The Janssen Pharmaceutical Companies of Johnson & Johnson announced positive results from two pivotal Phase 3 clinical studies (ASPIRE I & II) to evaluate the efficacy and safety of SPRAVATO™ (esketamine) CIII nasal spray in addition to comprehensive standard of care (SOC) in adult patients with major depressive disorder who have active suicidal ideation with intent.
The double-blind, randomized, placebo-controlled, multicenter 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, SPRAVATO™ 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 these studies, comprehensive SOC included initial hospitalization and newly initiated and/or optimized antidepressant therapy.
"These data are particularly important because patients with major depressive disorder presenting with active suicidal ideation with intent constitute a psychiatric emergency that requires immediate intervention," said Carla Canuso, M.D., Senior Director, Clinical Research, Janssen Research & Development, and clinical leader of the ASPIRE I & II studies. "Although currently available antidepressants are effective for many patients, their onset of effect can take four to six weeks, offering limited benefit to those in urgent need."
In these studies, both SPRAVATO™ 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 utilized in the clinical trial, including the impact of inpatient psychiatric hospitalization in diffusing the acute suicidal crisis in patients in both treatment groups.
The 456 patients who participated in the trials had moderate-to-severe major depressive disorder. More than 85 percent 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 SOC, which included initial hospitalization and a newly initiated and/or optimized antidepressant regimen.
In the ASPIRE I & II trials, SPRAVATO™ plus SOC was 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 SPRAVATO™ in patients with treatment-resistant depression. In the SPRAVATO™ plus SOC group, the most common adverse events (≥10%), with a frequency of more than twice that of the placebo plus SOC group, were dizziness, dissociation, nausea, somnolence, blurred vision, vomiting, paresthesia, increased blood pressure and sedation.
"These are the first global clinical studies in this severely ill patient population, who are typically excluded from antidepressant treatment studies," said Husseini K. Manji, M.D., Global Head, Neuroscience Therapeutic Area, Janssen Research & Development. "At Janssen, we are committed to continued clinical research excellence that leads to discovery and development of new and more effective treatment options for people living with mental illnesses, including severe mood disorders. The esketamine nasal spray development program is a demonstration of that commitment and our recognition of the great unmet need among individuals with major depressive disorder who experience suffering from a serious, biologically-based disease which has a significant negative impact on various aspects of life."
At 24 hours after the first dose of study medication in ASPIRE I & II, the mean difference observed in the reduction of depressive symptoms between the SPRAVATO™ plus SOC group and the placebo plus SOC group was 3.8 points and 3.9 points, respectively, as measured by MADRS.
The benefit of SPRAVATO™ 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 SPRAVATO™ 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 & II trials, 54 percent and 47 percent, respectively, of the SPRAVATO™ 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.
SPRAVATO™ is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor – an ionotropic glutamate receptor. It has a novel mechanism of action, meaning it works differently than currently available therapies for major depressive disorder.
SPRAVATO™ in conjunction with a newly initiated antidepressant is approved in the US for the treatment of treatment-resistant depression (TRD) 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.
Major depressive disorder affects nearly 300 million people of all ages globally and is the leading cause of disability worldwide. Individuals with major depressive disorder experience suffering from a serious, biologically-based disease which has a significant negative impact on all aspects of life, including quality of life and function.
Depression is one of the most relevant risk factors associated with suicide.
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