12 September 2019 - - US-based healthcare company Johnson and Johnson's (NYSE: JNJ) Janssen business has received positive results from two pivotal Phase 3 clinical studies (ASPIRE I and II) to evaluate the efficacy and safety of esketamine nasal spray in addition to comprehensive standard of care in adult patients with major depressive disorder who have active suicidal ideation with intent, the company said.

These studies were presented at the 32nd European College of Neuropsychopharmacology, taking place September 7–10 in Copenhagen.

The double-blind, randomised, placebo-controlled, multicentre studies both met their respective primary efficacy endpoint, which was a reduction in depressive symptoms at 24 hours after the first dose, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS).

In both studies, esketamine nasal spray 84 mg plus SOC showed clinically meaningful and statistically significant superiority (p=0.006) over placebo plus SOC in rapidly reducing symptoms of major depressive disorder.

In the ASPIRE I and II trials, esketamine nasal spray plus SOC was generally well-tolerated with no new safety signals.

The safety profile observed was consistent across the two Phase 3 studies in patients with major depressive disorder who have active suicidal ideation with intent, as well as previous studies of esketamine in patients with treatment-resistant depression.

In the esketamine plus SOC group, the most common adverse events, with a frequency of more than twice that of the placebo plus SOC group, were dizziness, dissociation, nausea, somnolence, vision blurred, vomiting, paresthesia, increased blood pressure and sedation.

In these studies, both esketamine plus comprehensive SOC and placebo plus comprehensive SOC resulted in improvement in severity of suicidality as measured by the revised Clinical Global Impression of Severity of Suicidality (CGI-SS-R) at 24 hours after the first dose.

The treatment difference between the two groups on this secondary endpoint was not statistically significant.

This may be due to the substantial beneficial effects of comprehensive SOC utilised in the clinical trial, including the impact of inpatient psychiatric hospitalisation in diffusing the acute suicidal crisis in subjects in both treatment groups.

The 456 patients who participated in the trials had moderate-to-severe major depressive disorder. More than 85 % were rated by clinicians to be moderately to extremely suicidal.

In order to safely and ethically conduct the study in this vulnerable patient population, all patients were treated with the comprehensive standard of care, which included initial hospitalisation and a newly initiated or optimised antidepressant regimen.

At 24 hours after the first dose of study medication in ASPIRE I and II, the mean difference observed in the reduction of depressive symptoms between the esketamine plus SOC group and the placebo plus SOC group was 3.8 points and 3.9 points, respectively, as measured by the MADRS.

The benefit of esketamine plus SOC on symptoms of major depressive disorder was apparent at four hours after the first dose. Between four hours and 25 days, both the esketamine and placebo groups continued to improve, and the magnitude of difference between the groups generally remained throughout the 25-day double-blind period.

In the ASPIRE I and II trials, 54 % and 47 %, respectively, of the esketamine plus SOC group achieved remission (MADRS score ≤ 12) by the end of the double-blind period. The clinical improvement during the double-blind period was maintained over the nine-week follow-up period in both treatment groups.

Esketamine is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate receptor an ionotropic glutamate receptor.

It has a novel mechanism of action, meaning it works differently than currently available therapies for major depressive disorder.

Esketamine nasal spray in conjunction with a newly initiated antidepressant is approved in the US for the treatment of treatment-resistant depression and has been submitted for Health Authorities review for TRD in other markets around the world, including Europe.

The FDA granted Breakthrough Therapy designation to esketamine nasal spray for treatment-resistant depression in November 2013 and for reduction of major depressive disorder symptoms in patients with active suicidal ideation in August 2016.

Janssen submitted a Marketing Authorisation Application to the European Medicines Agency for the esketamine treatment-resistant depression indication in Europe in October 2018.