Aphase IIclinical trial for MDD failed to meet the primary depression endpoint (MADRSTooltip Montgomery–Åsberg Depression Rating Scale) in July 2017, although statistically significant improvements have been reported on a number of secondary depression and cognition endpoints.[4][5]
The compound's activity was discovered using phenotypic screening with a library of 10,269 compounds to identify compounds that promoted neurogenesisin vitro.[3] As of 2016 the target of the compound was unknown but it appeared to promote neurogenesis in rodents.[2][3]
NSI-189 completed a phase I clinical trial for MDD in 2011, where it was administered to 41 healthy volunteers.[6] A phase Ib clinical trial for treating MDD in 24 patients started in 2012 and completed in July 2014, with results published in December 2015.[1][7] In July 2017, it was announced that a phase II clinical trial with 220 patients failed to meet its primary effectiveness endpoint in MDD.[8] Upon the announcement, Neuralstem stock plummeted by 61%.[9] More detailed analysis of the trial results was released in December 2017 and January 2018. It revealed statistically significant improvements on patient-reported depression scales and in aspects of cognition for the 40 mg/day dose. Of particular note are improvements in memory (effect sizeCohen's d = 1.12, p = 0.002), working memory (d = 0.81, p = 0.020), and executive functioning (d = 0.66, p = 0.048) as measured by the CogScreen computerized test.[5]
In August 2020 another phase 2 study with 220 participants was done. An 80 mg dose of NSI-189 showed significant benefit over placebo in the subgroup of patients who were moderately depressed (MADRS <30) but was not significant in patients who were severely depressed (MADRS ≥ 30). The study concludes that NSI-189 is effective as a safe adjunctive therapy, with most compelling antidepressant and procognitive benefits noted in patients with moderate depression.[10]
^Clinical trial number NCT01310881 for "Single-Dose Pharmacokinetics (PK) Study of Novel Neurogenic Compound NSI-189" at ClinicalTrials.gov
^Clinical trial number NCT01520649 for "Multiple-Dose Pharmacokinetics (PK), and Pharmacodynamic (PD) Effect of NSI-189 Phosphate in Depression Patient Subjects" at ClinicalTrials.gov
^Johe KK, Kay G, Kumar S, Burdick KE, McIntyre RS, Papakostas GI, Fava M (August 2020). "NSI-189 phosphate, a novel neurogenic compound, selectively benefits moderately depressed patients: A post-hoc analysis of a phase 2 study of major depressive disorder". Annals of Clinical Psychiatry. 32 (3): 182–196. PMID32722729.
McIntyre RS, Johe K, Rong C, Lee Y (June 2017). "The neurogenic compound, NSI-189 phosphate: a novel multi-domain treatment capable of pro-cognitive and antidepressant effects". Expert Opinion on Investigational Drugs. 26 (6): 767–770. doi:10.1080/13543784.2017.1324847. PMID28460574. S2CID205768353.
