Sage Impresses With Second Postpartum Depression Therapy
Executive Summary
Positive top-line Phase III data with Sage's second lead positive allosteric modulator at GABA receptors, SAGE-217, in postpartum depression continues to back the US biotech's approach to the devastating condition.
The value of Cambridge, Mass.-based SAGE Therapeutics Inc.'s shares surged by 50% on Jan. 7 as the CNS-focused biotech released positive top-line Phase III results for its second lead compound, the orally administered SAGE-217, in postpartum depression, and the company's management presented an update of its commercial strategy at the J. P. Morgan Healthcare conference.
As well as the positive data, analysts attributed some of the excitement surrounding the company to it being a potential takeout candidate in the currently active M&A space. The new data also showed no loss-of-consciousness events so far with SAGE-217, a potential concern with the company's lead intravenously administered investigational compound, Zulresso (brexanolone), which may have overhung the stock, according to Leerink analysts.
SAGE-217 has previously shown strong data in major depressive disorder, and the current interim data show the drug has a rapid onset of action and produces durable responses, the Leerink analysts said in a Jan. 7 note. There are indications that SAGE-217 has blockbuster potential and could change the way depression is treated, although it will have to compete in a therapeutic sector that is highly genericized.
Biomedtracker analysts have been similarly upbeat, saying SAGE-217's novel mechanism of action, large treatment effect and indication selection may enable Sage Therapeutics to avoid the common pitfalls of antidepressant drug development.
Sage executives believe SAGE-217 should complement Zulresso, because patients react differently to various drugs, noted analysts at BMO Capital Markets. Sage Therapeutics is hoping to have some better-sleeping data in the label, and are considering additional clinical studies involving longer-term maintenance therapy, and switching from other antidepressants. SAGE-217 may also have a significant commercial opportunity in major depressive disorder, the analysts add.
Short-Course Study
In the Phase III ROBIN study, the efficacy and safety of a short course of SAGE-217 is being evaluated in 151 adult women with severe postpartum depression, and Hamilton Rating Scale for Depression (HAMD-17) scores of greater than 26.
Patients treated with SAGE-217 had a statistically significant improvement of 17.8 points in the Hamilton Rating Scale for Depression (HAMD-17) score, compared with 13.6 for placebo (primary endpoint, p=0.0029), after two weeks of outpatient therapy, Sage Therapeutics reported on Jan. 7.
Statistically significant differences between the two arms of the study were seen after three days and were maintained at each time point through the two weeks. The statistically significant reductions in HAMD-17 also continued through to the end of four weeks of follow-up, the company added.
45% of patients treated with SAGE-217 for two weeks achieved disease remission as measured by the HAMD-17, compared with 23% of patients receiving placebo (p=0.0122). Results from secondary endpoints were statistically significant and consistent with the primary endpoint, the company said.
SAGE-217 was generally well-tolerated with a safety profile consistent with that seen in earlier studies. Overall reports of adverse events were similar between SAGE-217 (58%) and placebo (51%) and included somnolence (12.8% with SAGE-217 versus 8.2% with placebo), headache (9% vs 12.3%), dizziness (7.7% vs 5.5%) and upper respiratory tract infection (7.7% vs 1.4%).
Two subjects experienced serious adverse events, one subject in each group. There were no reports of loss of consciousness or syncope, and no signal for increased suicidal ideation or suicidal behavior compared to baseline.
Postpartum depression is believed to be a distinct major depressive disorder that affects around one in nine women who give birth in the US, that is around 400,000 women annually, and is associated with functional impairment, depressed mood, lack of sleep and other symptoms.
Sage says SAGE-217 is a next-generation positive allosteric modulator that acts at synaptic and extra-synaptic GABA-A receptors and is also being developed for major depressive disorder and other mood disorders. The compound has already attracted attention from big pharma, with Shionogi & Co. Ltd. entering into an agreement in mid-2018 to develop and commercialize SAGE-217 in Japan, Taiwan and South Korea, with a large upfront of $90m. (Also see "Shionogi Deal Opens Asia To Sage’s Fast-Acting Antidepressant" - Scrip, 14 Jun, 2018.)
A second pivotal Phase III trial of SAGE-217, MOUNTAIN, in patients with major depressive disorder, started in December 2018. Sage Therapeutics's lead compound, Zulresso, is awaiting US FDA approval, also for use in postpartum depression, with a PDUFA date for its priority review extended by three months to March 19, 2019. (Also see "Sage Gets More Time For Zulresso Launch Preparations With Delay Of US FDA Approval" - Scrip, 20 Nov, 2018.)
Launch of Zulresso, if approved, is projected for June 2019, following scheduling by the US Drug Enforcement Agency.
Also in development at Sage Therapeutics are SAGE-324, which has potential in essential tremor and epileptiform disorders and is in Phase I, and SAGE-718, a first-in-class NMDA receptor positive allosteric modulator, also in Phase I for cognition-related disorders.