The European Commission has approved H. Lundbeck's marketing authorization application for Brintellix (vortioxetine) in treatment of adults with major depressive episodes, commonly referred to as depression. The European approval follows approval by the US Food and Drug Administration (FDA) in September 2013.
"The approval of Brintellix marks yet another step for Lundbeck in a very successful year," said executive vice president Anders Gersel Pedersen, Head of Research & Development at Lundbeck. "With its novel multimodal mechanism of action, we are confident that Brintellix advances both the science and the treatment of a complex and heterogeneous disease consisting of emotional, physical and cognitive symptoms that make it difficult for many patients to achieve full recovery from their disease.”
The approval of Brintellix was based on the review of one of the most comprehensive global clinical development programmes in depression, involving more than 7,000 patients. Approximately 4,000 patients were treated with Brintellix in 12 short-term (six to eight weeks), placebo-controlled studies of patients with an acute episode of major depression. In nine of the 12 studies, Brintellix showed statistically significant and clinically relevant effects on depression relative to placebo. One of these studies was a dedicated study in the elderly.
The symptoms of depression were assessed using the Montgomery and Åsberg Depression Scale (MADRS) or Hamilton Depression Rating Scale (HAM-D24). The clinical relevance was supported by significant effects observed in the proportions of responders and remitters and in the improvement in the Clinical Global Impression — Global Improvement (CGI-I) score. A dose response was observed with the efficacy of Brintellix increasing with higher doses.
Furthermore, efficacy of Brintellix has also been demonstrated in patients with an acute episode of major depression and with a suboptimal response to treatment with an SSRI or SNRI. In a 12-week head-to-head study (REVIVE) versus the most recently approved antidepressant in the EU, agomelatine. Brintellix was significantly superior to agomelatine after both 8 (primary end point) and 12 weeks, as measured by improvement in the MADRS total score and by the proportion of remitters and improvement in the CGI-I and Sheehan Disability Scale (SDS) scores.
The recommended starting and treatment dose of Brintellix is 10 mg once daily in adults less than 65 years of age. The dose may be increased to a maximum of 20 mg once daily or decreased to a minimum of 5 mg once daily, depending on individual patient response.
The multimodal pharmacological profile of Brintellix is considered responsible for the antidepressant and anxiolytic-like effects of the compound and the potential improvement of cognitive performance, learning and memory observed with the product in pre-clinical studies.
The approval will be applicable to all 28 European Union member states plus Iceland, Liechtenstein and Norway. Subject to the completion of pricing and reimbursement discussions, Lundbeck expects to launch Brintellix in its first markets in the second half of 2014.
The mechanism of action of vortioxetine is thought to be related to its direct modulation of serotonergic receptor activity and inhibition of the serotonin (5-HT) transporter. Nonclinical data 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 5-HT transporter, leading to modulation of neurotransmission in several systems. In vivo non-clinical studies have demonstrated that Brintellix modulates neuronal firing and neurotransmitter release in multiple systems, resulting in enhanced levels of serotonin, noradrenaline, dopamine, acetylcholine and histamine, reduction of GABA and increase of glutamate in specific areas of the brain. This multimodal activity is considered responsible for the antidepressant and anxiolytic-like effects and the improvement of cognitive function, learning and memory observed with vortioxetine in animal studies. However, the precise contribution of the individual targets to the observed pharmacodynamic profile remains unclear and caution should be applied when extrapolating animal data directly to man.
The World Health Organization has issued a new Anatomical Therapeutic Chemical (ATC) code for Brintellix for implementation in 2014.