Long-Term Phase 3 Study Shows Esketamine Nasal Spray Plus an Oral Antidepressant Delayed Time to Relapse in Patients with Treatment-Resistant Depression

TITUSVILLE, N.J., May 31, 2018 /PRNewswire/ -- The Janssen Pharmaceutical Companies of Johnson & Johnson today announced results from two long-term Phase 3 clinical studies of the investigational compound esketamine nasal spray in patients with treatment-resistant depression. These studies, one that showed a delayed time to relapse and a second that provided evidence of safe long-term use of esketamine, were presented at the Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP) today in Miami Beach, FL. This follows the presentation of two short-term Phase 3 studies of esketamine nasal spray in patients with treatment-resistant depression earlier this month.

The first long-term study assessed relapse prevention in adults with treatment-resistant depression. Data from this study showed that continuing treatment with esketamine nasal spray plus an oral antidepressant beyond 16 weeks demonstrated clinically meaningful and statistically significant superiority to treatment with standard of care (oral antidepressant) plus placebo nasal spray in delaying time to relapse of symptoms of depression. The maintenance phase was of variable duration, continuing until the pre-specified number of relapse events was reached.

The results additionally indicated that patients treated with esketamine nasal spray plus an oral antidepressant had a 51% lower risk of relapse than patients in the oral antidepressant plus placebo nasal spray group. Overall, esketamine nasal spray plus an oral antidepressant demonstrated safety and tolerability with repeated, intermittent long-term dosing.

"At least 300 million people worldwide live with treatment-resistant depression, and it is important we continue to study and report the results of studies such as these two^1,2," said Maurizio Fava, MD, Executive Vice Chair of the Massachusetts General Hospital (MGH) Department of Psychiatry and Executive Director of the MGH Clinical Trials Network and Institute (CTNI). "The first study shows that esketamine may be beneficial in terms of extending time to relapse for patients with treatment-resistant depression, and the second provides insights related to its safety over the long-term in this patient population."

The second study had an open-label design and was the first to assess the long-term safety and efficacy of esketamine nasal spray for up to one year (52 weeks). Data from the study showed that treatment with esketamine nasal spray plus an oral antidepressant was tolerable with no new safety signals after repeated long-term dosing. The safety profile of esketamine in the study was similar to that observed in previous completed short-term Phase 2 and 3 studies in patients with treatment-resistant depression, with a low drop-out rate observed due to adverse events (6.8% in the initial four-week induction phase and 3.8% in the 48-week optimization/maintenance phase).

The data from this open-label study also indicated that treatment with esketamine nasal spray plus an oral antidepressant appeared to be associated with sustained improvement in depressive symptoms at up to 52 weeks. Although this data is derived from an open label, Phase 3 study, whereby both the researchers and study participants knew the treatment the participants received, the efficacy, response and remission rates from the study support data from the relapse prevention study and earlier esketamine studies that were double-blind in design³.

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"We are pleased to share these results from our Phase 3 program for esketamine nasal spray. They reinforce its potential to help patients who haven't responded to available therapies," said Mathai Mammen, MD, PhD, Global Head, Janssen Research & Development, LLC. "We look forward to submitting all results from our esketamine treatment-resistant depression studies to regulatory authorities, with a view to bringing a new treatment option to people in need."

If approved by the U.S. Food and Drug Administration (FDA), esketamine would be one of the first new approaches to treat refractory major depressive disorder available to patients in the last 50 years.

Janssen has conducted five pivotal Phase 3 studies of esketamine nasal spray in patients with treatment-resistant depression. These clinical studies include three short-term randomized, double-blind, active-controlled studies (fixed dose, flexible dose, and flexible dose study in patients ≥ 65 years), one double-blind randomized withdrawal maintenance of effect study and one open-label long-term safety study. The results from these studies will inform regulatory filings for esketamine nasal spray in treatment-resistant depression.

The studies defined treatment-resistant as patients who had not responded to two or more currently available antidepressants of adequate dose and duration in the current episode of depression.

Results of the Relapse Prevention Study
This was a Phase 3, randomized, double-blind, multi-center study, in which 705 adult patients were directly enrolled or transferred from other esketamine Phase 3 studies. Two distinct groups of patients, who had been treated with esketamine nasal spray plus an oral antidepressant for 16 weeks, were enrolled in this study: those who were in stable remission and those who had a stable response, but were not in stable remission. Patients received esketamine nasal spray (56 mg or 84 mg) plus an oral antidepressant or an oral antidepressant plus placebo nasal spray with repeated, intermittent dosing over 16 weeks. Stable remission criteria were met when a patient achieved a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of ≤12 in at least three of the four weekly assessments conducted during weeks 12-16, with one excursion or missed MADRS allowed. Relapse criteria in the study were met when a patient had a MADRS total score of ≥22 for two consecutive weeks or was hospitalized for worsening depression or had a clinically relevant event indicative of relapse.

Remission is clinically defined as virtually complete relief of symptoms, generally accompanied by improvement in functioning across a variety of areas⁴. Relapse is clinically defined as having symptoms that return after improvement of depression and which meet Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for depression⁵.

Primary Efficacy Endpoint
The primary efficacy endpoint was time to relapse among patients who were in stable remission after 16 weeks of treatment with esketamine nasal spray plus an oral antidepressant. The results significantly favored esketamine nasal spray plus an oral antidepressant in delaying relapse compared to an oral antidepressant plus placebo nasal spray. Overall, among stable remitters, 24 (26.7%) patients in the esketamine plus an oral antidepressant group and 39 (45.3%) patients in the oral antidepressant plus placebo nasal spray group experienced a relapse event during the maintenance phase. Based on a weighted combination log-rank test, the difference between groups for the time to relapse was clinically and statistically significant (two-sided p=0.003).

Secondary Efficacy Endpoint
For the secondary efficacy endpoint, time to relapse among patients with stable response (but without remission), 16 (25.8%) patients in the esketamine nasal spray plus an oral antidepressant group and 34 (57.6%) patients in the oral antidepressant plus placebo nasal spray group relapsed. The estimated hazard ratio of esketamine nasal spray plus an oral antidepressant relative to an oral antidepressant plus placebo nasal spray based on the Cox proportional hazards model was 0.30 (95% Confidence Interval: 0.16, 0.55), indicating that patients treated with esketamine plus an oral antidepressant had a 70% reduced risk of relapse. The difference between treatment groups for the time to relapse was clinically and statistically significant (p<0.001) using a two-sided log-rank test.

Safety Results
Safety results were consistent with previous findings from completed Phase 2 and 3 studies of esketamine nasal spray. The most common treatment-emergent adverse events (>10%) reported in the esketamine group during the maintenance phase were metallic taste (27.0%), vertigo (25.0%), dissociation (22.4%), drowsiness (21.1%), dizziness (20.4%), headache (17.8%), nausea (16.4%), vision blurred (15.8%) and oral hypoaesthesia (diminished sense of touch or sensation) (13.2%). Adverse events and associated symptoms were seen predominately on the day of dosing, were generally transient and resolved on the day of dosing. There were no treatment-emergent adverse events reported in ≥10% of patients in the oral antidepressant and placebo nasal spray group. No deaths were reported. Thirty-four patients reported 41 serious adverse events. Of these, 6 patients in the esketamine plus an oral antidepressant group reported seven events which were considered possibly, probably, or very likely related to study drug.

Results of the Long-term Safety Study
This was a Phase 3, open-label, safety study, in which 802 adult patients (≥18 years) were directly enrolled or transferred from another Phase 3 study of elderly (≥65 years) patients. Patients received esketamine nasal spray (28 mg, 56 mg or 84 mg) plus an oral antidepressant with repeated, intermittent dosing for up to one year.

Primary Safety Endpoints
The most common treatment-emergent adverse events during the treatment phases (≥10% patients) were dizziness (32.9%), dissociation (27.4%), nausea (25.1%), headache (24.9%), drowsiness (16.7%), metallic taste and oral hypoaesthesia (diminished sense of touch or sensation) (11.8% each), vertigo (11.0%), vomiting (10.8%), and viral upper respiratory tract infection (10.2%). Fifty-five (6.9%) patients experienced 68 serious treatment-emergent adverse events. Of these, five serious treatment-emergent adverse events from four subjects were assessed by the investigator as esketamine nasal spray-related. There were two deaths which the investigator determined to be unrelated to esketamine nasal spray or oral antidepressant use. Laboratory tests, physical examination, and nasal tolerability revealed no trends of clinical concern in patients treated with esketamine nasal spray for up to 52 weeks. No clinically meaningful changes in cognition were found. No cases of interstitial or ulcerative cystitis were reported.

Secondary Efficacy Endpoints
Due to its open label design, this study was not intended to formally evaluate the efficacy of esketamine. However, esketamine nasal spray appeared to sustain improvement in depressive symptoms for up to 52 weeks in patients with treatment-resistant depression. The mean change in MADRS total score from the induction baseline to the four-week endpoint was −16.4 (8.76) and from the optimization/maintenance baseline to endpoint was 0.3 (8.12). At the induction phase endpoint (day 28), the response rate was 78.4% and the remission rate was 47.2%. Of those who responded to treatment and proceeded to the optimization/maintenance phase, 76.5% were responders and 58.2% were remitters at the 52-week endpoint.

More information about these two Phase 3 long-term esketamine nasal spray studies can be found at the links below:
https://clinicaltrials.gov/ct2/show/NCT02493868?term=esketamine&cond=depression&rank=9 
https://clinicaltrials.gov/ct2/show/NCT02497287?term=esketamine&cond=depression&rank=1 

About Esketamine
Esketamine nasal spray is an investigational compound being studied by Janssen Research & Development, LLC as part of a global development program. Esketamine is a glutamate receptor modulator, thought to help restore synaptic connections in brain cells in people with major depressive disorder. It has a novel mechanism of action, meaning it works differently than currently available therapies for depression.

The U.S. FDA has granted Breakthrough Therapy Designations for esketamine for treatment-resistant depression and for a second indication, major depressive disorder with imminent risk for suicide.⁶

About Major Depressive Disorder
Major depressive disorder affects nearly 300 million people of all ages globally and is the leading cause of disability worldwide.² 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.² Although currently available antidepressants are effective for many patients, about one third of patients do not respond to treatment and are thought to have treatment-resistant depression.⁷

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

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. National Institute of Mental Health. Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study. Available at: http://www.nimh.nih.gov/about/director/2011/antidepressants-a-complicated-picture.shtml#_edn2. Accessed May 2018.
2. World Health Organization. Depression. Available at: http://www.who.int/mediacentre/factsheets/fs369/en/. Accessed May 2018.
3. Medscape. Clinical Trials Glossary. Available at: https://www.medscape.com/resource/clinical-trials/glossary. Accessed May 2018.
4. Rush, John, et.al., "Report by the ACNP Task Force on Response and Remission in Major Depressive Disorder," Neuropsychopharmacology, (2006) 31, 1841–1853.
5. Thase, M. E. (2003). Achieving remission and managing relapse in depression. The Journal of Clinical Psychiatry, 64(Suppl18), 3-7.
6. Johnson & Johnson 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 May 2018.
7. Thase ME. Update on partial response in depression. J Clin Psychiatry. 2009;70[suppl 6]:4-9.

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