Takeda Pharmaceutical Company Limited and H Lundbeck have announced the  new data from four studies which evaluated effectiveness in treating the overall symptoms of depression in patients taking vortioxetine, an investigational agent under review with the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). These data presented at the 2013 American Psychiatric Association Annual Meeting (APA) in San Francisco.

The objective of these four studies was to evaluate the efficacy and safety profile of vortioxetine in doses ranging from 10-20 mg per day, complementing other studies in the New Drug Application (NDA) submission package that included dose ranges of 5-20 mg per day. Three of the four pivotal studies met the primary efficacy endpoint as measured by the change from baseline of the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week eight. Statistically significant improvements in overall symptoms of depression were demonstrated, as compared to placebo. A fourth study did not meet the primary endpoint. Results of all four studies provided additional information regarding the safety profile of vortioxetine.

“It is important that we continue to seek new options in depression because, even though there are effective treatments available, many patients remain symptomatic,” said Madhukar Trivedi, MD, professor of psychiatry, UT Southwestern Medical Centre. “As a clinician, I’m encouraged by these data. They represent an important addition to the broader clinical profile for vortioxetine and support its potential as a new treatment for patients living with MDD.”

Dr Trivedi, director of UT’s Southwestern Depression Centre, serves as scientific advisor for Lundbeck and Takeda.

The studies were multi-centre, randomized, double-blind, parallel-group trials of adult patients taking vortioxetine designed to assess improvement in overall symptoms of depression at week 8 with vortioxetine, compared to placebo. Two studies included an established depression therapy, duloxetine, as an active reference arm that validated the studies and confirmed “assay sensitivity”. The four studies were also conducted to assess and provide further information on vortioxetine’s safety profile.

These four pivotal studies presented during the meeting are part of a larger NDA data package that is currently under review by the US FDA that includes data from seven positive studies – six short-term studies and one long-term maintenance study – conducted in regions throughout the world. The vortioxetine global clinical program evaluated the effectiveness and safety profile of vortioxetine in a broad dose range of 5-20 mg per day and included more than 7,500 total subjects.

Vortioxetine (currently under review with the FDA) is an investigational antidepressant with multimodal activity that is thought to work through a combination of two mechanisms of action: receptor activity modulations and reuptake inhibition.

In vitro studies indicate that vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the serotonin (5-HT) transporter (SERT). In vivo non-clinical studies have demonstrated that vortioxetine enhances levels of the neurotransmitters serotonin, noradrenaline, dopamine, acetylcholine and histamine in specific areas of the brain.

Across the doses of 5-20mg, the most commonly observed adverse reactions in MDD patients treated with vortioxetine in placebo-controlled studies (incidence =5% and at least twice the rate of placebo) were: nausea, constipation and vomiting. Overall, 6.5 per cent of the patients who received vortioxetine discontinued treatment due to an adverse reaction, compared with 3.8 per cent of placebo-treated patients in these studies. Nausea was the most common adverse reaction reported as a reason for discontinuation and considered to be drug-related.

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