Depression (Treatment-Resistant)

December 18, 2017

Sage Therapeutics announced positive top-line results from the phase II, double-blind, placebo-controlled clinical trial of SAGE-217 in the treatment of 89 adult patients with moderate to severe major depressive disorder (MDD). In the trial, treatment for 14 days with SAGE-217 was associated with a statistically significant mean reduction in the Hamilton Rating Scale for Depression (HAM-D) 17-Item total score from baseline to Day 15 (the time of the primary endpoint) of 17.6 points for SAGE-217, compared to 10.7 for placebo (p<0.0001). Statistically significant improvements were observed in the HAM-D compared to placebo by the morning following the first dose through Week 4 and the effects of SAGE-217 remained numerically greater than placebo through the end of follow-up at week six. At day 15, 64% of patients who received SAGE-217 achieved remission, defined as a score of seven or less on the HAMD scale, compared with 23% of patients who received placebo (p=0.0005). Other secondary endpoints were all similarly highly significant at day 15 (p≤0.002). SAGE-217 was generally well-tolerated with no serious or severe adverse events; the most common adverse events (AEs) in the SAGE-217 group were headache, dizziness, nausea, and somnolence. A low rate of discontinuations due to AEs was reported; overall reports of AEs were similar between drug (53%) and placebo (46%), with a safety profile consistent with that seen in earlier trials. SAGE-217 was granted Fast Track Designation by the FDA in May 2017.

April 24, 2017

Allergan reported data from a multicenter, randomized, double-blind, placebo-controlled, phase II study of BOTOX for major depressive disorder (MDD). The study evaluated two different doses of BOTOX (30 units or 50 units) relative to placebo in adult females with MDD over duration of up to 24 weeks. The BOTOX 30 U dose demonstrated numerically superior efficacy in MADRS total score compared to placebo. The treatment (LS mean) difference for 30 U was -4.2 at three weeks (p=0.005); -3.7 at week six (p=0.053) and -3.6 at week nine (p=0.049). The primary end point was at week six. The 50 U did not demonstrate superior efficacy over placebo (LS mean difference was 1.3). Both secondary efficacy variables (CGI-S and HAMD-17) showed numerically superior efficacy over placebo and trended in the same direction as the primary efficacy variable for 30 U, but not for 50 U. Both 30 U and 50 U were well-tolerated. The company plans to move forward and develop a phase III program. 

February 2, 2015

Minerva Neurosciences issued preliminary results of phase I clinical studies of MIN-202. for improvements in sleep onset and sleep duration in patients with comorbid insomnia related to major depressive disorder (MDD). MIN-202 in MDD patients, trial I, was a double-blind, placebo-controlled, randomized, four-way crossover, single-dose study in 20 male and female patients with MDD and insomnia. The primary endpoint was the effect of MIN-202 (dosed PM) on latency to persistent sleep (LPS). Some additional endpoints were evaluated by PSG (polysomnography). Preliminary results demonstrated a statistically significant effect on LPS in all three doses tested (10mg, 20mg and 40mg). Treatment with MIN-202 also resulted in prolonged total sleep duration by approximately 45 minutes. MIN-202 in healthy volunteers, trial II, was a double-blind, placebo-controlled, randomized multiple-ascending-dose study in sequential cohorts of healthy males and females. MIN-202 was administered in the morning at dose levels ranging from 5mg to 60mg for 10 days. A dose level as low as 5mg was shown to elicit sedation, while dose levels =20mg induced (daytime) somnolence. MIN-202 plasma exposure was dose proportional from 5mg to 20mg. At higher doses, the exposure was less than dose proportional. In the phase I studies, MIN-202 was found to be generally well-tolerated.

January 26, 2015

Alkermes reported results of a phase III study of ALKS 5461 for the adjunctive treatment of major depressive disorder (MDD). The randomized, double-blind, parallel-arm, FORWARD-1 study evaluated the safety, tolerability and efficacy of two titration schedules of ALKS 5461 administered once daily as adjunctive treatment in 66 patients with MDD who had an inadequate response to commonly prescribed drugs for depression, including selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Patients were assigned to either a one-week or two-week titration schedule of oral ALKS 5461, for a total treatment period of eight weeks. ALKS 5461 was generally well-tolerated in both of the two titration schedules evaluated. The exploratory efficacy analyses showed ALKS 5461 significantly reduced depressive symptoms from baseline starting at week one and continued to the end of the treatment period at week eight in patients who received either of the two titration schedules. The observed changes from baseline were clinically meaningful and statistically significant (p<0.001). These data support the one-week titration schedule being utilized in the core phase III efficacy studies in the FORWARD program.

December 15, 2014

Otsuka Pharmaceutical and H. Lundbeck issued results of a phase III study of brexpiprazole as adjunctive treatment to antidepressant therapy (ADT) in patients with major depressive disorder (MDD). Patients with MDD who failed to reach adequate response during one to three treatment attempts with ADT were enrolled and received an additional trial with a (single-blind) ADT for eight weeks. Those patients who still failed to reach an adequate response throughout this phase were then randomized (double-blind) to ADT and brexpiprazole or ADT and placebo for six weeks. Adjunctive brexpiprazole showed greater improvement than adjunctive placebo in MADRS (Montgomery–Åsberg Depression Rating Scale) total score at week six in the efficacy population per final protocol in study 1 (2mg+ADT [N=175]: -3.21, p=0.0002), and in study 2 (1mg+ADT [N=211]: -1.30, p=0.0737; 3mg+ADT [N=213]: -1.95, p=0.0079). Similar results were observed for the efficacy population in both studies. Discontinuations due to adverse events were low across all groups (1mg = 1.3%, 2mg = 3.2%, 3mg = 3.5%, placebo = 0.7%) and only one patient discontinued due to lack of efficacy (in the brexpiprazole 1mg group). A NDA for brexpiprazole has been filed with the FDA and the PDUFA date is in July 2015.

November 24, 2014

Neuralstem released results of a phase Ib study of NSI-189 for major depressive disorder (MDD). In this single-site study, 24 patients with confirmed diagnosis of recurrent MDD were treated orally with NSI-189 in three equal dose cohorts (8/dose cohort; 40mg QD, 40mg BID and 40mg TID) for 28 days. Each dose cohort consisted of randomized, double-blinded, placebo controls at 1:3 ratio of placebo:drug. All subjects stayed in-clinic for the 28-day treatment period. After this period, the subjects returned to the clinic for follow-up measures for up to an additional eight weeks post-dosing. A significant number of patients on active treatment demonstrated clinical improvement by a reduction in total Montgomery-Asberg Depression Rating Scale (MADRS) scores >/= 15.9 points, which continued eight weeks after dosing stopped. The company plans to launch a large, multi-site, phase II study in the second quarter of 2015.

July 28, 2014

Neuralstem released result of a phase I study of NSI-189 for major depressive disorder (MDD). The single-site study enrolled 24 patients with confirmed diagnosis of recurrent MDD who were treated orally with NSI-189 in three equal dose cohorts (8/dose cohort; 40mg QD, 40mg BID, and 40mg TID) for 28 days. Each dose cohort consisted of randomized, double-blinded, placebo controls at 1:3 ratio of placebo: drug. In a comprehensive assessment scale for depression (Symptoms of Depression Questionnaire or SDQ), the combined treatment group showed statistically significant improvement (p=0.02) after 28 days of the drug treatment compared to its randomized, double-blinded, placebo control group. There was a large effect size of 0.90. As measured by the assessment scale of cognitive and functioning deficits specifically designed for depressed patients (Cognitive and Physical Functioning Questionnaire or CPFQ), the treatment group was significantly better than the placebo group (p=0.01) at Day 28 with a large effect size of 0.94. As measured by both by SDQ and CPFQ, NSI-189’s significant and large treatment effects continued for eight weeks, even after the drug was withdrawn. Neuralstem plans to launch a large, multi-site phase II study by the first quarter of 2015.

June 10, 2013

Alkermes reported results from a phase II trial of ALKS 5461 for the treatment of major depressive disorder (MDD). This randomized, double-blind, multicenter, placebo-controlled study involved two four-week stages run in-sequence that enrolled 142 patients with MDD who had an inadequate response to a stable dose of either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). Two doses of ALKS 5461 were evaluated, each with a 1:1 ratio of buprenorphine and ALKS 33 (lower dose of 2mg/2mg and higher dose of 8mg/8mg). The trial met the primary endpoint, met key secondary endpoints and demonstrated significant reduction in depressive symptoms versus placebo. ALKS 5461 significantly reduced Hamilton Depression Rating Scale (HAM-D17) scores from baseline (p=0.013), with a reduction of 5.3 points, compared to a reduction of 1.2 points in the placebo group at the end of the four-week treatment period. ALKS 5461 also significantly reduced Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline (p=0.004), with a reduction of 8.7 points, compared to a reduction of 1.8 points in the placebo group at the end of the four-week treatment period. ALKS 5461 was well tolerated. The most common adverse events observed in the study were nausea, headache and dizziness. Alkermes plans to initiate clinical development.