NSI-189, a benzylpiperizine-aminiopyridine, is a novel chemical developed by Neuralstem Inc.for the treatment of major depressive disorder, based on preclinical evidence of neurogenesis inhuman hippocampus-derived neural stem cells in vitro and in mouse hippocampus in vivo. NSI-189 has also shown behavioral efficacy in the novelty suppressed feeding after daily oral administration for 28 days. This is an early phase, double-blind, randomized, placebo-controlled, multiple-dose study with three ascending cohorts. The first cohort received 40 mg QD, these cond cohort 40 mg BID, and the third cohort 40 mg TID. 24 patients with major depressive disorder (MDD) were recruited, with their diagnosis and illness severity confirmed through an independent, remote SAFER interview from the MGH CTNI raters. Each cohort included at least 3 female subjects. Each patient underwent a Screening for eligibility (Day -37 to Day -6 or -3) and eligible patients were admitted into the unit on Day -5 to complete their wash-out and bere confirmed for eligibility and for baseline assessments. Eligible patients receive daily dosing of investigational medicinal product (NSI-189 Phosphate or placebo) for 28 days starting on Day 1and were followed for safety, PK, and PD until discharge. At the conclusion of in-house dosing(Day 28), patients remained in the unit for up to 3 additional days, at the psychiatrist’s discretion.On Day 35 (± 3), Day 42 (± 3), Day 49 (± 3) and Day 70 (± 3) outpatient follow-up visits took place. Patients returned to the unit for extensive follow-up on Day 56 (± 3) and Day 84 (± 3)(End-of-study). The efficacy assessments included the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinician Global Impression – Improvement (CGI-I), the Symptoms of Depression Questionnaire (SDQ) and the Cognitive and Physical Functioning Questionnaire(CPFQ). Despite the minimal improvement observed among the placebo-treated patients, at day28, the efficacy measurements showed a clinically meaningful reduction in depressive and cognitive symptoms across all measures for the two lower doses (40 mg/day and 80 mg/day) but not for the highest dose (120 mg/day). These improvements appeared to persist over time during the follow-up for MADRS, SDQ, and CPFQ. In terms of safety, no serious AEs occurred and the drug was well tolerated. The main limitations of this study are the relatively small sample size ofeach cohort and the fact that efficacy analyses were not the primary aim, and were meant to beonly descriptive in nature. In summary, a novel neurogenic compound, NSI-189, has shown promise as a potential treatment for MDD in a Phase 1B, double-blind, randomized, placebo-controlled, multiple-dose study with three ascending cohorts. These preliminary findings support the view that a neurogenesis-based platform can identify promising new treatments for MDD(Fava et al, 2012). The possible inverted U dose-response curve observed in this study is consistent with previously reported inverted U dose-response curve of compounds enhancing synaptic plasticity (Lavergne and Jay, 2010). Further studies are necessary to confirm these preliminary observations.
http://ascpmeeting.org/wp-content/uploads/2014/05/ASCP-Oral-Abstract-Book-Online.pdf
Looks promising for NSI-189. Let's hope that it completes all phases and reaches the market.
