27 August 2014 - 27 August 2014 - US Avanir Pharmaceuticals Inc (NASDAQ:AVNR) said Tuesday it had enrolled the first patient in a Phase II trial to study the effectiveness, safety and tollerability of its agent, AVP-786, as an adjunctive therapy of major depressive disorder (MDD).

The multi-centre, randomised, double-blind, placebo-controlled proof-of-concept trial will examine the efficacy and safety of AVP-786 versus placebo for 10 weeks in about 200 patients with MDD who have had an inadequate response to commonly used antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). The trial will use novel methods to decrease the placebo response, which is frequently seen in depression studies. The primary efficacy measure is the Montgomery-Çsberg Depression Rating Scale (MADRS) total score, whereas the secondary outcome measures include evaluations of disease severity, activities of daily living and quality of life. The study will also comprise pharmacokinetics and standard safety evaluations.

AVP-786, Avanir's next-generation AVP-923 compound, contains a combination of deuterium modified dextromethorphan, an uncompetitive NMDA receptor antagonist, sigma-1 receptor agonist and inhibitor of the serotonin transporter (SERT) and norepinephrine (NET) transporter, in addition to ultra-low dose quinidine, a CYP2D6 enzyme inhibitor.

On a separate note, Avanir said it expects to disclose top-line results from the Agitation in Alzheimer's disease trial in late September or early October. The goal of the proof of concept study, including 220 Alzheimer's patients in the United States, is to assess the safety, tolerability, and efficacy of AVP-923 for the treatment of agitation in Alzheimer's patients.

The study is a 10-week, multicenter, randomized, double-blind, placebo-controlled study, also using a SPCD design intended to decrease placebo response rates. Patients were initially randomised 3:4 to get either AVP-923 (dose escalated from DM 20mg/ Q 10mg to DM 30mg/ Q 10mg) or placebo. At the end of week five, patients who initially took placebo were stratified according to their response to treatment and subsequently re-randomised 1:1 to get either AVP-923 or placebo for the remainder of the study (an additional 5 weeks of treatment). Patients who were initially given AVP-923 continued to take AVP-923 DM 30mg/ Q 10mg for the remainder of the trial.

The trial's main efficacy measure is the agitation/aggression subscale of the Neuropsychiatric Inventory or NPI. The main objective follows a standard analysis of SPCD by combining the change from baseline to week 5 (full analysis population) and change from week 5 to week 10 on the NPI agitation/aggression domain (patients who were considered "non-responders" to placebo during the initial 5 weeks). Secondary outcome measures include global assessments of disease severity, other neuropsychiatric symptoms, cognition, activities of daily living, quality of life and caregiver strain. Standard safety assessments will also be performed.