The therapy becomes the first novel mechanism of action-driven drug approved for depression in 30 years.
The US Food and Drug Administration (FDA) has approved the New Drug Application (NDA) for esketamine nasal spray (Spravato), in conjunction with an oral antidepressant, as a therapy for patients with treatment-resistant depression.
The approval makes the Janssen Pharmaceuticals therapy the first of its kind indicated for the treatment of depression, and the first novel treatment approved for depression in 3 decades. The glutamate receptor modulator provides a novel mechanism of action that restores synaptic connections between neurons, and its benefits are supported by data from 4 cinical trials.
One such study, presented last June, compared 56 and 84 mg esketamine nasal spray plus oral antidepressant to placebo-antidepressant in patients over a 16-week period. Patients treated with the therapy reported significant delayed response versus the placebo group. Among patients stabilized in remission, just 24 (26.7%) treated with esketamine reported a relapse event during maintenance, versus 39 (45.3%) of those treated with placebo (P= .003).
The safety profile of esketamine nasal spray was confirmed in the data from a long-term, 52-week phase 3 trial included in the NDA.
Because of patient risks to serious adverse events caused by the drug's sedative and dissociative effects—as well as its potential for abuse or misuse—the therapy will only be available through a restricted distribution system, under an FDA Risk Evaluation and Mitigation Strategy (REMS).
Tiffany Farchione, MD, acting director of the Division of Psychiatry Products in the FDA's Center for Drug Evaluation and Research, said there has been a long-standing need for more effective therapies addressing treatment-resistant depression, a "serious and life-threatening condition."
"Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process including a robust discussion with our external advisory committees, were important to our decision to approve this treatment," Farchione said in a statement. "Because of safey concerns, the drug will only be available through a restricted distribution system and it must be administered in a certified medical office where the health care provider can monitor the patient."
Labeling for the esketamine nasal spray will contain a Boxed Warning that advises patients on risks of sedation and difficulty with attention, dissociation, abuse and misuse, as well and suicidal thoughts and behaviors following treatment.
Two weeks prior to the approval, the FDA Psychopharmacologic Drug Advisory Committee and Drug Safety and Risk Management Advisory Committee voted 14-2 to recommend esketamine for approval. The vote, which included 1 abstention, indicated the novel therapy’s benefits outweighed its risks.
In an interview with MD Magazine® following the committee’s supporting vote, Jeffrey Lieberman, MD, praised the esketamine nasal spray as a groundbreaking depression therapy delivered in a more practical manner. But, the Chair and Professor of Psychiatry at Columbia University College of Physicians and Surgeons also expressed desire for better dosing parameters set by clinical evidence for the new therapy.
“And it's a question of practice leaping ahead of research, because research takes a long time to do and is dependent on funding, availability, and the NIH is not funding very much and the pharmaceutical companies are funding only limited things that are in their specific product development interest,” Lieberman explained. “So it falls to Janssen and J&J to now fund phase 4 studies which would determine who should get it, what are the optimal doses, modes of administration, and how long should they take it.”
Lieberman added that physicians will initially have to improvise their patient dosing strategies— and though he trusts them to do so in a judicious way, it could have been avoided with better developed treatment guidelines.