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Euthymics’ EB-1010 acts on three neurotransmitters—serotonin, norepinephrine and dopamine—in a ratio of 1 to 2 to 8. EB-1010 is intended for patients with major depressive disorder who do not respond adequately to a single course of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), the most common medications in the $20 billion global antidepressant market. However, a large subset of patients with major depressive disorder, about 66%, do not experience remission after initial treatment with SSRIs, according to the STAR*D study, a large seven-year study sponsored by the National Institute of Mental Health. Even substituting an SNRI did not improve outcomes. However, STAR*D also showed that outcomes improved when patients were treated with multiple medications to modulate serotonin, norepinephrine and dopamine. EB-1010 recapitulates this triple profile in a single molecule.

There is great need for an effective medication with a favorable side effect profile for the millions of patients who do not respond fully to or are not compliant with current antidepressant treatments, such as SSRIs or SNRIs,�?? said the principal investigator of the TRIADE study Maurizio Fava, M.D., Professor of Psychiatry at Harvard Medical School and Executive Vice Chair of the Department of Psychiatry at Massachusetts General Hospital. �??It is exciting to be involved in the study of this novel serotonin-preferring triple reuptake inhibitor.�??

Results of a previous phase 2 trial presented at the 2010 annual meeting of the American College of Neuropsychopharmacology (ACNP) showed that EB-1010 was effective in treating MDD based on multiple standard measures of outcome. The trial also showed that EB-1010 improved measures of anhedonia and was well tolerated, without the weight gain or sexual dysfunction associated with the most common pharmacological treatments for depression.

Anthony A. McKinney, President and CEO of Euthymics, said, �??The promising results we reported previously at ACNP provided important validation for the potential of EB-1010’s unique profile to treat a large segment of the patient population with major depression. We believe EB-1010 has the potential to become the first triple reuptake inhibitor to achieve the efficacy of multiple neurotransmitter reuptake inhibitors in a single medication, and we are eager to further evaluate its potential with the TRIADE clinical trial.�??

As a serotonin-preferring triple reuptake inhibitor, EB-1010 demonstrates greatest affinity for the transporters for serotonin reuptake; it is half as potent for norepinephrine and has one-eighth the potency for dopamine, resulting in a ratio of 1:2:8. This is in contrast to balanced triple reuptake inhibitors which have equal affinity for the three monoamines, and have not demonstrated efficacy in depression. EB-1010 is delivered as monotherapy without the cost or complexity of multiple prescriptions.

The Sequential Parallel Comparison Design (SPCD), developed by TRIADE principal investigator Dr. Maurizio Fava and Dr. David Schoenfeld, identifies placebo non-responders and adds an active comparator arm to increase efficiency and cancel out confounding placebo responses, a major issue in clinical trials for psychiatric disorders. Dr. Fava and his colleagues developed this trial design with the aim of reducing both the overall placebo response rate and the sample size required for such trials. An SPCD trial involves two stages of treatment. Stage I is aimed at: (1) comparing drug and placebo, as in a conventionally designed single phase trial and (2) generating a cohort of placebo non-responders. Stage II is aimed at comparing drug and placebo, as in a conventionally designed single phase trial design. However, stage II includes only individuals who were placebo non-responders (Psychotherapy and Psychosomatics 2003;72:115–127). The TRIADE trial adds an active comparator, paroxetine, in order to confirm the trial is working, and also to highlight possible differences in EB-1010 versus paroxetine in terms of sexual function, weight gain and cognition.

Euthymics Bioscience, Inc. is a neuroscience-focused clinical-stage company developing next-generation treatments for central nervous system disorders. The company’s lead product candidate, EB-1010 for depression, is a triple reuptake inhibitor that acts on serotonin, norepinephrine and dopamine in a specific ratio and is given as monotherapy (a single capsule). EB-1010 has demonstrated proof-of-concept efficacy as treatment for major depression without causing weight gain or loss of sexual function, which often lead to poor adherence to standard antidepressants.

Euthymics is also developing a second triple reuptake inhibitor, EB-1020, which is at the pre-IND stage, for adult ADHD. Unlike EB-1010, EB-1020 is a norepinephrine and dopamine-preferring triple in a ratio of 1 to 6 to 14 for norepinephrine, dopamine and serotonin, respectively.