FDA approves major depressive drug after rejecting it multiple times in 24-year saga

The FDA approved a Houston drugmaker’s tablet for adults with major depressive disorder last week, capping a decades-long back-and-forth between multiple companies and the regulator over questions of efficacy.

On Thursday, the privately held Fabre-Kramer Pharmaceuticals disclosed the FDA’s Sept. 22 greenlight. Exxua, known investigationally as gepirone, will become available “in pharmacies in early 2024.” The FDA had originally set a decision deadline of June 23.

Fabre-Kramer couldn’t immediately be reached for comment on pricing and reasoning for the FDA’s three-month delay. In the NDA approval letter, the FDA said “major amendments” were made multiple times in April and May.

FDA and outside experts had previously given Fabre-Kramer’s tablet a thumbs-down in 2002, 2004, 2007 and 2016, following a late-2015 advisory committee hearing. Before the 2007 no-go, when GSK had the rights to the drug from Fabre-Kramer, industry analysts had predicted up to $1.6 billion in annual sales for the drug, per Reuters. In the late 90s and early aughts, the drug was under the control of Organon.

The depression drug R&D field has been besieged by FDA rejections and failed studies, with the most recent red light causing Sage Therapeutics to restructure. Other biotechs, like Neumora, are pressing ahead with late-stage studies of newer antidepressants.

Exxua’s nod comes almost 24 years to the day since it was first submitted to the FDA in September 1999. The drug had passed two key clinical trials, but multiple other studies of the investigational medicine had flopped, leading to the multiple previous rejections. In 2015, FDA’s outside advisors weren’t convinced of its efficacy, voting 9 to 4 against approval. The panel voted 11 to 2 that the drug was safe, though, per a MedPage Today article at the time.

In 2016, Fabre-Kramer said the FDA granted an appeal in a formal dispute resolution process. At the time, Exxua was known as Travivo. Years later, in December 2022, the company submitted an NDA amendment for the antidepressant.

Fabre-Kramer’s previous submissions “demonstrated substantial evidence of efficacy with two positive, adequate, and well-controlled trials in major depressive disorder,” an FDA spokesperson told Endpoints News via email. “During this review cycle, the Applicant submitted new chemistry, manufacturing, and controls data as well as a new study on the effect of the drug on heart electrical activity (this type of study is a standard study done during drug development).”

In the approval label, FDA pointed to the two trials in which Exxua was better than placebo at improving patients’ depression at week eight on a scale known as the Hamilton Depression Rating Scale.

Known as gepirone, the extended-release tablet is an agonist of the serotonin 1A receptor. Bristol Myers Squibb began working on it in the 1980s and had hoped gepirone would add to its CNS disorder portfolio, following up on its anxiety disorder drug BuSpar, approved in 1986.

Unlike other serotonin depression drugs, the goal is to avoid sexual dysfunction and weight-gain concerns, Fabre-Kramer has said.

Stephen Kramer

“There is value in providing prescribers and patients with a wide range of effective options for use in clinical practice,” Stephen Kramer, the company’s CEO, said in a press release. “We are proud to bring this innovative therapy to patients who need a new option to manage their depression and improve their quality of life.”

The most common side effects were dizziness, nausea, insomnia, abdominal pain and dyspepsia, per the drug’s prescribing information, which comes with a warning for suicidal thoughts and behaviors.

Fabre-Kramer said the drug’s mechanism “is not fully understood but is believed to be related to its modulation of serotonin activity in the CNS through selective agonist activity at 5HT1a receptors.”

The FDA recommends patients start on a once-daily 18.2 mg dose. At day four, they can move up to 36.3 mg once-daily, then 54.5 mg per day starting the second week. After week two, patients can move to 72.6 mg once-daily. Exxua is supplied in bottles of 100 tablets.

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