Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Psychoanaleptics; Other antidepressants, ATC code: N06AX27.

Mechanism of action
Esketamine is the S-enantiomer of racemic ketamine. It is a non-selective, non-competitive, antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. Through NMDA receptor antagonism, esketamine produces a transient increase in glutamate release leading to increases in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) stimulation and subsequently to increases in neurotrophic signalling which may contribute to the restoration of synaptic function in these brain regions involved with the regulation of mood and emotional behaviour. Restoration of dopaminergic neurotransmission in brain regions involved in the reward and motivation, and decreased stimulation of brain regions involved in anhedonia, may contribute to the rapid response.

Pharmacodynamic effects

Abuse potential
In a study of abuse potential conducted in recreational polydrug users (n=41), single doses of esketamine nasal spray (84 mg and 112 mg) and the positive control drug intravenous ketamine (0.5 mg/kg infused over 40 minutes) produced significantly greater scores than placebo on subjective ratings of “drug liking” and on other measures of subjective drug effects.

Clinical efficacy and safety

The efficacy and safety of esketamine nasal spray was investigated in five Phase 3 clinical studies (TRD3001, TRD3002, TRD3003, TRD3004, and TRD3005) in adult patients (18 to 86 years) with treatment-resistant depression (TRD) who met DSM-5 criteria for major depressive disorder and were non-responders to at least two oral antidepressants (ADs) treatments of adequate dosage and duration, in the current major depressive episode. 1,833 adult patients were enrolled, of which 1,601 patients were exposed to esketamine. Additionally, 676 patients were randomised (334 patients received esketamine) in Phase 3 study TRD3013.

The efficacy and safety of esketamine nasal spray was investigated in two Phase 3 clinical studies in adult patients (18 to 64 years) with moderate to severe MDD (MADRS total score >28) who had affirmative responses to Mini International Neuropsychiatric Interview (MINI) questions B3 (“Think [even momentarily] about harming or of hurting or of injuring yourself: with at least some intent or awareness that you might die as a result; or think about suicide [i.e., about killing yourself]?”) and B10 (“Intend to act on thoughts of killing yourself in the past 24 hours?”). 456 adult patients were enrolled, of which 227 patients were exposed to Spravato.

Treatment-resistant depression – Short-term studies

Esketamine was evaluated in three Phase 3 short-term (4-week) randomised, double-blind, active-controlled studies in patients with TRD. Studies TRANSFORM-1 (TRD3001) and TRANSFORM-2 (TRD3002) were conducted in adults (18 to < 65 years) and Study TRANSFORM-3 (TRD3005) was conducted in adults ≥ 65 years of age. Patients in TRD3001 and TRD3002 initiated treatment with esketamine 56 mg plus a newly initiated daily oral AD or a newly initiated daily oral AD plus placebo nasal spray on day 1. Esketamine dosages were then maintained on 56 mg or titrated to 84 mg or matching placebo nasal spray administered twice-weekly during a 4-week double-blind induction phase. Esketamine doses of 56 mg or 84 mg were fixed in Study TRD3001 and flexible in Study TRD3002. In Study TRD3005, patients (≥ 65 years) initiated treatment with esketamine 28 mg plus a newly initiated daily oral AD or a newly initiated daily oral AD plus placebo nasal spray (day 1). Esketamine dosages were titrated to 56 mg or 84 mg or matching placebo nasal spray administered twice-weekly during a 4-week double-blind induction phase. In the flexible dose studies, TRD3002 and TRD3005, up titration of esketamine dose was based on clinical judgement and dose could be down titrated based on tolerability. A newly initiated open-label oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) was initiated on day 1 in all studies. The selection of the newly initiated oral AD was determined by the investigator based on the patient’s prior treatment history. In all short-term studies, the primary efficacy endpoint was change in MADRS total score from baseline to day 28.

Baseline demographic and disease characteristics for patient in TRD3002, TRD3001, and TRD3005 are presented in Table 5.

Table 5:     Baseline demographic characteristics for TRD3002, TRD3001, and TRD3005 (full analysis sets)
Study TRD3002         Study TRD3001     Study TRD3005
(N=223)               (N=342)           (N=137)
Age, years
Median (Range)                      47.0 (19; 64)            47.0 (18; 64)        69.0 (65; 86) Sex, n (%)
Male                                 85 (38.1%)              101 (29.5%)           52 (38.0%) Female                              138 (61.9%)              241 (70.5%)           85 (62.0%) Race, n (%)
White                               208 (93.3%)              262 (76.6%)          130 (94.9%) Black or African American            11 (4.9%)                19 (5.6%)                 -- Prior oral antidepressants with nonresponse (i.e., failed antidepressants) Number of specific antidepressants, n (%)
2                               136 (61.0%)              167 (48.8%)           68 (49.6%)
3 or more                        82 (36.8%)              167 (48.8%)           58 (42.3%) Newly initiated oral antidepressant medication initiated at randomisation, n (%) SNRI                            152 (68.2%)              196 (57.3%)           61 (44.5%) SSRI                             71 (31.8%)              146 (42.7%)           76 (55.5%) Withdrawn from study (for
30/227 (13.2%)            31/346 (9.0%)        16/138 (11.6%) any reason), n/N (%)

In the flexible dose study TRD3002, at day 28, 67% of the patients randomised to esketamine were on 84 mg. In study TRD3002, esketamine plus a newly initiated oral AD demonstrated clinically meaningful and statistical superiority compared to a newly initiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plus placebo nasal spray (Table 6), and symptom reduction was observed as early as 24 hours post-dose.

In study TRD3001, a clinically meaningful treatment effect in change in MADRS total scores from baseline at the end of the 4-week induction phase was observed favouring esketamine plus newly initiated oral AD compared with a newly initiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plus placebo nasal spray (Table 6). In Study TRD3001, the treatment effect for the esketamine 84 mg plus oral AD group compared with oral AD plus placebo was not statistically significant.


In study TRD3005, at day 28, 64% of the patients randomised to esketamine were on 84 mg, 25% on 56 mg, and 10% on 28 mg. In study TRD3005, a clinically meaningful but not statistically significant treatment effect in change in MADRS total scores from baseline at the end of the 4-week induction phase was observed favouring esketamine plus newly initiated oral AD compared with a newly initiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plus placebo nasal spray (Table 6). Subgroup analyses suggest limited efficacy in the population over 75 years old.

Table 6:     Primary efficacy results for change in MADRS total score for 4-week clinical trials (ANCOVA BOCF*)
LS mean
Mean           change from LS mean
Number of
Study no.     Treatment group§                     baseline score baseline to   difference patients
(SD)           end of week 4 (95% CI)†
(SE)
Spravato                                                                  -4.3 115         37.4 (4.8)     -18.9 (1.3)
56 mg + oral AD                                                      (-7.8, -0.8)# Spravato                                                                  -1.2 TRD3001                                   114         37.8 (5.6)     -16.2 (1.3) 84 mg + oral AD                                                       (-4.7, 2.3)# Oral AD + placebo
113         37.5 (6.2)     -14.7 (1.3) nasal spray
Spravato (56 mg or                                                        -3.5 114         37.0 (5.7)     -17.7 (1.3)
84 mg) + oral AD                                                     (-6.7, -0.3)‡ TRD3002
Oral AD + placebo
109         37.3 (5.7)     -14.3 (1.3) nasal spray
Spravato (28 mg,
-2.9
56 mg or                    72          35.5 (5.9)     -10.1 (1.7)
TRD3005                                                                             (-6.5, 0.6)# 84 mg) + oral AD
(≥ 65 years)
Oral AD + placebo
65          34.8 (6.4)      -6.8 (1.7) nasal spray
SD = standard deviation; SE = standard error; LS Mean = least-squares mean; CI = confidence interval; AD = antidepressant
* ANCOVA analysis using Baseline Observation Carried Forward, which means that for a patient who discontinues  from treatment, it is assumed that the depression level returns to the baseline level (i.e. the depression level is the same as before start of treatment)
§
Nasally administered esketamine or placebo; oral AD = a newly initiated AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline)
†
Difference (Spravato + oral AD minus Oral AD + placebo nasal spray) in least-squares mean change from baseline ‡
Treatment group that was statistically significantly superior to Oral AD + placebo nasal spray #
Median unbiased estimate (i.e., weighted combination of the LS means of the difference from Oral AD + placebo nasal spray), and 95% flexible confidence interval

Response and remission rates

Response was defined as ≥ 50% reduction in the MADRS total score from baseline of the induction phase. Based on the reduction in MADRS total score from baseline, the proportion of patients in Studies TRD3001, TRD3002 and TRD3005 who demonstrated response to esketamine plus oral AD treatment was greater than for oral AD plus placebo nasal spray throughout the 4-week double-blind induction phase (Table 7).

Remission was defined as a MADRS total score ≤ 12. In all three studies, a greater proportion of patients treated with esketamine plus oral AD were in remission at the end of the 4-week double-blind induction phase than for oral AD plus placebo nasal spray (Table 7).


Table 7:       Response and remission rates in 4-week clinical trials based on BOCF* data Number of patients (%)
Response rate†                                   Remission
Treatment                                                                                      rate‡ Study No.           group§            24 hours        Week 1         Week 2         Week 3         Week 4         Week 4 Spravato
20             21             29             52             61              40 56 mg + oral
(17.4%)        (18.3%)        (25.2%)        (45.2%)        (53.0%)         (34.8%) AD
Spravato
17              16             25             33             52              38 TRD3001          84 mg + oral
(14.9%)#        (14.0%)        (21.9%)        (28.9%)        (45.6%)         (33.3%) AD
Oral AD +
8               5             15             25             42              33 placebo nasal
(7.1%)          (4.4%)        (13.3%)        (22.1%)        (37.2%)         (29.2%) spray
Spravato
56 mg or                  18             15             29             54             70              53 84 mg + oral           (15.8%)        (13.2%)        (25.4%)        (47.4%)        (61.4%)         (46.5%) TRD3002          AD
Oral AD +
11             13             23             35             52              31 placebo nasal
(10.1%)        (11.9%)        (21.1%)        (32.1%)        (47.7%)         (28.4%) spray
TRD3005          Spravato
(≥ 65 years)     28 mg, 56 mg                              4              4             9              17              11 NA or 84 mg +                             (5.6%)         (5.6%)        (12.5%)        (23.6%)         (15.3%) oral AD
Oral AD +
3             8              8              8                4 placebo nasal            NA
(4.6%)        (12.3%)        (12.3%)        (12.3%)          (6.2%) spray
AD = antidepressant; NA = not available
*
Baseline Observation Carried Forward, which means that for a patient who discontinues from treatment, it is assumed that the depression level returns to the baseline level (i.e. the depression level is the same as before start of treatment).
§
Nasally administered Spravato or placebo; oral AD = a newly initiated AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline)
†
Response was defined as ≥ 50% reduction in the MADRS total score from baseline ‡
Remission was defined as MADRS total score ≤ 12
#
First dose was Spravato 56 mg + oral AD

Treatment-resistant depression – Long-term studies

Relapse-prevention study
The maintenance of antidepressant efficacy was demonstrated in a relapse prevention trial. Study SUSTAIN-1 (TRD3003) was a long-term randomised, double-blind, parallel-group, active-controlled, multicentre, relapse prevention study. The primary outcome measure to assess the prevention of depressive relapse was measured as time to relapse. Overall a total of 705 patients were enrolled; 437 directly enrolled; 150 transferred from TRD3001, and 118 transferred from TRD3002. Patients directly enrolled were administered esketamine (56 mg or 84 mg twice weekly) plus oral AD in a 4-week open label induction phase. At the end of the open label induction phase, 52% of patients were in remission (MADRS total score ≤ 12) and 66% of patients were responders (≥ 50% improvement in MADRS total score). Patients who were responders (455), continued receiving treatment with esketamine plus oral AD in a 12-week optimisation phase. After the induction phase, patients received esketamine weekly for 4 weeks and starting from week 8, an algorithm (based on the MADRS) was used to determine the dosing frequency; patients in remission (i.e., MADRS total score was ≤ 12) were dosed every other week, however, if the MADRS total score increased to > 12, then the frequency was increased to weekly dosing for the next 4 weeks; with the objective of maintaining the patient on the lowest dosing frequency to maintain response/remission. At the end of 16 weeks of treatment period, patients in stable remission (n=176) or stable response (n=121) were randomised to continue with esketamine or stop esketamine and switch to placebo nasal spray. Stable remission was defined as MADRS total score ≤ 12 in at least 3 of the last 4 weeks of the optimisation phase and stable response was defined as ≥ 50% reduction in the MADRS total score from baseline for the last 2 weeks of the optimisation phase, but not in stable remission.

Stable remission

Patients in stable remission who continued treatment with esketamine plus oral AD experienced a statistically significantly longer time to relapse of depressive symptoms than did patients on a newly initiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plus placebo nasal spray (Figure 1). Relapse was defined as a MADRS total score ≥ 22 for 2 consecutive weeks or hospitalisation for worsening depression or any other clinically relevant event indicative of relapse. The median time to relapse for a newly initiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plus placebo nasal spray group was 273 days, whereas the median was not estimable for esketamine plus oral AD, as this group never reached 50% relapse rate.

Figure 1:   Time to relapse in patients in stable remission in study TRD3003 (full analysis set) 


For patients in stable remission, the relapse rate based on Kaplan-Meier estimates during the 12- and 24-weeks double-blind follow up period was 13% and 32% for esketamine and 37% and 46% for placebo nasal spray, respectively.

Stable response

The efficacy results were also consistent for patients in stable response who continued treatment with esketamine plus oral AD; patients experienced a statistically significantly longer time to relapse of depressive symptoms than did patients on a newly initiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plus placebo nasal spray (Figure 2). The median time to relapse for a newly initiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plus placebo nasal spray group (88 days) was shorter compared to esketamine plus oral AD group (635 days).

Figure 2:    Time to relapse in patients in stable response in study TRD3003 (full analysis set) 


For patients in stable response, the relapse rate based on Kaplan-Meier estimates during the 12- and 24-weeks double-blind follow up period was 21% and 21% for Spravato and 47% and 56% for placebo nasal spray, respectively.

Enrollment in TRD3003 was staggered over approximately 2 years. The maintenance phase was of variable duration and continued until the individual patient had a relapse of depressive symptoms or discontinued for any other reason, or the study ended because the required number of relapse events occurred. Exposure numbers were influenced by the study stopping at a pre-determined number of relapses based on the interim analysis. After an initial 16 weeks of treatment with esketamine plus oral AD, the median duration of exposure to esketamine in the maintenance phase was 4.2 months (range: 1 day to 21.2 months) in Spravato-treated patients (stable remission and stable response). In this study, 31.6% of patients received esketamine for greater than 6 months and 7.9% of patients received esketamine for greater than 1 year in the maintenance phase.

Dosing frequency

The dosing frequency used the majority of the time during the maintenance phase is shown in Table 8.
Of the patients randomised to Spravato, 60% received 84 mg and 40% received 56 mg dose.


Table 8:    Dosing frequency used the majority of the time; maintenance phase (Study TRD3003)
Stable Remission                 Stable Responders
Oral AD +                        Oral AD +
Spravato +     Placebo Nasal      Spravato +     Placebo Nasal
Oral AD           Spray          Oral AD            Spray
(N=90)          (N=86)           (N=62)           (N=59)
Majority dosing frequency
Weekly                         21 (23.3%)      27 (31.4%)       34 (54.8%)      36 (61.0%) Every other week               62 (68.9%)      48 (55.8%)       21 (33.9%)      19 (32.2%) Weekly or every other week      7 (7.8%)       11 (12.8%)        7 (11.3%)        4 (6.8%) 

Study TRD3013 (ESCAPE-TRD)
The efficacy of Spravato was evaluated in a long-term randomised, open-label, rater-blinded, active- controlled study (TRD3013) where esketamine was compared with quetiapine prolonged/extended- release (XR) in 676 adult patients (18-74 years) with TRD who continued to take their current oral AD (an SSRI or SNRI). Patients received treatment with flexibly dosed esketamine (28, 56, or 84 mg) or quetiapine XR, in line with the dosing recommendations in the SmPCs in use at the time of study initiation.

The primary efficacy endpoint was remission (MADRS total score of ≤ 10) at Week 8 and the key secondary endpoint was remaining relapse-free through Week 32 after remission at Week 8. Relapse was defined as a MADRS total score ≥ 22 for 2 consecutive weeks or hospitalisation for worsening depression or any other clinically relevant event indicative of relapse.

The baseline demographic and disease characteristics of patients were similar between the esketamine plus oral AD and quetiapine XR plus oral AD groups. The mean (SD) baseline MADRS total scores were 31.4 (6.06) for the esketamine plus oral AD group and 31.0 (5.83) for the quetiapine XR plus oral AD group.

Esketamine plus oral AD demonstrated clinically meaningful and statistical superiority compared to quetiapine XR plus oral AD on both the primary (Table 9) and key secondary (Table 10) efficacy measure.

Table 9:     Primary efficacy results for TRD3013 Studya
Treatment group                  Spravato + oral AD                              Quetiapine XR + oral AD Number of patients in                    91/336 (27.1%)                                 60/340 (17.6%) remission at Week 8
Adjusted risk difference in               9.5 (3.3, 15.8)                                          – b percentage (95% CI)
P-value c                                   P = 0.003                                              – CI = confidence interval; AD = antidepressant; XR = extended release a
A patient who discontinued study intervention before Week 8 was considered as a negative outcome (i.e. non-remission).
For patients for whom no MADRS result was available at the Week 8 visit but who did not discontinue study intervention or withdraw from study before Week 8, LOCF of MADRS was applied.
b
Mantel-Haenszel estimate of the risk difference, stratified by age groups (18-64; ≥65) and total number of treatment failures is used. This estimated difference indicates an advantage for esketamine.
c
Cochran–Mantel–Haenszel (CMH) test, adjusting for age groups (18-64; ≥65) and total number of treatment failures.


Table 10: Key secondary efficacy results for TRD3013 Studya
Treatment group              Spravato + oral AD             Quetiapine XR + oral AD Number of patients both in           73/336 (21.7%)                48/340 (14.1%) remission at Week 8 and relapse-free at Week 32
Adjusted risk difference in           7.7 (2.0, 13.5)                    – b percentage (95% CI)
P-value c                               P = 0.008                        – CI = confidence interval; AD = antidepressant; XR = extended release a
A patient who discontinued study intervention was considered as a negative outcome. For patients for whom no MADRS result was available at the Week 8 visit but who did not discontinue study intervention or withdraw from study before Week 8, LOCF of MADRS was applied.
b
Mantel-Haenszel estimate of the risk difference, stratified by age groups (18-64; ≥65) and total number of treatment failures is used. This estimated difference indicates an advantage for esketamine.
c Cochran–Mantel–Haenszel (CMH) test, adjusting for age groups (18-64; ≥65) and total number of treatment failures.


Treatment discontinuation rates over the 32-week treatment period due to adverse events, lack of efficacy, and overall were 4.2%, 8.3%, and 23.2% respectively for patients in the Spravato plus oral AD group and 11.5%, 15.0%, and 40.3% respectively for patients in the quetiapine XR plus oral AD group.


Acute short-term treatment of psychiatric emergency due to Major Depressive Disorder Spravato was investigated in two identical Phase 3 short-term (4-week) randomised, double-blind, multicentre, placebo-controlled studies, Aspire I (SUI3001) and Aspire II (SUI3002) in adult patients with moderate to severe MDD (MADRS total score >28) who had affirmative responses to MINI questions B3 (“Think [even momentarily] about harming or of hurting or of injuring yourself: with at least some intent or awareness that you might die as a result; or think about suicide [i.e., about killing yourself]?”) and B10 (“Intend to act on thoughts of killing yourself in the past 24 hours?”). In these studies, patients received treatment with esketamine 84 mg or placebo nasal spray twice-weekly for 4 weeks. All patients received comprehensive standard of care (SOC) treatment, including an initial inpatient hospitalisation and a newly initiated or optimised oral antidepressant (AD) therapy (AD monotherapy or AD plus augmentation) as determined by the investigator. In the physician’s opinion, acute psychiatric hospitalisation was clinically warranted due to the subject’s immediate risk of suicide. After the first dose, a one-time dose reduction to esketamine 56 mg was allowed for patients unable to tolerate the 84 mg dose.

The baseline demographic and disease characteristics of patients in SUI3001 and SUI3002 were similar between the esketamine plus SOC or placebo nasal spray plus SOC groups. The median patient age was 40 years (range 18 to 64 years), 61% were female; 73% Caucasian and 6% Black; and 63% of patients had at least one prior suicide attempt. Prior to entering the study, 92% of the patients were receiving antidepressant therapy. During the study, as part of standard of care treatment, 40% of patients received AD monotherapy, 54% of patients received AD plus augmentation regimen, and 6% received both AD monotherapy/AD plus augmentation regimen.

The primary efficacy measure was the reduction of symptoms of MDD as measured by the change from baseline MADRS total score at 24 hours after first dose (Day 2).

In SUI3001 and SUI3002, Spravato plus SOC demonstrated statistical superiority on the primary efficacy measure compared to placebo nasal spray plus SOC (see Table 11).

Table 11:       Primary efficacy results for change from baseline in MADRS total score at 24 hours after first dose (Studies SUI3001 and SUI3002) (ANCOVA BOCF*)


Study No.          Treatment Group‡              Number           Mean             LS Mean Change                 LS Mean of           Baseline          from Baseline to              Difference Patients       Score (SD)          24 hr Post First             (95% CI)§ Dose (SE)
-3.7
Study 1          Spravato 84 mg + SOC                 112         41.2 (5.87)           -15.7 (1.05)            (-6.41; -0.92)# (SUI3001)                                                                                                          P=0.006 Placebo nasal spray + SOC            112         41.0 (6.29)           -12.1 (1.03)                   – -3.9
Study 2          Spravato 84 mg + SOC                 114         39.5 (5.19)           -15.9 (1.02)            (-6.65; -1.12)# (SUI3002)                                                                                                          P=0.006 
Placebo nasal spray + SOC            113         39.9 (5.76)           -12.0 (1.06)                   – -3.8
Pooled           Spravato 84 mg + SOC                 226         40.3 (5.60)           -15.8 (0.73)            (-5.69; -1.82) Studies 1 and 2            Placebo nasal spray + SOC            225         40.4 (6.04)           -12.1 (0.73)                   – SD=standard deviation; SE=standard error; LS Mean=least-squares mean; CI=confidence interval; SOC=standard of care * ANCOVA analysis using Baseline Observation Carried Forward: In SUI3001, 2 subjects (1 subject in each group) did not have the Day 2 (24 hours post first dose) MADRS total score and in SUI3002, 6 subjects (4 subjects in Esketamine and 2 subjects in Placebo) did not have the Day 2 (24 hours post first dose) MADRS total score. For these subjects, it is assumed that the depression level returns to the baseline level (i.e. the depression level is the same as the start of treatment) and the MADRS total scores from baseline were carried forward for the analysis ‡ Nasally administered esketamine or placebo
§ Difference (Spravato + SOC minus placebo nasal spray + SOC) in least-squares mean change from baseline # Treatment groups that were statistically significantly superior to placebo nasal spray + SOC.

The treatment differences (95% CI) in change from baseline in MADRS total score at Day 2 (24 hours post first dose) between esketamine + SOC and placebo + SOC were -4.70 (-7.16; -2.24) for the subpopulation that reported a prior suicide attempt (N=284) and -2.34 (-5.59; 0.91) for the subpopulation that did not report a prior suicide attempt (N=166).

Time course of treatment response
In both SUI3001 and SUI3002, esketamine’s treatment difference compared to placebo was observed starting at 4 hours. Between 4 hours and Day 25, the end of the treatment phase, both the esketamine and placebo groups continued to improve; the difference between the groups generally remained but did not appear to increase over time through Day 25. Figure 3 depicts time course of the primary efficacy measure of change in MADRS total score using pooled studies SUI3001 and SUI3002.


Figure 3:        Least squares mean change from baseline in MADRS total score over time in SUI3001 and SUI3002* (pooled data, safety analysis set) – ANCOVA BOCF 


*
Note: In these studies, after the first dose, a one-time dose reduction to Spravato 56 mg was allowed for patients unable to tolerate the 84 mg dose. Approximately 16% of patients had reduction in Spravato dosage from 84 mg to 56 mg twice weekly.



Remission rates
In the Phase 3 studies, the percentage of patients who achieved remission (MADRS total score ≤12 at any given time during the study) was greater in the Spravato + SOC group than in the placebo + SOC group at all timepoints during the 4-week double-blind treatment phase (Table 12).
Table 12: Patients who achieved remission of MDD; double-blind treatment phase; full efficacy analysis set


SUI3001                               SUI3002                           Pooled Studies (SUI3001 and
SUI3002)
Placebo           Spravato            Placebo          Spravato             Placebo          Spravato +                 +                   +                + SOC                +                + SOC SOC               SOC                 SOC              114                  SOC              226 112               112                 113                                   225 Day 1, 4 hours post first dose                 9 (8.0%)          12 (10.7%)          4 (3.5%)         12 (10.5%)           13 (5.8%)        24 (10.6%) Patients with
Remission of
MDD

Day 2, 24 hours post first dose             10 (8.9%)      21 (18.8%) 12 (10.6%) 25 (21.9%)                  22 (9.8%)      46 (20.4%) Patients with
Remission of
MDD
Day 25 (predose)
Patients with              38 (33.9%)      46 (41.1%) 31 (27.4%) 49 (43.0%)                 69 (30.7%) 95 (42.0%) Remission of
MDD
Day 25 (4 hours postdose)                  42 (37.5%)      60 (53.6%) 42 (37.2%) 54 (47.4%)                 84 (37.3%) 114 (50.4%) Patients with
Remission of
MDD
SOC = standard of care
Note: Remission is based on a MADRS total score of ≤12. Subjects who did not meet such criterion or discontinued prior to the time point for any reason are not considered to be in remission.


Effects on suicidality
Overall patients in both treatment groups experienced improvement in the severity of their suicidality as measured by the Clinical Global Impression – Severity of Suicidality - revised (CGI- SS-r) scale at the 24-hour endpoint, though there was no statistically significant difference between treatment groups.

The long-term efficacy of esketamine to prevent suicide has not been established.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
Absorption

The mean absolute bioavailability of 84 mg esketamine administered as a nasal spray is approximately 48%.

Esketamine is rapidly absorbed by the nasal mucosa following nasal administration and can be measured in plasma within 7 minutes following a 28 mg dose. The time to reach maximum plasma concentration (tmax) is typically 20 to 40 minutes after the last nasal spray of a treatment session (see section 4.2).

Dose-dependent increases in the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC∞) of esketamine nasal spray were produced by doses of 28 mg, 56 mg and 84 mg.

The pharmacokinetic profile of esketamine is similar after a single dose and repeat dose administration with no accumulation in plasma when esketamine is administered twice a week.

Distribution

The mean steady-state volume of distribution of esketamine administered by the intravenous route is 709 L.

The proportion of the total concentration of esketamine that is bound to proteins in human plasma is on average 43 to 45%. The degree to which esketamine is bound to plasma proteins is not dependent on hepatic or renal function.

Esketamine is not a substrate of transporters P-glycoprotein (P-gp; multidrug resistance protein 1), breast cancer resistance protein (BCRP), or organic anion transporter (OATP) 1B1, or OATP1B3.
Esketamine does not inhibit these transporters or multi-drug and toxin extrusion 1 (MATE1) and MATE2-K, or organic cation transporter 2 (OCT2), OAT1, or OAT3.

Biotransformation

Esketamine is extensively metabolised in the liver. The primary metabolic pathway of esketamine in human liver microsomes is N-demethylation to form noresketamine. The main cytochrome P450 (CYP) enzymes responsible for esketamine N-demethylation are CYP2B6 and CYP3A4. Other CYP enzymes, including CYP2C19 and CYP2C9, contribute to a much smaller extent. Noresketamine is subsequently metabolised via CYP-dependent pathways to other metabolites, some of which undergo glucuronidation.

Elimination

The mean clearance of esketamine administered by the intravenous route was approximately 89 L/hour. After Cmax was reached following nasal administration, the decline in esketamine concentrations in plasma was rapid for the first few hours and then more gradual. The mean terminal half-life following administration as a nasal spray generally ranged from 7 to 12 hours.

Following intravenous administration of radiolabelled esketamine, approximately 78% and 2% of administered radioactivity was recovered in urine and faeces, respectively. Following oral administration of radiolabelled esketamine, approximately 86% and 2% of administered radioactivity was recovered in urine and faeces, respectively. The recovered radioactivity consisted primarily of esketamine metabolites. For the intravenous and oral routes of administration, < 1% of the dose was excreted in the urine as unchanged drug.

Linearity/non-linearity

Esketamine exposure increases with dose from 28 mg to 84 mg. The increase in Cmax and AUC values was less than dose-proportional between 28 mg and 56 mg or 84 mg, but it was nearly dose proportional between 56 mg and 84 mg.

Interactions

Effect of other medicinal products on esketamine
Hepatic enzyme inhibitors
Pre-treatment of healthy subjects with oral ticlopidine, an inhibitor of hepatic CYP2B6 activity, (250 mg twice daily for 9 days prior to and on the day of esketamine administration) had no effect on the Cmax of esketamine administered as a nasal spray. The AUC∞ of esketamine was increased by approximately 29%. The terminal half-life of esketamine was not affected by ticlopidine pre-treatment.

Pre-treatment with oral clarithromycin, an inhibitor of hepatic CYP3A4 activity, (500 mg twice daily for 3 days prior to and on the day of esketamine administration) increase the mean Cmax and AUC∞ of nasally administered esketamine by approximately 11% and 4%, respectively. The terminal half-life of esketamine was not affected by clarithromycin pre-treatment.

Hepatic enzyme inducers
Pre-treatment with oral rifampicin, a potent inducer of the activity of multiple hepatic CYP enzymes such as CYP3A4 and CYP2B6, (600 mg daily for 5 days prior to esketamine administration) decreased the mean Cmax and AUC∞ values of esketamine administered as a nasal spray by approximately 17% and 28%, respectively.


Other nasal spray products
Pre-treatment of subjects with a history of allergic rhinitis and pre-exposed to grass pollen with oxymetazoline administered as a nasal spray (2 sprays of 0.05% solution administered at 1 hour prior to nasal administration of esketamine) had minor effects on the pharmacokinetics of esketamine.

Pre-treatment of healthy subjects with nasal administration of mometasone furoate (200 mcg per day for 2 weeks with the last mometasone furoate dose administered at 1 hour prior to nasal administration of esketamine) had minor effects on the pharmacokinetics of esketamine.

Effect of esketamine on other medicinal products

Nasal administration of 84 mg esketamine twice a week for 2 weeks reduced the mean plasma AUC∞ of oral midazolam (single 6 mg dose), a substrate of hepatic CYP3A4, by approximately 16%.

Nasal administration of 84 mg esketamine twice a week for 2 weeks did not affect the mean plasma AUC of oral bupropion (single 150 mg dose), a substrate of hepatic CYP2B6.

Special populations

Elderly (65 years of age and older)
The pharmacokinetics of esketamine administered as a nasal spray was compared between elderly but otherwise healthy subjects and younger healthy adults. The mean esketamine Cmax and AUC∞ values produced by a 28-mg dose were 21% and 18% higher, respectively, in elderly subjects (age range 65 to 81 years) compared with younger adult subjects (age range 22 to 50 years). The mean esketamine Cmax and AUC∞ values produced by an 84-mg dose were 67% and 38% higher in elderly subjects (age range 75 to 85 years) compared with younger adult subjects (age range 24 to 54 years). The terminal half-life of esketamine was similar in the elderly and younger adult subjects (see section 4.2).

Renal impairment
Relative to the subjects with normal renal function (creatinine clearance [CLCR], 88 to 140 mL/min), the Cmax of esketamine was on average 20 to 26% higher in subjects with mild (CLCR, 58 to 77 mL/min), moderate (CLCR, 30 to 47 mL/min), or severe (CLCR, 5 to 28 mL/min, not on dialysis) renal impairment following administration of a 28-mg dose of esketamine nasal spray. The AUC∞ was 13 to 36% higher in the subjects with mild to severe renal impairment.

There is no clinical experience with esketamine administered as a nasal spray in patients on dialysis.

Hepatic impairment
The Cmax and AUC∞ of esketamine produced by a 28-mg doses were similar between subjects with Child-Pugh class A (mild) hepatic impairment and healthy subjects. The Cmax and AUC∞ of esketamine were 8% higher and 103% higher, respectively, in subjects with Child-Pugh class B (moderate) hepatic impairment, relative to healthy subjects.

There is no clinical experience with esketamine administered as a nasal spray in patients with Child-Pugh class C (severe) hepatic impairment (see section 4.2 and 4.4).

Race
The pharmacokinetics of esketamine nasal spray was compared between healthy Asian subjects and Caucasian subjects. Mean plasma esketamine Cmax and AUC∞ values produced by a single, 56-mg dose of esketamine were approximately 14% and 33% higher, respectively, in Chinese subjects compared to Caucasians. Both parameters were approximately 40% higher in Japanese subjects, relative to Caucasian subjects. On average, esketamine Cmax was 10% lower and AUC∞ was 17% higher in Korean subjects, relative to Caucasian subjects. The mean terminal half-life of esketamine in the plasma of Asian subjects ranged from 7.1 to 8.9 hours and was 6.8 hours in Caucasian subjects.


Gender and body weight
No significant differences in the pharmacokinetics of esketamine nasal spray were observed for gender and total body weight (> 39 to 170 kg) based on population PK analysis.

Allergic rhinitis
The pharmacokinetics of a single, 56-mg dose of esketamine administered as a nasal spray was similar in subjects with allergic rhinitis who were exposed to grass pollen compared to healthy subjects.