First patient enrolled in phase 2 trial in major depressive disorder.
NSI-189, the lead compound in Neuralstem's neurogenic small molecule program, is a proprietary new chemical entity that stimulates neurogenesis, synap ogenesis 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 Maurizio Fava.
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 Fava. "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.
In animal models, there were 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 an 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, 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.
The 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 rerandomized 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 percent powered to show an improvement in primary endpoint, compared to placebo, with an effect size of d=0.5 (p [less than or equal to] 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.
In related news, the company announced that it will sell 2,700,000 shares of its common stock and warrants to purchase 2,700,000 shares of common stock in a private placement.
The securities are being sold in a private offering at a price of $0.40 a share and one common stock purchase warrant.
The warrants have an exercise price of $0.40 per share, are immediately exercisable and expire on the fifth anniversary of the date of issuance.
The shares of common stock and warrants are immediately separable and will be issued separately.
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|Title Annotation:||In The Clinic...|
|Publication:||Stem Cell Business News|
|Article Type:||Clinical report|
|Date:||May 16, 2016|
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