Neurocrine Biosciences has launched a pivotal Phase 3 clinical trial program evaluating NBI-1117568, its investigational oral muscarinic M4 selective orthosteric agonist, for the treatment of adults with schizophrenia. The announcement follows promising Phase 2 results reported in August 2024, which demonstrated significant symptom improvement with a favorable safety profile.
"There is a significant need for new and innovative medicines to treat schizophrenia, a disorder that impacts millions of people and their families," said Eiry W. Roberts, M.D., Chief Medical Officer at Neurocrine Biosciences. "With positive Phase 2 data in hand, we're excited to advance this investigational novel compound that works directly and selectively at the muscarinic M4 receptor."
Phase 3 Trial Design and Endpoints
The global Phase 3 program is designed as a double-blind, placebo-controlled trial that will evaluate NBI-1117568 in adults with a primary diagnosis of schizophrenia who are experiencing an acute exacerbation or relapse of symptoms. Approximately 280 patients are expected to participate in the study.
The trial's primary endpoint is reduction from baseline in the Positive and Negative Syndrome Scale (PANSS), a standardized tool for assessing symptom severity in schizophrenia. The key secondary endpoint is improvement in the Clinical Global Impression of Severity (CGI-S) scale, which measures overall illness severity.
Promising Phase 2 Results
The decision to advance to Phase 3 was supported by positive Phase 2 data, which met its primary endpoint for the once-daily 20 mg dose. Key findings from the Phase 2 study included:
- A clinically meaningful and statistically significant reduction in PANSS total score at Week 6, with a placebo-adjusted mean reduction of 7.5 points (p=0.011, effect size of 0.61) and an 18.2-point reduction from baseline
- Statistically significant improvements across several secondary endpoints, including the CGI-S scale and Marder Factor Scores for both positive and negative symptoms
- A favorable safety and tolerability profile across all doses, with minimal gastrointestinal and cardiovascular adverse events
Novel Mechanism of Action
NBI-1117568 represents a significant innovation in schizophrenia treatment as the first and only investigational oral muscarinic M4 selective orthosteric agonist in clinical development for this indication.
Muscarinic receptors play a crucial role in brain function and have been validated as drug targets for psychosis and cognitive disorders. There are five muscarinic acetylcholine receptors involved in neurotransmission, with the M4 subtype being particularly relevant to schizophrenia pathophysiology.
As an M4 selective orthosteric agonist, NBI-1117568 offers potential advantages over existing therapies, including:
- A novel mechanism with potentially improved safety profile
- No requirement for combination therapy to minimize off-target side effects
- Direct activation of the receptor without dependence on acetylcholine for efficacy
Addressing a Significant Unmet Need
Schizophrenia represents a substantial global health burden, affecting approximately 24 million people worldwide according to the World Health Organization. In the United States alone, the annual associated costs for schizophrenia are estimated to exceed $150 billion.
The condition is characterized by heterogeneous symptoms and is one of the leading causes of disability worldwide. It often results in significant emotional and functional burden for patients and their families. Current treatment approaches rely heavily on antipsychotic medications that can cause considerable short- and long-term health impacts.
Neurocrine's Broader Muscarinic Portfolio
NBI-1117568 is part of Neurocrine's expanding portfolio of compounds targeting muscarinic receptors. The company's muscarinic agonist portfolio also includes NBI-1117567, NBI-1117569, and NBI-1117570, which were acquired from Nxera Pharma. Additionally, Neurocrine is developing NBI-1076986, an investigational selective M4 antagonist discovered and developed internally.
This muscarinic portfolio complements Neurocrine's broader focus on neurological, neuroendocrine, and neuropsychiatric disorders. The company already markets FDA-approved treatments for conditions including tardive dyskinesia, Huntington's disease chorea, classic congenital adrenal hyperplasia, endometriosis, and uterine fibroids.
Looking to the Future
If successful in Phase 3 trials, NBI-1117568 could represent an important new treatment option for schizophrenia patients, potentially offering improved efficacy and tolerability compared to current antipsychotic medications.
The advancement of this compound into late-stage clinical development highlights the ongoing innovation in the schizophrenia treatment landscape and the potential for novel mechanisms to address the significant unmet needs that remain in this challenging neuropsychiatric condition.
