Results demonstrate potential to address a significant unmet for more than 30% of those suffering from treatment-resistant depression.
Husseini Manji, MD
Janssen Pharmaceuticals announced results from 2 phase 3 clinical studies of the investigational compound esketamine nasal spray in patients with treatment-resistant major depressive disorder (MDD).
The studies, presented at the 2018 American Psychiatric Association’s Annual Meeting, concluded that flexibly dosed esketamine nasal spray plus a newly initiated oral antidepressant, demonstrated a statistically significant rapid reduction of depressive symptoms compared to placebo nasal spray and a newly initiated oral antidepressant.
The study defined treatment-resistant patients as those who hadn’t responded to 2 or more currently available antidepressants of adequate dose and duration in the current depression episode.
“With about 30% of patients with major depressive depression failing to respond to currently available antidepressants, treatment-resistant depression represents a major public health need,” Husseini Manji, MD, global head, neuroscience therapeutic area, Janssen Research and Development, said in a statement. “The positive phase 3 results for esketamine nasal spray in adults with treatment-resistant depressions are exciting, particular as they mark the first time an antidepressant has achieved superiority versus an active comparator in any clinical trial for major depressive disorder.
The first study focused on adults with treatment-resistant depression where patients were randomized to flexibly dosed esketamine nasal spray (56 mg or 84 mg twice weekly) added to a newly initiated oral antidepressant or placebo nasal spray added to a newly initiated oral antidepressant.
The primary efficacy endpoint included the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score and demonstrated statistically significant clinical improvement in patients’ depressive symptoms for esketamine nasal spray plus an oral antidepressant at day 28 (Least Squares Mean Difference Standard Error from placebo nasal spray plus a newly initiated oral antidepressant: -4.0 [1.69], 95% Confidence Interval [CI]: -7.31, -0.64; one-sided p=0.010).
The first key secondary endpoint, onset of clinical response by 24 hours post-dose maintained through day 28, favored esketamine nasal spray plus an oral antidepressant versus placebo, but did not meet statistical significance (1-sided p=0.161).
Additional secondary endpoints, Sheehan Disability Scale (SDS) and Patient Health Questionnaire-9 (PHQ-9), could not be formally evaluated since onset of clinical response was not statistically significant. Response rate was notable with 69.3% responding in the esketamine group versus 52% in the placebo group at 28 days (response ≥50% improvement in MADRS from baseline). Day 28 remission rate (MADRS total score ≤12) was 52.5% and 31% for the esketamine and placebo groups, respectively.
Most common treatment-emergent adverse effects >10% reported in the esketamine group were metallic taste, nausea, vertigo, dizziness, headache, drowsiness, dissociation, blurred vision, paranesthesia and anxiety, while in the placebo group metallic taste and headache were reported.
Data from a second study, a first of its kind, was conducted in elderly patients 65 years and older with treatment-resistant depression. Patients were given a lower starting dose of esketamine nasal spray (flexibly dosed at 28 mg, 56 mg or 84 mg) plus a newly initiated oral antidepressant or placebo nasal spray plus a newly initiated oral antidepressant.
Findings showed that treatment with flexibly dosed esketamine plus a newly initiated oral antidepressant demonstrated clinically meaningful effects versus placebo nasal spray and a newly initiated oral antidepressant. The study, however, missed statistical significance for its primary efficacy endpoint.
Safety results were consistent with previous studies with similarly reported treatment-emergent adverse effects with the addition of increased blood pressure. There were no effects reported in the >10% of patients in the placebo group.
Associated symptoms and adverse effects were predominately seen on the day of dosing and were generally transient, resolving on the day of dosing.
These studies represent 2 of the 5 phase 3 studies that comprise the treatment-resistant depression program with esketamine nasal spray.
Esketamine addresses a significant unmet need for more than 30% of people suffering from MDD who do not respond to 2 or more currently available antidepressant treatments.
The non-competitive N-methyl-D-aspartate receptor antagonist, thought to help restore synaptic connections in brain cells, has a novel mechanism of action that works differently than currently available therapies.
The drug received breakthrough therapy designation from the US Food and Drug Administration (FDA) November 2013 for treatment-resistant depression and in August 2016 for the indication of MDD with imminent risk for suicide.
If approved by the FDA, esketamine would be one of the first new approaches to treat refractory MDD available to patients in the last 50 years.
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