Takeda Pharmaceutical Company Limited (Takeda) and H. Lundbeck A/S (Lundbeck) announced the US Food and Drug Administration (FDA) has accepted a supplemental New Drug Application (sNDA) for review to add clinical data regarding the effect of Brintellix (vortioxetine) on certain aspects of cognitive function in adults with major depressive disorder (MDD) to the current product label.

Brintellix is currently approved and available in the US for the treatment of MDD in adults. The FDA is expected to take action on this filing by March 28, 2016.

Depression includes a range of symptoms including cognitive ones. The cognitive symptoms of depression may go unrecognised by both healthcare providers and patients. Common cognitive complaints include difficulty concentrating, indecisiveness, trouble thinking and forgetfulness. These symptoms are common and many of them often persist between major depressive episodes. According to a three-year prospective study of people treated for depression, cognitive symptoms (defined as diminished ability to think or concentrate and/or indecisiveness) were reported 94 per cent of the time during major depressive episodes and 44 per cent of the time between major depressive episodes (or during periods of partial remission).

“Cognitive symptoms are often present in patients suffering from MDD and reducing these symptoms can be challenging,” explains John Zajecka, M.D., associate professor of psychiatry, Rush University Medical Center, in Chicago. “Many patients continue to experience certain cognitive and other symptoms even after improvement in their MDD.”

The sNDA is primarily based on the FOCUS and CONNECT studies, which were specifically designed to assess the effect of Brintellix on certain aspects of cognitive function in adult patients with MDD utilising objective measures of cognitive function. These two 8-week, randomized, double-blind, placebo-controlled studies of Brintellix 10 and 20 mg/day used a well-established neuropsychological test (the Digit Symbol Substitution Test or DSST). The DSST performance measurement involves executive function, processing speed and attention.

“If approved by the FDA, Brintellix would be the first treatment for MDD to include clinical trial data showing an effect on certain aspects of cognitive function in the US label. We look forward to working with the Agency as it considers this important need for patients with MDD,” said Charlie Baum, M.D., vice president, US medical affairs, Takeda.

“The rigorous studies we have conducted with Brintellix evaluating the effects on certain aspects of cognitive functioning in patients with MDD are examples of the commitment our companies have to assessing prevalent cognitive symptoms in patients with MDD - in particular, a core set of symptoms that remain problematic for many people with depression,” said Staffan Schuberg, president, Lundbeck U.S.

“We look forward to contributing to this emerging area of clinical understanding with the hopes of increasing the awareness of the burden of this disorder.”

The FDA approved Brintellix on September 30, 2013 for the treatment of MDD in adults. The mechanism of the antidepressant effect of Brintellix is not fully understood. It is an inhibitor of serotonin (5-HT) reuptake and that is thought to be a mechanism of its action. It is also an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors and an antagonist at 5-HT3, 5-HT1D and 5-HT7 receptors. The contribution of each of these activities to Brintellix’s antidepressant effect has not been established. It is considered to be the first and only compound with this combination of pharmacodynamic activity. The clinical relevance of this is unknown.

Brintellix was discovered by Lundbeck researchers in Copenhagen, Denmark. The clinical trial programme in the US was conducted jointly by Lundbeck and Takeda, and Takeda holds the new drug application for the US market. Brintellix is a trademark of H. Lundbeck A/S and is used under license by Takeda Pharmaceuticals USA, Inc.

The World Health Organisation has issued an Anatomical Therapeutic Chemical (ATC) code for Brintellix that places it in the category of “other” antidepressants.

The most commonly observed adverse events in MDD patients treated with Brintellix in 6-8 week placebo-controlled studies (incidence greater than or equal to 5 per cent and at least twice the rate of placebo) were nausea, constipation and vomiting. Overall, 5 to 8 per cent of the patients who received Brintellix 5 to 20 mg/day in short-term trials discontinued treatment due to an adverse reaction, the most common being nausea, compared with 4 per cent of placebo-treated patients in these studies. Brintellix and other antidepressants may cause serious side effects.

In clinical studies, Brintellix had no significant effect on body weight as measured by the mean change from baseline in 6-8 week placebo-controlled studies. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to Brintellix during the initial 12-week, open-label phase, there was no significant effect on body weight between Brintellix and placebo-treated patients. Brintellix has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.

The recommended starting dose of Brintellix is 10 mg once daily without regard to meals. The dose should then be increased to 20 mg/day, as tolerated, because higher doses demonstrated better treatment effects in trials conducted in the USA dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses. The available doses provide important flexibility for physicians to help address the variability of patient needs.

Brintellix is available as 5 mg, 10 mg and 20 mg tablets.

Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals.

Lundbeck is a global pharmaceutical company specialized in brain diseases.