A Promising Option: Exxua

After being rejected five times by regulators over two decades, Exxua (gepirone extended-release), long heralded as a potential breakthrough in mental health treatment, proved to stand the test of time. The drug, today developed by Fabre-Kramer Pharmaceuticals, was approved in September 2023 for the treatment of major depressive disorder (MDD) in adults. It was the first antidepressant cleared by the FDA with a novel mechanism of action that selectively targets serotonin 1A. This receptor is known to be a key regulator of mood and emotion. Notably, Exxua reportedly addresses associated issues with sexual dysfunction and weight gain, two major physician and patient complaints about available therapies for this condition.

“Exxua represents an important milestone in the treatment of MDD, a serious and debilitating condition that affects millions of people worldwide,” said Stephen Kramer, MD, CEO, Fabre-Kramer, in a statement upon Exxua’s approval. “There is value in providing prescribers and patients with a wide range of effective options for use in clinical practice. 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.”

ALTERNATIVE INVESTMENT

It is believed that Exxua’s approval will impact mental health treatment significantly. A January blog entry by Joao De Quevedo, MD, PhD, of the Department of Psychiatry and Behavioral Sciences, McGovern Medical School, argued that approval of Exxua provides tangible hope for patients who have experienced little support from existing treatments.¹

“The extended-release nature of gepirone ER not only enhances its convenience but also underscores the commitment to fostering long-term stability for those managing mental health conditions,” wrote De Quevedo in the post on McGovern’s website.

De Quevedo also noted that Exxua is poised to address a number of unmet needs in mental health treatment. He pointed to the heterogeneous nature of MDD, which, he said, necessitates a more “diversified toolkit” for healthcare providers. Given these dynamics, he cited gepirone ER’s particular potential to treat patients who have not responded significantly to other forms of therapy.

ELUSIVE TARGET

A 2017 study published online by F1000 Research found that previous research implicated the serotonin 1a receptor as the biggest influencer of depression and depression-related behaviors. Serotonin 1a also heavily modulates anxiety, bipolar disorder, and post-traumatic stress disorder.²

Targeting the receptor with a therapeutic has been a long journey fraught with setbacks. Gepirone was first synthesized by Bristol Myers Squibb (BMS) and Mead Johnson in 1986 as a treatment for anxiety and depression. By 1992, however, BMS shut down clinical trials for the treatment and subsequently sold it to Fabre-Kramer a year later. A few years later, the asset was acquired by Organon, which eventually returned it to Fabre-Kramer after the FDA rejected its approval in 1999, 2002, and 2004. By 2007, Fabre-Kramer, which began collaborating on the treatment with GSK, again submitted a new drug application (NDA), only to be declined on the grounds that the agency believed there was a considerable lack of evidence in two clinical trials that gepirone was effective in treating MDD.^2,3

It wasn’t until nearly five years later that Fabre-Kramer was ready to appeal the decision. However, this, according to reports, resulted in a number of correspondences, including a Type C meeting, an NDA amendment in support of an informal appeal, a general advice letter from the FDA, and finally, a formal dispute resolution request acceptance.

In 2016, the FDA granted a dispute appeal, leading to Fabre-Kramer revising its NDA for gepirone in late 2022. The updated application included pediatric studies, a dedicated quality tolerance study, a re-analysis of a long-term efficacy study, requests for pediatric exclusivity, and a new review of sexual dysfunction. In turn, the new NDA was submitted in January 2023 with approval for the treatment of MDD in adults granted in September.

Currently, according to Fabre-Kramer, the mechanism of the antidepressant effect of Exxua is not fully realized, although the company believes that it could be associated with the modulation of serotonin activity in the central nervous system through selective agonist activity at 5HT1a receptors.1 Amid the approval and promise of Exxua, published reports note that there are lingering concerns about the number of clinical trials for Exxua that yielded negative results or no benefits over the years.⁴

“Over time, the sponsors conducted 25 studies with gepirone ER and 35 total trials with gepirone ER and IR. As stated in the FDA [Psychopharmacologic Drugs Advisory Committee] review held on October 13, 2015, the question surrounding approval of the drug hinged on weighing negative/failed trials in determining the efficacy of a drug for a disease in which many effective treatment options exist,” explained Neha Nadkarni, PharmD, RPh, and Peter Kim, PharmD, RPh, in a May 2024 story published by Pharmacy Times, a sister publication to Pharmaceutical Executive.⁴

However, the writers also point to another debate surrounding gepirone that was in favor of its approval. Supporters of the agent argue that denying approval would send a negative message to drug manufacturers that could discourage further research and development—ultimately adversely impacting mental health patients with unmet needs.

According to the National Institute of Mental Health, an estimated 21 million adults in the US experienced at least one major depressive episode in 2021.⁵ The prevalence was higher among adult females (10.3%) compared to males (6.2%). When looking at age, the prevalence of those with a major depressive episode was highest among individuals aged 18-25 (18.6%). The NIH, in past reports, have found that adults with a depressive disorder or symptoms have a 64% greater risk of developing coronary artery disease.

References

1. De Quevedo, J. New Dawn: FDA Greenlights Exxua (Gepirone ER) for Major Depressive Disorder. McGovern Medical School. January 29, 2024. https://med.uth.edu/psychiatry/2024/01/29/a-new-dawn-fda-greenlights-exxua-gepirone-er-for-major-depressive-disorder/

2. Nautiyal, K.M.; Hen, R. Serotonin Receptors in Depression: From A to B. F1000Res. 2017. 2 (6), 123. https://f1000research.com/articles/6-123/v1

3. Drug Profile: Gepirone - Fabre-Kramer Pharmaceuticals. AdisInsight. October 5, 2023. https://adisinsight.springer.com/drugs/800000684

4. Nadkarni, N.; Kim, P. Exxua: A Lengthy Approval Under a Regulatory Lens. Pharmacy Times. May 7, 2024. https://www.pharmacytimes.com/view/exxua-a-lengthy-approval-under-a-regulatory-lens

5. Major Depression. National Institute of Mental Health. July 2023. https://www.nimh.nih.gov/health/statistics/major-depression