Trouble surfaced early in the joint FDA panel meeting to deliberate the drug-device combo esketamine 28-mg single-use nasal spray from Johnson & Johnson unit Janssen Pharmaceuticals Inc. when an agency official said U.S. gatekeepers didn't necessarily agree about the efficacy offered to support the ketamine-derived therapy for treatment-resistant depression (TRD).

The Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee took up the proposed treatment for the scourge of TRD, a condition wherein patients turn up with major depressive disorder and, despite at least two trials of antidepressant treatment given at the right doses for an adequate duration in their episodes, have not responded to treatment. Just one drug for the indication has been approved by U.S. regulators: a fixed-dose combination of fluoxetine (a selective serotonin reuptake inhibitor) and olanzapine (an atypical antipsychotic), marketed as Symbyax by Indianapolis-based Eli Lilly and Co.

Ultimately, voting went in Janssen's favor. On the question, "Has the applicant provided substantial evidence of the effectiveness of esketamine for the treatment of treatment-resistant depression?" the vote was 14 yes, 2 no, and 1 abstention. Steven Meisel of the Fairview Health Services/Healtheast Care System in Minneapolis said he voted yes because "there isn't an option to say, 'yes but,'" adding that "it occurred to me that we don't really understand how this drug works." Esketamine could function not so much as an antidepressant but by "providing some sort of a high" like a party drug, he added. "At the same time, I said to myself, 'If that's the case, so what?'" Some who voted in favor of recommending approval expressed a wish that the data had been more robust, though Anne-Michelle Ruha from the University of Arizona College of Medicine in Phoenix seemed satisfied. "I was convinced that there was a significant effect and it's a hopeful treatment," she said.

On the question, "Has the applicant adequately characterized the safety profile of esketamine for the treatment of treatment-resistant depression?" the vote was 15 yes, 2 no. Walter Dunn from the University of California Los Angeles department of psychiatry was in the majority and said "adverse effects are consistent" with intravenous ketamine use off label at higher doses. He was concerned about long-term cognitive effects, which "can't be addressed in some of these studies" but if the drug is approved would be a factor to "keep an eye out for."

On the question, "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 treatment-resistant depression?" the vote was 14 yes, 2 no, and 1 abstain. Ruha from Arizona voted yes but said she was "very happy to see that there's going to be a strict REMS." Fairview's Meisel called ketamine "a nasty drug" as used in anesthesia and elsewhere with plenty of adverse effects. He pointed to surveys that indicate patients are willing to gamble on esketamine. "We don't take the patient voice into account as often as perhaps we should," he said, though it's important that they "know what they're getting themselves into" by way of "heart to heart talks up front as to what those risks are." He also noted that two of three short-term efficacy studies missed their primary endpoints and asked what precedent the agency might set by approving esketamine, while allowing that such a question is "sort of philosophical and beyond the scope of this committee." Consumer representative Kim Witczak voted no and suggested that regulators might be "relying on the REMS program to save us," and found "a lot of potential for people who just want that quick fix." Meisel called his negative ballot "a close call." Ketamine is well characterized, but what happens when a cousin drug such as esketamine is used "once a week or thereabouts for life" remains unclear, he said. Janssen's longer-term trial enrolled about 297 patients. "That's not a lot, and a lot of them didn't last for a whole year," he added. "We know that [esketamine] can raise blood pressure transiently. What we don't know is the impact of that constantly raising and lowering blood pressure with every dose, and pulse rate for that matter, with every dose week after week? That hasn't been characterized at all or well-studied." He also pointed to five or six suicides on the drug. "It's interesting that we didn't see that in the placebo arm," he said. "Is there something there that we haven't fully understood?"

Esketamine, granted breakthrough therapy designation, is a glutamate receptor modulator that apparently works by restoring synaptic connections and takes effect quicker than other drugs. Janssen went all out to prove the candidate's value, conducting four phase II studies and five phase III in the development program. Last October, data on esketamine nasal spray that detailed efficacy, tolerability, and predictors of response and remission, were presented in four poster abstracts at Psych Congress 2018 in Orlando, Fla.

Opinion (still) divided on ketamine

Phase III experiments with esketamine included two short-term, double-blind, placebo-controlled studies – one fixed-dose and one flexible dose – 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; one randomized withdrawal design study; and one long-term, open-label safety study. Patients in all of these studies had failed at least two prior antidepressant trials and, at study entry, had more severe symptoms on average than patients entering antidepressant trials for previously approved drugs.

Rather than randomizing severely ill patients to placebo alone, each study involved the addition of a new antidepressant at the same time that either esketamine or placebo was started, ensuring that all patients were receiving some form of active treatment. Because of the purported rapid action of esketamine, researchers found it feasible to start all patients on a new antidepressant without compromising the ability to detect a treatment effect in the esketamine treatment group. Given that approved antidepressants typically take six to eight weeks to exert their full effect, if an effect was observed as early as 24 hours post-dose and was maintained throughout the treatment period, such a finding would help prove that esketamine works – a point that the FDA highlighted in briefing documents published before the meeting. "This is an important distinction as one considers whether, if approved, this drug would be indicated for the treatment of TRD or as an adjunct to treatment with an oral antidepressant," regulators said. The evidence in support of esketamine's effectiveness derives primarily from two positive phase III trials: the flexible-dose trial in adults younger than 65 years of age and the randomized withdrawal study. In the fixed-dose study of adults younger than 65 years of age, the prespecified analysis plan dictated that efficacy of the 84-mg dose would be evaluated first, followed by evaluation of the 56-mg dose. "But the 84-mg dose did not separate from placebo and the testing sequence ended there," the documents noted.

The geriatric study included flexible doses ranging from 28 mg to 84 mg, and esketamine's effect in the combined dose group did not beat placebo. "For most approved antidepressants, the evidence of effectiveness comes from at least two positive adequate and well-controlled short-term trials, with additional maintenance data provided via a randomized withdrawal trial conducted as a post-marketing commitment," the FDA pointed out. "In this application, there is only one positive short-term trial. The second positive trial is the randomized withdrawal study." The agency's Division of Psychiatry Products has not previously considered the latter as one of the necessary experiments for approval although, officials, "it is not unreasonable to do so." The agency also emphasized that "the population randomized to continue drug or switch to placebo in a randomized withdrawal study is an enriched population – these are individuals who have already tolerated the drug, and have already experienced clinical benefit. Whether and how these details would be reflected in labeling has not yet been determined."

Interest in ketamine has been growing in recent years. An article in the November 2016 Frontiers of Human Neuroscience headlined "Ketamine: 50 Years of Modulating the Mind" traced how the compound "was introduced into clinical practice in the 1960s and continues to be both clinically useful and scientifically fascinating. With considerably diverse molecular targets and neurophysiological properties, ketamine's effects on the central nervous system remain incompletely understood," although "evidence indicates that ketamine-mediated anesthesia may occur via disruption of corticocortical information transfer in a frontal-to-parietal ('top down') distribution." The mechanism has been demonstrated with anesthetics in other pharmacological classes as well, and ketamine "remains invaluable to the fields of anesthesiology and critical care medicine, in large part due to its ability to maintain cardiorespiratory stability while providing effective sedation and analgesia," the article said, citing refractory depression and post-traumatic stress disorder as potential indications.

The following year, a paper in The Lancet found that "based on current evidence, ketamine use for severe, treatment-resistant depression does not violate ethical principles; however, clinicians and professional bodies must take steps to ensure that guidelines for good practice are enacted, that all experimental and trial data are made available through national registries, and that the risk potential of ketamine treatment continues to be monitored and modelled." The Journal of the American Medical Association Psychiatry the same year warned in a paper about the "relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety" with ketamine in depression.

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