TITUSVILLE, N.J., Sept. 21, 2018 /PRNewswire/ -- The Janssen
Pharmaceutical Companies of Johnson & Johnson today announced
results from a Phase 3 clinical study of the investigational
product esketamine nasal spray in patients with treatment-resistant
depression. Janssen researchers presented these results at the
Ninth Biennial Conference of the International Society for
Affective Disorders (ISAD) and the Houston Mood Disorders
Conference, taking place September 20-22,
2018 in Houston, TX.
This clinical trial was a randomized, double-blind study of two
fixed doses of esketamine, 56 mg and 84 mg. The study did not
demonstrate statistical significance for the primary endpoint,
change in a depression severity rating scale score from baseline to
four weeks, for esketamine 84 mg plus oral antidepressant compared
to oral antidepressant plus placebo. Therefore, based on the
prespecified analysis plan, the esketamine 56 mg plus oral
antidepressant group could not be formally evaluated in this
study.
Importantly, results of analyses of the primary endpoint and key
secondary endpoints numerically favored both esketamine plus oral
antidepressant treatment groups over the oral antidepressant plus
placebo group.
"Together with the recently announced results from four other
Phase 3 studies, these data provide continued support for a
positive benefit-risk assessment for esketamine nasal spray as a
potentially novel treatment approach for patients living with
treatment-resistant depression," said Husseini K. Manji, M.D, Global Head,
Neuroscience Therapeutic Area, Janssen Research & Development,
LLC. "One-third of patients with major depressive disorder do not
respond to existing therapies, and they need new treatment
options." 1
Janssen announced on September 4,
2018 that it submitted a New Drug Application (NDA) to the
U.S. Food and Drug Administration (FDA) for esketamine.2
Janssen is seeking FDA approval of esketamine for
treatment-resistant depression in adults. The NDA is based on five
pivotal Phase 3 studies of esketamine in patients with
treatment-resistant depression: three short-term studies; one
withdrawal maintenance of effect study; and one long-term safety
study. Data from these studies demonstrate that treatment with
esketamine plus a newly initiated oral antidepressant compared to
placebo plus a newly initiated antidepressant was associated with
rapid reduction of depressive symptoms and delayed time to relapse
of symptoms of depression.3,4 The long-term safety study
showed that the esketamine doses studied were generally tolerated,
with no new safety signals with dosing up to 52
weeks.5
This study defined treatment-resistant depression as patients
who had not responded to two or more antidepressants of adequate
dose and duration in the current episode of depression.
The results of this study showed that esketamine plus an oral
antidepressant demonstrated safety and tolerability consistent with
safety results reported in earlier esketamine Phase 2 and Phase 3
studies.6
Study Design
The study was an international,
Phase 3, double-blind, active-controlled, multi-center study of 346
adults with treatment-resistant depression. Its purpose was to
evaluate the efficacy and safety of fixed doses of esketamine plus
an oral antidepressant. The primary objective was to evaluate the
efficacy of switching adult patients with treatment-resistant
depression from a prior antidepressant treatment (to which they had
not responded) to a fixed dose of esketamine (56 mg or 84 mg) plus
a newly initiated oral antidepressant compared with switching to a
newly initiated oral antidepressant plus placebo, in improving
depressive symptoms. Improvement in symptoms was assessed by the
change from baseline in the Montgomery-Asberg Depression Rating
Scale (MADRS) total score from day one (pre-randomization) to the
end of the four-week double-blind induction phase.
Primary Efficacy Endpoint
Results of the study
were based on a mixed-effects model for repeated measures (MMRM)
analysis of change in MADRS total score from baseline to day 28.
The results numerically favored both esketamine plus an oral
antidepressant groups over the oral antidepressant plus placebo
group. The median unbiased estimate of the difference (95%
confidence interval) between esketamine 84 mg plus oral
antidepressant and the oral antidepressant plus placebo treatment
groups was -3.2 (-6.88, 0.45), and that of esketamine 56 mg plus
oral antidepressant and the oral antidepressant plus placebo
treatment groups was -4.1 (-7.67, -0.49).
Using a weighted combination test, the difference between the
esketamine 84 mg plus oral antidepressant group and oral
antidepressant plus placebo group was not statistically significant
(two-sided p=0.088). Therefore, in accordance with the predefined
testing sequence, esketamine 56 mg plus oral antidepressant
treatment group could not be formally evaluated.
Secondary Efficacy Endpoints
The key secondary
endpoints included onset of clinical response by day two, and
change from baseline to day 28 in total scores from the Sheehan
Disability Scale (SDS), a subject-reported outcome measure widely
used and accepted for assessment of functional impairment and
associated disability, and Patient Health Questionnaire-9 (PHQ-9),
a self-report scale assessing depressive symptoms. These endpoints
could not be formally evaluated due to the predefined testing
sequence, however the proportion of subjects with onset of clinical
response by day two maintained to four weeks was numerically
higher, and the change in SDS and PHQ-9 total scores at day 28
numerically favored, both esketamine plus oral antidepressant
groups compared to the oral antidepressant plus placebo group.
As observed in the other Phase 3, short-term studies of
esketamine, overall response rates (≥50% improvement from baseline)
and remission rates (MADRS total score ≥12) at day 28 were higher
for both esketamine plus oral antidepressant groups compared with
the oral antidepressant plus placebo group. Response rate at day 28
was 53.1% and 54.1% in patients treated with esketamine 84 mg plus
oral antidepressant and 56 mg plus oral antidepressant,
respectively, compared to 38.9% for oral antidepressant plus
placebo. Remission rate at day 28 was 38.8% and 36.0% in patients
treated with esketamine 84 mg plus oral antidepressant and 56 mg
plus oral antidepressant, respectively, compared to 30.6% with
placebo plus oral antidepressant.
Safety Results
Safety results were consistent
with previously reported findings from completed Phase 2 and 3
studies of esketamine. There were no clinically meaningful
differences in safety between the esketamine 56 mg plus oral
antidepressant and esketamine 84 mg plus oral antidepressant
groups, and no new or dose-related safety concerns were identified.
Most adverse events were mild or moderate in severity, and were
typically observed on nasal spray dosing days, and generally
resolved the same day. The most common treatment-emergent adverse
events (TEAEs) (reported by ≥10% of study patients) in the
esketamine 84 mg plus oral antidepressant group during the
double-blind induction phase were nausea, dissociation, dizziness,
headache, vertigo, somnolence (sleepiness), dysgeusia (taste
disturbance), hypoesthesia (diminished sense of touch or
sensation), vomiting, and hypoesthesia oral; and in the esketamine
56 mg plus oral antidepressant group were dizziness, nausea,
dissociation, somnolence, vertigo, headache, paresthesia (tingling
sensation), dysgeusia, hypoesthesia oral, hypoesthesia, and
fatigue. A slightly higher incidence of severe events of
dissociation and nausea was observed in the esketamine 84 mg plus
oral antidepressant treatment group as compared to the esketamine
56 mg plus oral antidepressant treatment group.
More information about this Phase 3 study of esketamine plus
oral antidepressant can be found at the link below:
https://clinicaltrials.gov/ct2/show/NCT02417064
About Esketamine
Esketamine nasal spray is an investigational product 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 major depressive disorder.
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.7
About Treatment-Resistant Depression
Major
depressive disorder affects nearly 300 million people of all ages
globally and is the leading cause of disability worldwide.
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.8 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.1
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 December 31, 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.
- National Institute of Mental Health. Questions and Answers
about the NIMH Sequenced Treatment Alternatives to Relieve
Depression (STAR*D) Study — Background. Available at:
https://www.nimh.nih.gov/funding/clinical-research/practical/stard/backgroundstudy.shtml.
Accessed September 2018.
- Johnson & Johnson Press Release. Janssen Submits Esketamine
Nasal Spray New Drug Application to U.S. FDA for
Treatment-Resistant Depression. Available at:
https://www.jnj.com/janssen-submits-esketamine-nasal-spray-new-drug-application-to-u-s-fda-for-treatment-resistant-depression.
Accessed September 2018.
- V Popova, EJ Daly, M Trivedi, K Cooper, R Lane, P Lim, C
Mazzucco, D Hough, ME Thase, RC Shelton, P Molero, E Vieta, M
Bajbouj, H Manji, WC Drevets, JB Singh. Randomized, Double-Blind
Study of Flexibly Dosed Intranasal Esketamine Plus Oral
Antidepressant Versus Active Control in Treatment-Resistant
Depression. Poster presented at: 2018 Annual Meeting of the
American Psychiatric Association (APA); May
2018; New York, New
York.
- EJ Daly, M Trivedi, A Janik, H Li, Y Zhang, X Li, R Lane, P
Lim, AR Duca, D Hough, ME Thase, J Zajecka, A Winokur, I Divacka, A
Fagiolini, WJ Cubala, I Bitter, P Blier, RC Shelton, P Molero, H
Manji, WC Drevets, JB Singh. A Randomized Withdrawal, Double-blind,
Multicenter Study of Esketamine Nasal Spray Plus an Oral
Antidepressant for Relapse Prevention in Treatment-resistant
Depression. Poster presented at: The American Society of Clinical
Psychopharmacology; May 2018;
Miami, Florida.
- E Wajs, L Aluisio, R Morrison, EJ Daly, R Lane, P Lim, R
Holder, G Sanacora, AH Young, S Kasper, AH Sulaiman, C Li, J Paik,
H Manji, D Hough, WC Drevets, JB Singh. Long-Term Safety of
Esketamine Nasal Spray Plus an Oral Antidepressant in Patients with
Treatment-Resistant Depression: Phase 3, Open Label Safety and
Efficacy Study (SUSTAIN-2). Poster presented at: The American
Society of Clinical Psychopharmacology Meeting; May 2018; Miami,
Florida.
- M Fedgchin, M Trivedi, EJ Daly, R Melkote, R Lane, P Lim, D
Vitagliano, P Blier, M Fava, M Liebowitz, A Ravindran, R Gaillard,
H Ameele, H Manji, D Hough, WC Drevets, JB Singh. Randomized,
Double-Blind Study of Fixed-Dosed Intranasal Esketamine Plus Oral
Antidepressant vs. Active Control in Treatment-Resistant
Depression. Poster presented at: 9th Biennial Conference of the
International Society for Affective Disorders (ISAD) and the
Houston Mood Disorders Conference; September
2018; Houston, TX.
- 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 September 2018.
- World Health Organization. Depression. Available at:
http://www.who.int/mediacentre/factsheets/fs369/en/. Accessed
September 2018.
Media Contact:
Greg Panico
609-730-3061 (office)
908-240-2011 (mobile)
Investor Contacts:
Christopher
DelOrefice
732-524-2955 (office)
Lesley Fishman
732-524-3922 (office)
View original content to download
multimedia:http://www.prnewswire.com/news-releases/janssen-announces-results-of-esketamine-nasal-spray-phase-3-study-in-patients-with-treatment-resistant-depression-300717094.html
SOURCE Janssen Pharmaceutical Companies of Johnson &
Johnson