Spravato®▼ (Esketamine) Nasal Spray authorised in Europe for Adults with Treatment-Resistant Major Depressive Disorder
Posted in Industry News on 20th Dec 2019
Authorised for patients who have not responded to at least two different treatments with antidepressants in the current moderate to severe depressive episode and in combination with a Selective Serotonin Reuptake Inhibitor (SSRI) or Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)
Esketamine nasal spray offers the ﬁrst new mechanism of action in 30 years to treat major depressive disorder (MDD)
European Commission (EC) authorisation is based on data from a robust clinical trial programme in adult patients with treatment-resistant major depressive disorder (TRD), including five phase III trials
“This new treatment represents an exciting new therapeutic option for a common, debilitating and difficult to treat condition,” says Professor Allan Young, Chair of Mood Disorders and Director of the Centre for Affective Disorders, King’s College London.* “I believe both clinicians and patients will welcome this treatment option for this often-devastating illness.”
MDD affects approximately 40 million people across Europe and 1.8 million adults in England alone.[ii],[iii],—[iv] It is a major health condition that is recognised as the most common mental health condition in Europe that causes significant ill-health, disability and suffering for patients and their families.[v],[vi] People with MDD can suffer with episodes for many months or even years before being diagnosed and the effects go beyond the psychiatric and physical symptoms.[vii] It may also affect employment and education, relationships, health and overall quality of life.[viii] One-third of people in Europe living with MDD are considered to have TRD, that can cause significantly lower health-related quality of life, reduced productivity at work and increased absenteeism.[ix],[x]
“The marketing authorisation of esketamine nasal spray is a testament to Janssen’s dedication to improving outcomes for people struggling to overcome the devastating effects of treatment-resistant major depressive disorder,” said Bernardo Soares, Medical Director UK, Janssen-Cilag Ltd. “We are proud to be introducing this innovative treatment option, which we hope will help to address a significant unmet need.”
The European marketing authorisation was based on data from a robust clinical trial programme in patients with TRD, including over 1,600 patients treated with esketamine nasal spray. The five phase III trials included three short-term studies, one randomised withdrawal and maintenance of effect study, and one long-term safety study.[xi],[xii],[xiii],[xiv],—[xv]
The short-term (one-month) flexible dosing study in adults under 65 years of age demonstrated statistically significant reductions in depressive symptoms at 28 days for esketamine nasal spray and oral antidepressant compared to oral antidepressant and placebo nasal spray. Approximately 70 percent of esketamine nasal spray-treated patients responded to treatment, with a ≥50 percent symptom reduction. Furthermore, approximately half of all esketamine nasal spray-treated patients achieved remission at the end of the 4-week study.†11
The short-term (one-month) fixed dosing study in adults under 65 years of age demonstrated clinically meaningful (not statistically significant) reductions in depressive symptoms at 28 days for either 54 mg or 84 mg esketamine nasal spray and oral antidepressant compared to oral antidepressant and placebo nasal spray. Approximately 54 percent and 53 percent of patients treated with 56 mg and 84 mg esketamine nasal spray, respectively, responded to treatment. Approximately 36 percent and 38 percent of patients treated with 56 mg and 84 mg esketamine nasal spray, respectively, achieved remission at the end of the 4-week study.†13
The short-term (one-month) flexible dosing study in elderly adults over 65 years of age demonstrated clinically meaningful (not statistically significant) reductions in depressive symptoms at 28 days for esketamine nasal spray and oral antidepressant compared to oral antidepressant and placebo nasal spray. Of all esketamine nasal spray-treated patients, 27 percent responded to treatment and approximately 17 percent achieved remission at the end of the 4-week study.†12
Continued treatment with esketamine nasal spray plus an oral antidepressant reduced the risk of relapse by 70 percent among patients with stable response and by 51 percent in patients in stable remission, compared to continuing treatment with an oral antidepressant alone.†14
Across the five phase III and one phase II clinical trials, esketamine nasal spray demonstrated a favourable benefit-risk profile, with sustained efficacy and no new safety concerns when observed over a period of up to 52 weeks.11—,12,13,14,15 The most commonly observed adverse events in TRD patients treated with esketamine nasal spray were dizziness, nausea, dissociation, headache, somnolence, vertigo, dysgeusia, hypoaesthesia, and vomiting.11—[xvi] These side effects were generally mild-to-moderate, transient (resolving within 2 hours) and occurred on the day of dosing.
Esketamine nasal spray is a controlled drug which is intended to be self-administered by the patient under the direct supervision of a healthcare professional. Risk of harm and abuse is minimised through; safe storage, a single-use disposable nasal spray device, which prevents multi-use and safeguards against more than one dose of the drug being delivered in a single administration, and patient risk for abuse or misuse is assessed before administration. A treatment session consists of nasal administration of esketamine nasal spray and a post-administration observation period. Both administration and post-administration observation of esketamine nasal spray should be carried out in an appropriate clinical setting.
†The analysis used to calculate the primary efficacy endpoint in the acute Phase 3 clinical trial publications is the Mixed Model for Repeated Measurements (MMRM) analysis. As per the request of the European Medicines Agency (EMA), the European SPRAVATO®▼ Summary of Product Characteristics (SmPC) uses an analysis of covariance – best observation carried forward (AVCOVA BOCF). Both the MMRM and the AVCOVA BOCF are appropriate methods for analysing the change in depressive symptoms from baseline on the Montgomery–Åsberg Depression Rating Scale (MADRS). The methods yield slightly different results, but do not change the statistical significance of the study results.
In addition, response and remission rates at day 28 in the publications were calculated using patients who completed the double-blind induction period; response and remission rates in the SmPC were calculated using all patients who were randomised.16
*Professor Allan Young is a paid consultant for Janssen. He has not been compensated for any media work.
[i] European Commission. Union Register. Available at: https://ec.europa.eu/health/documents/community-register_en/. Accessed December 2019.
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[iv] Office for National Statistics (2018) Population estimates for the UK, England and Wales, Scotland and Northern Ireland: mid-2017. Available at: www.ons.gov.uk/peoplepopulationandcommunity/populationandmigration/populationestimates/bulletins/annualmidyearpopulationestimates/previousReleases. Accessed December 2019.
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[xi] Popova V, et al. (2019) Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry;176(6):428-43.
[xii] Ochs-Ross R, Daly E, Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant
in elderly patients with treatment-resistant depression. Poster W27 presented at ASCP 2018, 19 May–01 June,
[xiii] Fedgchin M, et al. (2019) Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral
Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled
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[xvi] Summary of Product Characteristics Spravato 28 mg nasal spray. Janssen-Cilag International.
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