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

Mol Psychiatry. 2016 Oct;21(10):1372-80. doi: 10.1038/mp.2015.178. Epub 2015 Dec 8.

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.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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