative studies. Effectiveness is another area of concern, as an earlier phase 2 study of KarXT showed a placebo-adjusted reduction in PANSS score of 11.6 points, while phase 3 trials demonstrated reductions of 8–10 points. 

Neurocrine faces challenges as well, notably the lack of efficacy of NBI-1117568 at higher doses, which has caused some apprehension among investors, reflected in an approximate 20% drop in share price following the announcement. Despite this, the company remains committed to developing the drug and plans to advance to phase 3 trials in 2025.

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