title: 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.affiliation: Massachusetts General Hospital, Clinical Trials and Network Institute, Boston, MA, USA.|Harvard Medical School, Department of Psychiatry, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Fava
authors.affiliation: Neuralstem Inc., Germantown, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Johe
authors.affiliation: PAREXEL International, Los Angeles Early Phase Unit, Los Angeles, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ereshefsky
authors.affiliation: California Clinical Trials Medical Group, Glendale, CA, USA.
authors.forename: L G
authors.initials: LG
authors.lastname: Gertsik
authors.affiliation: PAREXEL International, Los Angeles Early Phase Unit, Los Angeles, CA, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: English
authors.affiliation: Ridge Diagnostics, Research Triangle Park, NC, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Bilello
authors.affiliation: Ridge Diagnostics, Research Triangle Park, NC, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Thurmond
authors.affiliation: Q-Metrx, Inc., Glendale, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Johnstone
authors.affiliation: Center for Morphometric Analysis, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Dickerson
authors.affiliation: Center for Morphometric Analysis, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Makris
authors.affiliation: Massachusetts General Hospital, Clinical Trials and Network Institute, Boston, MA, USA.|Harvard Medical School, Department of Psychiatry, Boston, MA, USA.
authors.forename: B B
authors.initials: BB
authors.lastname: Hoeppner
authors.affiliation: Massachusetts General Hospital, Clinical Trials and Network Institute, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Flynn
authors.affiliation: Massachusetts General Hospital, Clinical Trials and Network Institute, Boston, MA, USA.|Harvard Medical School, Department of Psychiatry, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Mischoulon
authors.affiliation: Massachusetts General Hospital, Clinical Trials and Network Institute, Boston, MA, USA.|Harvard Medical School, Department of Psychiatry, Boston, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Kinrys
authors.affiliation: Massachusetts General Hospital, Clinical Trials and Network Institute, Boston, MA, USA.|Harvard Medical School, Department of Psychiatry, Boston, MA, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Freeman
mesh_terms: D000328:Adult; D000631:Aminopyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D054316:Biomarkers, Pharmacological / Q000097:blood; D003863:Depression / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D003865:Major Depressive Disorder / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011569:Psychiatric Status Rating Scales; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000631:Aminopyridines; D054316:Biomarkers, Pharmacological; D010879:Piperazines; D017367:Selective Serotonin Reuptake Inhibitors; C000620627:NSI-189