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Brexanolone - Sage Therapeutics

Drug Profile

Brexanolone - Sage Therapeutics

Alternative Names: Allopregnanolone/sulfobutylether‐beta‐cyclodextrin; brexanolone IV; SAGE-547; SGE-102; ZULRESSO

Latest Information Update: 26 Mar 2019

At a glance

  • Originator University of California, Davis
  • Developer SAGE Therapeutics
  • Class Antidepressants; Antiepileptic drugs; Small molecules; Steroids
  • Mechanism of Action GABA A receptor modulators
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    Yes - Status epilepticus
  • New Molecular Entity Yes

Highest Development Phases

  • Registered Postnatal depression
  • Discontinued Essential tremor; Major depressive disorder; Status epilepticus

Most Recent Events

  • 19 Mar 2019 Registered for Postnatal depression in USA (IV)- First global approval
  • 19 Feb 2019 Sage Therapeutics has patent protection for Brexanolone in several countries worldwide
  • 19 Feb 2019 Sage Therapeutics intends to launch Brexanolone for Postnatal depression in USA in June 2019, following expected scheduling by the Drug Enforcement Administration

Development Overview

Introduction

A proprietary intravenous formulation of brexanolone, a neuroactive steroid and positive allosteric modulator of both synaptic and extra-synaptic GABAA receptors, is being developed by Sage Therapeutics, under a license from the University of California, for the treatment of postnatal depression. The formulation is a mixture of allopregnanolone, an endogenous inhibitory pregnane neurosteroid and sulfobutylether‐beta‐cyclodextrin. Brexanolone is approved in the US for the treatment of postnatal depression. Clinical development for status epilepticus and essential tremor and preclinical development for major depressive disorder was ongoing in several countries worldwide. However, development of brexanolone for these indications is discontinued and the indications are no longer present on the pipeline.

This compound was developed utilising Sage's proprietary Positive and Negative Allosteric Modulator (PANAM) chemistry platform to develop potent and highly-selective, small-molecule positive and negative modulators of GABAA and NMDA receptors to restore disrupted neuronal activity in CNS disorders and Ligand Pharmaceuticals' Captisol® technology which involves the use of a chemically modified cyclodextrin to optimise the solubility and stability of associated drugs.

Brexanolone has emerged from Sage's research programme on CNS disorders [see AdisInsight drug profile 800035109].

Company Agreements

In June 2015, Sage Therapeutics entered into an exclusive license agreement with the University of California, whereby the University granted an exclusive license to certain patent rights related to the use of allopregnanolone to treat various diseases. In exchange for such license, Sage Therapeutics paid an upfront payment of $US 50 000 and will make annual maintenance fees of $US15,000 until the calendar year following the first sale, if any, of a licensed product. Milestone payments following the achievement of specified regulatory and sales milestones of up to $US 0.7 million and $US 2.0 million in the aggregate are to be made. Earlier, in October 2013, Sage Therapeutics entered into a non-exclusive license agreement with the University of California, Davis which was amended in May 2014. Pursuant to this agreement, the University granted Sage Therapeutics a non-exclusive, non-transferable license for allopregnanolone as a treatment of status epilepticus (SE), essential tremor and postpartum depression and the use the material or modifications of the material to develop a pharmaceutical formulation for clinical trials for SE, essential tremor and postpartum depression. The rights licensed are not sublicenseable. Pursuant to the agreement, Sage Therapeutics to pay $US0.1 million in milestone payments in connection with the first derived product that meets the relevant milestones and pay royalties of less than 1% to the University for each derived product for a period of 15 years following the first commercial sale of such derived product. [1] [2]

In August 2013, Sage Therapeutics entered into a platform license agreement with Ligand Pharmaceuticals for the development and commercialisation of compounds modified with Ligand's Captisol® technology for the treatment of central nervous system disorders. According to Ligand's 2013 annual report, this replaced a prior agreement between Sage and Ligand's subsidiary, CyDex. Under the terms of the current agreement, Ligand is eligible to receive milestone payments of up to $US4.5 million plus royalties of 3% based on net sales of products utilising the Captisol® technology. Ligand may also receive commercial revenue from the shipment of Captisol® to Sage for clinical and commercial activities. In May 2014, Ligand announced that it had received a $US150 000 milestone payment from Sage related to the initiation of a phase I/II trial of SAGE 547 [3] .

Key Development Milestones

Postnatal depression

In March 2019, the US FDA approved brexanolone for the treatment of postpartum depression [4] . 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 [5] . 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 [6] . 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 Program, 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 [7] [8] [9] .

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 [10] .

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] [11] [12] [13] .

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 [14] .

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 [15] . Dosing for the trial was initiated in August 2016 [16] [17] [16] [18] . 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 [16] [19] . In September 2018, Sage Therapeutics released the efficacy and safety data from an integrated analysis of two phase III trials in postnatal depression [20] .

In May 2018, Sage Therapeutics initiated 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). The randomised, double-blind, placebo-controlled trial intends to enrol approximately 80 participants in the US [21] .

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 [22] [16] [23] .

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 [24] [23] [25] [26] [27] .

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 [28] [29] [30] [31] .

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 [16] .

Status epilepticus

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 [2]

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) [32] . 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 [16] .

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 [33] [34] [35] .

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 [36] [28] [37] [38] [34] [39] [40] [41] [42] [43] [44] [45] .

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 [46] [47] . The drug had received an orphan drug designation in the same indication, in May 2014 [48] .

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 [49] [50] [42] [43] [44] [47] [51] [52] [53] . 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 [34] . The company presented results at the 69th Annual Meeting of the American Academy of Neurology (AAN-2017) [54] .

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 [51] . 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 [55] . 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 [42] [43] [44] [56] . 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 [57] [58] .

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 [59] . 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.

Essential tremor

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 [60] [61] [62] . The company intends to use data from this exploratory trial for the development of second-generation molecule for the treatment of chronic SRSE [44] .

Financing information

Sage Therapeutics announced pricing of an initial public offering of common stock, the proceeds from which will be used to support development of brexanolone [47] . The offering was completed in July 2014 resulting in net proceeds of $US94 million after deduction of underwriting discounts, commissions and offering expenses [63] [64] . 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 [65] .

Labelling information: The USA FDA label of brexanolone carries a black box warning of excessive sedation and sudden loss of consciousness [66] .

Patent Information

As of March 2019, Sage Therapeutics has patent protection for brexanolone formulation, including courses of treatment, dosage regimens, and methods for manufacturing brexanolone IV injection for postpartum depression, various CNS disorders in the US and other countries worldwide. The patent will expire in 2033 [67] [10] .

Drug Properties & Chemical Synopsis

  • Route of administration IV
  • Formulation Infusion, Injection, unspecified
  • Class Antidepressants, Antiepileptic drugs, Small molecules, Steroids
  • Mechanism of Action GABA A receptor modulators
  • WHO ATC code

    N03A-X (Other antiepileptics)

    N04 (Anti-Parkinson Drugs)

    N06A-X (Other antidepressants)

  • EPhMRA code

    N3 (Anti-Epileptics)

    N4A (Anti-Parkinson Drugs)

    N6A9 (Antidepressants, all others)

  • Chemical name 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethanone
  • Molecular formula C21-H34-O2
  • Chemical Structure
  • CAS Registry Number 516-54-1

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Essential tremor - - Discontinued (II) USA IV / Infusion SAGE Therapeutics 25 Oct 2016
Major depressive disorder - - Discontinued (Preclinical) USA IV / unspecified SAGE Therapeutics 11 May 2017
Postnatal depression - - Registered USA IV / Injection SAGE Therapeutics 19 Mar 2019
Postnatal depression - - Phase III New Zealand IV / Injection SAGE Therapeutics 01 Jul 2016
Postnatal depression - In adolescents Phase III USA IV / Injection SAGE Therapeutics 17 May 2018
Status epilepticus For super-refractory status epilepticus In adolescents, In adults, In children Discontinued (III) Austria, Belgium, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Israel, Italy, Netherlands, Serbia, Spain, Sweden, USA (fast track) IV / Infusion SAGE Therapeutics 22 Feb 2018

Priority Development Status

Type Region Indication
Fastrack US Status epilepticus
PRIME European Union Postnatal depression

Orphan Status

Indication Patient Segment Country Organisation Event Date
Status epilepticus - USA SAGE Therapeutics 01 May 2014

Commercial Information

Involved Organisations

Organisation Involvement Countries
University of California, Davis Originator USA
University of California, Davis Owner USA
SAGE Therapeutics Licensee USA
Ligand Pharmaceuticals Technology Provider USA
The Regents of the University of California Technology Transfer USA

Brand Names

Brand Name Organisations Indications Countries
ZULRESSO SAGE Therapeutics Postnatal depression USA

Scientific Summary

  • Adverse Events Frequent: Dizziness; Headache; Somnolence

Pharmacokinetics

Results from a phase I/II trial showed that the standard and high dosing of brexanolone injection resulted in plasma concentrations in line with target exposures, and clearance was not dose dependent. The standard brexanolone injection dose regimen yielded a mean (SD) steady-state concentration of 66.2 (21.93) ng/mL, whereas the high dose regimen yielded a mean (SD) steady state concentration of 113.6 (42.08) ng/mL. The steady-state concentrations of allopregnanolone were nearly dose proportional in both the standard and high dose regimens. The clearance (mean (SD) of 1.36 (0.56) L/h/kg) was independent of dose. The half-life and volume of distribution could not be determined due to insufficient sampling after the cessation of infusion [54] [53] .

Adverse Events

Top-line results from the phase III STATUS trial indicated that consistent with the severity and complexity of SRSE, patients' underlying conditions, and ongoing ICU treatment, nearly all patients experienced adverse events. Similar serious adverse events and rates of death were observed across the two treatment groups. The rate of adverse events leading to study drug discontinuation was also similar in the brexanolone and placebo groups and was low overall [36] [45] .

The phase II study in patients with essential tremor, showed brexanolone was well tolerated, with no serious adverse event reported during the treatment or follow-up period. A greater number of adverse events were reported in the placebo arm (8/11) than in the treatment arm of the trial (4/10). The most commonly reported adverse events in the trial were dizziness (2 brexanolone-treated subjects; 3 placebo-treated subjects) and somnolence (2 brexanolone-treated subjects; no placebo-treated subjects) and an equal number of patients reported the cluster of dizziness, sedation or somnolence (3 in brexanolone group and 3 in the placebo group). At higher doses of the drug, eight out of seventeen patients reported at least one adverse event. One patient discontinued the treatment, due to hypotension. The double-blind, placebo-controlled, phase II study enrolled 25 patients with essential tremor, of which 17 received escalating doses [72] [24] [60] .

Top-line results from a phase II placebo-controlled, double-blind, 1:1 randomised trial in 32 patients with postpartum depression demonstrated that brexanolone was well tolerated with no serious adverse events, no deaths and no discontinuations during the treatment and follow-up periods. A greater number of adverse events were reported in the placebo arm than in the treatment arm of the trial [23] [29] [27] .

Brexanolone injection was safe and well tolerated without any immediate or sustained haemodynamic changes in a phase I/II trial in adult patients with SRSE. The mean changes in haemodynamic parameters from baseline in patients receiving the standard (n=19) or high dose brexanolone (n=6) were limited. Of the 25 patients enrolled, three and five patients reported at least one adverse event on blinded brexanolone, and on placebo, respectively. Of the 17 patients in the open-label, higher dose brexanolone portion, eight patients reported at least one adverse event. The only adverse events reported more than once across all brexanolone treatment periods were fatigue and dizziness, predominantly at the higher dose of brexanolone. There was one discontinuation in the higher dose brexanolone portion due to hypotension, with recovery following drug discontinuation. There were no reports of serious adverse events. Overall, 64% of patients experienced at least one serious adverse event and six deaths were seen, though none were drug-related, as determined by the Safety Review Committee [74] [71] [49] [50] [42] [43] [44] [51] [53] .

No drug-related serious adverse events were reported in two paediatric patients, with SRSE, treated with brexanolone under emergency-use INDs [55] .

Top-line data from the two 202B and 202C trials in the Hummingbird programme for post-partum depression (PPD)demonstrated that brexanolone was generally well tolerated in both studies with similar rates of adverse events across all treatment groups. In each trial, there was one patient who experienced a serious adverse event; neither required hospitalisation and one of which was deemed by the investigator not to be study-drug related. The most common adverse events in the studies were headache, dizziness, and somnolence. The two trials enrolled 122 and 104 patients with PPD [17] [19] [15] .

Integrated Analysis

In an integrated analysis of one phase II and two phase III trials from women with moderate and severe postpartum depression (PPD) receiving brexanolone injection at 90 µg/kg/h, the most common (10% of patients) adverse events reported were headache, dizziness, and somnolence [69] .

In an analysis of the integrated comparative efficacy of brexanolone injection at the dosage of 90 µg/kg/hr versus placebo groups across two phase III studies in patients with postpartum depression, two (1%) brexanolone patients had at least one serious adverse event compared with no placebo patients and three (2%) brexanolone patients had at least one severe adverse event compared with two (2%) placebo patients. There were no death reported. A similar percentage of patients with at least one adverse event between treatments (50% on brexanolone injection versus 51% on placebo) were observed [20] .

Pharmacodynamics

Summary

Continuous EEG was evaluated as an exploratory endpoint in 14 patients with status epilepticus in a phase I/II trial; brexanolone was associated with a significant increase in EEG suppression with peak suppression occurring approximately one hour into the loading phase (mean = 19.6, p < 0.001; paired t-test comparison of baseline to mean suppression ratio during the one hour after the start of infusion) and terminal suppression being significantly greater than that observed during the pre-SAGE 547 baseline period (mean = 9.8 percent, p < 0.005; paired t-test). This effect was seen regardless of underlying third-line agents [49] .

Therapeutic Trials

Top-line results from a phase II placebo-controlled, double-blind, 1:1 randomised trial in 21 patients with postpartum depression demonstrated that brexanolone achieved the primary endpoint of a significant reduction in the HAM-D score compared to placebo at 60 hours (p = 0.008). brexanolone achieved a 20.97 point mean reduction in the depression scores of the brexanolone group at the primary endpoint of 60 hours through trial completion with a 12.2 point difference from placebo [95 %CI: -3.67, -20.77]. Statistically significant improvements from baseline were observed in depression within 24 hours of treatment initiation with brexanolone (-19.37 vs -8.12; p = 0.006), and the effect was maintained at similar magnitude through to the 30-day follow-up (-20.77 vs -8.84; p = 0.01). Remission, as determined by a HAM-D = 7, measured at 60 hours, was observed in 7/10 and 1/11 patients, with a sustained remission observed at 30 days, in 7/10 and 2/11 patients in the brexanolone and placebo groups, respectively. In addition, consistent improvements based on the Clinical Global Impression-Improvement scale were observed in all four patients. Additional results from the secondary endpoints of the phase II trial demonstrated a significant difference in improvement from baseline in secondary endpoints for brexanolone compared with plaecbo over three weeks following end of treatment. The secondary endpoints, the Edinburgh Perinatal Depression Scale (EPDS) (p = 0.024) and the Patient Health Questionnaire (PHQ-9) showed improvement through 30 days (p = 0.024). Improvements were also observed in the the Montgomery-Åsberg Depression Rating Scale (MADRS) and Remission from depression, as determined by a HAM-D of less than 7. Statistically significant improvements from baseline were observed in depression within 24 hours of treatment with brexanolone, in four patients with post natal depression in a phase II study. All four patients achieved remission, with mean Hamilton Rating Scale for Depression score of 26.5 and 1.8 at baseline and at end of treatment, respectively. [72] [24] [29] [27] .

Top-line data from the two 202B and 202C trials in the Hummingbird programme for post-partum depression demonstrated that the primary endpoint was met in the two trials, with a significant mean reduction from baseline in the HAM-D total score at 60 hours compared to placebo. In the 202B trial in 122 patients, brexanolone 90 µg/kg/hour treatment was associated with a statistically significant mean reduction in HAM-D total score of 17.7 points from baseline compared with a 14.0 point mean reduction in HAM-D total score associated with placebo (p = 0.0242). Brexanolone 60 µg/kg/hour treatment (19.9 points from baseline) was associated with a statistically significant mean reduction in HAM-D total score compared with placebo (14.0 point mean reduction) (p = 0.0011). Statistically significant differences in the reduction in HAM-D total score of brexanolone versus placebo were first observed at 48 hours and the effect at 60 hours was maintained through the 30-day follow-up with statistical significance for both brexanolone dose groups. Improvement in the Clinical Global Impression – Improvement scale (CGI-I) at 60 hours was consistent with the primary endpoint (p = 0.0096 for 90 µg/kg/h dose and p = 0.0124 for 60 µg/kg/h dose). In the 202C trial in 104 patients, brexanolone treatment was associated with a statistically significant mean reduction in HAM-D total score of 14.2 points from baseline at 60 hours (p = 0.0160) compared with a 12.0 point mean reduction in HAM-D total score associated with placebo. Statistical significance was first observed at 48 hours and remained through day 7, but not at day 30. However, the effect observed at 60 hours in the brexanolone group was maintained through the 30-day follow-up. Improvement in the Clinical Global Impression – Improvement scale (CGI-I) at 60 hours was consistent with the primary endpoint (p = 0.0005) [17] [19] [15] .

Integrated Analysis:

In an integrated analysis of one phase II and two phase III trials from women with moderate and severe postpartum depression (PPD), brexanolone injection at 90 µg/kg/h showed statistically significant reduction in depression severity with brexanolone injection cpmpared with placebo as early as 24 hours post dosing. The average reduction in patients' Hamilton Rating Scale for Depression (HAM-D or depression severity score) post 60 hr infusion was 17 points compared with 12.8 in the placebo group (p < 0.0001). The reduction of symptoms of postpartum depression was sustained throughout the last study visit at day 30 in the patients receiving brexanolone injection [69] .

In an analysis of the integrated comparative efficacy of brexanolone injection at the dosage of 90 µg/kg/hr versus placebo groups across two phase III studies in patients with postpartum depression, the mean pre-dose Hamilton Rating Scale for Depression (HAM-D) total scores for the integrated brexanolone arms and placebo arms were 25.5 and 25.7, respectively. At the 60-hour primary time point, significant mean reductions from baseline in HAM-D total scores with brexanolone compared with placebo (- 17.0 versus -12.8; p < 0.0001) were observed. The treatment differences at hour 60 were maintained at day 30 (brexanolone: -16.9; placebo: -14.3; p =0 .0213). Brexanolone injection showed similar results in subjects with and without a concomitant antidepressant use, with both subgroups demonstrating significant differences in change from baseline HAM-D total score versus placebo at hour 60 (no antidepressant: brexanolone: -16.9; placebo: -12.6; p < 0.0001; concomitant antidepressant: brexanolone: -17.4; placebo: -13.0; p = 0.0282). Additionally, the treatment with brexanolone injection showed higher rates of remission (defined as HAM-D total score ≤7; brexanolone: 50.0%; placebo: 26.4%; p < 0.0001) and response (defined as ≥50% reduction in HAM-D total score; brexanolone: 74.5%; placebo: 5.7%; p = 0.0003) than placebo at hour 60 [20] [15] [19] .

Treatment with brexanolone indicated that 77% of the 22 evaluable patients successfully weaned off their anaesthetic agent, in a phase I/II trial in patients with status epilepticus. Successful weaning off brexanolone without recurrence of SRSE in the 24-hour period following treatment was seen in 73% of the total evaluable patients. The weaning off the anaesthetic agents while brexanolone was being administered at the maintenance dose) was not related to age, gender, ethnicity, co-morbid medical condition, underlying medical condition, or previous antiepileptic or third line agent treatment. A response rate of 78% was observed in the emergency-use conditions. Patients, who responded to brexanolone, showed rapid improvement in the first five days after initiation of treatment and continued to improve during the 30-day follow-up period [71] [49] [50] [42] [43] [44] [51] [53] .

Seven out of nine patients treated with brexanolone in an emergency use setting achieved resolution of SRSE either during the course of or soon after treatment with brexanolone. The overall response rate was 78%, similar to the observed response rate in a phase I/II trial [41] [43] . Data from four patients treated with brexanolone showed that all four patients achieved resolution of SRSE during or soon after brexanolone therapy. These patients were aged from 2 - 28 years, and all had been placed in a medically-induced coma. One of the patients was an 11-year-old girl with SE due to an autoimmune disorder with anti-glutamic acid and antithyroid antibodies. This patient received infusions of brexanolone over five days, following which the administration of pentobarbital was gradually decreased and ultimately discontinued. The girl experienced intermittent controllable seizures, over the remainder of the hospitalisation. At the time of reporting this data, the girl was discharged and continued to show cognitive improvement. Another patient, a two-year-old girl had SE associated with febrile illness and was infused with brexanolone over a period of four days. The therapy was tapered off between 96 to 120 hours and SE resolved after the treatment. All anti-seizure therapies were discontinued in this patient 12 days following treatment completion. This patient was in inpatient rehabilitation and was able to speak and walk, at the time of reporting these data [51] . Data from 10 emergency-use cases showed that seven of nine evaluable patients receiving brexanolone had resolution of SRSE either during treatment or shortly after treatment, resulting in overall response rate of 78% [42] .

Top-line results from the phase III STATUS trial indicated that the trial did not meet its primary endpoint, which compared success in weaning of third-line agents and resolution of potentially life-threatening status epilepticus with brexanolone versus placebo (43.9% versus 42.4%; p=0.8775) when added to standard-of-care. Treatment response was achieved by approximately 37% of patients treated with open-label brexanolone after the end of the double-blind period. Between both treatment groups, demographics and baseline characteristics were well-balanced [36] [45] .

Essential tremor

In the phase II study, a 30% reduction in the tremor amplitude, from the baseline was observed in 33% of patients treated with brexanolone, and 16% of patients treated with placebo. Significant reduction in the accelerometer-measured upper limb kinetic tremor was also observed (p = 0.046). The data showed improvement in the the overall clinician ratings of large tremor motions, as well as small movements (p = 0.056). The Anti-tremor activity of the drug was observed at non-sedating doses, and the peak-tremor activity correlated with steady state brexanolone levels. In the extension study, 44% of the 17 patients, receiving a higher dose of brexanolone, demonstrated at least a 30% reduction in the tremor amplitude from the baseline. The double-blind, placebo-controlled, phase II study enrolled 25 patients with essential tremor, of which 17 received escalating doses [60] .

Future Events

Expected Date Event Type Description Updated
30 Jun 2019 Regulatory Status Sage Therapeutics intends to launch Brexanolone for Postnatal depression in USA in June 2019, following expected scheduling by the Drug Enforcement Administration [68] 21 Feb 2019
31 Dec 2018 Regulatory Status SAGE Therapeutics anticipates scientific advice from EMA for development in Postnatal depression in the fourth quarter of 2018 [8] 25 Mar 2019
31 Dec 2018 Regulatory Status Sage intends to file a New Drug Application with the US FDA in 2018 [17] 09 May 2018
02 Nov 2018 Regulatory Status The US FDA plans to hold an advisory committee meeting to discuss the applications of brexanolone in Postnatal depression [8] 13 Aug 2018
19 Mar 2018 Regulatory Status FDA reassigns PDUFA action date of (19/3/2019) for brexanolone for postpartum depression. [5] 25 Mar 2019

Development History

Event Date Update Type Comment
19 Mar 2019 Phase Change - Registered Registered for Postnatal depression in USA (IV)- First global approval [4] Updated 25 Mar 2019
19 Feb 2019 Patent Information Sage Therapeutics has patent protection for Brexanolone in several countries worldwide [10] Updated 25 Mar 2019
19 Feb 2019 Regulatory Status Sage Therapeutics intends to launch Brexanolone for Postnatal depression in USA in June 2019, following expected scheduling by the Drug Enforcement Administration [68] Updated 21 Feb 2019
20 Nov 2018 Regulatory Status FDA reassigns PDUFA action date of (19/3/2019) for brexanolone for postpartum depression. [5] Updated 25 Mar 2019
09 Nov 2018 Regulatory Status The USFDA Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee votes in support of benefit-risk profile of brexanolone injection for treatment of Postnatal depression [6] Updated 09 Nov 2018
01 Oct 2018 Regulatory Status Sage Therapeutics receives scientific advice from the EMA regarding the potential regulatory pathway for a marketing authorization application filing in the EU [10] Updated 26 Mar 2019
31 Aug 2018 Scientific Update Efficacy and adverse events data from an integrated analysis from a phase II and two phase III trial in Postnatal depression released by Sage Therapeutics [69] Updated 04 Sep 2018
31 Aug 2018 Scientific Update Efficacy and adverse events data from an integrated analysis of two phase III trials in Postnatal depression released by Sage Therapeutics [20] Updated 04 Sep 2018
07 Aug 2018 Regulatory Status SAGE Therapeutics anticipates scientific advice from EMA for development in Postnatal depression in the fourth quarter of 2018 [8] Updated 25 Mar 2019
07 Aug 2018 Regulatory Status The US FDA plans to hold an advisory committee meeting to discuss the applications of brexanolone in Postnatal depression [8] Updated 13 Aug 2018
07 Aug 2018 Regulatory Status The US FDA conditionally accepts the proprietary name ZULRESSO™ for brexanolone [8] Updated 13 Aug 2018
30 May 2018 Regulatory Status Brexanolone receives priority review status for Postpartum depression in the US [70] Updated 01 Jun 2018
30 May 2018 Regulatory Status The US FDA accepts NDA for brexanolone for Postpartum depression for review [70] Updated 01 Jun 2018
17 May 2018 Phase Change - III Phase-III clinical trials in Postnatal depression (In adolescents) in USA (IV) (NCT03665038) Updated 28 Sep 2018
23 Apr 2018 Phase Change - Preregistration Preregistration for Postnatal depression in USA (IV) [9] Updated 25 Apr 2018
22 Feb 2018 Phase Change - Discontinued(III) Discontinued - Phase-III for super refractory Status epilepticus (In adolescents, In children, In adults) in Austria, Hungary, Denmark, Sweden, Belgium, Germany, Serbia, Israel, Netherlands, Italy, Spain, Finland, Estonia, France, Canada, USA (IV) [2] Updated 25 Mar 2019
09 Nov 2017 Regulatory Status Sage intends to file a New Drug Application with the US FDA in 2018 [17] Updated 09 May 2018
09 Nov 2017 Scientific Update Top-line efficacy and adverse events data from phase III Hummingbird programme released by Sage Therapeutics [17] Updated 17 Nov 2017
02 Nov 2017 Trial Update Sage Therapeutics completes enrolment in its phase III trial for Postnatal depression in USA and New Zealand (NCT02942004) Updated 09 Nov 2017
02 Nov 2017 Trial Update Sage Therapeutics completes enrolment in its phase III trial for Postnatal depression in USA and New Zealand (NCT02942017) Updated 09 Nov 2017
19 Oct 2017 Trial Update Sage Therapeutics completes phase III trial for Postnatal depression in USA and New Zealand (NCT02942004) Updated 23 Nov 2017
11 Oct 2017 Trial Update Sage Therapeutics completes phase III trial for Postnatal depression in USA and New Zealand (IV) (NCT02942017) Updated 23 Nov 2017
12 Sep 2017 Scientific Update Top-line efficacy and adverse events data from a phase III trial in Status epilepticus released by Sage Therapeutics [36] Updated 14 Sep 2017
11 Aug 2017 Trial Update SAGE completes the phase III STATUS trial for Status epilepticus (In children, In adolescents, In adults) in USA, Estonia, Italy, Spain Netherlands, Finland, France, Canada, Israel, Serbia, Germany, Belgium, Sweden, Denmark, Hungary and Austria (IV) (NCT02477618) Updated 27 Sep 2017
03 Aug 2017 Regulatory Status Sage Therapeutics announces intention to submit MAA to EMA for Postnatal depression in the EU [11] Updated 07 Aug 2017
11 May 2017 Phase Change - Discontinued(Preclinical) Discontinued - Preclinical for Major depressive disorder in USA (IV) Updated 25 Mar 2019
22 Apr 2017 Scientific Update Pharmacokinetics data from a phase I/II trial in super-refractory Status epilepticus presented at the 69th Annual Meeting of the American Academy of Neurology (AAN-2017) Updated 13 Jun 2017
07 Mar 2017 Other Chemical structure information added Updated 07 Mar 2017
06 Dec 2016 Regulatory Status Sage Therapeutics announces intention to submit NDA to the US FDA in 2018 [14] Updated 29 Dec 2016
16 Nov 2016 Regulatory Status SAGE 547 receives Priority Medicine (PRIME) status for Postnatal depression in European Union [12] Updated 22 Feb 2017
25 Oct 2016 Phase Change - Discontinued(II) Discontinued - Phase-II for Essential tremor in USA (IV) (SAGE Therapeutics pipeline, October 2016) Updated 25 Mar 2019
28 Sep 2016 Scientific Update Efficacy and adverse events data from a phase II trial in Post natal depression released by Sage Therapeutics [24] Updated 05 Oct 2016
06 Sep 2016 Regulatory Status SAGE 547 receives Breakthrough Therapy status for Postnatal depression (Adjunctive treatment) in USA [13] Updated 07 Sep 2016
09 Aug 2016 Phase Change - Preclinical Preclinical trials in Major depressive disorder in USA (IV) [16] Updated 26 Aug 2016
09 Aug 2016 Trial Update Sage Therapeutics initiates enrolment in an expansion of the phase II clinical trial in Post natal depression in USA [16] Updated 25 Aug 2016
09 Aug 2016 Trial Update Sage Therapeutics initiates enrolment in clinical trials in Post natal depression [16] Updated 25 Aug 2016
09 Aug 2016 Trial Update Sage Therapeutics plans a phase II trial for Major depressive disorder [16] Updated 25 Aug 2016
12 Jul 2016 Scientific Update Top-line efficacy and adverse events data from a phase II trial in Post natal depression released by Sage Thetapeutics [23] Updated 25 Jul 2016
12 Jul 2016 Trial Update Sage Therapeutics plans an expansion of the phase II programme in Post natal depression [23] Updated 25 Jul 2016
01 Jul 2016 Phase Change - III Phase-III clinical trials in Postnatal depression in USA an New Zealand (IV) (NCT02942004) [18] Updated 07 Nov 2017
01 Jul 2016 Trial Update Sage Therapeutics initiates phase III trial for Postnatal depression in USA and New Zealand (IV) (NCT02942017) [18] Updated 07 Nov 2017
01 Jul 2016 Trial Update SAGE Therapeutics completes a phase II trial for Postnatal depression in USA (NCT02614547) Updated 03 Nov 2016
26 May 2016 Trial Update Sage therapeutics completes enrolment in its phase II trial for Postnatal depression in USA [25] Updated 27 May 2016
17 Apr 2016 Scientific Update Interim efficacy and adverse events data from a phase II trial in s epilepticus (Adjunctive treatment, In adolescents, In adults, In children) released by Sage Therapeutics [71] Updated 22 Apr 2016
05 Nov 2015 Trial Update SAGE Therapeutics initiates enrolment in a phase II clinical trial for Postnatal depression in USA (9186937; NCT02614547) Updated 16 Nov 2015
03 Sep 2015 Scientific Update Efficacy and safety data from a phase II trial in Essential tremor released by Sage Therapeutics [60] Updated 08 Sep 2015
06 Aug 2015 Regulatory Status SAGE receives Special Protocol Assessment for the phase III STATUS trial for SAGE 547 in Status epilepticus (Adjunctive treatment) from the FDA [38] Updated 09 Aug 2015
01 Aug 2015 Trial Update Sage Therapeutics completes a phase II trial in Essential tremor in USA (IV) (NCT02277106) Updated 10 Feb 2016
09 Jun 2015 Scientific Update Top-line efficacy and adverse events data from a phase IIa study in Postnatal depression released by SAGE Therapeutics [29] Updated 06 Jul 2015
01 Jun 2015 Patent Information Sage Therapeutics enters into license agreement with University of California, Davis for patents related to the use of allopregnanolone to treat various diseases [2] Updated 25 Mar 2019
01 Jun 2015 Trial Update Sage Therapeutics completes a phase II trial in Postnatal depression in USA (NCT02285504) Updated 24 Sep 2015
01 Jun 2015 Trial Update Sage Therapeutics completes a phase I/II trial in super-refractory Status epilepticus (Adjunctive treatment, In adolescents, In adults, In children) in USA (IV) (NCT02052739) Updated 28 Aug 2015
01 Jun 2015 Trial Update SAGE initiates enrolment in the phase III STATUS trial for Status epilepticus (In children, In adolescents, In adults) in USA (IV) (NCT02477618) Updated 09 Aug 2015
14 May 2015 Scientific Update Pharmacodynamics data from a phase I/II trial in Status epilepticus released by SAGE Therapeutics [49] Updated 29 Jun 2015
14 May 2015 Scientific Update Updated efficacy and adverse events data from a phase I/II trial in Status epilepticus released by SAGE Therapeutics [50] Updated 25 Jun 2015
20 Apr 2015 Phase Change - III Phase-III clinical trials in Status epilepticus (In adolescents, In children, In adults) in Austria, Hungary, Denmark, Sweden, Belgium, Germany, Serbia, Israel (IV) (NCT02477618) (EudraCT2015-002142-31) after April 2015 Updated 27 Sep 2017
20 Apr 2015 Phase Change - III Phase-III clinical trials in Status epilepticus (In adolescents, In adults, In children) in Finland, Estonia, Spain, Italy, Netherlands (IV) after April 2015 (NCT02477618) Updated 25 Aug 2016
20 Apr 2015 Phase Change - III Phase-III clinical trials in Status epilepticus (In adults, In children, In adolescents) in Canada, France (IV) after April 2015 (NCT02477618) Updated 28 May 2016
20 Apr 2015 Phase Change - III Phase-III clinical trials in Status epilepticus (In children, In adolescents, In adults) in USA (IV) (Study 302) (NCT02433314) Updated 28 Apr 2015
20 Apr 2015 Trial Update Sage Therapeutics completes enrolment in its phase I/II trial for super-refractory Status epilepticus (Adjunctive treatment, In adolescents, In adults, In children) in USA (IV) (NCT02052739) Updated 28 Apr 2015
20 Apr 2015 Trial Update Sage Therapeutics plans the phase III STATUS trial for super-refractory Status epilepticus in USA and Europe [34] Updated 28 Apr 2015
09 Apr 2015 Trial Update Sage Therapeutics plans a phase III trial for Status epilepticus in USA [40] Updated 09 Apr 2015
09 Jan 2015 Scientific Update Safety and efficacy data from the phase I/II trial in Status Epilepticus and emergency use programme released by SAGE Therapeutics [42] Updated 14 Jan 2015
10 Nov 2014 Scientific Update Top-line efficacy and adverse events data from a phase I/II trial in Status epilepticus released by Sage Therapeutics [44] , [43] Updated 13 Dec 2014
01 Sep 2014 Phase Change - II Phase-II clinical trials in Postnatal depression in USA (IV) (NCT02285504) Updated 15 Jan 2015
01 Sep 2014 Phase Change - II Phase-II clinical trials in Essential tremor in USA (IV) (NCT02277106) Updated 28 Oct 2014
22 Jul 2014 Regulatory Status SAGE 547 receives fast track designation for Status epilepticus in USA [47] Updated 25 Jul 2014
05 Jun 2014 Scientific Update Interim efficacy and adverse events data from a phase I/II trial in Status epilepticus released by Sage Therapeutics [51] Updated 16 Jun 2014
01 May 2014 Regulatory Status SAGE 547 receives Orphan Drug status for Status epilepticus in USA [48] Updated 05 May 2014
30 Jan 2014 Phase Change - I/II Phase-I/II clinical trials in super-refractory Status epilepticus (In adults, In adolescent, In children, Adjunctive treatment) in USA (IV) (NCT02052739) Updated 17 Feb 2014
23 Oct 2013 Licensing Status Sage Therapeutics in-licenses Allopregnanolone from University of California, Davis for the treatment of Postnatal depression and Status epilepticus [1] Updated 25 Mar 2019
04 Apr 2013 Phase Change - Preclinical Preclinical trials in Status epilepticus in USA (IV) Updated 17 Feb 2014

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