Following a long path to approval, gepirone hydrochloride extended-release tablets (Exxua) is the first FDA-approved medication with this novel mechanism of action for adults with MDD.
A new class of antidepressants has emerged, as the US Food and Drug Administration approved the first oral selective 5HT1A receptor agonist for the treatment of major depressive disorder in adults. Gepirone hydrochloride extended-release tablets (Exxua) is the first approved medication with this novel mechanism of action.1
This approval marks a number of unique accomplishments. Not only is Exxua the first in this class of antidepressants, but the FDA approval comes without warnings or adverse reactions related to sexual dysfunction or weight gain.1 It also overcame a number of obstacles, having been rejected 3 times by the FDA before finally receiving the green light.2
Exxua displayed an overall acceptable safety profile in studies of more than 5000 patients that led to this approval. As previously noted, rates of sexual side effects associated with the drug were comparable to that with placebo. In addition, there were no significant adverse effects on blood pressure, heart rate, and liver function. Dizziness and nausea were the most commonly reported adverse events reported in clinical trials, and they were “mild, of short duration, related to dose escalations and did not require discontinuation of treatment.”1
Gepirone, a pharmacologic analogue of buspirone,3 has been studied extensively over the years. In addition to its antidepressant properties, it has shown to have antianxiety effect in a placebo-controlled trial for generalized anxiety disorder.4 Although early clinical trials demonstrated efficacy, its short half-life meant frequent administration was needed. Complicating the picture, the high peak plasma concentrations associated with high doses often came with increased adverse events. The extended release formulation seemed to align efficacy with less adverse events.5
The FDA did not grant approval when the drug was originally submitted. The drug was backed by 2 well-designed randomized controlled trials, but other studies failed to support its use for MDD. Earlier this year, the FDA agreed to review a resubmission of the new drug application.6
Despite its long road to approval, the FDA decision is being applauded and heralded by many in the field. "I am thrilled for our patients that Exxua (gepirone ER) is now FDA approved for the treatment of major depressive disorder (MDD),” Anita H. Clayton, MD, chair of the Department of Psychiatry & Neurobehavioral Sciences at University of Virginia School of Medicine, and Psychiatric Times Editorial Board member said in a press statement.1 “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."
"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,” noted Stephen Stahl, MD, professor of psychiatry at the University of California.1 “It's an important addition to the armamentarium to treat depression."
Patient advocacy groups are also celebrating this new entry. “The need for new treatment options, particularly those with new mechanisms of action, could not be clearer and more urgent for those living with, or impacted by, major depressive disorder," Michael Pollack, Chief Executive Officer of the Depression and Bipolar Support Alliance said.1
According to the press release, Exxua should be available to patients in early 2024.
1. Fabre-Kramer Pharmaceuticals Announces FDA Approval of EXXUA™, the First and Only Oral Selective 5HT1a Receptor Agonist for the Treatment of Major Depressive Disorder in Adults. News Release. September 28, 2023. Accessed September 28, 2023. https://fabrekramer.com/fabre-kramer-pharmaceuticals-announces-fda-approval-of-exxua-the-first-and-only-oral-selective-5ht1a-receptor-agonist-for-the-treatment-of-major-depressive-disorder-in-adults/
2. Becker Z. Decades-long regulatory odyssey ends with FDA nod for Fabre-Kramer's depression med Exxua.Fierce Pharma September 28, 2023. Accessed September 28, 2023. https://www.fiercepharma.com/pharma/fourth-times-charm-fabre-kramers-novel-depression-med-exxua-finally-cross-fda-finish-line
3. Jenkins SW, Robinson DS, Fabre LF Jr, et al. Gepirone in the treatment of major depression. J Clin Psychopharmacol. 1990;10(3 Suppl):77S-85S.
4. Kaur Gill A, Bansal Y, Bhandari R, et al. Gepirone hydrochloride: a novel antidepressant with 5-HT1A agonistic properties. Drugs Today (Barc). 2019;55(7):423-437.
5. Robinson DS, Sitsen JM, Gibertini M. A review of the efficacy and tolerability of immediate-release and extended-release formulations of gepirone. Clin Ther. 2003;25(6):1618-1633.
6. Nonacs R. Gepirone: A Not-So-New Antidepressant Seeks Approval From the FDA (Again). MGH Psychiatry News. February 15, 2023. Accessed September 28, 2023. https://mghpsychnews.org/gepirone-antidepressant-seeks-fda-approval/