麻豆传媒

NEW YORK CITY -- Intranasal esketamine paired with an oral antidepressant improved symptoms of treatment-resistant depression, researchers reported here.

When compared to intranasal placebo plus an antidepressant, two phase III studies found twice-weekly flexibly-dosed intranasal esketamine added to a newly initiated antidepressant showed some benefit for depressive symptoms among adult and elderly populations, respectively, who had previously failed at least two prior treatments.

Presented at the , both analyses were led by Larry Alphs, MD, PhD, of Johnson & Johnson, and colleagues.

"Esketamine is thought to affect the glutamate system in the brain and is part of a class of investigational medicines known as glutamate receptor modulators," explained co-author David Hough, compound development lead for esketamine at Janssen Research & Development, to 麻豆传媒.

Esketamine is a chirally pure enantiomer of the anesthetic agent ketamine, which has shown promise for rapid relief of severe depression in previous studies. However, ketamine is available only as an IV drug.

Janssen focused on esketamine "because it could be formulated as an intranasal medicine, thus potentially allowing appropriate patients in need to have access to it -- if the medication is approved in the future," Hough said.

Adult Population

In a 90-patient study of adults 65 and younger, the intransal esketamine treatment group showed a significant improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score 4 weeks after starting treatment compared to intranasal placebo (least squares mean difference -4.0, 95% CI -7.31 to -0.64, one-sided P=0.010) -- meeting the study's primary efficacy endpoint. All patients also received a conventional oral antidepressant.

Patients received 56 mg/dose initially, which could be raised to 84 mg at clinicians' discretion.

However, the study missed an important secondary efficacy endpoint -- significant clinical response 24 hours after dosing -- although esketamine spray was still slightly favored compared to the placebo.

After 4 weeks, intranasal esketamine plus oral antidepressant also showed improvement in Sheehan Disability Scale (LS mean difference –4.7, P=0.015) and the Patient Health Questionnaire-9 (–2.9, P=0.033) compared to the placebo-plus-antidepressant group.

Around 69% of the study group responded to treatment after 4 weeks compared to 52% of the intranasal placebo group, measured by a 50% or greater improvement from baseline in MADRS score. Similarly, 52.2% of the esketamine group achieved remission -- marked by a MADRS total score of 12 of less -- versus only 31% of the placebo group 4 weeks after treatment.

Elderly Population

The analysis in the older population, which included 70 patients over the age of 65, reported a similar numerical improvement with the esketamine spray, although it fell short of statistical significance on the primary efficacy endpoint (median unbiased estimate of the MADRS difference -3.6, 95% CI -7.20 to 0.07, one-sided P=0.029).

This group was started on a lower dose of intranasal esketamine spray of 28 mg, but was also flexibly dosed at the higher 56 mg and 84 mg doses, similar to the adult population.

Overall, the safety profile for the investigational treatment was similar among both populations. The most common treatment-emergent events included nausea, vertigo, dizziness, metallic taste, headaches, drowsiness, blurred vision, paresthesia, dissociation and anxiety, generally occurring on the day of dosing.

The drug's side effect profile, particularly the dissociative effects, could be a problem in getting esketamine approved. Ketamine is a drug of abuse -- known as Special K on the street -- because of such effects. Regulators are sure to focus on this during the review process.

Hough said the treatment is currently being assessed in a phase III program for patients with major depressive disorder who are at imminent risk for suicide, as well as a phase II study in adolescents for the same indication.