NSI-189, a neurogenic compound, in Phase 1b trial demonstrates clinical and
QEEG effects in major depressive disorder patients
Ereshefsky L1, English, BA. 1,2, Johnstone J3, Johe K4, Gertsik L5, Sherman S1, Fava M6, Freeman
M6
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PAREXEL International, Los Angeles Early Phase Unit
Vanderbilt University
QMetrx Inc.
Neuralstem Inc.
California Clinical Trials Medical Group
Massachusetts General Hospital, Harvard Medical School
Methodological Question Being Addressed: Phase 1B trials typically evaluate safety and
efficacy in healthy controls and have limited pharmacodynamic assessments. The use of
patients rather than healthy volunteers in early development speeds drug development,
incorporates inclusion of relevant biomarkers and behavioral endpoints. Adjudication of
patients for diagnosis and severity of illness are important measures to insure maximal signal
detection in small early development studies. QEEG may provide greater sensitivity in small
trials to detect differences from placebo, and might serve as a surrogate for efficacy. Decisions
to proceed to larger POC studies can be better informed using small patient trials.
INTRODUCTION: NSI-189, a possible treatment of MDD, stimulates neurogenesis in human
hippocampus-derived neural stem cells in vitro,in mouse hippocampus in vivo, and shows
behavioral efficacy in novelty suppressed feeding paradigm with daily 28-day oral
administration. In previous trials with SSRI’s high frequency alpha in the left posterior temporal
region has correlated with changes in mood rating scales. Evaluation of clinical endpoints and
QEEG measurements in Phase 1b studies can provide information supporting progression to
POC.
METHODS: In previous reports of a Phase 1 single-dose study, NSI-189 was shown to be rapidly
absorbed and well tolerated. This double-blind, RPCT with 3 ascending cohorts, patients (n=24)
enrolled confirmed major depressive disorder (MDD) using remote SAFER interview. Patients
were randomized to receive NSI-189 40 mg QD, BID or TID or placebo (PBO) for 28 days. Safety
EEGs surrounding Tmax and QEEG measurements for antidepressant response were obtained
6hrs post-dose on Day 14 and 28. 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).
RESULTS: A clinically meaningful reduction in depressive and cognitive symptoms across the
MADRS (Day 28 d=0.95; Day 84=0.84), SDQ (Day 28 d=0.9; Day 84=1.10), and CPFQ (Day 28
d=0.94; Day 84=1.20) assessment scales was observed for patients on NSI-189 compared with
placebo. Safety EEGs consisted of the visual inspection of all of the 20 minute clinical EEG
recordings pre vs. post dose. Most subjects showed no abnormal findings at Screening. Several
cases showed minor findings that were not considered epileptiform in character. No new EEG
findings were identified by visual inspection post-dose that were persistent in final recordings.
No seizure activity was observed in any case. The quantitative EEG analyses showed increased
high frequency alpha with NSI-189 treatment (change from baseline to Day 14 and to Day 28) in
contrast to decreased high frequency alpha or less change with placebo. The NSI-189 effect is
most prominent in the left posterior temporal (T5) (t=2.45, p=0.0247) and left parietal regions
(P3) (t=3.31, p=0.004) and is similar when comparing QEEG at baseline to either Day 14 or Day
28 assessments.
CONCLUSIONS: NSI-189, a novel compound with preclinical antidepressant properties was safely
tolerated as monotherapy in patients with MDD. These findings demonstrate a measurable
impact on NSI-189 on brain electrical activity in a population of patients with major depressive
disorder. The largest effect was seen for the active treatment group in the higher frequency alpha
range in the left posterior temporal region. This type of finding is consistent with improvement
in left temporal lobe function but may also reflect changes in activity in left mesial temporal lobe
and hippocampus. Methodologically, small Phase Ib patient studies can yield relevant data to
contribute to go no-go decisions. These preliminary findings support the further development of
NSI-189 as a potential neurogenesis activator for the treatment of depression. Limitations of this
study include the small sample size, and the sequential escalating dose structure of a Phase 1
trial.
Disclosures:
All authors’ institutions received funding from Neuralstem Inc.
Each of the author’s institutions engages in clinical trials work supported by
numerous Pharmaceutical and biotechnology companies.