FDA Relents, Approves Novel Antidepressant After Many Rejections

Derick Alison
Derick Alison
5 Min Read

After multiple prior rejections, gepirone hydrochloride extended-release (ER; Exxua) gained FDA approval for the treatment of major depressive disorder (MDD) in adults, drugmaker Fabre-Kramer Pharmaceuticals announced.

Gepirone ER is the first approved antidepressant that selectively targets the serotonin 1A receptor, which regulates mood and emotion.

The drug was approved based on data from 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%).

Prior to the approval, gepirone ER had struggled to gain FDA approval for nearly 2 decades. It was rejected in 2004, in 2007, and then again in 2015 after an advisory panel voted against it. At that time, panel members said the treatment lacked “substantial evidence of effectiveness” in treating MDD. One of the main issues under discussion was how to weigh the evidence from two positive randomized trials — typically the gold standard for approval — in light of multiple negative trials.

Fabre-Kramer also highlighted that the approved labeling does not list sexual dysfunction (common with other antidepressants) or weight gain as adverse reactions to gepirone ER, which the company attributed to its “unique” mechanism of action.

Like other antidepressants, the drug does carry a black box warning for increased risk of suicidal thinking and behavior in young adults (and children, although it is not approved for that population).

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%).

Other less common risks are serotonin syndrome when gepirone ER is taken with certain other medicines and manic episodes in people with bipolar disorder.

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.

Fabre-Kramer, the third company to own the rights to the treatment since the early 1990s, is also developing gepirone ER for other psychiatric disorders. The treatment is expected to be available in pharmacies in early 2024.

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    Michael DePeau-Wilson is a reporter on MedPage Today’s enterprise & investigative team. He covers psychiatry, long covid, and infectious diseases, among other relevant U.S. clinical news. Follow

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