FDA Votes to Approve Janssen Pharma’s Esketamine Drug

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Drug/Device: Drug-device combination

Sponsor: Janssen Pharmaceuticals, Inc.

Committee: Joint Meeting of the Psychopharmacologic Drugs Advisory Committee (PDAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM)

Indications: a drug-device combination of esketamine for intranasal administration to be used for the treatment of treatment-resistant  depression (TRD)

Question 1: Has the Applicant provided substantial evidence of the effectiveness of esketamine for the treatment of TRD?

Question 2: Has the Applicant adequately characterized the safety profile of esketamine for the treatment of TRD?

Question 3: Given the effectiveness and safety of esketamine and the FDA’s proposed risk evaluation and mitigation strategy (REMS), do the benefits outweigh the risks of esketamine for the treatment of TRD?

Vote Results:  Yes  14   No  2  Abstain  1

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Background:

The applicant submitted a New Drug Application (NDA) for a drug-device combination of esketamine administered via intranasal spray for treatment of TRD.  Five phase 3 studies were conducted by the applicant in support of the TRD development program for esketamine.  Despite the fact that among these studies, only one short-term RCT study and one randomized withdrawal designed study met statistical superiority of esketamine versus placebo on the primary efficacy endpoint, the advisory committees unanimously agreed that the benefits of esketamine outweigh the risks for the treatment of TRD.

For most approved antidepressants, evidence from at least two adequately controlled short-term trials are needed.  The Division of Psychiatry Products at the FDA expressed that it has not previously considered randomized withdrawal trial as a substantial evidence of effectiveness, but also noted that it is not unreasonable to do so.

The agency cautioned that the effect observed in randomized withdrawal is from selected patients for whom the drug is already well tolerated and shown clinical benefit; and therefore these details should be reflected on labelling. FDA also proposed the applicant to submit a Risk Evaluation and Mitigation Strategy (REMS) to assure safe use of esketamine.

Unique Challenges:

Study design:

The designs of the phase 3 studies included two short-term, double-blind, placebo-controlled studies, one of which is fixed-dose and another flexible dose (studies 3001 and 3002, respectively) in adult patients younger than 65 years of age; one short-term, double-blind, placebo-controlled, flexible-dose study in geriatric patients >= 65 years of age (study 3005); one randomized withdrawal design study (study 3003); and one long-term, open-label safety study (study 3004).

The uniqueness of this study is its “randomized withdrawal study design” and how the sponsor was able to convince the committee via a single short-term RCT,  plus one maintenance trial – which is not usually used as evidence for efficacy(from Writer). The randomized withdrawal design study enrolled patients who were either of direct entry (following an open-label esketamine treatment protocol) or from studies 3001 and 3002.  All subjects who experienced ≥50% reduction from baseline in MADRS total score by the end of acute 4-week treatment were eligible to enter an optimization phase. Only subjects who either demonstrated stable remission or stable response (both of which were based on change in MADRS scores) during the optimization phase were entered into the maintenance phase. Stable remitters comprised the analysis population for the primary efficacy endpoint, whereas stable responders comprised the analysis population for the secondary efficacy endpoint.

Statistical analysis:

For studies 3001, 3002, and 3005, the endpoint evaluated was changes in MADRS score from baseline at day 28. The difference in LS Means between esketamine and placebo was compared using mixed model for repeated measures (MMRM).  Study 3003 evaluated number and average duration to relapse (in days) by treatment arms.

Efficacy:

Only studies 3002 and 3003 demonstrated superiority of esketamine compared with placebo.  In study 3002, the placebo group scored on average 4 points lower in MADRS scale with 1-sided p-value of 0.010.  In the randomized withdrawal study 3003, significantly higher number of subjects in the placebo arm experienced relapse (HR 0.49 95% CI [0.3-0.8]).  Placebo group also relapsed to depression significantly quicker than those who continued esketamine treatment, with most of the differentiation occurring within the first 2 to 4 weeks after randomization, despite continued treatment with oral antidepressants.  Typically, relapses on drug versus placebo begins to differentiate much later in other maintenance-of-effect studies for MDD. The agency expressed concern over observed effect being attributable to functional unblinding, with subjects realizing they are no longer on esketamine after switching to placebo for that one of the side effects of esketamine is the sense of dissociation. To address this concern, FDA conducted further exploratory analysis and found that both esketamine treatment and change in dissociative states scale were associated with time-to-relapse.  However, since FDA’s exploratory analysis cannot distinguish whether esketamine is truly effective; or that the delay is dependent upon the symptoms of dissociation, the agency has noted that it is possible, but not conclusive, that functional unblinding has partially impacted this study’s results.

Safety:

The review team identified sedation, dissociation, and increased blood pressure as the primary safety concerns related to this product.  FDA noted that the adverse effects generally reported with ketamine use in post-marketing data are not reported in esketamine.  The most commonly reported adverse events were dissociation, dizziness/vertigo, nausea/vomiting, sedation, paresthesia, hypoaesthesia, and blood pressure increase in the three trial studies.  It was also noted that most of these symptoms occurred within 2 hours post-administration of the treatment, deaths did not occur within this time frame/window.

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