Exxua: A Lengthy Approval Under a Regulatory Lens

On September 28, 2023, Fabre-Kramer Pharmaceuticals received FDA approval for gepirone extended release (Exxua) for the treatment of adults with major depressive disorder (MDD). MDD affects more than 8% (21 million) of American adults each year. With a lengthy approval history dating back to 2002 and controversies surrounding its basis of approval, the regulatory history of this drug is an interesting one to examine, with more than 20 years in the making.

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In the current treatment landscape of MDD, numerous pharmacological options already exist, primarily targeting the reuptake of serotonin [i.e., selective serotonin reuptake inhibitors (SSRIs)] or both serotonin and norepinephrine [i.e., serotonin and norepinephrine reuptake inhibitors (SNRIs)].¹ These medications are widely regarded as a first-line pharmacotherapy option for MDD.² Despite these options, many patients do not respond adequately or discontinue therapy due to common adverse events (AEs) such as decreased libido and weight changes. Although the currently approved drugs are effective for many patients, they have limitations that would be desirable to eliminate with other therapeutic choices, which act pharmacologically different.

Gepirone is the first and only oral selective serotonin 1A (5-HT1A) receptor agonist indicated for MDD in adults.³ The exact mechanism underlying gepirone’s antidepressant effect is not fully understood. It is believed to be related to the drug and its active metabolites, 3’‑OH gepirone and 1‑PP, which modulate serotonin activity in the CNS through selective agonist activity at 5-HT1A receptors, including both pre- and post-synaptic receptors. Although the precise significance of this subtype of serotonin receptor remains uncertain, there is a belief that individuals with depression exhibit decreased availability and function of pre- and post-synaptic 5-HT1A receptors. However, the connection between this abnormality and the symptoms of depression remains unclear and is still being studied.⁴

Gepirone offers a promising option for patients in need of an alternative antidepressant without the common AEs of sexual dysfunction associated with SSRIs and SNRIs or weight gain from tricyclic antidepressants and monoamine oxidase inhibitors.^5,6 However, it also comes with its share of warnings. Common side effects of gepirone are dizziness, nausea, light headedness, and QT prolongation.⁷ The recommended starting dose of gepirone extended release (ER) is 18.2 mg once daily with food at approximately the same time each day. Depending on clinical response and tolerability, the dose may be titrated to 54.5 mg once daily after day 7 and 72.6 mg once daily after an additional week.⁸

In looking at the traditional drug development and approval process, new medications initially require proper evaluation in non-clinical animal model studies to obtain information on pharmacology, pharmacodynamics, toxicity, and other characteristics. Clinical trials are then initiated in humans, typically consisting of phase 1, phase 2, and phase 3 trials. In this process, phase 3 trials are the pivotal studies used to deem whether substantial evidence of effectiveness exists for a compound in order to set regulatory standards for approving a drug. Although there is no legal requirement for sponsors to have a set number of positive clinical trials, historically 2 positive pivotal trials have been considered a reasonable expectation. However, this trend has shifted in the last decade. Between 1995 and 2017, the proportion of new drugs and biologics approved by the FDA using only 2 pivotal trials declined from 81% to 53%. This trend in the decline of using at least 2 pivotal trials as the basis for approval is not unique to the FDA. Between 2012 and 2016, 23 novel therapeutic drugs were approved by the European Medicines Agency based on a single pivotal trial.⁹ Interestingly, there is no written guideline on the number of negative trials which would disqualify a drug compound from the chance of regulatory approval. These observations appear to suggest that the research bar to approve new medications has been lowered with fewer positive studies required and no limit on how many studies with negative results may have been performed.

This changing drug approval climate provides an interesting view of the nonlinear pathway on which gepirone made its way on to the market. In 1986, the compound was originally synthesized by Mead Johnson and Bristol-Myers Squibb for the treatment of anxiety and depression, first as an immediate-release formulation and later as an ER product.¹⁰ The ER formulation, designed to be taken once daily, exhibited a pharmacokinetic profile which was believed to improve tolerability and treatment adherence.¹¹

In 1992, Bristol-Myers Squibb made the decision to pause phase 3 trials of gepirone ER and subsequently sold the rights of the compound to Fabre-Kramer in 1993. In May 1998, Organon acquired the rights to further develop and market the drug product. By September 1999, Organon had submitted the drug (named Ariza at this time) for approval in the US, with US and European launches expected in 2002 and 2003, respectively.

However, in November 1999, the FDA declined the approval due to a failure of the sponsor to provide 2 positive and well-controlled trials. Organon resubmitted the NDA in May 2001 which included 18 placebo-controlled trials [8 with ER and 10 with immediate-release (IR) dosage forms]. Organon specifically identified 4 of these trials as adequate and well-controlled evidence supporting proof of efficacy. However, only 1 of the 4 studies was conducted with the ER dosage form; the others were phase 2 studies conducted by Bristol-Myers Company with the IR formulation. Nonetheless, the NDA was successfully accepted by the FDA.

Unfortunately, a not approvable letter was issued by the FDA in April 2002, citing inadequate evidence of effectiveness and requesting an additional positive trial with the ER formulation for the claim of short-term efficacy for gepirone ER. By December 2003, Organon resubmitted the drug (now named Variza) for approval in the US, but was rejected in June 2004 by FDA, requesting additional clinical trials for gepirone in MDD.^12,13 Despite the sponsor’s initial aspirations, it would go on to take 2 more decades of clinical trials to collect adequate support for the drug to receive its first approval.

In May 2007, an amended NDA for gepirone ER (named Travivo at this time) was submitted by Fabre-Kramer and GSK. However, in November 2007, another not approvable letter was issued, noting a lack of substantial evidence of effectiveness in 2 positive trials and an unacceptably small treatment effect. An appeal of the decision was submitted by Fabre-Kramer in January 2012, which triggered a series of communications including a Type C meeting (i.e., FDA and sponsor interaction), an NDA amendment in support of an informal appeal, a General Advice Letter from the FDA, and then an acceptance of the Formal Dispute Resolution Request in January 2015. In September 2015, the Psychopharmacologic Drugs Advisory Committee (PDAC) held a session to discuss the value of information provided by failed trials in undermining evidence of effectiveness, as well as how to consider failed trials in determining efficacy for a drug. After an 11-2 vote in favor of gepirone’s safety profile but a vote of 9-4 that the sponsor failed to demonstrate the drug’s efficacy, a dispute appeal was granted by the FDA in March 2016.¹⁴

In response, Fabre-Kramer amended the NDA for geprione ER (now named Exxua) in December 2022,adding new pediatric studies, a dedicated QT study, a re-analysis of a long-term efficacy study, requests for pediatric exclusivity, and new review of sexual dysfunction. The original draft labeling text, previously unreviewed by the FDA, was also included. This amended submission was accepted in January 2023 and Gepirone finally gained approval in the US for the treatment of MDD in adults in September 2023.

One of the largest causes for concern with gepirone’s approval was the number of negative trials, which did not demonstrate benefit. Over time, the sponsors conducted 25 studies with gepirone ER and 35 total trials with gepirone ER and IR. As stated in the FDA PDAC 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. Upon initial review, FDA officials suggested the possibility that 2 positive studies may have occurred by chance, as the number of negative studies greatly outweigh them and that substantial evidence of effectiveness had not been provided. Additionally, the approved ER version has only been studied in the short term, and concern has been raised regarding the efficacy of the product long-term. Finally, another debate surrounding gepirone swings in favor of its approval. Supporters of gepirone argue that denying approval would send a negative message to drugmakers that could discourage further research and development, which could impact patients with unmet needs.¹⁴

As the regulatory landscape moves forward, there is a need for more clarity on how many positive and negative clinical trials are needed and what a true benefit/risk analysis means in the psychiatric space. As nuance in more advanced therapies grows, a lack of clarification around standards of effectiveness, while allowing for more outside-the-box drug development, leaves a question as to whether the regulatory systems in place are working effectively. In the case of gepirone, we look forward to seeing the long-term use data and fulfillment of postmarketing requirements, which will help shed light on the long-term benefit, safety, and efficacy of this drug. This is also applicable to other spaces of unmet need in which a clear answer on the threshold for positive and negative clinical trials may have more flexibility. The story of gepirone may spark new conversations for industry standards on drug development to facilitate future innovations.

References

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