Enrollment complete in Euthymics’ amitifadine phase 2b/3a trial for major depressive disorder

Oct 11 2012

Euthymics Bioscience, Inc. today announced completion of enrollment in the advanced clinical study of its lead product candidate amitifadine (formerly called EB-1010), a novel serotonin-preferring triple reuptake inhibitor for the treatment of major depressive disorder (MDD). The TRIADE (Triple Reuptake Inhibitor Anti-Depressant Effects) study is a phase 2b/3a clinical trial designed to assess the safety and efficacy of amitifadine. A total of 342 MDD patients were randomized at 39 centers in the US. Top-line results are expected by the end of 1Q 2013.    

Amitifadine acts on three neurotransmitters—serotonin, norepinephrine and dopamine—in a ratio of 1 to 2 to 8—and is intended to increase antidepressant efficacy while reducing the adverse effects that can limit compliance with antidepressants, including weight gain, sexual dysfunction and impaired cognition. TRIADE evaluated amitifadine for patients with MDD who did not respond adequately to one and only one course of first-line antidepressants including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion or tricyclic antidepressants, some of the most commonly used medications in the $11 billion US antidepressant market.

"We are developing amitifadine for its potential as a broad spectrum antidepressant for primary care physicians and psychiatrists to use after the patient fails to respond to a course of first-line antidepressants," said Anthony A. McKinney, President and CEO of Euthymics. "TRIADE is designed to support use of amitifadine as the next step once patients have failed initial therapy. This 'first of second-line' approach proposes amitifadine as a monotherapy for use after first-line generic antidepressants have failed but before more complex and costly drug combinations are tried."

TRIADE has incorporated advanced clinical trial techniques to reduce placebo effects and ensure quality control in patient selection. A novel clinical trial design, the Sequential Parallel Comparison Design (SPCD) was used to enhance the drug-placebo separation signal by reducing placebo response. Approximately half of all depression trials fail due to excessive placebo response and the SPCD was designed to address this intractable issue. SPCD has been previously used in three trials for depression and in each case the placebo response was substantially less, usually half of the typical 35-40% placebo response rate from typical antidepressant trials.

SPCD was co-invented by TRIADE study principal investigator Maurizio Fava, M.D., Executive Vice Chair of Psychiatry at Massachusetts General Hospital (MGH), who noted: "The TRIADE study is the largest and most advanced clinical study conducted using SPCD to-date. I was particularly interested in evaluating amitifadine in TRIADE because this is an ideal opportunity to further explore the triple monoamine concept that we first observed in the STAR*D study, a large seven-year study sponsored by the National Institute of Mental Health, where combined serotonin, norepinephrine and dopamine reuptake inhibition was shown to improve outcomes in patients with depression not responding to first-line SSRI."

Another technique, the SAFER Criteria Inventory, also developed by investigators at Massachusetts General Hospital, helps assure that only qualified patients with the appropriate severity of illness (neither too treatment-resistant nor too mild, as defined in the protocol) are admitted into the trial, addressing a second issue that has undermined recent depression trials. SAFER requires that a trained MGH psychiatrist independently confirms that the patient does in fact have MDD, is at the right clinical stage and duration, and has failed to respond to an allowed previous treatment. Although this independent screening tool can reduce the speed of enrollment, it can lead to a more homogenous target treatment population, hence strengthening the likelihood that the study will accurately detect treatment effects.

Results of a previous phase 2 trial published last year in the Journal of Psychiatric Research by Pierre Trân, M.D., Euthymics' Chief Medical Officer, and colleagues showed that at the end of the 6-week double-blind treatment, estimated mean change from baseline in MADRS was statistically superior for amitifadine compared to placebo with an overall statistical effect size of −0.601 (Cohen's d). Amitifadine was well tolerated, without the weight gain or sexual dysfunction associated with the most common pharmacological treatments for depression.