click to enlarge Representative sample of the effect of BCI-952 on human neural stem cells where blue is the nuclear marker; green is the neuronal marker and red is the non-neuronal marker. (Source: BrainCells)

During neurogenesis, pre-existing stem cells in the adult brain produce new brain tissue, including neurons. This process is at the core of BrainCells’ (San Diego, Calif.) approach to CNS drug development. Research published in Science in 2003 showed that antidepressant efficacy is correlated with neurogenesis and that knocking out neurogenesis blocked antidepressant action. In more recent years, scientists have discovered several other CNS diseases that may be impacted by stimulation of neurogenesis, particularly in the areas of cognition and neurodegeneration. Building on these principles, BrainCells developed an integrated assay platform to identify neurogenic drug candidates such as BCI-952, a novel combination not previously known to be effective in depression consisting of low dose buspirone (a 5HT1a partial agonist approved to treat general anxiety disorder) and melatonin. Using its proprietary, human neural stem-cell based and animal-based assays, BrainCells was able to confirm the combination’s neurogenic effects in vitro, in vivo, and activity in behavioral models for depression. Using this information, the company was also able to identify the appropriate ratio and dosage for an initial clinical trial.

Encouraged by BrainCells’ preclinical data, a group at Massachusetts General Hospital conducted a six week proof-of-concept clinical study with 142 patients to evaluate the efficacy of BCI-952 for the treatment of major depressive disorder (MDD). The study compared the neurogenic combination to both placebo and buspirone alone. After six weeks, BCI-952 demonstrated a positive clinical impact on depression symptoms with improvements in multiple clinical endpoints of depression including the Clinical Global Impressions Scale for improvement (CGI-I), the Inventory of Depressive Symptoms (IDSC30), the Hamilton Anxiety Scale, and the patient-rated Quick Inventory of Depressive Symptomatology (QIDS SR-16) as compared to placebo or buspirone alone. In addition, BCI-952 was well tolerated, with a safety profile similar to placebo.

Results from this trial validate neurogenesis as a therapeutic target for depression, with the potential to change the way depression—and potentially other CNS diseases—are treated. BrainCells plans to initiate additional studies to confirm the effectiveness of BCI-952.