Newly Published Phase 2 Study Found Esketamine Demonstrated Significantly Rapid Improvements in Depressive Symptoms and Suicidality

TITUSVILLE, N.J., April 16, 2018 /PRNewswire/ -- The Janssen Pharmaceutical Companies of Johnson & Johnson announced today that data from a Phase 2 proof of concept clinical study of esketamine nasal spray, published in the American Journal of Psychiatry, showed that treatment with esketamine resulted in a statistically significant, clinically meaningful improvement in depressive symptoms at four hours, including a measure of suicidal ideation, in patients with major depressive disorder who were at imminent risk for suicide, compared to placebo. Unlike previous clinical trials of antidepressants which typically excluded suicidal patients, this study included people who were severely depressed and actively suicidal. All participants in the study received comprehensive clinical care, including hospitalization and the initiation or optimization of standard antidepressant medication through the duration of the study.

Change in the Montgomery-Asberg Depression Rating Scale (MADRS) total scores, measured in the study, demonstrated the improvement in patients’ depressive symptoms. Decreases in MADRS total score showed significant clinical improvement as early as four hours after the initial dose. Suicidal ideation, as measured by the MADRS suicidal thoughts item, was also significantly reduced at this four-hour time point. The study also utilized the Suicide Ideation and Behavior Assessment Tool (SIBAT) to assess suicide risk. The SIBAT is a novel instrument developed by Janssen and external collaborators that includes both patient-reported and clinician-rated sections. The tool is designed to measure rapid changes in suicidality and to address the limitations of existing suicide scales, including their limited sensitivity to discriminate among the treatment differences associated with rapid change.

“Major depressive disorder is among the most prevalent mental health conditions, and the incidence of attempted suicide in people with this condition is approximately 20-fold higher than that of the general population,” ^1,2 said Carla Canuso, MD, Senior Director, Clinical Development, Janssen Research & Development, LLC. “This study begins to explore if esketamine can rapidly reduce depressive symptoms in acutely suicidal patients and bridge the gap of several weeks between when a patient begins a standard antidepressant and when that treatment begins to work. The results of this study reinforce the potential of esketamine as an acute treatment for patients in crisis. We look forward to the completion of our ongoing Phase 3 trials and to bringing this important, potential new therapy to patients in desperate need.”

Esketamine nasal spray belongs to a new class of investigational medicines in psychiatry known as glutamate receptor modulators that are thought to help restore synaptic connections in brain cells in people with major depressive disorder. If approved by the U.S. Food and Drug Administration (FDA) for this indication, esketamine would be the first treatment for patients with major depressive disorder assessed to be at imminent risk for suicide.^4,5

Primary Efficacy Endpoint
The primary efficacy endpoint - change from baseline to four hours post-dose on day 1 in the MADRS total score - was achieved, with the mean change from baseline at four hours post-dose showing a rapid, clinically meaningful and statistically significant improvement in depressive symptoms of -13.4 (9.03) for esketamine nasal spray 84 mg plus standard of care, compared to -9.1 (8.38) for placebo nasal spray plus standard of care (p=0.015; effect size=0.61).

Secondary Efficacy Endpoints
A statistically significant difference in the MADRS total score favoring esketamine was also seen at 24 hours (p=0.015; effect size=0.65), but not at the double-blind endpoint, at which time the placebo plus standard of care group had received 4 weeks of standard antidepressant therapy. Additionally, esketamine nasal spray showed a rapid and statistically significant effect on suicidal ideation, as measured by the MADRS suicidal thoughts (MADRS-SI) item at four hours post-dose (p=0.002, effect size=0.67), but not at the 24-hour or double-blind endpoints. Analysis of the measure of suicide risk from the SIBAT scores showed numerically greater, but not statistically significant, decreases in clinician’s judgment of suicide risk with esketamine nasal spray plus standard of care, compared to placebo nasal spray plus standard of care at the four-hour and double-blind endpoints. There were no differences between treatment groups in the measure of suicide risk at the end of double-blind treatment.⁶

Esketamine nasal spray is believed to be generally well-tolerated based on the adverse event data from this study. The most common (>20%) treatment-emergent adverse events (TEAEs) in the esketamine nasal spray group during the double-blind phase were: nausea (37.1%), dizziness (34.3%), unpleasant taste (31.4%), dissociation (31.4%), headache (31.4%), and vomiting (20.0%). There were no deaths during this study. Mild perceptual effects were observed in the esketamine nasal spray group and were consistent with previous studies of esketamine nasal spray. These symptoms were manageable and transient (resolved within two hours on the day of treatment), and subsided with repeated dosing. Adverse events leading to early termination in the double-blind phase occurred in five participants in the esketamine nasal spray group (agitation, aggression, unpleasant taste, and ventricular extrasystoles for one participant each and dizziness, dyspnea, and nausea for one participant) and one participant in the placebo nasal spray group terminated participation early because of dissociative disorder and panic attack. Three participants in the esketamine nasal spray group had a dose reduction due to intolerance.⁶

Esketamine nasal spray is currently being evaluated in two global Phase 3 clinical studies for patients with major depressive disorder who are at imminent risk for suicide. There is also an ongoing Phase 2 clinical study for adolescents with major depressive disorder who are at imminent risk for suicide.

About the Study
This 12-week Phase 2a, randomized, double-blind, placebo-controlled, multicenter study conducted in the U.S. enrolled 68 adults with major depressive disorder who presented to an Emergency Room or inpatient psychiatric unit and were assessed to be at imminent risk for suicide. The study consisted of a screening evaluation performed within 24 to 48 hours prior to the Day 1 dose, immediately followed by a 25-day double-blind treatment phase (Day 1 to 25) with twice-weekly dosing sessions, and a 56-day follow up phase (Day 26 to Day 81). The study was designed as an exploratory proof-of-concept study and therefore a two-sided 0.20 significance level was used.⁶

The participants were randomized in a 1:1 ratio to one of the two treatments: esketamine nasal spray 84 mg (N=36) plus standard of care or placebo nasal spray (N=32) plus standard of care. The randomization was balanced using randomly-permuted blocks and stratified by study center and type of standard of care antidepressant. The participants were severely depressed at enrollment, as evidenced by high baseline MADRS total score (mean [S.D.] score =38.6 [6.53]). The 66 dosed participants were assessed as having current active suicide ideation with intent to act on those thoughts. Forty-four (66.7%) participants reported having thoughts about suicide that were “severe,” and 36 (54.5%) reported having such thoughts “very often.” Half of participants required suicide precautions in addition to hospitalization.⁶

The study drug was provided in disposable nasal spray devices containing 200 μl of solution (i.e., two sprays), and administered under the supervision of a health care professional. A bittering agent was added to placebo nasal spray to simulate the taste of esketamine nasal spray, to help mask the treatment assignment.⁶

For additional study information, visit ClinicalTrials.gov.

About Esketamine
Esketamine nasal spray is an investigational compound being studied by Janssen Research & Development, LLC as part of a global development program. It is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also known as a glutamate receptor modulator, which has a novel mechanism of action, meaning it works differently than currently available therapies for depression.

Janssen is developing esketamine nasal spray for both treatment-resistant depression and major depressive disorder with imminent risk for suicide.⁷ The FDA granted Breakthrough Therapy Designations to esketamine for treatment-resistant depression in November 2013 and for major depressive disorder with imminent risk for suicide in August 2016.⁷

About Major Depressive Disorder
Major depressive disorder affects nearly 300 million people of all ages globally and is the leading cause of disability worldwide.⁸ Individuals with depression, including major depressive disorder, experience continuous suffering from a serious, biologically based disease which has a significant negative impact on all aspects of life, including quality of life and function.⁹ Depression is the psychiatric disorder most commonly associated with suicide.¹⁰ According to estimates from the Centers for Disease Control (CDC), over 44,000 Americans died by suicide in 2015.¹¹ While conventional antidepressants can be effective in treating major depressive disorder, and thereby suicidal ideation,¹¹ they are not specifically FDA-approved for patients with major depressive disorder who are at imminent risk for suicide.^12,13 Further, their delayed onset of effect, which can take four to six weeks, limits their value in treating acutely suicidal patients.

About the Janssen Pharmaceutical Companies of Johnson & Johnson
At the Janssen Pharmaceutical Companies of Johnson & Johnson, we are working to create a world without disease. Transforming lives by finding new and better ways to prevent, intercept, treat and cure disease inspires us. We bring together the best minds and pursue the most promising science.

We are Janssen. We collaborate with the world for the health of everyone in it. Learn more at www.janssen.com. Follow us at www.twitter.com/JanssenUS and www.twitter.com/JanssenGlobal.

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 and the potential benefits 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 materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC 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; competition, including technological advances, new products and patents attained by competitors; challenges to patents; manufacturing difficulties and delays; changes in behavior and spending patterns or financial distress of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and description 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 January 1, 2017, including in Exhibit 99 thereto, 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. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

 1. World Health Organization. Preventing suicide: a global imperative. Available at: http://www.who.int/mental_health/suicide- prevention/world_report_2014/en/. Accessed July 2017. 2. Holma KM, Melartin TK, Haukka J, et al: Incidence and predictors of suicide attempts in DSM-IV major depressive disorder: a five- year prospective study. Am J Psychiatry. 2010;167(7):801-808. 3. Deisenhammer EA, Ing CM, Strauss R, et al: The duration of the suicidal process: how much time is left for intervention between consideration and accomplishment of a suicide attempt? J Clin Psychiatry. 2009;70(1):19-24. 4. van der Feltz-Cornelis CM, Sarchiapone M, Postuvan V, et al: Best practice elements of multilevel suicide prevention strategies: a review of systematic reviews. Crisis. 2011;32(6):319-333. 5. Wasserman D, Rihmer Z, Rujescu D, et al: The European Psychiatric Association (EPA) guidance on suicide treatment and prevention: Eur Psychiatry. 2012;27(2):129-141. 6. Canuso C, Jaskaran S, et al: Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry. 2018, https://doi.org/10.1176/appi.ajp.2018.17060720 7. Janssen Research & Development Press Release. “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. Accessed July 2017. 8. World Health Organization. Depression. Available at: http://www.who.int/mediacentre/factsheets/fs369/en/. Accessed July 2017. 9. Thase ME. Update on partial response in depression. J Clin Psychiatry. 2009;70[suppl 6]:4-9. 10. Cavanagh JT, Carson AJ, Sharpe M, et al: Psychological autopsy studies of suicide: a systematic review. Psychol Med. 2003;33(3):395-405. 11. Centers for Disease Control and Prevention: Web-based Injury Statistics Query and Reporting System (WISQARS). Atlanta, GA: National Center for Injury Prevention and Control. Available at http://www.cdc.gov/injury/wisqars/leading_causes_death.html. Last updated June 2015. Accessed 26 January 2017Montgomery SA, Dunner DL, Dunbar GC: Reduction of suicidal thoughts with paroxetine in comparison with reference antidepressants and placebo. Eur Neuropsychopharmacol. 1995;5(1):5-13. 12. van der Feltz-Cornelis CM, Sarchiapone M, Postuvan V, et al: Best practice elements of multilevel suicide prevention strategies: a review of systematic reviews. Crisis. 2011;32(6):319-333. 13. Wasserman D, Rihmer Z, Rujescu D, et al: The European Psychiatric Association (EPA) guidance on suicide treatment and prevention: Eur Psychiatry. 2012;27(2):129-141. 

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