On 4 August, Sage Therapeutics and Biogen announced that the FDA approved Zurzuvae (zuranolone) for the treatment of postpartum depression (PPD). The approval was based on two Phase III clinical trials: ROBIN (NCT02978326) and SKYLARK (NCT04442503). Both trials met their primary endpoints, with Zurzuvae treatment resulting in a significant mean reduction from baseline in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score at Day 15 as compared to placebo.
Zurzuvae represents a major breakthrough for PDD, an indication with a high unmet need for therapies developed specifically for its treatment. It is only the second drug to be approved by the FDA for PDD, and the first oral medication approved for the indication. Its oral route of administration makes it significantly more convenient for patients than Sage Therapeutics’ previously approved intravenous (IV) drug for PPD, Zulresso (brexanolone). Zulresso has seen poor uptake since its FDA approval in 2019 as it is only available through a Risk Evaluation and Mitigation Strategy (REMS) program. The product’s IV infusion route of administration is time-consuming, taking 60 hours, with the requirement for continuous monitoring due to the risk of excessive sedation or sudden loss of consciousness during administration.
As a gamma-aminobutyric acid type A receptor subunit agonist, Zurzuvae provides a novel mechanism of action for treating depression. It has a rapid onset of action, with a reduction in depressive symptoms seen as early as three days after beginning medication, compared to the three to six weeks seen for common off-label therapies for PPD such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Additionally, as an acute therapy administered for just two weeks, Zurzuvae will be particularly attractive for patients who don’t want to be locked into taking long-term maintenance therapy, especially mothers who may be concerned about any medication they take entering their breast milk.
Despite its many advantages, Zurzuvae will still face challenges upon entering the market. It carries a boxed warning that the drug causes driving impairment due to central nervous system depressant effects for up to 12 hours after administration. Additionally, the FDA noted that the drug has potential for abuse and so, as a controlled substance, it will undergo a scheduling review before it can enter the market, which could hinder the overall potential uptake of Zurzuvae.
Although the approval for PPD is significant, the FDA rejected Zurzuvae for the treatment of major depressive disorder (MDD), issuing a complete response letter (CRL). This is very disappointing for Sage Therapeutics and Biogen, given the large patient population with MDD versus PPD and thus significant missed commercial potential. Although Zurzuvae met its primary endpoints in two Phase III trials—SHORELINE (NCT03864614) and WATERFALL (NCT04442490)—the size of the effect was small. This, combined with a previous Phase III failure (MOUNTAIN; NCT03672175), has meant that the FDA requires an additional clinical trial to confirm the efficacy of Zurzuvae for MDD. Sage Therapeutics and Biogen have yet to confirm whether this is the next step they will take, having previously terminated two additional planned Phase III trials—REDWOOD (NCT04007367) and RAINFOREST (NCT03771664)—believing them not to be necessary for a new drug application.
An unsure future for Zurzuvae in MDD is advantageous for Axsome Therapeutics’ Auvelity (bupropion + dextromethorphan), giving the product longer to fully establish itself on the market as the first oral, fast-acting antidepressant for MDD, having been approved by the FDA in August 2022. GlobalData forecasts strong sales in the eight major markets (8MM: US, France, Germany, Italy, Spain, UK, Japan, and Canada) of $1.3bn by 2029 for Auvelity.