Janssen Announces Positive Phase 3 Results of Spravato (esketamine) Nasal Spray Demonstrating Rapid Reduction in Depressive Symptoms in Adults with Major Depressive Disorder and Active Suicidal Ideation

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The 32nd Annual Meeting of the European College of Neuropsychopharmacology (ECNP) was held in Copenhagen, Denmark, from September 7 to 10, 2019. At the conference, Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, announced positive results from two pivotal Phase III clinical studies (ASPIRE I & II) evaluating Spravato (esketamine) CIII nasal spray for the treatment of adult patients with major depressive disorder (MDD) and acute suicidal ideation or behavior. The results demonstrated that Spravato nasal spray rapidly reduced depressive symptoms in patients compared with placebo.

Both studies were double-blind, randomized, placebo-controlled, multicenter trials that enrolled a total of 456 adult patients with moderate-to-severe major depressive disorder (MDD), among whom more than 85% were assessed by clinicians as having moderate to extremely severe suicidal ideation. To conduct the research safely and ethically in this vulnerable patient population, all patients received comprehensive standard of care (SOC), including initial hospitalization and initiation and/or optimization of antidepressant therapy. In the studies, patients were randomly assigned to receive either Spravato plus SOC or placebo plus SOC. The primary efficacy endpoint was the reduction in depressive symptoms 24 hours after the first dose, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). The secondary endpoint was the improvement in suicide severity 24 hours after the first dose, as measured by the Clinical Global Impression of Severity of Suicidality–Revised (CGI-SS-R) scale.

The results showed that both studies met their respective primary efficacy endpoints: the Spravato 84 mg intranasal spray plus SOC treatment group demonstrated a statistically significant advantage over the placebo plus SOC treatment group in rapidly reducing depressive symptoms of MDD (p=0.006).

Detailed data on the reduction of depressive symptoms are as follows: In two studies, the mean differences in MADRS scores at 24 hours after the first dose between the Spravato + SOC group and the placebo + SOC group were 3.8 points and 3.9 points, respectively. Furthermore, Spravato + SOC demonstrated significant efficacy in alleviating MDD symptoms as early as 4 hours after the first dose. From 4 hours to Day 25, both the Spravato group and the placebo group continued to show improvement, with the magnitude of difference between the two groups remaining largely consistent throughout the 25-day double-blind period. At the end of the double-blind period, remission rates (defined as a MADRS score ≤ 12) in the Spravato group were 54% and 47% in the two studies, respectively. The clinical improvements observed in both treatment groups during the double-blind phase were maintained during the subsequent 9-week follow-up period.

Regarding the secondary endpoint of improvement in suicide severity, there was no statistically significant difference in treatment effects between the two groups. This may be attributable to the substantial beneficial effects of the comprehensive standard of care (SOC) used in the clinical trial, including the distracting effect of hospitalization for acute suicidal crisis on patients in both treatment arms among hospitalized psychiatric patients.

In both studies, the Spravato + SOC regimen was well tolerated, with no new safety signals identified. The safety profile observed in the treatment of patients with major depressive disorder (MDD) and severe suicidal ideation across the two studies was consistent and aligned with previous clinical studies evaluating Spravato for treatment-resistant depression (TRD). In the Spravato + SOC treatment group, the most common adverse reactions (>10%) were dizziness, dissociation, nausea, somnolence, blurred vision, vomiting, paresthesia, increased blood pressure, and sedation, with incidence rates more than twice those observed in the placebo + SOC group.

The aforementioned data are particularly critical, as patients with major depressive disorder exhibiting severe suicidal ideation constitute a psychiatric emergency requiring immediate intervention. Although currently available antidepressants are effective for many patients, their onset of action may take 4 to 6 weeks, thereby offering only limited benefit to those with urgent needs.

Spravato: The First Antidepressant with a Novel Mechanism in 30 Years, Administered Intranasally for Rapid Onset of Action

Spravato is the first antidepressant with a novel mechanism of action in over 30 years. Approved by the U.S. FDA in March 2019, it is indicated, in combination with an oral antidepressant, for the treatment of adults with treatment-resistant depression (TRD). Currently, the TRD indication for this drug is also under review by regulatory authorities in multiple countries and regions, including Europe.

The active pharmaceutical ingredient in Spravato is esketamine, a non-competitive and subunit-nonselective, activity-dependent N-methyl-D-aspartate (NMDA) receptor antagonist. It features a novel and unique mechanism of action that differs from other antidepressant medications currently available on the market. NMDA receptors are a subtype of ionotropic glutamate receptors and play a critical role in synaptic plasticity and neuronal communication. In depression, blocking NMDA receptors is believed to improve brain plasticity and strengthen synaptic connections.

Major Depressive Disorder (MDD) affects nearly 300 million people of all ages worldwide and is a leading cause of global disability. Depression is one of the risk factors most strongly associated with suicide. For patients suffering from MDD, Treatment-Resistant Depression (TRD) is defined as a depressive episode that fails to achieve an adequate response to at least two different antidepressants administered at sufficient doses and for an adequate duration.

In the United States, the FDA had previously granted Spravato Breakthrough Therapy designation for the treatment of TRD and MDD with acute suicidal ideation or behavior. Compared to standard oral therapies, Spravato offers the advantage of rapid onset of action through intranasal administration.

Article Reference Source: New Data from Esketamine Nasal Spray Phase 3 Studies Showed Rapid Reduction of Depressive Symptoms in Adult Patients with Major Depressive Disorder Who Have Active Suicidal Ideation with Intent