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.

References

[i] European Commission. Union Register. Available at: https://ec.europa.eu/health/documents/community-register_en/. Accessed December 2019.

[ii] Dwight LE, et al. (2017) Depression and other common mental disorders: global health estimates. Available at: www.who.int/mental_health/management/depression/prevalence_global_health_estimates/en/. Accessed December 2019.

[iii] McManus S, et al. (2016) Mental Health and Wellbeing in England: Adult Psychiatric Morbidity Survey 2014. Available at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/556596/apms-2014-full-rpt.pdf. Accessed December 2019.

[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.

[v] Alonso, J et al. (2004) Prevalence of mental disorders in Europe: results from the European study of the epidemiology of mental disorders (ESEMeD) project. Acta Psychiatr Scand;109:21-7.

[vi] Blumenthal JA, et al. (2007) Exercise and pharmacotherapy in the treatment of major depressive disorder. Psychosom Med;69(7):587-96.

[vii] Üstün, T., & Kessler, R. (2002) Global burden of depressive disorders: The issue of duration. British Journal of Psychiatry;181(3):181-183.

[viii] Trivedi MH, et al. (2004) The Link Between Depression and Physical Symptoms. Prim Care Companion J Clin Psychiatry;6(Suppl 1):12-16.

[ix] Brown J, Johnson & Johnson. (2018). 4 things we now know about Treatment-Resistant Depression. Available at: www.jnj.com/health-and-wellness/4-facts-about-treatment-resistant-depression. Accessed December 2019.

[x] Woo J, et al. (2011) Impact of depression on work productivity and its improvement after outpatient treatment with antidepressants. Value Health;14(4):475-82.

[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,

Miami, Florida.

[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

Study (TRANSFORM-1). Int J neuropsychopharmacol;22(10):616-630.

[xiv] Daly E et al. (2019) Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention

in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. doi: 10.1001/

jamapsychiatry.2019.1189. [Epub ahead of print]

[xv] Wajs E, Alusio L, Morrison R, et al. (2018) Poster T67 – Long-Term Safety of Esketamine Nasal Spray Plus Oral

Antidepressant in Patients with Treatment-Resistant Depression: Phase 3, Open-Label, Safety and Efficacy Study

(SUSTAIN-2). Presented at ASCP 2018, 29 May–01 June, Miami, Florida.

[xvi] Summary of Product Characteristics Spravato 28 mg nasal spray. Janssen-Cilag International.

[xvii] Lener MS, Kadriu B and Zarate Jr C. (2017) Ketamine and Beyond: Investigations into the potential of glutamatergic agents to treat depression. Drugs; 77:381-401.

[xviii] Johnson & Johnson Ltd. Press release on February 2019. FDA advisory committee recommends approval of SPRAVATOTM (esketamine) nasal spray CIII for adults with treatment-resistant depression. Available at: https://www.jnj.com/fda-advisory-committee-recommends-approval-of-spravatotm-esketamine-nasal-spray-ciii-for-adults-with-treatment-resistant-depression. Accessed December 2019.

[xix] Duman R, (2018) Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide. F1000 Research; 7:659.

[xx] Duman R, (2014) Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections. Dialogues Clin Neurosci;16(1):11-27.

[xxi] European Medicines Agency. Spravato. Available at: https://www.ema.europa.eu/en/medicines/human/summaries-opinion/spravato. Accessed December 2019.

[xxii] American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.

[xxiii] Shah AJ, et al. (2010) Psychological Distress in Carers of People with Mental Disorders. BJMP;3(3):a327.

[xxiv] Al-Harbi KS. (2012) Treatment-resistant depression: therapeutic trends, challenges and future

directions. Patient Pref Adherence;6:369–388.

[xxv] Habert J et al. (2016) Functional Recovery in Major Depressive Disorder: Focus on Early Optimized Treatment. Prim Care Companion CNS Disord; 18(5).

[xxvi] Knoth RL et al. (2010) Effect of inadequate response to treatment in patients with depression. Am J Manag Care; 16:e188-96

[xxvii] Johnston K et al. (2019) The burden of treatment-resistant depression: A systematic review of the economic and quality of life literature. J Affect Disord;242:195-210.

[xxviii] Department of Health. (2011) No health without mental health: a cross-government mental health outcomes strategy for people of all ages. Supporting document –the economic case for improving efficiency and quality in mental health. Available at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/138253/dh_124058.pdf.  Accessed December 2019.

[xxix] McCrone P, et al. (2008) Paying the price. The cost of Mental health care in England to 2026. Available at: www.kingsfund.org.uk/sites/default/files/Paying-the-Price-the-cost-of-mental-health-care-England-2026-McCrone-Dhanasiri-Patel-Knapp-Lawton-Smith-Kings-Fund-May-2008_0.pdf. Accessed December 2019.

[xxx] Mrazek, D et al. (2014) A Review of the Clinical, Economic, and Societal Burden of Treatment-Resistant Depression: 1996–2013. Psychiatr Serv;65(8):977-87.

 

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