The Janssen Pharmaceutical Companies of Johnson & Johnson have announced the results of 2 long-term phase 3 clinical trials examining esketamine nasal spray in patients with treatment-resistant depression. One study showed that esketamine nasal spray plus an oral antidepressant delayed time to relapse compared with a placebo nasal spray plus an oral antidepressant; the other study showed evidence of safe long-term use of esketamine.
The trial results were presented on May 31, 2018 at the 2018 Annual American Society of Clinical Psychopharmacology (ASCP) Meeting held May 29-June 1 in Miami Beach, Florida. This follows the presentation of 2 short-term phase 3 trials of esketamine nasal spray in patients with treatment-resistant depression at the 2018 American Psychiatric Association (APA) Annual Meeting, held May 5-9 in New York.
The Relapse Prevention Study
The study assessing relapse prevention (clinicaltrials.gov Identifier NCT02493868) assessed 705 adults directly enrolled in or transferred from other esketamine phase 3 studies. Patients had previously been treated with esketamine nasal spray and an oral antidepressant and were either in stable remission or had a stable response but were not in stable remission. Patients received either esketamine nasal spray (56 mg or 84 mg) plus an oral antidepressant or placebo nasal spray plus an oral antidepressant with repeated, intermittent dosing over 16 weeks. Stable remission criteria were defined as a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of ≤12 in at least 3 of the 4 weekly assessments conducted during weeks 12 to 16, with 1 excursion or missed MADRS allowed. Relapse criteria were defined as MADRS total score of ≥22 for 2 consecutive weeks, hospitalization for worsening depression, or a clinically relevant event indicative of relapse.
The researchers found that in stable remitters, 24 (26.7%) patients in the esketamine plus an oral antidepressant group and 39 (45.3%) patients in the placebo nasal spray plus oral antidepressant group experienced a relapse event during the maintenance phase. Based on a weighted combination log-rank test, the difference between groups for the time to relapse was clinically and statistically significant (two-sided P =.003). “The results significantly favored esketamine nasal spray plus an oral antidepressant in delaying relapse compared to an oral antidepressant plus placebo nasal spray,” according to a May 31, 2018 Janssen Pharmaceutical press release.1
The Long-term Safety Study
The study assessing long-term safety (clinicaltrials.gov Identifier NCT02497287) examined 802 adults (aged ≥18) directly enrolled or transferred from another phase 3 study of older (≥65) adults. Patients received esketamine nasal spray (28 mg, 56 mg, or 84 mg) plus an oral antidepressant with repeated, intermittent dosing for up to 1 year.
The study had an open label design, and was therefore not intended to formally evaluate the efficacy of esketamine. However, laboratory tests, physical examination, and nasal tolerability revealed no trends of clinical concern in patients treated with esketamine nasal spray for up to 52 weeks. No clinically meaningful changes in cognition were found, and no cases of interstitial or ulcerative cystitis were reported. The most common treatment-emergent adverse events during the treatment phases (≥10% patients) were dizziness (32.9%), dissociation (27.4%), nausea (25.1%), headache (24.9%), drowsiness (16.7%), metallic taste and oral hypoesthesia (11.8% each), vertigo (11.0%), vomiting (10.8%), and viral upper respiratory tract infection (10.2%). Of the 802 adults, 55 (6.9%) experienced 68 serious treatment-emergent adverse events, and of these, 5 serious treatment-emergent adverse events from 4 patients were assessed by the investigator to be related to esketamine nasal spray. There were 2 deaths, which the investigator determined to be unrelated to esketamine nasal spray or oral antidepressant use.
Esketamine nasal spray appeared to sustain improvement in depressive symptoms for up to 52 weeks in patients with treatment-resistant depression. The mean change in MADRS total score from induction baseline to the 4-week end point was −16.4 (8.76), and from the optimization/maintenance baseline to end point was 0.3 (8.12). At the induction phase end point (day 28), the response rate was 78.4% and the remission rate was 47.2%. Of the participants who responded to treatment and proceeded to the optimization/maintenance phase, 76.5% were responders and 58.2% were remitters at 52 weeks.
“We are pleased to share these results from our phase 3 program for esketamine nasal spray. They reinforce its potential to help patients who haven’t responded to available therapies,” said Mathai Mammen, MD, PhD, Global Head, Janssen Research & Development, LLC. “We look forward to submitting all results from our esketamine treatment-resistant depression studies to regulatory authorities, with a view to bringing a new treatment option to people in need.”
If approved by the US Food and Drug Administration (FDA), esketamine would be one of the first new approaches available to patients to treat refractory major depressive disorder in the last 50 years.
Long-term phase 3 study shows esketamine nasal spray plus an oral antidepressant delayed time to relapse in patients with treatment-resistant depression [press release]. Janssen Pharmaceutical Companies. www.prnewswire.com/news-releases/long-term-phase-3-study-shows-esketamine-nasal-spray-plus-an-oral-antidepressant-delayed-time-to-relapse-in-patients-with-treatment-resistant-depression-300657458.html. May 31, 2018. Accessed May 31, 2018.