Date: 2014-06-16
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 29th International College of Neuropsychopharmacology (CINP) World Congress in Vancouver, Canada on 24 June 2014
Company: Lundbeck (Denmark)
Product: Brintellix™ (vortioxetine - Lu AA21004)
Action
mechanism: serotonin receptor agonist/serotonin receptor antagonist. Brintellix® is an inhibitor of serotonin (5-HT) reuptake and 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. Vortioxetine was discovered by Lundbeck researchers in Copenhagen, Denmark. The clinical trial program in the U.S. was conducted jointly by Lundbeck and Takeda, and Takeda holds marketing authorization for the U.S. market. Brintellix® is a trademark of H. Lundbeck A/S and is used under license by Takeda Pharmaceuticals America.
Disease: major depression
Therapeutic area: CNS diseases - Mental diseases
Country: Europe, USA, South Africa
Trial
details: 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. The four studies were also conducted to assess and provide further information on vortioxetine’s safety profile. In the CONNECT study (NCT01564862), a total of 602 subjects were randomized (198 on Brintellix, 210 on duloxetine, and 194 on placebo). Adults (18-65 years) with MDD, MADRS≥26 and self-reported cognitive dysfunction were enrolled. The primary endpoint was change from baseline to Week 8 on the Digit Symbol Substitution Test (DSST). Key secondary endpoints, patient-reported Perceived Deficits Questionnaire (PDQ) and Clinical Global Impression – Global Improvement (CGI–I) Scale at Week 8 were analyzed in a pre-specified testing sequence using the full-analysis set (FAS). Additional endpoints included the objective performance-based University of San Diego Performance-Based Skills Assessment (UPSA) to measure functionality, the Montgomery–Åsberg Depression Rating Scale (MADRS) to assess efficacy in depression, and a pre-specified path-analysis to detect direct vs indirect effects of Brintellix on cognitive function.
• 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):
• 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):
•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):
• 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).
Latest
news: * On June 16, 2014, Lundbeck announced results from the CONNECT study showing that Brintellix (vortioxetine) 10 mg/day to 20 mg/day in adults with major depressive disorder (MDD) met the primary study endpoint of demonstrating superiority versus placebo in cognitive function as measured by the Digit Symbol Substitution Test (DSST). These findings will be presented as a late-breaking poster at the 29th International College of Neuropsychopharmacology (CINP) World Congress in Vancouver, Canada on 24 June 2014. The objectives of this randomized, double-blind, placebo-controlled study were to evaluate the effects of Brintellix® on cognitive function using objective neuropsychological tests associated with executive function, processing speed and attention after eight weeks of treatment in adults with major depression (MDD), while also confirming efficacy on overall symptoms of depression. Brintellix® was statistically superior to placebo on the primary endpoint (the Digit Symbol Substitution Test or DSST) (p<0.05) and two key secondary endpoints – patient-reported Perceived Deficits Questionnaire (PDQ) and CGI-I. Brintellix was statistically superior to placebo on the MADRS (p<0.05) and UPSA (p<0.001) change from baseline at Week 8. A pre-specified path-analysis to detect direct vs. indirect effects of treatment on cognition supported that the beneficial impact of Brintellix on cognitive performance is mostly a direct effect and not only due to alleviation of overall depressive symptoms.Duloxetine was included in the study as an active reference to demonstrate assay sensitivity for depression. Duloxetine was not statistically significantly different from placebo on the primary study endpoint (DSST) or UPSA, but was significant on the PDQ, MADRS and CGI-I secondary endpoints. Common adverse events (>5%) for Brintellix were nausea, headache, and diarrhea. * On December 10, 2013, Lundbeck has announced results from FOCUS, a new study showing that Brintellix® (vortioxetine) 10 mg and 20 mg, met its primary endpoint in demonstrating superiority versus placebo in a composite score of two tests, the Digit Symbol Substitution Test (DSST) and Rey Auditory Verbal Learning Test (RAVLT), that measure cognitive function in adults with major depressioniv. In this study, Brintellix® was shown to improve measures of cognitive domains such as executive function, speed of processing and attention. FOCUS, a global, eight-week, randomized, double-blind, parallel-group, placebo-controlled, fixed-dose study evaluated the efficacy of Brintellix® on cognitive function and major depression across three arms in around 600 patients aged 18-65 with an acute episode of major depression. Cognitive function was measured in a series of validated tests that assessed changes from baseline to week 8 on specific cognitive domains known to be impaired in major depression, including executive function, speed of processing, attention and memory. On the study’s primary endpoint, Brintellix® 10 mg and 20 mg demonstrated a statistically significant improvement in cognitive performance versus placebo (0.36 and 0.33 respectively, p<0.0001)[iv], as assessed by a composite score of two validated neuropsychological tests, DSST and RAVLT. The improvement in cognitive performance was shown to include a direct effect of Brintellix® and was not solely due to improvement in depressive symptoms (MADRS score). The study also showed significant improvements in cognitive symptoms for both Brintellix 10 mg and 20 mg assessed with a patient-reported outcome questionnaire (PDQ), which supports the clinical relevance of the findings in the neuropsychological tests. The most commonly observed adverse events in patients treated with Brintellix® (incidence ?5%) were nausea (4.1%, 16.4%, and 20.8%) and headache (7.1%, 8.2%, and 12.6%) for placebo, Brintellix 10 mg and 20 mg, respectively. Overall, the most frequent primary reason for withdrawal was adverse events (AE) for placebo (4.1%), Brintellix 10 mg (3.6%) and Brintellix 20 mg (5.3%).iv. These findings also add to previously reported clinical data suggesting Brintellix improved cognitive performance in elderly patients with major depression first presented at the 2012 American Psychiatric Association Annual Meeting. Brintellix® was recently approved by the FDA for the treatment of adults with Major Depressive Disorder (MDD) and in October 2013 recommended for approval by the Committee for Medicinal Products for Human Use (CHMP) under the EMA for treatment of adult patients with Major Depressive Episodes. * On May 18, 2013, Lundbeck and partner Takeda Pharmaceutical have announced that the companies will be presenting new data on four pivotal studies on vortioxetine under review by the FDA and the EMA for the treatment of major depression. 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 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. In 2012, Lundbeck filed Brintellix® (formerly described as Lu AA21004) for regulatory approval for the indication of MDD in the EU, Canada and other markets, as well as in the US with its co-development partner, Takeda.
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. The four studies were also conducted to assess and provide further information on vortioxetine’s safety profile.
• Study 315; 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), -14.30(±0.89), -15.57(±0.880), -16.90(±0.884), respectively for placebo (n=161), vortioxetine 20 mg (p=.023, n=147), and duloxetine 60 mg (p<.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.
• Study 13267A; 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.
• 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.
• 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 (placebo=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.
* On April 8, 2013, Lundbeck has announced positive results for the REVIVE study, a double-blind randomized study of Brintellix™ (vortioxetine) versus agomelatine in adults with major depression (MDD) who changed antidepressant treatment after an inadequate response to SSRI or SNRI treatment. In this study, the objective was to compare the efficacy and tolerability of flexible dose treatment with Brintellix (10-20mg/day) versus agomelatine (25-50 mg/day) in this challenging MDD patient population. The study was conducted in Europe and one of the newest antidepressants agomelatine was chosen as a comparator because of its different mode of action from conventional SSRI/SNRI therapies.
Few randomized, double-blind studies comparing treatment strategies in MDD patients who were unresponsive to first-line antidepressant treatment have been conducted. This is one of these few studies which also shows a significant difference between treatments.
In the REVIVE study, the primary efficacy endpoint was change from baseline to week 8 in MADRS total score. Secondary endpoints included assessments of anxiety symptoms (HAM-A), global clinical judgment (CGI-S, CGI-I) and overall functioning (SDS). Patients were randomized to Brintellix (10-20 mg/day) or agomelatine (25-50 mg/day) for 12 week of double-blind treatment.
On the primary efficacy endpoint, Brintellix (n=252) was statistically significantly superior to agomelatine (n=241) (p<0.05) by 2.2 MADRS points. Significant differences in favor of Brintellix were also found for MADRS, HAM-A, CGI-S, CGI-I and SDS from week 4 onwards (p<0.05). Brintellix was well tolerated, with fewer patient withdrawals in the Brintellix group (5.9%) vs. agomelatine (9.5%). Adverse events were consistent with results from previous clinical phase III studies and included nausea (Brintellix 16% and agomelatine 9%) (incidence >5% and higher than agomelatine). Overall, this study confirms that Brintellix is efficacious and well tolerated.
Separately, Lundbeck plans to present further efficacy and safety data from its pivotal clinical programme at the 166th American Psychiatric Association (APA) Annual Meeting in San Francisco, USA, 18-22 May 2013.
