May 29, 2017
Sunovion Pharmaceuticals issued results of a phase III clinical study evaluating Latuda (lurasidone HCI) in children and adolescents (10 to 17 years of age) with major depressive episodes associated with bipolar I disorder (bipolar depression). In the six-week, randomized, double-blind, placebo-controlled study, 347 children and adolescents 10 to 17 years of age received LATUDA flexibly dosed (20 to 80mg/day) or placebo. LATUDA was associated with statistically significant and clinically meaningful improvement in bipolar depression symptoms compared to placebo, based on the primary efficacy endpoint of change from baseline to week six on the Children’s Depression Rating Scale, Revised (CDRS-R) total score (-21.0 vs. -15.3; effect size = 0.45, p<0.0001). Statistically significant and clinically relevant change from baseline to week six on the Clinical Global Impression-Bipolar Version, Severity of Illness (CGI-BP-S) score (depression) was also seen with LATUDA compared to placebo (-1.49 vs. -1.05; effect size = 0.44, p<0.0001). LATUDA was generally well-tolerated. The most common treatment-emergent adverse events (TEAEs) reported for LATUDA compared to placebo were nausea (16% vs. 5.8%), somnolence (9.1% vs. 4.7%), weight gain (6.9% vs. 1.7%), vomiting (6.3% vs. 3.5%), dizziness (5.7% vs. 4.7%) and insomnia (5.1% vs. 2.3%). LATUDA is currently indicated in the U.S. for the treatment of adults with bipolar depression as monotherapy and as adjunctive therapy with lithium or valproate and for the treatment of schizophrenia in adults and adolescents (13 to 17 years of age). These data have been submitted to the FDA to support an sNDA.
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.
July 18, 2016
Sage Therapeutics released results of a phase II trial of SAGE-547 for the treatment of severe postpartum depression (PPD). The multicenter, placebo-controlled, double-blind, 1:1 randomization trial was designed to enroll up to 32 women. The population studied were women with severe PPD (HAM-D ≥26) who developed severe depression either in the third trimester or within four weeks of childbirth. At baseline, the mean HAM-D scores for both groups was greater than 28. The primary objective of the trial was to evaluate the effect of SAGE-547 on depression as measured by the HAM-D score, compared to placebo, at 60 hours. In addition, patients were monitored during a 30-day follow-up period to assess both safety and efficacy. SAGE-547 achieved the primary endpoint of a significant reduction in the HAM-D score compared to placebo at 60 hours (p=0.008). This represented a greater than 20-point mean reduction in the depression scores of the SAGE-547 group at the primary endpoint of 60 hours through trial completion with a greater than 12-point difference from placebo. The statistically significant difference in treatment effect began at 24 hours, (p=0.006) with an effect that was maintained at similar magnitude through to the 30-day follow-up (p=0.01). Remission from depression, as determined by a HAM-D ≤7, measured at 60 hours, was seen in seven of 10 in the SAGE-547 group compared with one of 11 in the placebo group (p=0.008). Similarly, at 30 days, seven of 10 of the SAGE-547 group and two of 11 in the placebo group were in remission (p=0.03). SAGE-547 was found to be generally well-tolerated with no serious adverse events reported during the treatment and follow-up periods. The company has initiated an expansion program to determine optimal dosing of SAGE-547 in PPD.
May 25, 2015
Sunovion Pharmaceuticals issued results of Latuda (lurasidone HCl) related to adults with major depressive disorder (MDD) who presented with a limited number of associated manic symptoms (mixed features). In a randomized, double-
blind, placebo-controlled, six-week clinical trial, patients were randomized to receive six weeks of treatment with flexibly-dosed Latuda 20 – 60mg/day (N=109) or placebo (N=102). The primary efficacy endpoint in the study was change from baseline at week six in Montgomery-
Asberg Depression Rating Scale (MADRS) total score. The key secondary endpoint was change from baseline at week six in the Clinical Global Impression, Severity (CGI-S) score, which assessed global severity of illness. Results from the study showed treatment with Latuda was associated with a statistically significant reduction in MADRS total scores at the end of the study (week six) compared with placebo (-0.5 v. -13; p<0.0001; Cohen’s d effect size=0.80), with separation from placebo starting at the first post-baseline assessment (week one). In addition, patients treated with Latuda experienced a statistically significant reduction in change from baseline at week six in CGI-S scores compared with placebo (-1.83 v. -1.18; p<0.0001; Cohen’s d effect size=0.60), with separation from placebo starting at week two, as well as significant differences from placebo on all other secondary efficacy endpoints, including manic symptoms. Latuda was generally well-
tolerated with low rates of change in weight and metabolic parameters and an overall discontinuation rate lower than placebo (6.4% v. 14.7%). The most common adverse events reported with an incidence =5% and greater than placebo in patients receiving Latuda were nausea (6.4% v. 2%) and somnolence (5.5% v. 1%).
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.
November 17, 2014
Pfizer reported results of a phase IV study
of Pristiq Extended Release Tablets 50mg
and 100mg doses v. placebo focused on
sexual function in adult patients diagnosed
with major depressive disorder (MDD). In the
phase IV, multi-center, randomized, double-blind
placebo-controlled study, a total of 924
patients, 18-years or older, with a baseline
HAM-D17 score of ≥20, were randomly assigned
to Pristiq 50mg/day, Pristiq 100 mg/
day or placebo in a 1:1:1 ratio over an eight-week
period. The primary efficacy end point
for the study was the change from baseline in
HAM-D17 total score at week eight. Incidence
of sexual dysfunction was assessed using the
ASEX data. In adult outpatients with MDD
with baseline sexual activity and at least one
post-baseline assessment, effects on ASEX
total and item scores were comparable for
the Pristiq 50mg and Pristiq 100mg groups
and placebo. Rates of sexual dysfunction were
comparable between each Pristiq dose and
placebo at baseline (placebo, 52%; Pristiq
50mg/d, 56%; Pristiq 100mg/d, 54%) and at
week eight (placebo, 45%; Pristiq 50mg/d,
49%; Pristiq 100mg/d, 47%).
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.
April 29, 2013
Alkermes reported preliminary results from a phase II trial of ALKS 5461 for the treatment of major depressive disorder (MDD). This randomized, double-blind, multi-center, placebo-controlled study 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). Subjects received one of two dosing regimens of oral ALKS 5461 or placebo for four weeks. Data showed ALKS 5461 significantly reduced depressive symptoms across a range of standard measures including the study’s primary outcome measure, the Hamilton Depression Rating Scale (HAMD17) (p=0.026), the Montgomery–Åsberg Depression Rating Scale (MADRS) (p=0.004) and the Clinical Global Impression–Severity Scale (CGI-S) (p=0.035). ALKS 5461 was well tolerated. Based on these results, and positive phase I/II results, Alkermes plans to request a meeting with the FDA and advance ALKS 5461 into a pivotal development program.
January 9, 2012
Alkermes released results from a phase I/II trial of ALKS 5461 for major depressive disorder. This randomized, double-blind, placebo-controlled, parallel-group study enrolled 32 subjects who had an inadequate response to a stable dose of either a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor. The subjects received one of two sublingual dosing regimens of ALKS 5461 or placebo for seven days. In both dosing cohorts, subjects administered ALKS 5461 demonstrated greater reductions from baseline in depressive symptoms, as measured by the HAM-D17, compared to those administered placebo. In one dosing cohort, these differences in depressive severity were statistically significant. ALKS 5461 was generally well tolerated in both dosing cohorts.
October 26, 2009
Targacept issued positive results from a phase IIb trial of TC-5214 for the treatment of Major Depressive Disorder. The design of this study included two phases. In the first phase 579 subjects diagnosed with MDD received first-line treatment with Celexa (standard of care) for eight weeks, 20mg daily for the first four weeks and 40mg daily for the next four weeks, to determine the extent of therapeutic response. Subjects who did not respond well based on predefined criteria at the end of eight weeks were randomized into the double blind second phase of the trial. These subjects (n≡265) continued to received Cerexa with add-on TC-5214 or placebo for an additional eight weeks. The daily dosage of TC-5214 was initially 2mg, with an option to be increased to 4mg and to 8mg based on response. The primary endpoint , change from baseline as measured by the Hamilton Depression Rating Scale (HAM-D), was reached with statistical significance on an intent-to-treat basis. The clinical response (change from double blind baseline after eight weeks) on HAM-D was 6.0 points greater for the add-on TC-5214 arm than for the add-on placebo arm (13.75 point improvement vs. 7.75 point improvement; p<0.0001). In addition, all of the secondary outcome measures, including the Montgomery-Asberg Depression Rating Scale, the Quick Inventory of Depressive Symptomatology Self Reporting scale and assessments of irritability, disability, cognition, severity of illness and global improvement, were reached with statistical improvement (p<0.0001 for all measures). TC-5214 exhibited a favorable tolerability profile.
July 27, 2009
Targacept reported positive results from a phase IIb trial of TC-5214 for the treatment of Major Depressive Disorder (MDD). This two-stage study was conducted across India and the US. In the first stage, 579 subjects with MDD received first-line treatment with citalopram hydrobromide (standard of care) for eight weeks; 20mg daily for the first four weeks and 40mg daily for the next four weeks. The subjects who did not respond well based on predefined criteria (n≡265) were randomized into the double blind second phase of the trial where they continued their citalopram treatment and also received either add-on TC-5214 or add-on placebo for an additional eight weeks. The initial daily dosage of TC-5214 was 2mg and could be increased to 8mg based on tolerability and therapeutic response. The primary outcome measure was mean change between treatment (TC-5214 + citalopram) and placebo (placebo + citalopram) from double blind baseline as measured by the Hamilton Depression Rating Scale (HAM-D) at week 16. This endpoint was reached with statistical significance in favor of TC-5214 (p<0.0001). All secondary endpoints, including assessments of depression, irritability, disability, cognition, severity of illness and global improvement, were also highly statistically significant in favor of TC-5214.
December 3, 2007
Forest Laboratories and H. Lundbeck released positive preliminary top-line results from a phase III trial of Lexapro for the treatment of Major Depressive Disorder in adolescents. This double-blind, parallel-group, placebo-controlled study enrolled three hundred and sixteen adolescent subjects, aged twelve to seventeen, in the US. The subjects received either Lexapro (10-20 mg) or placebo for eight weeks. The primary endpoint was change from baseline to week eight on the Children's Depression Rating Scale - Revised (CDRS-R). A statistically significant improvement was observed in the subjects treated with Lexapro when compared to placebo (p=0.022). Treatment was determined to be safe and well tolerated. Pending positive final results, Forest and H. Lundbeck plan to file for regulatory approval in 2008.
October 3, 2005
DOV Pharmaceutical reported positive results of a phase II trial of their investigational triple-reuptake-inhibitor DOV 216,303 for the treatment of depression. Trial data indicated that the drug produced significant improvements relative to based line in symptom severity score on the HAM-D diagnostic scale (p<0.0001). These improvements were non-inferior to active control. No serious adverse events were noted, and to positive overall tolerability profile observed in earlier studies was maintained. This randomized, multicenter, double-blind, controlled study enrolled 67 patients, who received either 50 mg DOV 216,303 or 20 mg citalopram (an approved SSRI antidepressant), twice daily for 2 weeks.
January 18, 2005
Amarin Corporation has announced positive results of a phase IIa study of Miranox (LAX-101c), for the treatment of unresponsive major depression. Data from the first exploratory trial found that among subjects experiencing a new episode of depression, the drug produced a statistically significant improvement in symptoms on the Bech-Depression Scale over placebo, a standardized rating system for primary depressive symptomology. Retrospective analysis of a similar subset of patients from a previously completed trial with this methodology demonstrated a similarly significant efficacy profile. The placebo-controlled study randomized 77 subjects to receive either Miranox or placebo for 6 weeks; the previously completed study was a randomized, placebo-controlled trial which enrolled 70 subjects for 12 weeks.
Sepracor announced positive preliminary results of a phase IIIb/IV trial of their recently approved drug Lunesta (eszopiclone), for the treatment of insomnia in patients with co-morbid major depression. These data indicated that co-administration of Lunesta and fluoxetine (Prozac) significantly improved primary and secondary symptoms of insomnia vs. fluoxetine plus placebo, including sleep onset, wake time after sleep onset, and total sleep time (p<0.05). Furthermore, patients receiving Lunesta and fluoxetine experienced significant improvements in depression symptom severity and the proportion of patients achieving symptom response or remission vs. fluoxetine plus placebo, as measured by changes in total score on the HAM- D17 standardized scale. This double-blind, placebo-controlled ten-week study evaluated the efficacy and safety the drug in 545-patients who met DSM-IV(1) criteria for both insomnia and Major Depressive Disorder (depression). Subjects were randomized to receive either 3 mg Lunesta (n=270) or placebo (n=275) for eight weeks in addition to nightly fluoxetine, followed by a two-week Lunesta washout (fluoxetine treatment continued). Sepracor announced plans to present these data to the FDA, to discuss further development and expanded indications for the drug.