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Background Analysis: US FDA Advisory Committees to Review Janssen’s Esketamine for Treatment-Resistant Depression – FEB 12, 2019 (PDAC-DSRM)
The US FDA has scheduled a joint meeting of the Psychopharmacologic Drugs Advisory Committee (PDAC) and the Drug Safety and Risk Management (DSRM) Advisory Committee for Tuesday, February 12, 2019, to discuss the efficacy, safety, and risk-benefit profile of a new drug application (NDA) for esketamine nasal spray, submitted by Janssen Pharmaceuticals, Inc. (Janssen), for the treatment of treatment-resistant depression.
Description of Indication
According to the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), major depressive disorder (MDD) is a condition in which patients exhibit depressive symptoms, such as a depressed mood or a loss of interest or pleasure in daily activities, consistently for at least a two-week period, and demonstrate impaired social, occupational, educational, or other important functioning. According to the National Institute of Mental Health, an estimated 16.2 million people in the US suffered from MDD in 2016.
Treatment-resistant depression (TRD) is most commonly defined as MMD that has not responded to at least two adequately-timed courses of antidepressant treatment. It affects between 20 to 30% of the MDD population.
Esketamine is an isomer of ketamine. Its mechanism of action is antagonism to the N-methyl-D-aspartate (NMDA) receptor. Janssen proposes to market a 28 mg dose of esketamine in a single-use nasal spray device. The Phase 3 clinical trials studied 3 dosage strengths: 28 mg; 56 mg; and 84 mg).
Clinical Trials of Proposed Indication
Comprehensive data from the clinical development program for esketamine, including detailed analyses by the Company and by the FDA, will be presented in briefing materials that will be posted by the FDA ahead of the meeting. These briefing materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.
Presented below is a summary of the results from Phase 3 trials that were submitted in the NDA, based on information presented by Janssen in Company press releases.
TRANSFORM-1 (ClinicalTrials.Gov ID: NCT02417064) was an international, Phase 3, double-blind, active-controlled, multi-center study of 346 adults with TRD. 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 TRD 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.
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. Janssen says the results numerically favored both groups of esketamine plus an oral antidepressant (56 mg and 84 mg esketamine) 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.
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 Company reports that 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.
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.
Regarding safety, Janssen says 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 oral hypoesthesia; 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.
TRANSFORM-2 (ClinicalTrials.Gov ID: NCT0241858 was a study in 236 adults with TRD. Janssen says this study showed that flexibly dosed esketamine nasal spray (56 mg or 84 mg, every 3 days) plus a newly initiated oral antidepressant demonstrated a statistically significant, clinically meaningful rapid reduction of depressive symptoms as compared to placebo nasal spray plus a newly initiated oral antidepressant.
TRANSFORM-3 (ClinicalTrials.Gov ID: NCT02422186) was a study in 139 elderly patients aged 65 and older with TRD. Janssen says this study demonstrated that treatment with flexibly-dosed esketamine (28 mg, 56 mg, or 84 mg, every 3 days) plus a newly-initiated oral antidepressant demonstrated clinically meaningful effects compared to placebo. However, the study narrowly missed statistical significance for its primary efficacy endpoint.
SUSTAIN-1 (ClinicalTrials.Gov ID: NCT02493868) assessed relapse prevention in 703 patients with TRD. Janssen says data from this study showed that continuing treatment with esketamine nasal spray plus an oral anti-depressant 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 Company says study results 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, Janssen says esketamine nasal spray plus an oral antidepressant demonstrated safety and tolerability with repeated, intermittent long-term dosing.
SUSTAIN-2 (ClinicalTrials.Gov ID: NCT02497287) was an open-label design to assess the long-term safety and efficacy of esketamine nasal spray for up to one year (52 weeks). Janssen says 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 Company says 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). In addition, Janssen reports that 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.
US Regulatory Background
Unknown – PDUFA date
September 4, 2018 – Janssen announced their submission of NDA 211243.
Breakthrough Therapy Designation
Ex-US Regulatory Background
October 18, 2018 – Janssen announced their submission of an Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA).
Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.
Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.
METADATA: Sponsor: Janssen Pharmaceuticals, Inc. Drug Name: esketamine Drug Class: antagonist to the N-methyl-D-aspartate (NMDA) receptor Indication: treatment-resistant depression
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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.