In July 2019, Sage Therapeutics launched brexanolone injection, for the treatment of postpartum depression in the US. The drug was approved in March 2019, by the US FDA    . In May 2018, the US FDA accepted the NDA for the drug and granted priority review. PDUFA date of 19 December 2018 was initially assigned to the drug which was later extended to 19 March 2019  . In October 2018, SAGE Therapeutics announced that the US FDA Psychopharmacologic Drugs Advisory Committee (PDAC) and Drug Safety and Risk Management Advisory Committee (DSaRM) jointly voted 17-1 in support of benefit-risk profile of brexanolone Injection for treatment of postpartum depression when administered by qualified staff in a facility that has been certified under a Risk Evaluation and Mitigation Strategies (REMS) program  . In August 2018, Sage reported of the conditional acceptance of the proprietary name ZULRESSO™ for brexanolone, by the US FDA. Earlier in April 2018, Sage Therapeutics announced the submission of a New Drug Application (NDA) to the US FDA. The submission and subsequent approval was supported by data from the Hummingbird Programme, which included three trials: Study 202A, Study 202B and Study 202C [see below]. The approval triggers a milestone payment of $US 3 million to Ligand Pharmaceuticals    . In June 2019, the US Drug Enforcement Administration (DEA) placed brexanolone injection into Schedule IV of the Controlled Substances Act  .
In October 2018, Sage Therapeutics received scientific advice from the EMA regarding the potential regulatory pathway for a marketing authorization application filing in the EU  .
In November 2016, the EMA granted PRIority MEdicines (PRIME) status to brexanolone, for the treatment of postpartum depression. The drug was granted Breakthrough Therapy designation for this indication by the US FDA, in September 2016. The regulatory applications were based primarily on the positive results from the phase II PPD-202 A trial of brexanolone in patients with severe postpartum depression [see below]    .
In December 2016, Sage Therapeutics reported its expedited development plan for brexanolone based on the minutes from a formal breakthrough therapy meeting with the US FDA. The FDA agreed upon the unchanged primary clinical endpoint for these pivotal trials. If required, additional patient safety data may be acquired through an open label programme. The company intends to make an NDA filing in the US in 2018  .
In January 2021, Sage Therapeutics completed a phase III trial to evaluate the efficacy, safety, tolerability, and pharmacokinetics of brexanolone in the treatment of adolescent female subjects with postpartum depression (NCT03665038; 547-PPD-304; EudraCT2017-004356-34). The open-label trial initiated in May 2018 and enrolled 20 participants in the US  .
In October 2017, Sage Therapeutics completed two phase III trials. The first trial evaluated efficacy, safety and pharmacokinetics of brexanolone, in patients with moderate and severe postpartum depression (547-PPD-202 B; NCT02942004). The randomised, double-blind, placebo-controlled trial enrolled 138 patients in the US and New Zealand  . Dosing for the trial was initiated in August 2016     . The second trial evaluated the efficacy, safety and pharmacokinetics of brexanolone, in patients with moderate and severe postpartum depression (547-PPD-202 C; NCT02942017). The randomised, double-blind, parallel group, placebo-controlled trial was initiated in July 2016, and enrolled 108 patients in the US and New Zealand   . In September 2018, Sage Therapeutics released the efficacy and safety data from an integrated analysis of two phase III trials in postnatal depression  .
In August 2016, Sage Therapeutics announced about an expansion of the phase II clinical programme to determine optimal dosing of brexanolone in patients with moderate postpartum depression. This programme includes two phase III trials as an acute interventional treatment for postpartum depression, collectively called Hummingbird Study, that was completed in October 2017. In November 2017, the company released positive top-line results from the two phase III202B and 202C trials. The trials evaluated dose-ranging of brexanolone in severe PPD patients and efficacy in moderate PPD patients    .
In September 2016, Sage reported additional data from a placebo-controlled, proof-of-concept phase II trial of the drug in patients with severe postnatal depression; top-line data were released in July 2016 (547-PPD-202 A; NCT02614547). The company, in July 2016, completed the phase II trial that assessed intravenous brexanolone in patients with severe postnatal depression. The trial that validated the activity of the drug as observed in a previous trial, was initiated in November 2015, and enrolled 21 subjects in the US. Results from these trials showed that brexanolone improved depressive symptoms at the end of the first infusion as well as at the end of the 30-day follow-up period. Sleepiness, dry mouth, loss of consciousness and flushing were the most common adverse reactions reported      .
Sage Therapeutics initiated a phase IIa trial in September 2014 to investigate the safety, tolerability, pharmacokinetics and efficacy of brexanolone as an adjunctive therapy in patients with severe postpartum depression (547-PPD-201; NCT02285504). In this trial, patients were administered with brexanolone intravenously for 48 hours and were monitored for up to 30 days following treatment; the acute effect of the drug were assessed by the Hamilton Rating Scale for Depression (HAM-D) and Clinical Global Impression-Improvement Scale (CGI-I). First patient in this trial was administered with the drug in January 2015. The open-label was completed in June 2015 and the study enrolled 4 female patients with severe postpartum depression in the US. Based on the positive top-line results released in June 2015, the company initiated a placebo-controlled trial     .
SARS-COV-2 acute respiratory disease
In August 2021, Sage Therapeutics terminated a phase III study as it did not meet enrollment expectations. Earlier in December 2020, Sage Therapeutics had initiated a phase III study that was designed to evaluate the efficacy and safety of brexanolone in patients with ventilator support for acute respiratory distress syndrome (ARDS) due to COVID-2019 (NCT04537806, 547-ARD-301). This randomised, parallel, double-blind study intended to enroll 100 patients in the US    .
In August 2020, Sage Therapeutics announced that it has received clearance from US FDA under the Coronavirus Treatment Acceleration Program (CTAP), to initiate a phase III study with brexanolone in patients with advanced COVID-19 related acute respiratory distress syndrome (ARDS), plan if which will be disclosed in September 2020  .
Major depressive disorder
Development of brexanolone for major depressive disorders is discontinued and the indication is no longer present in the pipeline (Sage Therapeutics pipeline, May 2017)
Sage Therapeutics plans to initiate a proof-of-concept phase II clinical study of brexanolone in major depressive disorder (MDD) to guide future clinical development for SAGE 217 [see ADIS Insight profile 800043382]. The company is currently conducting preclinical probe studies for brexanolone in MDD  .
Development of brexanolone for super-refractory status epilepticus (SRSE) is discontinued and Sage Therapeutics does not plan to pursue brexanolone IV as a treatment for SRSE 
In November 2016, Sage Therapeutics received positive Scientific Advice from the EMA on the development of brexanolone in the treatment of patients with super-refractory status epilepticus (SRSE)  . Sage Therapeutics plans to launch brexanolone in 2018, subject to positive results from the phase III trial and approval from the EMA and other regulatory authorities  .
In April 2015, Sage Therapeutics completed treatment of the first patient enrolled in the open-label expanded access Study 302 in the US (547-SSE-302; NCT02433314), which triggered a milestone payment of $US500 000 to Ligand Pharmaceuticals from Sage. This first trial from the phase III development program is designed to evaluate the safety of brexanolone in patients with super-refractory status epilepticus (SRSE), aged two years or older, with limited treatment options and brexanolone will be administered as an adjunctive therapy for a six-day treatment regimen. The trial will have dose regimen, trial procedures and assessment of patient outcomes consistent with the STATUS trial (see below). Results from Study 302, the STATUS trial and other clinical data from the development program are intended to form the basis of the NDA submission for brexanolone    .
In August 2017, Sage Therapeutics completed the phase III STATUS trial (SAGE-547 Treatment as Adjunctive Therapy Utilized in Status Epilepticus) that evaluated the efficacy and safety of brexanolone in patients with super-refractory status epilepticus (SRSE), aged two years or older (547-SSE-301; NCT02477618; EudraCT2015-002142-31). The double-blind, placebo-controlled trial randomised 132 patients in the US, Estonia, Italy, Canada, France, Israel, Serbia, Germany, Belgium, Sweden, Denmark, Spain, the Netherlands, Finland, Hungary, and Austria. In August 2015, Sage Therapeutics reported that it had received Special Protocol Assessment for the trial . The US FDA had agreed on the design and key elements of the trial in April 2015 at the end-of-phase II meeting. Top-line data from the study were released by the company in September 2017             .
In July 2014, the US FDA granted fast track designation to brexanolone for the treatment of patients with status epilepticus, who have not responded to standard treatment regimens   . The drug had received an orphan drug designation in the same indication, in May 2014  .
An open-label phase I/II trial met primary and secondary endpoints of safety, tolerability and successful weaning off anaesthetic agents during brexanolone administration (547-SSE-201; NCT02052739). The trial assessed the safety, tolerability, efficacy and pharmacokinetics of IV infusion with brexanolone as adjunctive therapy for 5 days. The trial enrolled 25 patients in the US. Sage Therapeutics also enrolled paediatric patients aged two years and older in an expansion cohort of the trial and the cohort enabled increased dosing of brexanolone as per approved protocol amendment. Data from a total of 20 enrolled patients, including a 30-day follow-up data from the 12 previously enrolled patients as well as initial data from eight additional patients were announced in January 2015. Consistent with the top-line November 2014 data, all evaluated patients achieved the primary safety and tolerability endpoint          . In April 2015, Sage Therapeutics reported completion of trial enrolment. Addition of paediatric patients as a study population increased the number of patients to 25  . The company presented results at the 69th Annual Meeting of the American Academy of Neurology (AAN-2017)  .
In June 2014, Sage Therapeutics reported data from four patients with SRSE that were treated at independent centres under emergency use. All four patients achieved target resolution of SRSE  . The company reported detailed data from two of these patients in November 2014. Based on positive data from these patients, the company believes that brexanolone can be used as a treatment for paediatric population as well  . As of November 2014, seven patients received treatment with brexanolone under emergency-use. Five of these patients achieved resolution of SRSE, either during the course of treatment or soon after the treatment. The active pharmaceutical ingredient, treatment IND and support for emergency-use patients have been contributed under agreement by the Regents of the University of California and the University of California, Davis. Data from ten patients were reported in January 2015     . In April 2013, Sage Therapeutics announced that brexanolone had been successfully administered intravenously into a patient with refractory status epilepticus, under a compassionate-use exemption. The results from this first-in-man case study were presented at an international meeting   .
In in vitro studies, SAGE 547 was shown to have increased the number of receptors by inducing a metabotropic mechanism. The compound was also shown to exert sustained effects on GABAergic inhibition in vitro by selectively enhancing the trafficking of GABAA receptors that mediate tonic inhibition. The compound was also shown to increase the phosphorylation and surface expression of the ß3 subunit-containing extrasynaptic GABAA receptors in vitro, resulting in increased tonic current. The data were published in the journal Neuropharmacology  . Early preclinical data also demonstrated that brexanolone was more effective than standard-of-care benzodiazepines in the treatment of super-refractory status epilepticus (SRSE), due to its mechanism of positively modulating key GABAA receptor subtypes.
Development of brexanolone for essential tremor is discontinued and the indication is no longer present in the pipeline (Sage Therapeutics pipeline, October 2016)
In August 2015, Sage Therapeutics completed a two stage phase II trial, that evaluated the safety, tolerability, pharmacokinetics and efficacy of brexanolone, in patients with essential tremor, in the US (547-ETD-201; NCT02277106). The double-blind, placebo-controlled, crossover, proof-of-concept trial initiated in September 2014, enrolled 25 patients in the US. In August 2015, the company released data from the exploratory trial that showed administration of brexanolone resulted in reduction in the tremor amplitude, as compared to placebo treatment    . The company intends to use data from this exploratory trial for the development of second-generation molecule for the treatment of chronic SRSE  .
Sage Therapeutics announced pricing of an initial public offering of common stock, the proceeds from which will be used to support development of brexanolone  . The offering was completed in July 2014 resulting in net proceeds of $US94 million after deduction of underwriting discounts, commissions and offering expenses   . In March 2014, Sage Therapeutics closed a $US38 million Series C financing round in which it intends to use the proceeds to advance brexanolone and its other clinical and preclinical programmes in acute CNS disorders, including status epilepticus  .
Labelling information: The USA FDA label of brexanolone carries a black box warning of excessive sedation and sudden loss of consciousness  .