The U.S. Food and Drug Administration (FDA) has approved the resubmission of a New Drug Application (NDA) for gepirone hydrochloride extended-release [ER] (Exxua™) for the treatment of major depressive disorder (MDD) in adults. Gepirone ER is an antidepressant that modulates serotonergic neurotransmission as a selective partial agonist at the serotonin (5HT) 1A receptor (Figure 1).

The approval was based on two pivotal randomized, double-blind, placebo-controlled studies in patients with MDD. The primary endpoint in both studies was the change from baseline on the 17-item Hamilton Depression Rating Scale (HAM-D) at Week 8 or last visit. In both studies, patients in the gepirone ER groups experienced statistically significantly greater improvement on the primary endpoint compared to patients in the placebo groups.

In Study 1, the change from baseline in HAM-D total scores was -9.04 and -6.75 for gepirone ER and placebo, respectively (difference of -2.47, 95% CI: -4.41, -0.53; p = 0.013). In patients that received gepirone ER, the final daily dose of was 72.6 mg in 64% of patients, 54.5 mg in 20% of patients, and 36.3 mg in 17% of patients.In Study 2, the change from baseline in HAM-D total scores was -10.22 and -7.96 for gepirone ER and placebo, respectively (difference of -2.45, 95% CI: -4.47, -0.43; p = 0.018). In patients that received gepirone ER, the final daily dose was 72.6 mg in 66% of patients, 54.5 mg in 22% of patients, 36.3 mg in 10% of patients, and 18.2 mg in 2% of patients. The most common adverse events with gepirone ER use were dizziness, nausea, and headache.

The recommended starting dose is 18.2 mg administered orally once daily with food at approximately the same time each day. Depending on clinical response and tolerability, the dosage may be increased to 36.3 mg once daily on Day 4. Dosage may be further titrated to 54.5 mg once daily after Day 7 and to 72.6 mg once daily after an additional week.

Gepirone (Figure 1) unique mechanism of targeted single 5HT1A receptor agonism to relieve depressive symptoms without significant side effects. Because gepirone selectively works on 5HT1A receptors, by sparing other serotonin receptor subtypes, gepirone may reduce the risk of side effects associated with other commonly used antidepressants (e.g., SSRIs/SNRIs), such as sexual dysfunction and weight gain. Geprione belongs to the azapirone drug class, which is the same class of medicines as buspirone. Buspirone has been FDA-approved for decades as a treatment for generalized anxiety disorder but has also been used off-label for adjunctive treatment of MDD.

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