Janssen’s Spravato (Esketamine Nasal Spray) Approved in EU for Rapid Reduction of Depressive Symptoms in Psychiatric Emergency MDD Patients

February 10, 2021 News /BioValleyBIOON/ -- Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson (JNJ), recently announced that the European Commission (EC) has approved an expansion in the use of Spravato (esketamine) nasal spray as an acute short-term treatment, in combination with oral antidepressants, for the treatment of moderate to severeDepressionEpisodes of severe intensity that, based on clinical judgment, constitute a psychiatric emergencyDepression(MDD) Adult Patients, Rapid ReliefDepressionThis approval marks the second indication for Spravato in the EU, a milestone that makes Spravato the first NMDA antagonist approved in Europe for the treatment of patients with major depressive disorder (MDD) experiencing an acute psychiatric emergency.

In July 2020, Spravato nasal spray received U.S.FDAApproved, in combination with oral antidepressants, for the treatment of severe depression with acute suicidal ideation or behaviorDepression(MDD) adult patients, rapid reduction of depressive symptoms. In this challenging treatment population,Spravato demonstrated improvement in depressive symptoms after the first dose.

Notably, Spravato is the first and only regulatory-approved medication proven to alleviate depressive symptoms within 24 hours, offering a new option for significant symptom relief until a long-term, comprehensive treatment regimen takes effect.

Spravato is the first antidepressant with a novel mechanism of action to be approved in over 30 years.In the United States and the European Union, Spravato was approved in March and December 2019, respectively, in combination with oral antidepressants for the treatment of adult patients with treatment-resistant depression (TRD).

Depression is the leading cause of disability worldwide and the condition most commonly associated with suicide. Major Depressive Disorder (MDD) is a serious illness that exerts significant negative effects on an individual’s thoughts, feelings, and behaviors. The symptoms and severity of MDD vary from person to person. Patients with MDD who are assessed as having an imminent risk of suicide constitute a psychiatric emergency requiring immediate intervention. Although currently available antidepressants are effective in treating depression, they typically require several weeks (4–6 weeks) to achieve their full therapeutic effect. This delay poses potential dangers, particularly because the risk of suicide is highest during the early stages of treatment. Compared with standard oral medications, Spravato offers the advantage of rapid onset of action through intranasal administration.

The efficacy of Spravato in preventing suicide or reducing suicidal ideation or behavior has not been established. If clinically indicated, the use of Spravato does not eliminate the need for hospitalization, even if the patient’s symptoms improve after administration of the initial dose of Spravato.

Professor Maurizio Pompili†, Director of the University Psychiatric Outpatient Clinic at Sant’Andrea Hospital, Sapienza University of Rome, Italy, stated: “Depression is not merely feeling sad; it is a debilitating constellation of symptoms that varies from person to person and can progress to the point where patients may experience psychiatric emergencies, such as suicidal ideation. While many antidepressants are effective in treating depressive symptoms, they do not provide rapid relief and may take several weeks to achieve full efficacy. The rapid onset of action of Spravato nasal spray will address a critical unmet need in this patient population.”

The approval of this new indication is based on the positive results from two pivotal Phase III clinical studies (ASPIRE I & II). 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 extreme suicidal ideation. In these studies, all patients received comprehensive standard of care (SOC), including initial hospitalization and newly initiated and/or optimized antidepressant therapy. Patients were randomized to receive either Spravato plus SOC or placebo plus SOC. The primary efficacy endpoint was the reduction in depressive symptoms at 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 at 24 hours after the first dose, as measured by the Clinical Global Impression of Severity of Suicidality–Revised (CGI-SS-R) scale.

Notably, ASPIRE I & II were the first global clinical studies conducted in this patient population with severe disease, who are typically excluded from antidepressant treatment research. The results showed that,When combined with comprehensive standard of care (SOC), Spravato nasal spray rapidly reduced depressive symptoms compared with placebo in this high-risk patient population.

The specific results were as follows: Both studies met their respective primary efficacy endpoints—compared with the placebo + SOC treatment group, the Spravato 84 mg intranasal spray + SOC treatment group demonstrated a statistically significant advantage in rapidly reducing depressive symptoms in MDD (p=0.006).

Data on the reduction of depressive symptoms were as follows: In two studies, the mean differences in MADRS scores at 24 hours after the first dose between the Spravato + SOC treatment group and the placebo + SOC treatment group were 3.8 points and 3.9 points, respectively. Furthermore, Spravato + SOC therapy 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 and placebo groups continued to show improvement, with the magnitude of difference between the two groups remaining generally stable 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 treatment 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.

Secondary endpoint: improvement in suicide severity: the treatment difference between the two groups was not statistically significant, which may be due toClinical TrialThe substantial benefits of the comprehensive SOC used, including the diverting effect of inpatient treatment for hospitalized psychiatric patients on acute suicidal crises in both treatment groups.

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 commonAdverse Reactions(>10%) were dizziness, dissociation, nausea, somnolence, blurred vision, vomiting, paresthesia, increased blood pressure, and sedation, with an incidence rate more than twice that of the placebo + SOC group.

Globally, major depressive disorder (MDD) is the leading cause of disability, affecting individuals across all age groups. Patients with depression, including MDD, endure significant disease burden that substantially impairs physical functioning and all aspects of daily life. Although currently available antidepressants are effective for many patients, they typically require 4 to 6 weeks to take effect, and approximately one-third of patients do not respond to existing treatments.

The active pharmaceutical ingredient of Spravato is esketamine, a non-competitive and subtype-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 inter-neuronal communication. In depression, blockade of NMDA receptors is believed to improve brain plasticity and strengthen synaptic connections.

In the United States, Spravato was approved in March 2019 for the following indication: in combination with an oral antidepressant, for the treatment of adult patients with treatment-resistant depression (TRD). Previously,FDASpravato has been granted Breakthrough Therapy designation for the treatment of patients with TRD and for the treatment of patients with MDD accompanied by acute suicidal ideation or behavior.

In the European Union, Spravato was approved in December 2019 for the treatment of adults with treatment-resistant depression (TRD) in combination with a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI). According to the approval, patients with depression are considered to have TRD if they fail to respond to at least two different antidepressant treatments during their current moderate to severe depressive episode. (Bioon.com)

Original Source: SPRAVATO (Esketamine Nasal Spray) Authorised in Europe for the Rapid Reduction of Depressive Symptoms in a Psychiatric Emergency for Patients with Major Depressive Disorder