TECHBRIEF

HORIZON SCANNING REPORT

INTRANASAL ESKETAMINE
Report No: 001/2019

MaHTAS
Medical Development Division
“DOKUMEN TERHAD” Ministry of Health, Malaysia
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Prepared by:

Dr. Norrina Jamaluddin

Principal Assistant Director
Health Technology Assessment Section (MaHTAS)
Medical Development Division
Ministry of Health Malaysia

Reviewed by:

Dr. Izzuna Mudla bt Mohamed Ghazali

Public Health Physician/Senior Principal Assistant Director
Health Technology Assessment Section (MaHTAS)
Medical Development Division
Ministry of Health Malaysia

Dr. Junainah bt Sabirin

Public Health Physician/Deputy Director
Health Technology Assessment Section (MaHTAS)
Medical Development Division
Ministry of Health Malaysia

Disclosure: The author of this report has

no competing interest in this subject and
the preparation of this report is totally
funded by the Ministry of Health,
Malaysia.

Disclaimer: TechBrief report is prepared

based on information available at the time
of research and a limited literature. It is
not a definitive statement on the safety,
effectiveness or cost effectiveness of the
health technology covered. Additionally,
other relevant scientific findings may have
been reported since completion of this
report.

Horizon Scanning Unit,

MaHTAS,
Medical Development Division,
Ministry of Health, Malaysia,
Email: htamalaysia@moh.gov.my
Web: http://www.moh.gov.my

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INTRANASAL ESKETAMINE
(ESKETAMINE NASAL SPRAY)
SUMMARY
Intranasal esketamine is an
investigational compound being studied
by Janssen Research and
Development, LLC as part of a global
development programme.
Esketamine is a non-competitive N-
methyl-D-aspartate (NMDA) receptor
antagonist, also known as glutamate
receptor modulator. It helps to restore
synaptic connections in brain cells of
major depressive disorder patients. The
novel mechanism of action is different
than currently available therapies for
depression.
Seven Phase 3 clinical trials were
identified. Five studies had completed
and results were available for four
studies which showed positive
outcomes to treatment-resistant
depression patient with suicidality.
United States Food and Drug
Administration (US FDA) approved
intranasal esketamine on 6th March
2019. It is only available through a
restricted distribution system, under a
Risk Evaluation and Mitigation Strategy
(REMS). The administration must be
supervised and closely monitored by
certified doctors and strictly cannot be
taken home.
Keywords: nasal spray, ketamine,
esketamine, antidepressant, depression
HS08
TechBrief
Report No. : 001/2019
INTRODUCTION
In Malaysia, the prevalence of mental
health problems among adults of 16
years and above showed an increasing
trend, escalating from 10.7% (1996) to
29.2% (2015).1 Major depression
disorder (MDD) is the most common
mental illness affecting approximately
2.3 million people in Malaysia. A group
of patient with depression may have
treatment-resistant depression (TRD)
which is a failure to demonstrate
adequate treatment for an adequate
duration.
According to National Health Morbidity
Survey (NHMS) in 2011, the
prevalence of suicidal ideation, plan
and attempt were 1.7%, 0.9% and 0.5%
respectively.2
THE TECHNOLOGY
Esketamine is a new molecular entity
and a non-competitive glutamate N-
methyl-D-aspartate (NMDA) receptor
antagonist. In antidepressant activity,
esketamine targets the glutamate
NMDA receptor. The process is shown
in Figure 1 as depicted below:
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Figure 1 : Esketamine activity for treatment-resistant depression patient

In the activity, esketamine-induced NMDA receptor antagonism of inhibitory gamma-

aminobutyric acid (GABA)-ergic cortical interneurons has been shown to release
tonic inhibition of excitatory (glutamatergic) pyramidal neurons to increase synaptic
glutamate release (acute “glutamate surge”). Because postsynaptic NMDA receptors
are blocked, synaptic glutamate can then preferentially bind to and activate alpha-
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.
Postsynaptic membrane depolarisation then initiates intracellular second messenger
or signal transduction cascade, which lead to mammalian target of rapamycin
(mTOR) activation, increased brain-derived neurotrophic factor (BDNF) translation
and secretion, and glycogen synthase kinase-3 (GSK-3) inhibition. These acute
molecular and cellular responses to ketamine stimulate synaptic plasticity. 3

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Intranasal esketamine is expected to be

launched in 2019 (United States) and
early 2020 (United Kingdom).4

On 6th March 2019, United States Food

and Drug Administration (US FDA)
approved intranasal esketamine. It is
only available through a restricted
distribution system, under a Risk
Evaluation and Mitigation Strategy
(REMS). The administration must be
Figure 2: Esketamine nasal spray supervised and closely monitored by
Intranasal esketamine received Fast certified doctors and strictly cannot be
Track Designation by United States taken home.7
Food and Drug Administration (US
FDA) for major depressive disorder in
PATIENT GROUP AND
2013. Two years later, it was granted INDICATION
Breakthrough Therapy for treatment-
resistant depression and major Intranasal esketamine is indicated for
depression disorder (MDD) with high treatment-resistant depression in adults
risk of suicide.4 with Major Depressive Disorder (MDD)
who have not responded to at least two
Johnson & Johnson’s Janssen different treatments with
Pharmaceutical Companies has antidepressants in the current
submitted a new drug application moderate-to-severe depressive
(NDA) to US FDA and a marketing episode.
authorization application (MMA) to
European Medicines Agency (EMA) in CURRENT PRACTICE
September and October 2018
According to Clinical Practice
respectively for treatment-resistant
Guidelines on Management of Major
depression in patients with major
Depressive Disorder, Ministry of Health
depressive disorder. If this technology
(2007), the recommended treatment for
is approved, ketamine nasal spray
patients with resistant depression
becomes the first new approach to treat
includes switching antidepressant,
refractory major depressive disorder to
augmentation with lithium/antipsychotic
patients in the last 50 years.5,6
and/or combine with second
8
It has been developed as a twice antidepressant. Currently there are no
weekly intranasal therapy for treatment approved treatments for patients with
-resistant depression in a depression who are at an imminent risk
comprehensive programme by Janssen of suicide.9
company.

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SAFETY & EFFICACY
We identified five completed Phase 3
clinical trials, namely SUSTAIN-1,
SUSTAIN-2, TRANSFORM-1,
TRANSFORM-2 and TRANSFORM-3).
Two clinical trials which are still
ongoing (SUSTAIN-3 and ASPIRE-1).
However, the result of the
TRANSFORM-1 trial is not retrievable.
A) Efficacy
A Relapse Prevention Study, known as
SUSTAIN-1 (NCT02493868) among
703 adult patients reported treatment
group (intranasal esketamine plus
antidepressant, reduced relapse for
TRD patients with or without remission
when compared to control group
(antidepressant plus placebo group)
Estimated hazard ratio (HR) among
patients with remission for the
treatment group was 0.49 (95% Cl:
0.29, 0.84), which means that, patient
in the treatment group had a 51%
reduced risk of relapse as compared to
control group. For patients without
remission, the estimated hazard ratio
(HR) was 0.30 (95% Cl: 0.16, 0.55),
indicating that the treatment group had
a 70% reduced risk of relapse. The
difference between groups for the time
to relapse was clinically and statistically
significant (p<0.05).10
In another study, SUSTAIN-2 (NCT
02497287) the result showed
improvement in depressive symptoms
for up to one year among 821 of TRD
patients. During the induction phase
(four weeks), the response rate was
78.4% [n=644/821 (percentage of
patients with ≥50% reduction in the
Montgomery and Asberg Depression
Rating Scale (MADRS) total score)]
and remission rate (MADRS total score
≤12) was 47.2%. Subsequently, during
maintenance phase (48 weeks), 76.5%
of patients (n=628/821) responded to
treatment and the remission rate was
58.2%. The mean change in MADRS
total score from the induction baseline
to the four-week endpoint was -16.4
(8.76) and from the subsequent
maintenance baseline to endpoint was
0.3 (8.12).11
A short-term study, TRANSFORM-2
among TRD adult patients reported a
response rate of 69.3% (n=70/101) in
the treatment group (intranasal
esketamine plus oral antidepressant)
versus 52% (n=52/100) in the control
group (placebo nasal spray plus oral
antidepressant) at 28 days (response is
defined ≥50% improvement in MADRS
score from baseline). The remission
rate was 52.5% (n=53/101) for the
treatment group and 31% (n=31/100)
for the control group. 12
For elderly TRD patients (n=137), a
long term study known as
TRANSFORM-3 (NCT02422186)
showed an improvement in MADRS
score in the treatment group
(n=72/137). The mean (SD) change in
MADRS total scores from baseline to
day 28 was -10.0 (12.74) for the
treatment group and -6.3 (8.86) for the
control group (n=65/137). The median-
unbiased estimate of the difference
between the treatment group and the
placebo group was -3.6 (95% CI: -7.20,
0.07; one-sided p=0.029). The
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difference in least square mean (SE)
change at day 28 was -4.9 (2.04) for
65-74 years old (one-sided p=0.009)
and -0.4 (5.02) for ≥75 years old (one-
sided p=0.465). A treatment difference
favouring treatment group was reported
among 65-74 years subgroup.13
B) Safety
The safety results were consistent with
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.
For clinical trials of SUSTAIN-
1,SUSTAIN-2, TRANSFORM-2 and
TRANSFORM-3, the most common
adverse event (more than 10%)
reported in the esketamine group were
impairment sense of taste (11.8-27%),
vertigo (11-25%), nausea (16.4-25.1%),
headache (17.8-24.9%), drowsiness
(16.7-21.1%), blurred vision (15.8%)
and oral hypoaesthesia (11.8-13.2%).
Adverse events and associated
symptoms were seen predominantly on
the day of dosing, generally transient,
mild or moderate in severity, and
usually resolved on the same day. For
the control group, no adverse events
were reported. Two deaths were
reported, but unrelated to intranasal
esketamine and oral antidepressant
use. The patients were followed up until
one year, no trends of clinical concerns
in laboratory tests, physical
examination and nasal tolerability for
patients treated with esketamine nasal
spray. There was no cognitive changes
and no cases of interstitial or ulcerative
cystitis were reported.10,11,12,13
ESTIMATED COST
The price of esketamine nasal spray is
cheaper as compared to other
administration route. The estimated
price for esketamine nasal spray
(20mg/0.1ml) is about USD 70-100 (RM
290- RM 415).
For comparison, the estimated cost of
treatment for depression using
ketamine is about USD 1,000 (RM
4200 for intravenous), USD 750 (RM
3200 for intramuscular) and USD 500
(RM 2000 oral and sublingual).14
ORGANIZATIONAL ISSUES
In July 2018, a policy brief developed
by National Institute for Health
Research (NIHR), United Kingdom
recommends a requirement of license
for esketamine to be administered
under supervision in clinics, and
introduction of “pharmacy-based
checking system” that similar with
clozapine-like-system of checks. This
system will be linked to mandatory
data collection in a registry, restriction
of ketamine use in institutions with
mental health expertise such as NHS
Trusts United Kingdom. It also requires
satisfactory blood test before
dispensing esketamine to patient. This
will ensure high quality monitoring and
reduce mortality. A regional specialist
“hub” centres is required for network
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practice to inform development of
monitoring structures, procedures and
maximizing drug compliance. Besides,
it also needs to formalise experiences
(formulation, doses, and condition) with
ketamine for depression patients and
establishment of safe deployment and
clinic-based administration of
esketamine before expansion into
community settings within all secondary
mental health care. To ensure good
dispensing practices, it is
recommended to do a screening of
ketamine urine drug and a screening
questionnaire to patients by
prescriber. 15
Ethically, there are two main issues
being highlighted, namely “off-label”
prescription and potential “ketamine
abuse”.
The off-label usage refers to the
prescription of a medication to treat a
condition which has not been approved
by FDA, and there is insufficient
medical evidence to support such
application. In some countries, there
are established ketamine clinics which
provide off-label intranasal ketamine to
patients for extended periods. Despite
the use of lower doses, it may increase
the risk of developing dependence if it
is being used for extended periods. At
the moment, there was no available
research on the addictive potential of
ketamine used in the treatment of
depression.16
In some countries, ketamine is the most
common drug being abuse and the
prevalence of health and social
problems associated with ketamine
abuse are widely acknowledged.17,18
For example, Southeast and East Asia
have reported an escalating situation of
ketamine abuse. In these countries,
drug dependence, lower urinary tract
dysfunction, and sexual impulse or
violence were the most notable
ketamine-associated symptoms.17
In certain countries, the use of
ketamine along with other “club drugs”,
such as MDMA (ecstasy), gamma-
hydroxybutyric acid (GHB), and
flunitrazepam, have shown to be
associated with various adverse health
issues including dependence and
specific organ toxicity. Caution is much
required to avoid the potential of
abuse. 18
The administration of ketamine in sub-
anaesthetic and non-sedating doses
can be used safely for ambulatory and
domiciliary treatment. If domiciliary
treatment is considered, the risk of
abuse must be kept in mind and
periodically reviewed.17
If ketamine is indeed a remedy for
treating depression, it would be a
priority to learn its adverse effects such
as dependence potential, cognitive
impairment, and irreversible urinary
tract dysfunction for long-term use.17
In conclusion, ketamine use in treating
severe depression is associated with
major ethical concerns, including the
lack of safety data in off-label use and
its abuse potential.19
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POTENTIAL IMPACT
Intranasal esketamine is generally
more convenient, easier to use, less
invasive, more preferable and cheaper
than other route of administration.
It offers rapid antidepressant effect. The
effect of esketamine typically lasted for
seven to 14 days before another dose
is required. It rapidly reduced
symptoms of depression by improving
MADRS total score as reported from
two clinical trials. In addition, it reduced
relapse for patients with or without
remission.
As it has potential to be abused,
esketamine usage is preferably be
used in a clinic under supervision,
although theoretically an intranasal
medication potentially could be taken at
home. Furthermore, some short-term
side effects need to be monitored by a
healthcare professional.
REFERENCES
1. National Health and Morbidity
Survey of 2015, Available at:
http://www.iku.moh.gov.my/images/I
KU/Document/REPORT/nhmsreport
2015vol2.pdf, Retrieved on 2nd
October 2018
2. Malaysian Mental Healthcare
Performance, Technical Report
2016, Ministry of Health
3. Zarate Jr CA, Niciu MJ. Ketamine for
Depression: Evidence, Challenges
And Promise. World Psychiatry.
2015;14(3):348-350
4. Major Depressive Disorder – Global
Drug Forecast And Market
Assessment To 2025, Available at :
https://www.bioportfolio.co.uk/produc
tpdf.php?params=39918, Retrieved
on 18th September 2018
5. Janssen Submits Esketamine Nasal
Spray New Drug Application to U.S.
FDA for Treatment-Resistant
Depression. Available at:
https://www.prnewswire.com/news-
releases/janssen-submits.
Esketamine-Nasal-Spray-New-Drug-
Application-to-US-FDA-for-
Treatment-Resistant-Depression-
300705975.html, Retrieved on 18th
September 2018
6. Intranasal Ketamine, Available at:
http://www.medscape.com/viewarticl
e/896510, Retrieved on 18th
September 2018.
7. FDA News Release “FDA Approves
New Nasal Spray Medication for
Treatment-Resistant Depression;
Available Only at a Certified Doctor’s
Office or Clinic”, Available at:
https://www.fda.gov/news-
events/press-announcements/fda-
approves-new-nasal-spray-
medication-treatment-resistant-
depression-available-only-certified/,
Retrieved on 22nd February 2019
8. Clinical Practice Guideline
Management of Major Depression
Disorder, Ministry of Health , 2007
9. Esketamine for Treatment-Resistant
Depression, NIHR Innovation
Observatory Evidence Briefing,
December 2017.
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10. A Study of Intranasal Esketamine
Plus an Oral Antidepressant for
Relapse Prevention in Adult
Participants with Treatment-resistant
Depression, Preliminary findings
available at:
https://www.jnj.com/mediacenter/pre
ss-releases/long-term-phase-study-
shows-esketamine-nasal-spray-plus-
an-oral-antidepressant-delayed-time-
to-relapse-in-patients-with-treatment-
resistant-depression. (unpublished).
11. A Long-term, Safety and Efficacy
Study of Intranasal Esketamine in
Treatment-resistant Depression
(SUSTAIN-2), Preliminary findings
available at:
https://www.jnj.com/media-
center/press-releases/long-term-
phase-3-study-shows-esketamine-
nasal-spray-plus-an-oral-
antidepressant-delayed-time-to-
relapse-in-patients-with-treatment-
resistant-depression.(unpublished)
12. Popova V, Daly E, Trivedi M, et al.
Randomised, Double-Blind Study of
Flexibly-Dosed Intranasal
Esketamine Plus Oral
Antidepressant versus Active Control
in Treatment-Resistant Depression.
Biological Psychiatry.
2018;83(9):S390.
13. Ochs-Ross R, Daly EJ, Zhang Y, et
al. Efficacy and Safety of Intranasal
Esketamine Plus an Oral
Antidepressant in Elderly Patients
With Treatment-Resistant
Depression. Biological Psychiatry.
2018;83(9):S391.
14. Ketamine, American Brain
Stimulation Clinic, Available at:
http://brainstimulationclinic.squaresp
ace.com/ketaminedepression/,
Retrieved on 27th September 2018
15. Briefing Paper: New Rapidly Acting
Antidepressants: Policy Implications
And Risk Mitigation, July 2018.
Available at :
https://oxfordhealthbrc.nihr.ac.uk/wp
content/uploads/2018/07/Stakeholde
r-briefing-V3-9-July-2018.pdf,
Retrieved on 28th September 2018
16. Kolar D. Addictive Potential of Novel
Treatments For Refractory
Depression And Anxiety.
Neuropsychiatric Disease and
Treatment. 2018;14:1513.
17. Li JH, Vicknasingam B, Cheung YW,
et al. To Use Or Not To Use: An
Update On Licit And Illicit Ketamine
Use. Substance Abuse And
Rehabilitation. 2011;16(2):11–20.
18. Henden E, Baeroe K. Providing Free
Heroin To Addicts Participating In
Research – Ethical Concerns And
The Question Of Voluntariness. B J
Psych Bulletin. 2015;39:28
19. Singh I, Morgan C, Curran V, et al.
Ketamine Treatment for Depression:
Opportunities for Clinical Innovation
And Ethical Foresight. The Lancet
Psychiatry. 2017;4(5):4
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Prepared by:
Dr. Norrina binti Jamaluddin
Medical Officer
Principal Assistant Director
Health Technology Assessment Section (MaHTAS)
Medical Development Division
Ministry of Health Malaysia

Reviewed by:
Dr. Izzuna Mudla Binti Mohamed Ghazali
Public Health Physician
Senior Principal Assistant Director
Health Technology Assessment Section (MaHTAS)
Medical Development Division
Ministry of Health Malaysia

Dr. Junainah Binti Sabirin

Public Health Physician
Deputy Director
Health Technology Assessment Section (MaHTAS)
Medical Development Division
Ministry of Health Malaysia

Disclosure: The author of this report has no

competing interest in this subject and the
preparation of this report is totally funded by the
Ministry of Health, Malaysia.

Disclaimer: TechBrief report is prepared based on

information available at the time of research and a
limited literature. It is not a definitive statement on
the safety, effectiveness or cost-effectiveness of the
health technology covered. Additionally, other
relevant scientific findings may have been reported
since completion of this report.

Horizon Scanning Unit,

MaHTAS,
Medical Development Division,
Ministry of Health, Malaysia,
Email: htamalaysia@moh.gov.my
Web: http://www.moh.gov.my

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