On June 15, new Sage Therapeutics and Biogen announced positive results from a pivotal Phase III trial of their novel antidepressant zuranolone. The WATERFALL (NCT04442490) study was a double-blind, placebo-controlled study evaluating the efficacy and safety of zuranolone as an acute rapid response therapy (RRT) for adults with major depressive disorder (MDD). After 14 days of treatment, zuranolone met the study’s primary endpoint of demonstrating a statistically significant improvement in depressive symptoms compared with placebo at Day 15, as assessed by the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score. LS means (SE) change from baseline in HAMD-17 total score at Day 15 for patients who received zuranolone 50 mg was -14.1 (0.51) compared with -12.3 (0.50) for patients who received placebo. Zuranolone was generally well-tolerated in the WATERFALL study and demonstrated a safety profile that was consistent with previous clinical studies. The most common adverse events included somnolence, dizziness, headache and sedation.
Zuranolone is a gamma aminobutyric acid A (GABA A) receptor positive allosteric modulator, which would be a novel mechanism of action (MOA) for treating MDD and would help zuranolone to compete in the MDD market. Following the discovery of monoaminergic antidepressants, which modulate the transmission of serotonin and/or norepinephrine, many antidepressants with a similar MOA were developed, including the selective serotonin reuptake inhibitors (SSRIs) and the serotonin-norepinephrine reuptake inhibitor (SNRIs). This means that the MDD market is now both highly competitive and highly genericised. Therefore, one of the key trends seen in the MDD pipeline is the presence of a wide variety of MOAs, as companies are trying to develop novel products to give them a competitive edge in the market. Key opinion leaders interviewed by GlobalData were keen to see drugs with novel MOAs enter the MDD market to increase the variety of available treatment options.
There is a significant unmet need within the MDD market for pharmacotherapies that can demonstrate rapid antidepressant effects. Currently available products only show antidepressant effects after several weeks of treatment and require long-term, continuous administration to be effective. Zuranolone has demonstrated rapid antidepressant effects, and one course of zuranolone treatment is only 14 days long. This would be particularly advantageous for patients and could alter the way MDD is treated, shifting the focus to episodic treatment instead of maintenance treatment. However, as a short-course treatment, sales for zuranolone could be limited when compared with maintenance therapies for MDD. As such, GlobalData forecasts that zuranolone will generate global sales of approximately $137m by 2029.
The FDA granted zuranolone Fast Track designation in 2017 and Breakthrough Therapy designation in 2018 for the treatment of MDD. Two additional studies evaluating zuranolone in patients with MDD, the CORAL study (NCT04476030) and the SHORELINE study (NCT03864614), are expected to read out by the end of 2021. GlobalData expects zuranolone to launch in the US in early 2023.
Several other late-stage products have demonstrated rapid antidepressant effects in clinical trials and will provide significant competition for zuranolone, including Axsome Therapeutics’ AXS-05 (bupropion + dextromethorphan) and Relmada Therapeutics’ REL-1017. AXS-05 is expected to launch later this year, a couple of years before zuranolone and REL-1017, giving it first-to-market advantage. It has demonstrated very strong efficacy results. In the Phase III GEMINI (NCT04019704) clinical study, AXS-05 demonstrated a statistically significant mean reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 7.3 points, compared to 4.9 points for placebo, at Week 1 (p=0.007) from baseline. Statistical significance for this measure was maintained at all time points in the trial. Additionally, AXS-05 is being developed as both a monotherapy and an adjunctive therapy for MDD, enabling it to reach a wider patient population compared with zuranolone, which will be co-initiated with a new standard antidepressant, such as an SSRI. GlobalData anticipates that Axsome Therapeutics’ AXS-05 will have the potential to become a blockbuster drug and could generate global sales of approximately $1.3bn by 2029.