Fabre-Kramer Pharmaceuticals announced FDA approval of Exxua (gepirone hydrochloride extended-release tablets) for the treatment of major depressive disorder (MDD) in adults. This approval marks the introduction of a novel antidepressant with a unique mechanism of action, selectively targeting the serotonin 1A (5-HT1A) receptor. Exxua is anticipated to be available in pharmacies in early 2024.
A Novel Mechanism for MDD Treatment
Exxua distinguishes itself as the first and only approved antidepressant that functions as a selective agonist of the 5-HT1A receptor. This receptor plays a crucial role in regulating mood and emotional responses. The drug's mechanism is believed to modulate serotonin activity in the central nervous system through this selective agonism. Gepirone ER represents a new chemical entity (NCE) utilizing this single mechanism.
Clinical Efficacy and Safety Profile
Clinical trials involving over 5,000 patients have demonstrated Exxua's efficacy in alleviating depressive symptoms. Notably, the drug's approved labeling does not include warnings or adverse reactions related to sexual dysfunction or weight gain, common side effects associated with many other antidepressants. Sexual side effects experienced with EXXUA treatment in clinical trials were comparable to placebo and did not meet the incidence criteria for inclusion in the Adverse Reaction section of EXXUA's label. The most frequent adverse events observed were dizziness and nausea, generally mild, short-lived, and related to dose escalation.
In two 8-week randomized, double-blinded, placebo-controlled, flexible-dose clinical trials in outpatients ages 18 to 69 who met the DSM-IV criteria for MDD, both trials showed that gepirone ER was superior to placebo using the 17-item Hamilton Depression Rating Scale (HAMD-17). In the first trial, patients on gepirone ER showed greater improvement in their depression scores at 8 weeks than those in the placebo group with a mean difference of -2.47 (P=0.013). The second trial showed similar results.
In a maintenance study, patients with MDD who responded to gepirone ER during the open-label treatment study were randomized to continue the drug for up to 12 months or to switch to placebo. Patients in the treatment group had a statistically significantly lower rate of relapse than those in the placebo group (24% vs 38.7%).
Expert Commentary
Dr. Anita H. Clayton, Chair of the Department of Psychiatry & Neurobehavioral Sciences at the University of Virginia School of Medicine, commented, "I am thrilled for our patients that EXXUA (gepirone ER) is now FDA approved for the treatment of major depressive disorder (MDD). EXXUA is the first 5-HT1a agonist with superior efficacy vs. placebo as MDD monotherapy, yet did not differ from placebo in rates of sexual dysfunction in clinical trials. This provides an important new treatment option for patients."
Dr. Stephen Stahl, Professor of Psychiatry, University of California and founder of the Neuroscience Education Institute, stated, "EXXUA is the first truly selective agonist of the serotonin 1a receptor that has been consistently linked to mediation of mood disorders and suicide risk. It's an important addition to the armamentarium to treat depression."
Safety Information and Warnings
Exxua carries a black box warning for an increased risk of suicidal thoughts and behaviors in young adults, consistent with other antidepressants. Common adverse events (≥5%) that occurred in at least twice as many gepirone versus placebo patients included dizziness (49% vs 10%, respectively), nausea (35% vs 13%), insomnia (15% vs 5%), abdominal pain (7% vs 3%), and dyspepsia (6% vs 2%).
The drug is contraindicated for people with a prolonged QTc interval greater than 450 msec or congenital long QT syndrome. Due to risk of QT prolongation, any electrolyte abnormalities should be corrected prior to initiation and levels monitored during treatment, with more frequent checks for those with heart failure, a slow heart rate, or use of other drugs that can prolong the QT interval. ECGs should also be done prior to initiation, during dose titration, and periodically during treatment.
Other contraindications include use of the antidepressant in patients with severe liver problems; use with a monoamine oxidase inhibitor (MAOI; including linezolid and methylene blue) or within 14 days of their use; or use with strong CYP3A4 inhibitors, such as clarithromycin (Biaxin), erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir (Norvir), and verapamil. For those taking moderate CYP3A4 inhibitors, the gepirone ER dose should be halved.
Addressing a Critical Need
Major depressive disorder affects over 20 million American adults each year, a number that significantly increased during the COVID-19 pandemic. The approval of Exxua offers a valuable new treatment option for individuals seeking relief from depression, particularly those concerned about the sexual side effects associated with other antidepressants.
