Janssen responds to the national institute for health and care excellence (NICE) draft guidance for its novel antidepressant spravato�? (esketamine) nasal spray in treatment-resistant major depressive disorder

JANSSEN RESPONDS TO THE NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE (NICE) DRAFT GUIDANCE FOR ITS NOVEL ANTIDEPRESSANT SPRAVATO^®? (ESKETAMINE) NASAL SPRAY IN TREATMENT-RESISTANT MAJOR DEPRESSIVE DISORDER

Janssen responds to NICE’s preliminary decision not to recommend SPRAVATO^® (esketamine) nasal spray within its marketing authorisation

HIGH WYCOMBE, UK, 28 January 2020 – The Janssen Pharmaceutical Companies of Johnson & Johnson today announced that the National Institute for Health and Care Excellence (NICE) has issued draft guidance not to recommend SPRAVATO® (esketamine) nasal spray in combination with a selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI), for adults living with treatment-resistant major depressive disorder (TRD) who have not responded to at least two different treatments with antidepressants in the current moderate to severe depressive episode.^[i]

Janssen is deeply disappointed by the recommendation set out within the Appraisal Consultation Document (ACD). The company remains determined to ensure patients living with TRD are able to access an important new treatment option, despite the challenges posed by a national mental health care environment where the pace of change is slow, and adoption of innovation has historically been limited.

“This negative opinion from NICE is extremely disappointing as it is a decision which may potentially deny patients living with treatment-resistant major depressive disorder access to a much-needed new treatment option,” commented Jennifer Lee, Director of Health Economics, Market Access & Reimbursement (HEMAR) and Advocacy, Janssen-Cilag Limited. “It is evident from this initial draft guidance that current NICE technology appraisal processes are not fit for purpose in terms of evaluating innovative technologies for complex mental health conditions, an area that is already under-researched and underfunded. This decision further reinforces the need for reform through the NICE Methods Review, to allow a new generation of innovative treatments to reach patients.”

Major depressive disorder (MDD) is a major health condition with high unmet need, affecting approximately 1.45 million adults in England alone.^[ii],[iii], It is recognised as the most common mental health condition in Europe that causes significant ill-health, disability and suffering for patients and their families.^[iv],[v] Up to 30 percent 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.^{[vi][vii],—[viii]} People living 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, affecting employment and education, relationships, health and overall quality of life.^[ix],[x]

NICE has recognised the significant unmet need for new therapeutic options in MDD and the impact of the disease on the lives of patients and their families and carers. NICE also noted that clinical trials suggest that esketamine nasal spray with an oral antidepressant may be more effective at relieving the symptoms of depression than an oral antidepressant and placebo nasal spray. However, in the Appraisal Consultation Document, NICE concluded that the cost-effectiveness estimates for esketamine nasal spray are likely to be higher than what NICE would consider to be a cost-effective use of NHS resources. The committee cited some uncertainty around the duration of treatment used in the cost-effectiveness modelling and the clinical benefits of esketamine nasal spray over other oral antidepressants in combination with adjunctive therapies, as no direct comparisons are available.

Janssen believes, based on the evidence submitted, that esketamine nasal spray is a cost-effective use of NHS resources. Janssen is seeking to address each of NICE’s concerns and is confident that based on further technical responses and additional discussions with NICE, and all other stakeholders appraised during the forthcoming consultation period, it can find a route for patients and healthcare professionals in England and Wales to access esketamine nasal spray.

Esketamine nasal spray offers the ?rst new mechanism of action in 30 years to treat MDD, an area that has seen little innovation since the introduction of SSRIs or SNRIs. Esketamine nasal spray was granted European marketing authorisation in December 2019, which was based on data from a robust clinical trial programme in patients with TRD, including over 1,600 patients treated with esketamine nasal spray.^{11—,12,13,14,15} 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]}

Mental health is an area which is critically underfunded and remains at risk of industry disinvestment, with innovation in psychiatry negatively impacted by lack of patient access to new treatment options in the UK. Janssen is committed to patient access and believes the decision can be reversed. The company encourages all stakeholders to continue to engage with NICE to ensure that all perspectives are taken into account when the final guidance is being developed.

Whilst Janssen is disappointed with the outcome, the company is committed to working closely with NICE throughout the subsequent stages of this appraisal. The ACD is open to comment until 18th February 2020. A second committee meeting is due to be scheduled in either March or April 2020, and final guidance is expected to be published following this meeting.

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About SPRAVATO^® (esketamine) nasal spray

Esketamine nasal spray is a glutamate receptor modulator which works on the N-methyl-D-aspartate (NMDA) ionotropic glutamate receptor. It is thought that, by acting on the NMDA receptor, esketamine nasal spray increases signalling between certain cells in the brain, which may contribute to the restoration of synaptic function in these brain regions involved with the regulation of mood and emotional behaviour.^{[xvi],[xvii],[xviii],—[xix]} Based on its pharmacology, esketamine nasal spray has been appraised by the European Medicines Agency (EMA) as a distinct active substance.

The European Commission (EC) granted European license authorisation for esketamine nasal spray on 19 December 2019. It is licensed for use in combination with a selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI), for adults living with treatment-resistant major depressive disorder (TRD) who have not responded to at least two different treatments with antidepressants in the current moderate to severe depressive episode.^[xx]

Adverse events should be reported. ^?This medicinal product is subject to additional monitoring and it is therefore important to report any suspected adverse events related to this medicinal product. Reporting forms and information can be found at www.yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store. Adverse events should also be reported to Janssen-Cilag Limited on 01494 567447 or at dsafety@its.jnj.com.

About Major Depressive Disorder (MDD) and Treatment Resistant Depression (TRD)

Major depressive disorder (MDD) is a severe and chronic mood disorder that can have a profound and devastating impact on those affected, as well as their carers, families and loved ones around them.[xxi],[xxii] It causes severe and persistent symptoms of depression which can affect almost every aspect of a person’s life.²¹ Treatment-resistant depression (TRD) is defined as an inadequate response to two or more currently available treatments with antidepressants in a single, current episode of moderate-to-severe depression. Up to 30% of people who suffer from MDD do not respond to treatment and are considered to have TRD.⁸

According to the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders 5th edition, American Psychiatric Association, 2013) MDD is diagnosed when at least 5 symptoms of depression, which must include depressed mood and/or loss of interest or pleasure in activities, cause clinically significant distress or impaired functioning almost every day for at least a 2-week period.²¹ Other symptoms may also include: irritability, disturbances in sleep, appetite or sexual desire, constipation, suicidal thoughts and slowing of speech and action.^21,[xxiii]

Although MDD is diagnosed when symptoms are present for at least 2 weeks, episodes usually last significantly longer – months or even years, so people living with MDD may delay seeking help.

The impact of Major Depressive Disorder (MDD) and Treatment Resistant Depression (TRD)

Depression, including MDD, and TRD represent a substantial burden both for patients and the wider society. Research suggests patients with TRD are impacted by multiple negative health outcomes including poorer health-related quality of life, higher work productivity loss and increased healthcare use including hospitalisations, compared to the general population.^[xxiv],[xxv]

In addition, this critical unmet health need carries a significant societal and economic burden. In 2007, the estimated cost of MDD in England was £1.7 billion, and this is projected to reach £3 billion by 2026.^{[xxvi],[xxvii]} It is believed that TRD may add up to 68% in societal costs.^[xxviii]

About the Janssen Pharmaceutical Companies of Johnson & Johnson

At Janssen, we’re creating a future where disease is a thing of the past. We’re the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology, and Pulmonary Hypertension.

Janssen-Cilag Limited is a Janssen Pharmaceutical Company of Johnson & Johnson. Learn more at www.janssen.com/uk. Follow us at www.twitter.com/JanssenUK.

Cautions Concerning Forward-Looking Statements

This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding SPRAVATO^® (esketamine) nasal spray. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialise, actual results could vary materially from the expectations and projections of Janssen-Cilag Limited, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behaviour and spending patterns of purchasers of healthcare products and services; changes to applicable laws and regulations, including global healthcare reforms; and trends toward healthcare cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 30, 2018, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in the company’s most recently filed Quarterly Report on Form 10-Q, and the company’s subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. Neither the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.       

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[i] National Institute For Health And Care Excellence. Appraisal consultation document. Available at: https://www.nice.org.uk/guidance/proposed/gid-ta10371. Accessed January 2020.

[ii] 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 January 2020.

[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 January 2020.

[iv] 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.

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

[vi] 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 January 2020.

[vii] 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.

[viii] Al-Harbi KS. (2012) Treatment-resistant depression: therapeutic trends, challenges and future directions. Patient Pref Adherence;6:369–388.

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

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

[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. (2019) Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression-TRANSFORM-3. Am J Geriatr Psychiatry;S1064-7481(19)30533-0.

[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] 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.

[xvii] 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 January 2020.

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

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

[xx] European Medicines Agency. Available at: https://www.ema.europa.eu/documents/product-information/spravato-epar-product-information_en.pdf. Accessed January 2020.

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

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

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

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

[xxv] 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.

[xxvi] 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 January 2020.

[xxvii] 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 January 2020.    

[xxviii] 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.