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

The Janssen Pharmaceutical Companies of Johnson & Johnson today announced positive results from two pivotal Phase 3 clinical studies (ASPIRE I & II) to evaluate the efficacy and safety of esketamine nasal spray in addition to comprehensive standard of care (SOC) in adult patients with major depressive disorder who have active suicidal ideation with intent. These studies were presented at the 32^nd European College of Neuropsychopharmacology (ECNP), taking place September 7–10 in Copenhagen.

The double-blind, randomised, placebo-controlled, multicentre studies both met their respective primary efficacy endpoint, which was a reduction in depressive symptoms at 24 hours after the first dose, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). In both studies, esketamine nasal spray 84 mg plus SOC showed clinically meaningful and statistically significant superiority (p=0.006) over placebo plus SOC in rapidly reducing symptoms of major depressive disorder.^{[i] [ii]}

In the ASPIRE I & II trials, esketamine nasal spray plus SOC was generally well-tolerated with no new safety signals. The safety profile observed was consistent across the two Phase 3 studies in patients with major depressive disorder who have active suicidal ideation with intent, as well as previous studies of esketamine in patients with treatment-resistant depression. In the esketamine plus SOC group, the most common adverse events (≥10%), with a frequency of more than twice that of the placebo plus SOC group, were dizziness, dissociation, nausea, somnolence, vision blurred, vomiting, paresthesia, increased blood pressure and sedation.^{[i] [ii]}

“These data are particularly important because patients with major depressive disorder presenting with active suicidal ideation with intent constitute a psychiatric emergency that requires immediate intervention,” said Carla Canuso, M.D., Senior Director, Clinical Research, Janssen Research & Development, LLC, leading the ASPIRE I & II studies. “Although currently available antidepressants are effective for many patients, their onset of effect can take four to six weeks,^[iii] offering limited benefit to those in urgent need.”

In these studies, both esketamine plus comprehensive SOC and placebo plus comprehensive SOC resulted in improvement in severity of suicidality as measured by the revised Clinical Global Impression of Severity of Suicidality (CGI-SS-R) at 24 hours after the first dose. The treatment difference between the two groups on this secondary endpoint was not statistically significant. This may be due to the substantial beneficial effects of comprehensive SOC utilised in the clinical trial, including the impact of inpatient psychiatric hospitalisation in diffusing the acute suicidal crisis in subjects in both treatment groups.

The 456 patients who participated in the trials had moderate-to-severe major depressive disorder. More than 85 percent were rated by clinicians to be moderately to extremely suicidal. In order to safely and ethically conduct the study in this vulnerable patient population, all patients were treated with the comprehensive standard of care, which included initial hospitalisation and a newly initiated or optimized antidepressant regimen.

“These are the first global clinical studies in this severely ill patient population, who are typically excluded from antidepressant treatment studies,” said Husseini K. Manji, M.D., Global Head, Neuroscience Therapeutic Area, Janssen Research & Development, LLC. “At Janssen, we are committed to continued clinical research excellence that leads to discovery and development of new and more effective treatment options for people living with mental illnesses, including severe mood disorders. The esketamine nasal spray development program is a demonstration of that commitment and our recognition of the great unmet need among individuals with major depressive disorder who experience suffering from a serious, biologically based disease which has a significant negative impact on various aspects of life.”

Study Details: Reduction in Depressive Symptoms
At 24 hours after the first dose of study medication in ASPIRE I & II, the mean difference observed in the reduction of depressive symptoms between the esketamine plus SOC group and the placebo plus SOC group was 3.8 points and 3.9 points, respectively, as measured by the MADRS.

The benefit of esketamine plus SOC on symptoms of major depressive disorder was apparent at four hours after the first dose. Between four hours and 25 days, both the esketamine and placebo groups continued to improve, and the magnitude of difference between the groups generally remained throughout the 25-day double-blind period. In the ASPIRE I & II trials, 54 percent and 47 percent, respectively, of the esketamine plus SOC group achieved remission (MADRS score ≤ 12) by the end of the double-blind period. The clinical improvement during the double-blind period was maintained over the nine-week follow-up period in both treatment groups.

About Esketamine
Esketamine is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor – an ionotropic glutamate receptor. It has a novel mechanism of action, meaning it works differently than currently available therapies for major depressive disorder.^{[iv] [v] [vi] [vii] [viii]}

Esketamine nasal spray in conjunction with a newly initiated antidepressant is approved in the US for the treatment of treatment-resistant depression (TRD) and has been submitted for Health Authorities review for TRD in other markets around the world, including Europe.^[ix] The FDA granted Breakthrough Therapy designation to esketamine nasal spray for treatment-resistant depression in November 2013 and for reduction of major depressive disorder symptoms in patients with active suicidal ideation in August 2016.^[x]

Janssen submitted a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for the esketamine treatment-resistant depression indication in Europe in October 2018.^[xi]

About Patients with Major Depressive Disorder Who Have Active Suicidal Ideation with Intent
Major depressive disorder affects nearly 300 million people of all ages globally and is the leading cause of disability worldwide.^[xii] Individuals with major depressive disorder experience suffering from a serious, biologically based disease which has a significant negative impact on all aspects of life, including quality of life and function.

Depression is one of the most relevant risk factors associated with suicide.^[xiii]

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 Research & Development, LLC is one of the Janssen Pharmaceutical Companies of Johnson & Johnson.

Learn more at www.janssen.com/emea. Follow us at www.twitter.com/JanssenEMEA.

Cautions Concerning Forward-Looking Statements
This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development of esketamine. 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 International NV, 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 31, 2018, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” in the company’s most recently filed Quarterly Report on Form 10-Q, and in 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] Fu DJ, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients at imminent risk for suicide. ASPIRE-1 study. Poster P323 presented at ECNP 2019, 7–10 September, Copenhagen, Denmark.
^[ii] Ionescu DF, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients at imminent risk for suicide. ASPIRE-2 study. Poster P607 presented at ECNP 2019, 7–10 September, Copenhagen, Denmark.
^[iii] Haggerty, J. PsychCentral.com. An Overview of Depression Treatment Options. Available at: https://psychcentral.com/lib/an-overview-of-depression-treatment-options/. (last accessed September 2019).
^[iv] Popova V, et al. Am J Psychiatry 2019. doi: 10.1176/appi/ajp.2019.19020172 [Epub ahead of print].
^[v] Daly E, et al. JAMA Psychiatry 2019. doi: 10.1001/jamapsychiatry.2019.1189 [Epub ahead of print].
^[vi] Wajs E, et al. Poster T67 presented at ASCP 2018, 29 May–01 June, Miami, Florida.
^[vii] Fedgchin M, et al. Int J Neuropsychopharmacol. 2019 Jul 10. pii: pyz039. doi: 10.1093/ijinp/pyz039. [Epub ahead of print]
^[viii] Ochs-Ross R, et al. Poster W27 presented at ASCP 2018, 19 May–01 June, Miami, Florida.
^[ix] Janssen. Press Release March 2019. Janssen Announces U.S. FDA Approval of SPRAVATO™ (esketamine) CIII Nasal Spray for Adults with Treatment-Resistant Depression (TRD) Who Have Cycled Through Multiple Treatments Without Relief. Available at: https://www.janssen.com/janssen-announces-us-fda-approval-spravato-esketamine-ciii-nasal-spray-adults-treatment-resistant. (last accessed September 2019).
^[x] Johnson & Johnson Ltd. Press Release August 2016. Esketamine Receives Breakthrough Therapy Designation from U.S. Food and Drug Administration for Major Depressive Disorder with Imminent Risk for Suicide. Available at: https://www.jnj.com/media-center/press-releases/esketamine-recieves-breakthrough-therapy-designation-from-us-food-and-drug-administration-for-major-depressive-disorder-with-imminent-risk-of-suicide. (last accessed September 2019).
^[xi] Johnson & Johnson Ltd. Press release October 2018. Janssen Submits European Marketing Authorisation Application for Esketamine Nasal Spray for Treatment-Resistant Depression. Available at: https://www.jnj.com/janssen-submits-european-marketing-authorisation-application-for-esketamine-nasal-spray-for-treatment-resistant-depression. (last accessed September 2019).
^[xii] World Health Organization. Depression. Available at: https://www.who.int/en/news-room/fact-sheets/detail/depression. (last accessed September 2019).
^[xiii] Bachmann S. Int J. Environ. Res. Public Health 2018 Jul 6; 15(7). Pii: E1425. doi: 10.3390/ijerph15071425.

EM-16761
September 2019

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