In September 2024, Shionogi & Co., Ltd submitted a New Drug Application (NDA) in Japan for zuranolone, a gamma aminobutyric acid (GABA) type A receptor subunit agonist in development for major depressive disorder (MDD). Despite its rapid onset of action, zuranolone is expected to face challenges in Japan’s MDD market due to its severe side effect profile, says GlobalData.
The NDA submission is based on a Phase III trial conducted in Japan in 412 MDD patients to evaluate the efficacy, safety, and tolerability of zuranolone (SAGE-217), who were not on other anti-depressants. In this study, improvement in the change from baseline in the Hamilton Depression (HAM-D) total score was observed in the zuranolone group at Day 15, achieving the primary endpoint. Zuranolone also showed an improvement in MDD symptoms as early as Day 3, demonstrating its rapid onset of action.
In Japan, the standard of care (SOC) treatments for MDD are selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI), which typically take four to six weeks to work. Following inadequate response to SOC, drugs with differentiated mechanisms, such as zuranolone, are typically prescribed as a second-line treatment. However, zuranolone is unlikely to displace first-line antidepressants for MDD treatment due to their long history of use, well-established clinical profiles, and widely available cheap generic alternatives.
Nelluri Geetha, Pharma Analyst at GlobalData, states, “The studies of MDD patients showed that depression is accompanied by reduced concentration of the inhibitory neurotransmitter GABA in the brain as well as alterations in the subunit composition of the principal receptors (GABA A receptors) mediating GABAergic inhibition.”
Zuranolone is a positive allosteric modulator, GABA type A receptor subunit agonist and may potentially offer rapid and sustained antidepressant benefits. Despite its novel mechanism and rapid onset of action, zuranolone carries a risk of driving impairment for up to 12 hours after administration, and the drug has potential for abuse.
According to GlobalData’s Pharmaceutical Intelligence Center, in Japan, two GABA type A receptor agonists are approved for MDD: Benzodiazepines, clotiazepam (Rize) from Mitsubishi Tanabe Pharma Corp and etizolam (Dezolam) from Taisho Pharmaceutical Co Ltd.
Rize and Dezolam are associated with unfavorable side effect profiles with common adverse events including leukopenia, headache, confusion, ataxia, and drowsiness upon waking when the drug is taken late in the evening. Additionally, benzodiazepines carry a high risk of abuse or dependence potential, making them less attractive as second-line options for MDD treatment, limiting their use. Zuralone may also see a similar limitation to its uptake given its safety profile.
Zuranolone is already approved in the US under the brand name Zurzuvae and is the first and only oral treatment in the country for postpartum depression (PPD). In August 2023, the FDA rejected zuranolone for the treatment of MDD, requiring an additional clinical trial to confirm the efficacy of the drug in MDD.
Geetha concludes, “In Japan, despite numerous innovations for the treatment of MDD, there remains an unmet need for therapies targeting patients with inadequate responses to SOC drugs with faster onset of action and cleaner safety profiles. Whether zuranolone will address these needs will remain to be seen.”
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