NSI-189, the lead compound in Neuralstem’s neurogenic small molecule program, is a proprietary, new chemical entity that stimulates neurogenesis, synaptogenesis and increases hippocampal volume, all of which are believed to be effective in reversing depression, enhancing cognition, and promoting neuroregeneration. The Phase 2 trial will randomize 220 patients, in three cohorts (two doses plus placebo), at 12 select MDD trial sites, under the direction of principal investigator (PI) Maurizio Fava, MD, Executive Vice Chair, Department of Psychiatry and Executive Director, Clinical Trials Network and Institute, Massachusetts General Hospital.. The primary efficacy endpoint is a reduction in depression symptoms, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary endpoints encompass additional clinical outcomes, including cognition improvement measures. The trial, designed to reduce the placebo effect and site variability, will last for 12 weeks, with an observational follow-up period of six months to assess NSI-189’s long-lasting durability of benefits. Neuralstem expects to report results in the second half of 2017.
“A new class of treatment is needed in major depression, where existing compounds are not effective for all patients and have a high side effect profile, so patients discontinue treatment,” said Maurizio Fava, MD, Executive Vice Chair, Department of Psychiatry and Executive Director, Clinical Trials Network and Institute, Massachusetts General Hospital. “We were encouraged by the signs of improvement in the depression and cognitive symptoms of MDD patients, as witnessed in Phase 1 with NSI-189, and look forward to validating in Phase 2.”
“NSI-189 works via a new pathway that is different from current antidepressants. It appears to create long-lasting, positive structural changes in the brain with long-lasting clinical benefits,” commented Karl Johe, Ph.D., Chairman and Chief Scientific Officer, Neuralstem. “In animal models, we saw significant increases in neurogenesis, synaptogenesis, and hippocampal volume. In humans, the therapeutic effects seen in Phase 1b patients after completion of the 28- day dosing, persisted for additional 56 days without the drug, which supports the hypothesis of a new mechanism of action that induces long-lasting structural changes in key areas of the brain.”
In Phase 1b safety trial data in patients with MDD, published in Molecular Psychiatry. NSI-189 was shown to be safe and demonstrated large treatment effects in two key depression outcome measures. These were Symptoms of Depression Questionnaire (SDQ) and MADRS, with large effect sizes (d=0.90, p=0.02; d=0.95, p=0.09 respectively), compared to control. Effect sizes of all four measured outcomes were consistent with a medium-to- large effect size. The study also showed significant improvement in cognitive symptoms, as measured by the Cognitive and Physical Functioning Questionnaire (CPFQ), compared to placebo. Brain imaging (Quantitative EEG) showed increase in alpha brain waves in two parts of the brain (left posterior temporal and left parietal region), both involved in depression and cognition, compared to placebo. Pharmacologically, a steady state was reached after 96-120 hours across all doses. Mean time to maximal peak concentration ranged from 1 to 2 hours at day one and at day 28 of dosing. There were no significant adverse effects.
About the Trial
This Phase 2 double-blind, placebo-controlled study will test NSI-189 in a study of 220 patients with major depressive disorder (MDD) in an out-patient setting. Patients will be randomized to three cohorts: NSI-189 40 mg twice daily (BID), NSI-189 40 mg once daily (QD), or placebo. After the initial screening period, the randomized portion of the trial will be 12 weeks in duration. To reduce the placebo effect, patients who do well on placebo during the screening period will remain on placebo, whereas those who do not, will be re-randomized across the three trial arms. Patients will be evaluated along several depression measurement scales, including the MADRS and SDQ, with a primary efficacy endpoint of a reduction in depression symptoms. Secondary endpoints will include improved cognition. The study is 80% powered to show an improvement in primary endpoint, compared to placebo, with an effect size of d=0.5 (p ≤ 0.05). If either arm shows efficacy the trial can be a registration trial. Patients will continue to be followed for an additional six months after the 12-week trial period.