A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients.

Abstract

We wanted to examine tolerability and efficacy of NSI-189, a benzylpiperizine-aminiopyridine neurogenic compound for treating major depressive disorder (MDD). This was a Phase 1B, double blind, randomized, placebo controlled, multiple-dose study with three cohorts. The first cohort received 40 mg q.d. (n=6) or placebo (n=2), the second cohort 40 mg b.i.d. (n=6) or placebo (n=2), and the third cohort 40 mg t.i.d. (n=6) or placebo (n=2). Twenty-four patients with MDD were recruited, with the diagnosis and severity confirmed through remote interviews. Eligible patients received NSI-189 or placebo for 28 days in an inpatient setting with assessments for safety, pharmacokinetics (PK) and efficacy. Outpatient follow-up visits were conducted until day 84 (±3). NSI-189 was relatively well tolerated at all doses, with no serious adverse effects. NSI-189 area under the curve increased in a dose-related and nearly proportional manner across the three cohorts, with a half-life of 17.4-20.5 h. The exploratory efficacy measurements, including Symptoms Of Depression Questionnaire (SDQ), Montgomery-Asberg Depression Scale (MADRS), Clinical Global Impressions-Improvement (CGI-I), and The Massachusetts General Hospital (MGH) Cognitive and Physical Functioning Questionnaire (CPFQ) showed a promising reduction in depressive and cognitive symptoms across all measures for NSI-189, with significant improvement in the SDQ and CPFQ, and a medium to large effect size for all measures. These improvements persisted during the follow-up phase. In summary, NSI-189 shows potential as a treatment for MDD in an early phase study. The main limitation of this preliminary study was the small sample size of each cohort.

• Authors: M Fava, K Johe, L Ereshefsky, L G Gertsik, B A English, J A Bilello, L M Thurmond, J Johnstone, B C Dickerson, N Makris, B B Hoeppner, M Flynn, D Mischoulon, G Kinrys, M P Freeman
• Journal: Molecular psychiatry (Mol Psychiatry) Vol. 21 Issue 10 Pg. 1372-80 (10 2016) ISSN: 1476-5578 [Electronic] England
• PMID: 26643541 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Biomarkers, Pharmacological
• NSI-189
• Piperazines
• Serotonin Uptake Inhibitors

Topics

• Adult
• Aminopyridines (administration & dosage, pharmacokinetics)
• Biomarkers, Pharmacological (blood)
• Depression (blood, drug therapy, metabolism)
• Depressive Disorder, Major (blood, drug therapy, metabolism)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Humans
• Male
• Middle Aged
• Piperazines (administration & dosage, pharmacokinetics)
• Psychiatric Status Rating Scales
• Selective Serotonin Reuptake Inhibitors (administration & dosage, pharmacokinetics, therapeutic use)
• Treatment Outcome