for Major Depressive Disorder
- Product status: NSI-189 Phase I trial completed; Phase II commencement expected in 2014
- Mechanism of Action: Stimulating neurogenesis
- Route of Administration: Oral
Most current major depressive disorder (MDD) treatments are oral medications that modulate levels of different neurotransmitters in the brain. One class, selective serotonin reuptake inhibitors (SSRIs), is commonly believed to be the most widely-prescribed type of antidepressants in the world.
However, a new theory on major depressive disorder is emerging. It implicates brain physiology in the disease rather than brain chemistry alone. Researchers now know that depressed patients have reduced hippocampal volume. The healthy hippocampus is a rich source of neural stem cells, from which new neurons are generated, making vital new connections throughout life. Neuralstem believes that stimulating the generation of new neurons in the hippocampus could potentially address the pathology of the depression itself.
Neuralstem’s NSI-189 Major Depressive Disorder Trial
The NSI-189/MDD trial is a randomized, double-blind, placebo-controlled, multiple-dose escalating trial evaluating the safety, tolerability, pharmacokinetics and pharmacodynamic effect of NSI-189 in the treatment of major depressive disorder. Phase Ia, initiated in February 2011 and completed in October 2011, tested escalating doses of single administration of NSI-189 in healthy normal volunteers. Phase Ib, approved by the FDA in December 2011 and commenced in June 2012, tests the safety of escalating doses of NSI-189 for 28 daily administrations in 24 depressed patients. The FDA approved dosing of the third and final cohort of depression patients in April 2013. Neuralstem completed the Phase I NSI-189/MDD trial in 4Q13.
Data presented by Marlene Freeman, MD, Medical Director, Clinical Trials Network and Institute, Massachusetts General Hospital, and Associate Professor of Psychiatry, Harvard Medical School, in June 2014, reported clinically meaningful improvement across all depressive and cognitive measures. Further, the patients’ improvement persisted throughout the full duration of the study: 28-day dosing and two-month follow-up period. Trial investigators concluded that a neurogenesis-based platform could identify promising new treatments for MDD.
Specifically, a large effect was seen in all four scales employed in the study that are commonly used to assess clinical levels of depression and improvement: CGI-I (Clinical Global Impression Improvement); MADRS (Montgomery-Asberg Depression Scale); SDQ (Symptoms of Depression Questionnaire) and CPFQ (Massachusetts General Cognitive and Physical Functioning Questionnaire). In particular, the Symptoms of Depression Questionnaire (SDQ) showed 0.02 p value at day 28 of dosing, with large effect size (Cohen’s d = 0.90), and 0.03 p value at day 84, 8 weeks after cessation of drug administration, also with large effect size (Cohen’s d = 1.10). Also in cognitive testing, measured by the CPFQ, the study recorded 0.01 p value with large effect size (Cohen’s d = 0.94) at day 28 and 0.01 p value also with large effect size (Cohen’s d = 1.20) at day 84, 8 weeks after cessation of drug administration. Effect size is a statistical term measuring the overall effect of the treatment. A value above .80 is considered to be a large effect.
Of note are two unusual findings that have not been seen in clinical trials of current depression treatments. First, the large and significant effect size of the antidepressant activity, as measured by MADRS and SDQ scores, continued for the full duration of the monitoring period, eight weeks after NSI-189 administration had been ceased. Secondly, in addition to its antidepressive effects, NSI-189 showed a significant effect size in cognitive function improvement. This cognitive improvement also continued for eight weeks after the last dose.
Neuralstem expects to commence a larger NSI-189 Phase II trial to confirm this strong data in 2014.
For more information on the trial:
- Phase Ib: http://clinicaltrials.gov/ct2/show/NCT01520649?term=neuralstem&rank=1
- Phase Ia: http://clinicaltrials.gov/ct2/show/NCT01310881?term=neuralstem&rank=1
For more information on major depressive disorder:
- National Institute of Mental Health http://www.nimh.nih.gov/health/topics/depression/index.shtml