Lundbeck files for regulatory approval of the novel multimodal antidepressant, vortioxetine, in Europe

• Lundbeck has filed an MAA via centralised procedure for regulatory approval of vortioxetine (Lu AA21004) in Europe
• The file is based on an extensive data package consisting of ten short and long-term studies and includes statistically significant results supporting the dose range from 5-20mg
• Vortioxetine represents the first European centralised filing of a novel antidepressant treatment since 2007
• The multimodal activity profile of vortioxetine may translate into therapeutic benefits in depression that current therapies do not sufficiently address
• Major depression is a leading cause of disability[1]. The WHO predicts depression will become the leading cause of disability by the year 2030[2]

H. Lundbeck A/S (Lundbeck) today announced the submission to the European Medicines Agency (EMA) of a marketing authorisation application (MAA) for the approval of the investigational multimodal antidepressant vortioxetine (Lu AA21004), and the dossier has been accepted for review. Vortioxetine belongs to a new generation of antidepressants that has been developed for the treatment of patients with major depressive episodes (MDE).

"I am very pleased that we now have filed vortioxetine in Europe as many people suffering from major depression still struggle to find an effective treatment," says Executive Vice President Anders Gersel Pedersen, Head of Research & Development at Lundbeck, and continues: "I am confident that the efficacy and safety data available will support a successful MAA submission for vortioxetine in major depression and we are currently working with our partner, Takeda, to file the application in the US later in the year and in Japan next year."

The data package supporting the file is substantial, consisting of ten large, placebo-controlled clinical short and long term studies in major depression using dosages from 5 to 20 mg of vortioxetine. This data package includes studies in relapse prevention and in elderly patients with major depression, both of which were presented at the 165^th Annual Psychiatric Association (APA) Annual Meeting in May 2012.

Across the programme vortioxetine was generally well-tolerated. The most common adverse event (AE) observed in patients receiving vortioxetine was nausea.

More than 5,000 individuals have been exposed to vortioxetine worldwide, including the US, across the entire clinical trial programme. Statistically significant results were established in major depression on all doses from 5 to 20mg in these studies.

Lundbeck plans to submit a new drug submission (NDS) to Health Canada for vortioxetine during the second half of this year as well. Separately, Lundbeck and Takeda, its partner in the US and Japan, plan to submit a new drug application (NDA) to the US Food and Drug Administration (FDA) during the fourth quarter of 2012 and in Japan during 2013. 

Lundbeck plans to present further efficacy and safety data from its pivotal clinical programme at the 166^th APA Annual Meeting in San Francisco, USA, 18-22 May 2013.

Lundbeck is committed to further investigate the long-term efficacy and tolerability of vortioxetine as well as its effects on cognitive symptoms (expressed as difficulty concentrating, forgetfulness and inability to make decisions) associated with depression. Vortioxetine’s potential effect on cognitive symptoms was recently shown in a study in elderly patients suffering from major depression, which was presented in May 2012 at the APA Annual Meeting in Philadelphia[3] (Poster no. 8-44) and published in the journal International Clinical Psychopharmacology[4]. 

About vortioxetine (Lu AA21004)
Vortioxetine is under investigation as a multimodal antidepressant that is thought to work through a combination of two mechanisms of action: receptor activity modulation and reuptake inhibition. In vitro studies indicate that vortioxetine is a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the serotonin 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.

The multimodal activity profile of vortioxetine may translate into therapeutic benefits in depression that current therapies do not sufficiently address.

About major depression
Major depression is a highly prevalent, serious and debilitating medical condition and is associated with significant functional impairment and reduced quality of life[5]. Depression is the leading worldwide cause of years lost due to disability, and projected to be the biggest contributor to the worldwide burden of disease by 2030. It is estimated that between a quarter and a third of the population will develop at least one episode of major depression during their life-time and of these as many as two thirds will have recurrent episodes, and one third will develop a chronic condition.

While several pharmacological treatments are available, around 50% of patients remain symptomatic following first-line treatment, and a third fail to achieve full resolution of depressive symptoms after four established treatments. This limited effectiveness by antidepressant treatments is multifactorial and can be explained by, among other factors, the significant clinical heterogeneity of the disease, tolerability factors and treatment adherence factors. 

Both in clinical practise and clinical research the main focus in major depressive disorder has been on mood symptoms. Primary measures in clinical trials, eg the MADRS, reflect changes in a range of symptoms with an emphasis on mood symptoms. The disease can though be described as a complex syndrome of emotional, cognitive and somatic symptoms. The range of symptoms patients experience includes cognitive symptoms such as difficulty concentrating, forgetfulness and inability to make decisions. Persistence of cognitive symptoms in patients with major depression can contribute to impaired work function and predict poor occupational outcome.  

The tolerability of antidepressants and patients' concerns about side effects negatively affect patient outcomes. Patients with major depression who experience at least one severe side effect are twice as likely to discontinue treatment prematurely. Common reasons for premature treatment discontinuation include weight gain, and gastrointestinal and sexual side effects.

Additional treatment strategies are needed to prevent and treat the common and debilitating symptoms of depression.

Financial guidance
The content of this release will have no influence on the Lundbeck Group's financial guidance for 2012, which was provided on 8 February 2012 in connection with the release of the financial results for 2011, and further specified in connection with the announcement of the restructuring plan on 14 June 2012.
 

Lundbeck contacts

About Lundbeck
H. Lundbeck A/S (LUN.CO, LUN DC, HLUYY) is an international pharmaceutical company highly committed to improving the quality of life for people suffering from brain disorders. For this purpose, Lundbeck is engaged in the research, development, production, marketing and sale of pharmaceuticals across the world. The company’s products are targeted at disorders such as depression and anxiety, psychotic disorders, epilepsy and Huntington’s, Alzheimer’s and Parkinson’s diseases.

Lundbeck was founded in 1915 by Hans Lundbeck in Copenhagen, Denmark. Today Lundbeck employs approximately 6,000 people worldwide. Lundbeck is one of the world’s leading pharmaceutical companies working with brain disorders. In 2011, the company's revenue was DKK 16.0 billion (approximately EUR 2.1 billion or USD 3.0 billion). For more information, please visit www.lundbeck.com.

Safe Harbor/Forward-Looking Statements
The above information contains forward-looking statements that provide our expectations or forecasts of future events such as new product introductions, product approvals and financial performance.

Such forward-looking statements are subject to risks, uncertainties and inaccurate assumptions. This may cause actual results to differ materially from expectations and it may cause any or all of our forward-looking statements here or in other publications to be wrong. Factors that may affect future results include interest rate and currency exchange rate fluctuations, delay or failure of development projects, production problems, unexpected contract breaches or terminations, government-mandated or market-driven price decreases for Lundbeck's products, introduction of competing products, Lundbeck's ability to successfully market both new and existing products, exposure to product liability and other lawsuits, changes in reimbursement rules and governmental laws and related interpretation thereof, and unexpected growth in costs and expenses.

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[1] World Health Organisation; http://www.who.int/mental_health/management/depression/definition/en/

[2] Murray CJL, Lopez AD: “The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries and Risk Factors in 1990 and Projected to 2020”.  Geneva, Switzerland; World Health Organization, 1996.

[3] Olsen et al: “Efficacy and Safety of Lu AA21004 in a Randomised, Double-Blind, Placebo-controlled, Active-referenced, Fixed-dose Study in Elderly Depressed Patients”; Poster NR8-44, APA2012

[4] Cornelius Katona et al: “A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder”; International Clinical Psychopharmacology; May 2012

[5] Tracy L. Greer et al.: "Defining and Measuring Functional Recovery from depression"; CNS Drugs 2010; 24 (4): 264-284