Studies reported for esketamine nasal spray in patients with treatment-resistant depression.- Janssen Pharma.

The Janssen Pharmaceutical Companies of Johnson & Johnson announced the results from two Phase III clinical studies of the investigational compound esketamine nasal spray in patients with treatment-resistant depression. These studies will be presented at the American Psychiatric Association Annual Meeting, taking place May 5-9 in New York, NY.

Data from a study in adults with treatment-resistant depression showed that flexibly dosed esketamine nasal spray plus a newly initiated oral antidepressant demonstrated a statistically significant, clinically meaningful rapid reduction of depressive symptoms as compared to placebo nasal spray plus a newly initiated oral antidepressant. The study defined treatment-resistant as patients who had not responded to two or more currently available antidepressants of adequate dose and duration in the current episode of depression.

Data from a second study, in elderly patients aged 65 and older with treatment-resistant depression, which is the first study of its kind, showed treatment with flexibly dosed esketamine plus a newly initiated oral antidepressant demonstrated clinically meaningful effects compared to placebo nasal spray plus a newly initiated oral antidepressant. However, the study narrowly missed statistical significance for its primary efficacy endpoint. If approved by the FDA, esketamine would be one of the first new approaches to treat refractory major depressive disorder available to patients in the last 50 years.

Results of the Study in Adults with Treatment-Resistant Depression : In the Phase III study of adults with treatment-resistant depression, patients were randomized to flexibly dosed esketamine nasal spray (56 mg or 84 mg) added to a newly initiated oral antidepressant or placebo nasal spray added to a newly initiated oral antidepressant.Primary Efficacy Endpoint- The primary efficacy endpoint, change from baseline in the Montgomery-�sberg Depression Rating Scale (MADRS) total score, demonstrated the 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).Secondary and Other Efficacy Endpoints- The first key secondary endpoint (onset of clinical response by 24 hours post-dose that is maintained through day 28) numerically favored esketamine nasal spray plus an oral antidepressant vs. placebo nasal spray plus an oral antidepressant, but did not meet statistical significance (1-sided p=0.161). The other two key secondary endpoints (Sheehan Disability Scale [SDS], a subject-reported outcome measure widely used and accepted for assessment of functional impairment and associated disability, and Patient Health Questionnaire-9 [PHQ-9], a self-report scale assessing depressive symptoms) could not be formally evaluated since onset of clinical response was not statistically significant. Among other endpoints, response rate was notable with 69.3% responding in the esketamine group vs. 52% in the placebo group at 28 days (response greater than 50% improvement in MADRS from baseline). Remission rate (MADRS total score ?12) at day 28 was 52.5% and 31.0% for the esketamine and placebo groups, respectively.

Results of the Study in Elderly Patients with Treatment-Resistant Depression : Janssen conducted a separate Phase III study in elderly patients with treatment-resistant depression. Elderly populations with major depressive disorder are historically hard to treat and often have co-morbidities and long-standing depression. To improve tolerability, patients were given a lower starting dose (28 mg) 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. Primary Efficacy Endpoint- Although statistical significance for the primary endpoint for the overall patient population studied was narrowly missed, results favored the esketamine nasal spray plus a newly initiated oral antidepressant group (median unbiased estimate of the difference from placebo nasal spray plus a newly initiated oral antidepressant: -3.6, 95% CI: -7.20, 0.07; one-sided p=0.029). To put this into context, an analysis of placebo-controlled data from three prior studies conducted by Duru and Fantino determined that a minimum change in MADRS of 1.9 was clinically meaningful. In addition, the average difference is between 2-3 points for currently approved antidepressants vs. placebo. Safety results were consistent with previous studies of esketamine in younger adult populations.

Esketamine nasal spray has an acceptable safety and tolerability profile, based on the adverse event data from both Phase III studies. Adverse events and associated symptoms were seen predominately on the day of dosing and were generally transient and resolved on the day of dosing. These findings represent two of the five Phase III studies that comprise Janssen�s treatment-resistant depression program with esketamine nasal spray. The results from these studies will inform regulatory filings for esketamine nasal spray in treatment-resistant depression, for which Janssen has received Breakthrough Therapy Designations from the U.S. FDA. Data from other Phase III studies will be presented later in 2018.