NEW YORK—“Bipolar depression affects 6 million Americans, or about 2.8 percent of the U.S. population age 18 and older, who are at 15 times the risk of suicide as the rest of the population,” said Dr. Sharon Mates, founder, chairman and CEO of Intra-Cellular Therapies Inc. “Bipolar depression has a limited number of approved treatments.”
The National Institute of Mental Health defines bipolar disorder as a serious psychiatric condition characterized by episodes of mania or hypomania interposed with episodes of depression. Bipolar depression is the most common clinical presentation of bipolar disorder. Episodes tend to last longer, recur more often and have a worse prognosis than the manic/hypomanic episodes. During periods of depression, there may be risky behavior, crying, a negative outlook on life and poor eye contact with others. The risk of suicide among those with the illness is high at greater than 6 percent over 20 years, while self-harm occurs in 30 to 40 percent. The causes are not clearly understood, but both environmental and genetic factors play a role.
Intra-Cellular Therapies, a biopharmaceutical company focused on the development of therapeutics for central nervous system disorders, has had top-line results in two Phase 3 clinical trials evaluating lumateperone as monotherapy in the treatment of major depressive episodes associated with bipolar I or bipolar II disorder. Mates believes that the results indicate the potential of lumateperone as a treatment option in a broad range of psychiatric conditions, citing its “unique pharmacology.”
Study 404 met its primary endpoint of change from baseline at week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score versus placebo (p<0.001; effect size = 0.56). Benefits of lumateperone were statistically significant in both bipolar I and bipolar II patients. The study also met its key secondary objective on the Clinical Global Impression Scale for Bipolar for Severity of Illness (CGI-BP-S) Total Score (p<0.001; effect size = 0.46), and was positive on the CGI component that specifically assesses depression (CGI-BP-S Depression Score; p<0.001; effect size = 0.50). In Study 401, lumateperone did not separate from placebo. A high placebo response was observed in the trial.
Both trials had favorable safety and tolerability profiles, consistent with prior results. Rates of akathisia (fidgeting), restlessness and extrapyramidal symptoms (drug-induced movements) combined were less than 1 percent, and similar to placebo in both studies. The randomized, double-blind, fixed-dose, placebo-controlled outpatient clinical trials were designed to evaluate lumateperone as a monotherapy in patients with major depressive episodes associated with either bipolar I or II disorder, who were experiencing a major depressive episode.
Study 404 was conducted worldwide in 57 sites. It included 381 patients randomized (1:1) to receive lumateperone 42 mg or placebo once daily for six weeks. Study 401 was conducted in 58 sites in the U.S. and included 554 patients randomized (1:1:1) to receive lumateperone 42 mg or 28 mg, or placebo once daily for six weeks.
Intra-Cellular Therapies is developing its lead drug candidate, lumateperone (also known as ITI-007), for the treatment of schizophrenia, bipolar disorder, behavioral disturbances in patients with dementia, depression and other neuropsychiatric and neurological disorders. Lumateperone is a molecule that provides selective and simultaneous modulation of serotonin, dopamine and glutamate, three neurotransmitter pathways implicated in severe mental illness. The compound is a potent serotonin 5-HT2A receptor antagonist, a dopamine receptor phosphoprotein modulator (DPPM) acting as a presynaptic partial agonist and postsynaptic antagonist at dopamine D2 receptors, a dopamine D1 receptor-dependent indirect modulator of glutamate (both NDMA and AMPA), and a serotonin reuptake inhibitor.
The biopharmaceutical company is also developing novel drugs for the treatment of neuropsychiatric and neurodegenerative diseases and diseases of the elderly, including Parkinson's and Alzheimer's diseases. It is leveraging technology from the lab of Nobel laureate Dr. Paul Greengard.
As of this writing, the U.S. Food and Drug Administration had canceled an advisory committee meeting that had been scheduled for July 31 to review lumateperone, saying that there was “new information regarding the application.” Thus far, ICTI had not issued a statement about the canceled meeting.