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

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, 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

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.

Figures

Figure 1
Figure 1
Consort chart.
Figure 2
Figure 2
Mean±s.e. plasma concentrations of NSI-189 on days 1, 14 and 28 during oral administration of 40 mg Q24H to subjects with MDD—linear axes (left panel) and semi-logarithmic axes (right panel). MDD, major depressive disorder.
Figure 3
Figure 3
Mean±s.e. plasma concentrations of NSI-189 on days 1, 14, and 28 during oral administration of 40 mg Q12H to subjects with MDD—linear axes (left panel) and semi-logarithmic axes (right panel). MDD, major depressive disorder.
Figure 4
Figure 4
Mean±s.e. plasma concentrations of NSI-189 on days 1, 14, and 28 during oral administration of 40 mg Q8H to subjects with stable depression — linear axes (left panel) and semi-logarithmic axes (right panel). MDD, major depressive disorder.
Figure 5
Figure 5
(a–d) Efficacy outcomes in means over time.
Figure 6
Figure 6
The means over time of the hippocampal and amygdala volumes (a–d).
Figure 7
Figure 7
Topographs of high-frequency alpha (10–12 Hz) comparing baseline with day 28.

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