Esketamine

Articles · New Medicines ·

30068311000001106

Articles

New Medicines

Spravato · Treatment-resistant depressive disorder

Information

Spravato
New formulation
Janssen
Janssen

Development and Regulatory status

Launched
Launched
Launched
December 2019
Dec 19 · Available in the UK. Price 1 x 28mg nasal spray = £163 [22,23].
Dec 19 · Approved in EU [21]
Oct 19 · Recommended for EU approval by CHMP - the full indication is "in combination with a SSRI or SNRI, [...] for adults with treatment-resistant major depressive disorder, who have not responded to at least two different treatments with antidepressants in the current moderate to severe depressive episode”. The proposed authorisation states that treatment should be initiated by psychiatrists to ensure a correct diagnosis of treatment-resistant major depressive disorder. [20].
Jun 19 · In the US, an Institute for Clinical and Economic Review report concluded esketamine (Spravato) is not cost effective at its current list price [18].
Mar 19 · Launched in the US [16].
Mar 19 · Approved in US for use in combination with oral antidepressants in patients who have tried at least two antidepressants without success. Patients will start on a twice weekly dose for a month at a cost of $4,720 to $6,785, followed by weekly or alternate weekly dosing at a cost of $2,360 to $3,540 per month. Spravato will launch under an FDA-mandated “controlled distribution model” because of safety risks. It will not be dispensed directly to patients for home use. Instead, it will be self-administered by the patient under the direct observation of a healthcare provider in a certified treatment centre, and the patient will then be observed for at least two hours. All patients will be enrolled in a registry to record serious adverse outcomes from sedation, dissociation, abuse and misuse, and to support safe use [13,14].
Feb 19 · FDA advisory panel supported approval of esketamine nasal spray for the treatment of major depression [12] .
Oct 18 · Filed in the EU for treatment-resistant depression (TRD) in adults with MDD who have not responded to at least two different treatments with antidepressants in the current moderate-to-severe depressive episode [10].
Sep 18 · Filed in the US. The application is based on five pivotal phase III trials [11].
May 18 · Janssen Pharmaceuticals announced plans to seek regulatory approval this year [9].
Jan 17 · Plans to file between 2016 and 2019 according to company pipeline [6].
Aug 16 · Johnson & Johnson receives a second breakthrough therapy designation from the FDA for esketamine for an indication of major depressive disorder with imminent risk for suicide; the prior designation is for treatment-resistant depression, which the pharma received in Nov 13 [5].
Oct 15 · In PIII development in the US [3].
Apr 15 · Fast-track status for treatment-resistant depression in US; J&J plan to file in US / EU / China by 2017 [1].

Category

NMDA receptor antagonist; (S)-enatiomer of ketamine
An episode of depression serious enough to require treatment occurs in about 1 in 4 women and 1 in 10 men at some point in their lives. Some people have two or more episodes of depression at various times in their life. Prevalence of major depression in primary care is between 5% and 10%; two to three times as many people have depressive symptoms but do not meet criteria for major depression. Depression is the third most common reason for a consultation in primary care.
Treatment-resistant depressive disorder
Intranasal

Further information

Yes
To be confirmed

Trial or other data

Jun 19 · Results of PIII TRANSFORM-2 trial are published; the RCT (n=227) reported that change in MADRS score with esketamine+antidepressant (AD) was significantly greater than with AD+placebo at day 28 (difference of least square means=−4.0, SE=1.69, 95% CI=−7.31, −0.64) supporting potential use in patients with treatment-resistant depression [19].
Jun 19 · PIII SUSTAIN-1 RCT (NCT02493868; n=297) found continued treatment with esketamine and antidepressant (ESAD) demonstrated statistically significant superiority vs antidepressant (AD) and placebo in delaying relapse in patients who had achieved stable remission or stable response after 16 weeks of ESAD [17].
May 19 · New data from a cost-efficiency analysis presented at the International Society for Pharmacoeconomics and Outcomes Research Annual Meeting illustrating the value of Spravato (esketamine) nasal spray for treatment-resistant depression (TRD) in the US. Based on response, remission, and relapse rates from PIII clinical trials, managing TRD with Spravato in conjunction with an oral antidepressant was predicted to cost at least $20,000 less per patient in those achieving remission than patients receiving an oral antidepressant plus placebo [15].
May 18 · Data reported from a PIII double-blind, multicenter, active-controlled study (TRANSFORM-3, NCT02422186) in elderly pts with treatment-resistant depression. Pts were randomised 1:1 to esketamine nasal spray (flexibly dosed at 28 mg, 56 mg or 84 mg) plus a new oral antidepressant (N=72) or placebo nasal spray plus a new oral antidepressant (N=66). Results favored the esketamine gp but statistical significance for the primary endpoint was missed; median unbiased estimate of the difference in MADRS score from day 1 (baseline) to day 28 for esketamine vs. placebo gp: -3.6, 95% CI: -7.20, 0.07; one-sided p=0.029. Safety results were consistent with previous studies of esketamine in younger adults. The most common treatment-emergent adverse events (>10%) reported in the esketamine group were dizziness, nausea, headache, fatigue, increased blood pressure, vertigo and dissociation. There were no treatment-emergent adverse events reported in >10% of patients in the placebo gp [9].
May 18 · Positive PIII data announced from a double-blind, active-control, flexibly dosed, multi-centre study (NCT02418585, TRANSFORM-2) using blinded raters, conducted at 39 sites in Czech Republic, Germany, Poland, Spain and the US in adults with moderate-to-severe, non-psychotic, recurrent or persistent depression, and history of non-response to ≥2 antidepressants. Non-responders were randomised (1:1) to flexibly-dosed esketamine nasal spray (56 or 84 mg twice weekly) plus a newly initiated oral antidepressant (N=114) or placebo nasal spray plus a newly initiated oral antidepressant (N=109). The primary efficacy endpoint, change from baseline in the MADRS total score at day 28 (Least Squares Mean Difference for eskatamine gp vs. placebo gp: -4.0 [1.69], 95% Confidence Interval [CI]: -7.31, -0.64; p=0.010). The most common treatment-emergent adverse events (>10%) for esketamine were metallic taste, nausea, vertigo, dizziness, headache, drowsiness, dissociation, blurred vision, paraesthesia (tingling sensation) and anxiety. The most common adverse events (>10%) in the placebo group were metallic taste and headache [9].
Dec 17 · Data from the PII study (NCT01998958, SYNAPSE) published in JAMA Psychiatry. This multicentre study (13 sites in the US, 1 in Belgium) enrolled 126 pts with treatment resistant major depressive disorder and a history of inadequate response to ≥2 antidepressants. Sixty pts were randomised [3:1:1:1] to placebo (n=33), esketamine nasal spray 28mg (n=11), 56mg (n=11), or 84 mg (n=12) twice-weekly. The remainder were treated in an open label phase in which dosing frequency was reduced from twice-weekly to weekly, then every two weeks. All pts were also taking oral antidepressants throughout the study. Symptom improvement (measured as change in MADRS total score from baseline to day 8 in all esketamine treatment groups) was observed after one week with intranasal esketamine for all three doses; esketamine 28 mg: -4.2 [2.09], p=0.02; 56 mg: -6.3 [2.07], p=0.001; 84 mg: -9.0 [2.13], p2-fold higher for esketamine than for placebo. Other adverse events included dysgeusia and sedation [8].
Nov 17 · PIII studies NCT02417064 (TRANSFORM-1), NCT02418585 (TRANSFORM-2) and NCT02422186 (TRANSFORM-3) have finished recruiting patients. Collection of primary outcome data due to complete Apr 18, Jun 17 and Aug 17 [5].
Dec 15 · The PIII programme started in Aug 15. Five PIII studies are registered to date. NCT02417064 (TRANSFORM-1), NCT02418585 (TRANSFORM-2) and NCT02422186 (TRANSFORM-3) are short-term RCTs (4 weeks) of esketamine plus an oral antidepressant in adult and elderly patients with treatment resistant depression. These studies are due to complete by Q3 2017. NCT02493868 (SUSTAIN-1) is a 104-week RCT evaluating esketamine + oral antidepressant in relapse prevention and NCT02497287 (SUSTAIN-2) is an open-label study of esketamine of 56 weeks duration. They are due to complete in 2017/8 [4].
Apr 15 · Three Phase 2 trials of intranasal esketamine are either in progress or waiting to start - NCT02133001, NCT01998958 (SYNAPSE), AND NCT02418585 (TRANSFORM-2) [1,2].

Evidence based evaluations

Spravato · Major depressive disorder in adults who have acute suicidal ideation with intent

Information

Spravato
Licence extension / variation
Janssen
Janssen

Development and Regulatory status

Pre-registration (Filed)
Pre-registration (Filed)
Pre-registration (Filed)
Jan 20 · Filed in the EU [10].
Oct 19 · Janssen submit sNDA to FDA for esketamine CIII nasal spray (Spravato) for rapid reduction of depressive symptoms in adults with major depressive disorder who have active suicidal ideation with intent [9].
Jan 19 · Company plans to file in the US for this indication; no details provided of EU plans [6].
Dec 17 · Johnson & Johnson has a second breakthrough therapy designation from the FDA for esketamine for the indication of major depressive disorder with imminent risk for suicide [3].
Jul 17 · PIII in EU & US [1].

Category

NMDA receptor antagonist; (S)-enatiomer of ketamine
An episode of depression serious enough to require treatment occurs in about 1 in 4 women and 1 in 10 men at some point in their lives. Some people have two or more episodes of depression at various times in their life. Prevalence of major depression in primary care is between 5% and 10%; two to three times as many people have depressive symptoms but do not meet criteria for major depression. Depression is the third most common reason for a consultation in primary care.
Major depressive disorder in adults who have acute suicidal ideation with intent
Intranasal

Further information

Yes
To be confirmed

Trial or other data

Sep 19 · Positive results from PIII double-blind, randomised, placebo-controlled, multicentre trials, ASPIRE I and ASPIRE II (n=456), reported. Both studies met their respective primary efficacy endpoint, a reduction in depressive symptoms at 24 hours after the first dose, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) with esketamine nasal spray 84 mg plus SOC showing superiority (p=0.006) vs placebo plus SOC. The studies also reported that both esketamine+SOC and placebo+SOC resulted in improvement in severity of suicidality as measured by the revised Clinical Global Impression of Severity of Suicidality (CGI-SS-R) at 24 hours after the first dose. The treatment difference between the two groups on this secondary endpoint was not statistically significant. The company suggest this may be due to the substantial beneficial effects of comprehensive SOC used in the trial. Esketamine nasal spray was well-tolerated with no new safety signals. In the esketamin+SOC group, the most common adverse events (≥10%), with a frequency of more than twice that of the placebo+SOC group, were dizziness, dissociation, nausea, somnolence, vision blurred, vomiting, paresthesia, increased blood pressure and sedation [8].
Jun 19 · PIII Aspire II study (NCT03097133) has finished recruiting and collecting primary outcome data [7].
Nov 18 · PIII Aspire II study (NCT03097133) is still recruiting; collection of primary outcome data now expected to complete Jul 19 [5].
Apr 18 · Positive data from 12-week, PIIa, randomised, double-blind, placebo-controlled, multicentre study in 68 adults with major depressive disorder who were assessed to be at imminent risk for suicide. Pts were randomised 1:1 to receive standard of care (SOC) plus esketamine nasal spray 84 mg (N=36) or placebo nasal spray (N=32) for 25 days. The primary efficacy endpoint was achieved, with the mean change from baseline at 4 hours post-dose showing a rapid, clinically meaningful and statistically significant improvement in depressive symptoms of -13.4 (9.03) for esketamine nasal spray 84 mg plus SOC, compared to -9.1 (8.38) for placebo nasal spray plus SOC, p=0.015; p=0.61. Esketamine nasal spray was generally well-tolerated based on the adverse event data from this study. The most common (>20%) treatment-emergent adverse events (TEAEs) in the esketamine nasal spray group during the double-blind phase were: nausea (37.1%), dizziness (34.3%), unpleasant taste (31.4%), dissociation (31.4%), headache (31.4%), and vomiting (20.0%).[4]
Sep 17 · PIII trial to evaluate the efficacy and safety of intranasal esketamine in addition to comprehensive standard of care for the rapid reduction of the symptoms of MDD, including suicidal ideation, in adult patients assessed to be at imminent risk for suicide starts (Aspire II; NCT03097133). Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at 24 hours post first dose will be the primary endpoint. It will enrol approximately 224 patients in the US, Argentina, Austria, Belgium, Brazil, Canada, Czech Republic, France, Lithuania, Poland, Turkey and the UK. Collection of primary outcome data is expected to complete Sep 19 [2].

Evidence based evaluations

Acute inner ear tinnitus - first-line up to 3 months from onset

Information

New formulation
Auris Medical
Auris Medical

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

NMDA receptor antagonists. Biocompatible gel formation of a cochlear N-methyl-D-aspartate (NMDA) receptor antagonist.
As many as 1 in 10 people have persistent tinnitus that is mild and not very troublesome. However, about 1 in 100 people have tinnitus which persists most of the time, and severely affects their quality of life [2].
Acute inner ear tinnitus - first-line up to 3 months from onset
Intratympanic