for Major Depressive Disorder
- Product status: NSI-189 Phase Ia and Ib trials completed. Multi-center Phase II first patient enrollment expected in 1Q 2016
- 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 Phase Ia and Ib trials were randomized, double-blind, placebo-controlled, multiple-dose escalating trials 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, tested 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 NSI-189/MDD Phase Ib trial in 4Q13.
In June 2014, Neuralstem’s NSI-189/MDD Phase Ib data was reported at the annual meetings of both the American Society of Clinical Psychopharmacology (ASCP), and the International College of Neuropyschopharmacology (CINP).
Data presented at the ASCP Annual Meeting by Marlene Freeman, MD, Medical Director, Clinical Trials Network and Institute, Massachusetts General Hospital, and Associate Professor of Psychiatry, Harvard Medical School, showed a clinically meaningful reduction in cognitive and depressive symptoms across all measures in depressed patients on NSI-189 active therapy against the control group, continuing for the duration of the trial, eight weeks after the 28-day treatment had stopped. Data further showed that results continued for eight weeks post-trial, despite the fact that there was no accumulation of the drug in the patients’ systems. A large effect was reported in all four scales employed in the study that are commonly used to assess clinical levels of depression and improvement: Montgomery-Asberg Depression Rating Scale (MADRS), Clinician Global Impression–Improvement (CGI-I), Symptoms of Depression Questionnaire (SDQ), and Cognitive and Physical Functioning Questionnaire (CPFQ). Based on the results, the investigators concluded that a neurogenesis-based platform could identify promising new treatments for MDD.
“Effects of NSI-189, a neurogenic compound, on quantitative electroencephalography (qEEG) in patients with major depressive disorder (MDD) during a phase 1b randomized, double-blinded, placebo controlled, multiple ascending dose study” was the title of a poster presented by Brett English, PharmD, PhD, Adjunct Assistant Professor at USC School of Pharmacy and Senior Director for Scientific Affairs at PAREXEL at the CINP Annual Meeting. The NSI-189/MDD Phase Ib qEEG data showed significantly increased brain wave patterns in the hippocampal region of the brain, and increased electrical coherence in the prefrontal cortical region, which is a pro-cognitive signal. Researchers concluded that these electrophysiological changes are consistent with the neurogenic hypothesis of the drug mechanism, which involves long-term structural changes in the hippocampus. View poster here.
In December 2015, Maurizio Fava, MD, Executive Vice Chair, Department of Psychiatry and Executive Director, Clinical Trials Network and Institute, Massachusetts General Hospital, and his study colleagues published the NSI-189/MDD Phase Ib data in the scientific journal, Molecular Psychiatry. View paper here. With such positive data supporting this novel neurogenesis-based platform, the company plans to launch a multi-center NSI-189/Phase II MDD study, with the first patient enrolled in the first quarter of 2016. This next clinical trial is expected to test two doses (40mg once a day and 40mg twice a day), along with a randomized, double-blinded, placebo control group, in approximately 200 patients with confirmed diagnosis of recurrent MDD, with the aim of confirming these extremely promising results in a larger clinical setting.
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