Takeda And Lundbeck Present Results From Pivotal Phase 3 Clinical Trials With Vortioxetine, An Investigational Compound For Major Depressive Disorder

SAN FRANCISCO, May 18, 2013 /PRNewswire/ -- Takeda Pharmaceutical Company Limited (Takeda) and H. Lundbeck A/S (Lundbeck) today announced that the companies will be presenting new data from four studies that evaluated effectiveness in treating the overall symptoms of depression in patients taking vortioxetine, an investigational agent under review with the U.S. Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). These data will be 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-Asberg Depression Rating Scale (MADRS) total score at week 8. 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 , M.D., professor of psychiatry, UT Southwestern Medical Center. "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 Center, serves as scientific advisor for Lundbeck and Takeda.

About the Studies
The studies were multicenter, 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. 

A Duloxetine-referenced Fixed Dose Study Comparing Efficacy and Safety of 2 Vortioxetine Doses in the Acute Treatment of Adult MDD Patients (Study 315 conducted in the U.S.; Poster #NR9-01):

• Vortioxetine 20 mg demonstrated significantly improved overall symptoms of MDD using the MADRS. Specifically, declines from baseline in MADRS total score +/-standard error [SE] at week 8 were -12.83(+/-0.834), -15.57(+/-0.880), ‑16.90(+/-0.884), respectively for placebo (n=161), vortioxetine 20 mg (p=0.023, n=147), and duloxetine 60 mg (p<0.001, n=152) confirming assay sensitivity. Vortioxetine 15 mg did not meet statistical significance (p=NS, n=147).
• Adverse events (AEs) reported in >/=5% of the vortioxetine group were nausea, headache, dry mouth, dizziness, diarrhea, constipation, vomiting, insomnia, fatigue, nasopharyngitis, and respiratory tract infection.

A Randomized, Double-blind, Placebo-controlled, Duloxetine-referenced Study of the Efficacy and Safety of Vortioxetine in Acute Treatment of MDD (Study 13267A conducted in Europe/South Africa; Poster #NR3-055):

• Both 15 mg and 20 mg doses of vortioxetine were statistically significantly superior to placebo in mean change from baseline in MADRS total score at Week 8, with a mean treatment difference to placebo (n=158) of -5.6 (vortioxetine 15 mg, p<0.0001, n=148) and -7.1 points (vortioxetine 20 mg, p<0.0001, n=151). Duloxetine (n=146) separated from placebo, confirming assay sensitivity.
• The most commonly reported AEs (>/=5%) in the vortioxetine group were nausea, headache, diarrhea, dry mouth, dizziness and hyperhidrosis.

A Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of Vortioxetine 10 mg and 20 mg in Adults with Major Depressive Disorder (Study 316; Poster #NR9-06):

• Vortioxetine 20 mg significantly improved overall symptoms of MDD. Specifically, mean declines from baseline in MADRS total score at week 8 were -10.77 (+/- 0.807) (n=157) for placebo and -14.41 (+/-0.845) (p=0.002, n=150) for vortioxetine 20 mg. Vortioxetine 10 mg did not meet statistical difference (p=0.58, n=155).
• The most frequently reported AEs (>/=5%) in the vortioxetine group were nausea, headache, diarrhea, dizziness, constipation, vomiting, viral upper respiratory infection, and fatigue.

A Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of Two Doses of Vortioxetine in Adults with Major Depressive Disorder (Study 317; Poster #NR9-02):

• Vortioxetine 10 mg and 15 mg did not differ significantly in improvement of overall symptoms of MDD from placebo. Specifically, mean declines from baseline in MADRS total score +/-standard error [SE] at week 8 were -12.87(+/-1.043), -13.66(+/-1.064), -13.36(+/-1.087), respectively, for placebo (n=160), vortioxetine 10 mg (n=157) and vortioxetine 15 mg (n=152).
• AEs reported by >/=5% in either vortioxetine group were nausea, headache, dry mouth, vomiting, constipation, diarrhea, dizziness and flatulence.

The four pivotal studies presented during the meeting are part of a larger NDA data package that is currently under review by the U.S. 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.

About Vortioxetine
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 percent of the patients who received vortioxetine discontinued treatment due to an adverse reaction, compared with 3.8 percent 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.

About Lundbeck                     
Lundbeck is a global pharmaceutical company highly committed to improving the quality of life of people living with brain diseases. For this purpose, Lundbeck is engaged in the entire value chain throughout research, development, production, marketing and sales of pharmaceuticals across the world. The company's products are targeted at disorders such as depression and anxiety, psychotic disorders, epilepsy, Huntington's, Alzheimer's and Parkinson's diseases. Lundbeck's pipeline consists of several mid- to late-stage development programs. Lundbeck's U.S. business is based in Deerfield, Illinois. To learn more about Lundbeck in the U.S., visit www.lundbeckus.com.

Lundbeck employs more than 5,800 people worldwide, 2,000 of whom are based in Denmark. We have employees in 57 countries and our products are registered in more than 100 countries. We have research centers in Denmark, China and the United States and production facilities in Italy, France, Mexico, China and Denmark. Lundbeck generated revenue of approximately DKK 15 billion in 2012. Lundbeck's shares are listed on the stock exchange in Copenhagen under the symbol "LUN." Lundbeck has a sponsored Level 1 ADR programme listed in the US (OTC) under the symbol "HLUYY." For additional information, we encourage you to visit our corporate site www.lundbeck.com.

About Takeda Pharmaceutical Company Limited
Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for patients worldwide through leading innovation in medicine. Additional information about Takeda is available through its corporate website, www.takeda.com.

About Takeda Pharmaceuticals U.S.A., Inc. and Takeda Global Research & Development Center, Inc.  
Based in Deerfield, Ill., Takeda Pharmaceuticals U.S.A., Inc. and Takeda Global Research & Development Center, Inc. are subsidiaries of Takeda Pharmaceutical Company Limited, the largest pharmaceutical company in Japan. The respective companies currently market oral diabetes, insomnia, rheumatology, gastroenterology and cardiovascular disease treatments and seek to bring innovative products to patients through a pipeline that includes compounds in development for diabetes, gastroenterology, neurology and other conditions. To learn more about these Takeda companies, visit www.takeda.us.

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SOURCE Takeda Pharmaceutical Company Limited; Lundbeck