Euthymics Bioscience, Inc. today will present Phase II clinical data demonstrating that its lead product candidate EB-1010, a next-generation antidepressant, is effective for treating major depressive disorder (MDD) based on multiple standard measures of outcome for depression. EB-1010 also improved measures of anhedonia, a hallmark symptom of MDD, which is characterized by the inability to experience pleasure. The data further demonstrate that EB-1010 is well tolerated, without the weight gain or sexual dysfunction associated with the most common pharmacological treatments for depression. The data are being presented at the 49th annual meeting of the American College of Neuropsychopharmacology (ACNP) in Miami, Florida.
Euthymics' EB-1010 is a novel unbalanced triple reuptake inhibitor antidepressant intended for patients with MDD who do not respond adequately to selective serotonin reuptake inhibitors (SSRIs), a class which comprises the most common medications in the antidepressant market, which is currently valued at nearly $20 billion worldwide, according to IMS. However, a large subset of patients with major depression - about 66% - do not experience remission after an adequate initial treatment with SSRIs, according to the STAR*D study, a large seven-year study sponsored by the National Institutes of Mental Health. STAR*D also showed that outcomes improved when patients were treated with multiple medications to modulate the key monoamines associated with depression, namely, serotonin, norepinephrine and dopamine. EB-1010 replicates this triple profile in a single medication.
"These data represent convincing Phase II proof-of-concept efficacy for EB-1010 in MDD. More importantly, they validate the potential of a unique unbalanced triple reuptake inhibition profile to treat a large segment of MDD patients with significant unmet medical need," said Pierre V. TrÃ¢n, M.D., Euthymics Chief Medical Officer, and lead author on the presentation. "These results clearly support further development of EB-1010."
As an unbalanced triple reuptake inhibitor, EB-1010 demonstrates greatest affinity for the transporters that inhibit serotonin reuptake, half as much against norepinephrine reuptake and one-eighth as much against dopamine reuptake, resulting in a ratio of 1:2:8. Balanced triples have equal affinity for the three monoamines, but have not demonstrated efficacy in depression, which makes these data even more striking.
The data presented are from a multicenter, randomized, placebo-controlled, double-blind, six-week study in patients with major depressive disorder (MDD). Sixty-three patients in the U.S. and in Eastern Europe were randomized, and 56 patients were included in the modified intent-to-treat population (MITT) at a titrated dose of 50 mg/day for two weeks and then 100 mg/day for the remaining four weeks. Efficacy results were "statistically significantly" superior when compared to placebo on the primary outcome measure, the Montgomery-Ã…sberg Depression Rating Scale (MADRS, 18.16 vs. 21.99; p=0.028). Secondary measures including the Clinical Global Impression-Improvement (CGI-I) scale, compared to placebo (p=0.03) as well as anhedonia factor scores derived from the MADRS (p=0.049), were also improved. The safety evaluation showed a benign adverse event profile with no marked difference between EB-1010 and placebo. EB-1010 did not cause a loss in sexual function over the course of the trial and the study indicated a weight-neutral profile.
"Using treatment effect analysis to compare among antidepressants, EB-1010 achieved roughly double the efficacy of SSRIs with a Cohen's d of -0.63 without the side effects associated with first-line treatments for depression," said Anthony A. McKinney, President and CEO of Euthymics. "These data, when carefully analyzed, were so compelling they supported our ability to close a $24 million Series A financing, which we anticipate will be sufficient to fund a major Phase II/III trial to commence in spring 2011."
Euthymics plans to initiate TRIADE (Triple Reuptake Inhibitor Anti-Depressant Effects), a large multicenter Phase II/III clinical trial of EB-1010 in major depression in the first half of 2011. Maurizio Fava, M.D., Professor of Psychiatry at Harvard Medical School and Executive Vice Chair of the Department of Psychiatry at Massachusetts General Hospital will serve as principal investigator for TRIADE.
A second presentation at the ACNP meeting reviewed the preclinical pharmacology of EB-1010 including its inhibition of serotonin, norepinephrine and dopamine uptake transporters. The addition of dopamine to SSRIs has been shown to improve many symptoms of depression that are poorly treated by SSRIs alone. These poorly treated symptoms of depression include cognitive impairment, anhedonia, fatigue and sleepiness. Dopamine neurotransmission also diminishes troublesome effects of many current treatments including sexual dysfunction and weight gain. Dopamine likely plays an important role in the preservation of sexual function as well as the improvement in the ability to perceive pleasure (anhedonia).