Can a horse tranquilizer and notorious party drug be reinvented as a safe and effective breakthrough therapy to swiftly treat major depression and suicidal thinking?
J&J $JNJ has been working on that task for years and is now hammering away at a pivotal late-stage program. This week they’re rolling out some detailed Phase II results that underscore the potential, as well as the problems, that seem inextricably linked to this drug.
J&J’s team took ketamine — Special K as it’s called in certain social circles — and created an intranasal version dubbed esketamine. The pharma giant picked up its first breakthrough designation for this drug more than four years ago. And the pharma giant believes it’s a blockbuster to be, one of the biggest potential earners in its late-stage pipeline.
Researchers took three doses of esketamine into a Phase II study with 126 patients, separating them into three dose groups. And the drug performed as they had expected, offering a quick uptake over a two-week study with a dose-dependent reaction that offered fast relief for major depressive disorder, as tracked in a commonly used trial assessment tool.
The good news: By day 8 there was a major improvement in the MADRS score for the high dose, more than twice what was registered in the low-dose group — which was also still clinically significant. Over a two-month followup, the response appeared to improve.
The bad news: Among the side effects was “perceptual changes/dissociative symptoms,” which ran at more than twice the rate seen in the placebo arm. One in four of the patients taking the drug experienced dissociative symptoms. Sedation was another common symptom. The dissociative symptoms occurred shortly after dosing and generally resolved after a couple of hours. In other words, the Phase II version of this drug still carries risks linked to Special K.
Academic groups have been researching straight ketamine in humans for years, and their results generally match, with a rapid lifting of depression, even among the patients who appear resistant to anything else available. It is an amazingly effective treatment, and would be an unambiguous boon without the side effects. It’s also transient, with a dose effect that wears off relatively quickly, requiring repeated dosing to remain effective.
That repeated dosing, and the longterm impact of a version of a drug that’s been used to induce schizophrenic symptoms in healthy volunteers, hasn’t been studied so closely.
Currently, as anyone with depression will tell you, the crop of depression drugs available is wildly inconsistent and often transient in nature. Ketamine works on NMDA receptors, and that in turn has led to a surge of new drug development programs, including a late-stage effort at Allergan after that company acquired Naurex for $560 million upfront. Sage has also attracted widespread interest in its own approach for depression.
Whoever wins this race, if it is won, will have access to an enormous market, even if its side effects limit the drug to a group of the most severely afflicted patients.
“If approved by the FDA,” says J&J’s Husseini Manji, “esketamine would be one of the first new approaches to treat refractory major depressive disorder available to patients in the last 50 years.”
But the very size of the market also raises the bar on safety and efficacy. And that jury will remain out until Phase III data are complete.
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