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Adi Eldarlissai - One of the best experts on this subject based on the ideXlab platform.
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Brexanolone in postpartum depression post hoc analyses to help inform clinical decision making
Journal of Womens Health, 2021Co-Authors: Margaret E Gerbasi, Stephen Kanes, Paul Hodgkins, Samantha Meltzerbrody, Sarah Acaster, Moshe Fridman, Vijayveer Bonthapally, Adi EldarlissaiAbstract:Background: Brexanolone (BRX) injection was approved by the United States Food and Drug Administration in 2019 for the treatment of adults with postpartum depression (PPD) based on two Phase 3 clin...
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cost effectiveness of Brexanolone versus selective serotonin reuptake inhibitors for the treatment of postpartum depression in the united states
Journal of managed care & specialty pharmacy, 2020Co-Authors: Adi Eldarlissai, Paul Hodgkins, Joshua T Cohen, Samantha Meltzerbrody, Margaret E Gerbasi, Elizabeth Chertavian, Julia C Bond, Scott J JohnsonAbstract:BACKGROUND: Brexanolone injection (BRX) was approved by the FDA in 2019 for the treatment of adult patients with postpartum depression (PPD), but its cost-effectiveness has not yet been evaluated. ...
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using matching adjusted indirect comparisons and network meta analyses to compare efficacy of Brexanolone injection with selective serotonin reuptake inhibitors for treating postpartum depression
CNS Drugs, 2019Co-Authors: Miranda C Cooper, Hannah S Kilvert, Paul Hodgkins, Neil Roskell, Adi EldarlissaiAbstract:Brexanolone injection, the first therapy approved by the US FDA for the treatment of postpartum depression (PPD) in adults, has been shown to produce a significantly greater decrease in the Hamilton Rating Scale for Depression (HAM-D) total score than placebo in randomised controlled trials (RCTs) of women with PPD. Given the rapid effect of Brexanolone injection (within 60 h) sustained throughout the length of the trials (30 days), we sought to compare its efficacy data against selective serotonin reuptake inhibitors (SSRIs), the class of antidepressants most commonly prescribed for PPD, using HAM-D and Edinburgh Postnatal Depression Scale (EPDS) outcomes from currently available RCTs. We extracted data from 26 studies identified in a systematic literature review of pharmacological and pharmacological/nonpharmacological combination therapies in PPD. Six studies were suitable to form evidence networks through which to perform indirect treatment comparisons (ITCs) of HAM-D and EPDS outcomes between Brexanolone and SSRIs. Having assessed the comparability and suitability of the available evidence for analysis, we discovered significant heterogeneity in the study designs, most notably in the placebo arms of the trials. We therefore conducted matching-adjusted indirect comparisons (MAICs) between Brexanolone and the placebo arms of comparator studies, subsequently using the MAIC results of Brexanolone versus placebo, and results for SSRIs versus placebo, to form ITCs of Brexanolone versus SSRIs at three separate time points—day 3, week 4 and last observation. ITCs were calculated as the differences in change from baseline (CFB) in HAM-D and, separately, CFB in EPDS, between treatments, and reported with 95% confidence intervals (CIs). For all time points, MAICs showed larger differences in CFB for Brexanolone compared with SSRIs. Differences (95% CIs) between Brexanolone and SSRIs were 12.79 (8.04–17.53) [day 3], 5.87 (− 1.62 to 13.37) [week 4] and 0.97 (− 6.35 to 8.30) [last observation] for the HAM-D. For the EPDS, the differences in CFB were 7.98 (5.32–10.64) [day 3], 6.35 (3.13–9.57) [week 4] and 4.05 (0.79–7.31) [last observation]. Other analytical approaches are also presented to demonstrate the similarity of results, using a network meta-analysis approach, and the importance of using the MAIC method to control for the important heterogeneity between placebo arms. Acknowledging the limitations of ITCs and this evidence base, when compared with SSRIs, these analyses suggest that Brexanolone demonstrated larger differences in CFB for both patient- and clinician-reported PPD outcomes and at all investigated time points after adjusting for differences between placebos in the included studies.
Samantha Meltzerbrody - One of the best experts on this subject based on the ideXlab platform.
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Brexanolone in postpartum depression post hoc analyses to help inform clinical decision making
Journal of Womens Health, 2021Co-Authors: Margaret E Gerbasi, Stephen Kanes, Paul Hodgkins, Samantha Meltzerbrody, Sarah Acaster, Moshe Fridman, Vijayveer Bonthapally, Adi EldarlissaiAbstract:Background: Brexanolone (BRX) injection was approved by the United States Food and Drug Administration in 2019 for the treatment of adults with postpartum depression (PPD) based on two Phase 3 clin...
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cost effectiveness of Brexanolone versus selective serotonin reuptake inhibitors for the treatment of postpartum depression in the united states
Journal of managed care & specialty pharmacy, 2020Co-Authors: Adi Eldarlissai, Paul Hodgkins, Joshua T Cohen, Samantha Meltzerbrody, Margaret E Gerbasi, Elizabeth Chertavian, Julia C Bond, Scott J JohnsonAbstract:BACKGROUND: Brexanolone injection (BRX) was approved by the FDA in 2019 for the treatment of adult patients with postpartum depression (PPD), but its cost-effectiveness has not yet been evaluated. ...
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steroides neuroactifs modulateurs allosteriques positifs du recepteur gabaa la Brexanolone brx et sage 217 dans le traitement des troubles depressifs
French Journal of Psychiatry, 2019Co-Authors: F Gressier, Helen Colquhoun, H Gunduzbruce, Samantha Meltzerbrody, Abdul J Sankoh, Robert Lasser, K M Deligiannidis, Brian Werneburg, S KanesAbstract:La Brexanolone (BRX) et SAGE-217 sont des steroides neuroactifs modulateurs allosteriques positifs du recepteur GABAA, evalues dans des essais randomises, en double aveugle versus placebo (RCT) dans la depression du post-partum (PPD) et le trouble depressif majeur (MDD). Trois RCT ont evalue l’efficacite et la tolerance de la BRX : perfusion de 60 h de BRX 90 μg/kg/h (BRX90), BRX 60 μg/kg/h (1 seule etude), ou placebo chez des femmes avec PPD moderee-severe (HAM-D ≥ 20). Deux RCT ont evalue la prise orale de SAGE-217 30 mg 1×/j pendant 14 j versus placebo dans le traitement du MDD modere-severe (HAM-D ≥ 22) et chez des femmes avec PPD severe (HAM-D ≥ 26). L’analyse groupee des etudes sur la BRX90 a montre une reduction des scores moyens a l’HAM-D superieure au placebo a la 60e heure (H60) (p
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Brexanolone injection in post partum depression two multicentre double blind randomised placebo controlled phase 3 trials
The Lancet, 2018Co-Authors: Samantha Meltzerbrody, Helen Colquhoun, Amy Schacterle, Neill C Epperson, Kristina M Deligiannidis, Robert Riesenberg, David R Rubinow, Abdul J Sankoh, Christine Clemson, Jeffrey JonasAbstract:Summary Background Post-partum depression is associated with substantial morbidity, and improved pharmacological treatment options are urgently needed. We assessed Brexanolone injection (formerly SAGE-547 injection), a positive allosteric modulator of γ-aminobutyric-acid type A (GABA A ) receptors, for the treatment of moderate to severe post-partum depression. Methods We did two double-blind, randomised, placebo-controlled, phase 3 trials, at 30 clinical research centres and specialised psychiatric units in the USA. Eligible women were aged 18–45 years, 6 months post partum or less at screening, with post-partum depression and a qualifying 17-item Hamilton Rating Scale for Depression (HAM-D) score (≥26 for study 1; 20–25 for study 2). Women with renal failure requiring dialysis, anaemia, known allergy to allopregnanolone or to progesterone, or medical history of schizophrenia, bipolar disorder, or schizoaffective disorder were excluded. Patients were randomly assigned (1:1:1) to receive a single intravenous injection of either Brexanolone 90 μg/kg per h (BRX90), Brexanolone 60 μg/kg per h (BRX60), or matching placebo for 60 h in study 1, or (1:1) BRX90 or matching placebo for 60 h in study 2. Patients, the study team, site staff, and the principal investigator were masked to treatment allocation. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all patients who started infusion of study drug or placebo, had a valid HAM-D baseline assessment, and had at least one post-baseline HAM-D assessment. The safety population included all randomised patients who started infusion of study drug or placebo. Patients were followed up until day 30. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT02942004 (study 1) and NCT02942017 (study 2). Findings Participants were enrolled between Aug 1, 2016, and Oct 19, 2017, in study 1, and between July 25, 2016, and Oct 11, 2017, in study 2. We screened 375 women simultaneously across both studies, of whom 138 were randomly assigned to receive either BRX90 (n=45), BRX60 (n=47), or placebo (n=46) in study 1, and 108 were randomly assigned to receive BRX90 (n=54) or placebo (n=54) in study 2. In study 1, at 60 h, the least-squares (LS) mean reduction in HAM-D total score from baseline was 19·5 points (SE 1·2) in the BRX60 group and 17·7 points (1·2) in the BRX90 group compared with 14·0 points (1·1) in the placebo group (difference −5·5 [95% CI −8·8 to −2·2], p=0·0013 for the BRX60 group; −3·7 [95% CI −6·9 to −0·5], p=0·0252 for the BRX90 group). In study 2, at 60 h, the LS mean reduction in HAM-D total score from baseline was 14·6 points (SE 0·8) in the BRX90 group compared with 12·1 points (SE 0·8) for the placebo group (difference −2·5 [95% CI −4·5 to −0·5], p=0·0160). In study 1, 19 patients in the BRX60 group and 22 patients in the BRX90 group had adverse events compared with 22 patients in the placebo group. In study 2, 25 patients in the BRX90 group had adverse events compared with 24 patients in the placebo group. The most common treatment-emergent adverse events in the Brexanolone groups were headache (n=7 BRX60 group and n=6 BRX90 group vs n=7 placebo group for study 1; n=9 BRX90 group vs n=6 placebo group for study 2), dizziness (n=6 BRX60 group and n=6 BRX90 group vs n=1 placebo group for study 1; n=5 BRX90 group vs n=4 placebo group for study 2), and somnolence (n=7 BRX60 group and n=2 BRX90 group vs n=3 placebo group for study 1; n=4 BRX90 group vs n=2 placebo group for study 2). In study 1, one patient in the BRX60 group had two serious adverse events (suicidal ideation and intentional overdose attempt during follow-up). In study 2, one patient in the BRX90 group had two serious adverse events (altered state of consciousness and syncope), which were considered to be treatment related. Interpretation Administration of Brexanolone injection for post-partum depression resulted in significant and clinically meaningful reductions in HAM-D total score at 60 h compared with placebo, with rapid onset of action and durable treatment response during the study period. Our results suggest that Brexanolone injection is a novel therapeutic drug for post-partum depression that has the potential to improve treatment options for women with this disorder. Funding Sage Therapeutics, Inc.
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open label proof of concept study of Brexanolone in the treatment of severe postpartum depression
Human Psychopharmacology-clinical and Experimental, 2017Co-Authors: Stephen Kanes, Shane Raines, Ethan Hoffmann, Helen Colquhoun, James J Doherty, David R Rubinow, Samantha MeltzerbrodyAbstract:Objective Preclinical evidence indicates that rapid changes in levels of allopregnanolone, the predominant metabolite of progesterone, confer dramatic behavioral changes and may trigger postpartum depression (PPD) in some women. Considering the pathophysiology of PPD (i.e., triggered by reproductive steroids), the need for fast-acting, efficacious treatments and the negative consequences of untreated PPD, there is an increasing focus on developing PPD therapies. Brexanolone (USAN; formerly SAGE-547 Injection), a proprietary injectable allopregnanolone formulation, was evaluated as a treatment for severe PPD in a proof-of-concept, open-label study. Methods Four women with severe PPD, defined as a baseline 17-item Hamilton Rating Scale for Depression (HAMD) score of ≥20, received Brexanolone, titrated to a dose reflecting third-trimester allopregnanolone levels. After a 36-hour maintenance infusion, tapering occurred over 12 hours. Primary outcomes were measures of safety. Secondary outcomes were assessments of efficacy, including HAMD. Results All enrolled patients completed the study. Fourteen adverse events were reported, of which none was severe. Starting at the first measure after infusion initiation and continuing through Hour 84, mean HAMD total scores were reduced to levels consistent with remission of symptoms. All other efficacy assessments showed similar improvements. Conclusions Brexanolone was well tolerated and demonstrated activity in severe PPD. Larger, double-blind trials are needed for further evaluation.
Stephen Kanes - One of the best experts on this subject based on the ideXlab platform.
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Brexanolone in postpartum depression post hoc analyses to help inform clinical decision making
Journal of Womens Health, 2021Co-Authors: Margaret E Gerbasi, Stephen Kanes, Paul Hodgkins, Samantha Meltzerbrody, Sarah Acaster, Moshe Fridman, Vijayveer Bonthapally, Adi EldarlissaiAbstract:Background: Brexanolone (BRX) injection was approved by the United States Food and Drug Administration in 2019 for the treatment of adults with postpartum depression (PPD) based on two Phase 3 clin...
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Brexanolone as adjunctive therapy in super refractory status epilepticus
Annals of Neurology, 2017Co-Authors: Eric Rosenthal, Jan Claassen, Mark S Wainwright, Aatif M Husain, Henrikas Vaitkevicius, Shane Raines, Ethan Hoffmann, Helen Colquhoun, James J Doherty, Stephen KanesAbstract:Objective Super-refractory status epilepticus (SRSE) is a life-threatening form of status epilepticus that continues or recurs despite 24 hours or more of anesthetic treatment. We conducted a multicenter, phase 1/2 study in SRSE patients to evaluate the safety and tolerability of Brexanolone (USAN; formerly SAGE-547 Injection), a proprietary, aqueous formulation of the neuroactive steroid, allopregnanolone. Secondary objectives included pharmacokinetic assessment and open-label evaluation of Brexanolone response during and after anesthetic third-line agent (TLA) weaning. Methods Patients receiving TLAs for SRSE control were eligible for open-label, 1-hour Brexanolone loading infusions, followed by maintenance infusion. After 48 hours of Brexanolone infusion, TLAs were weaned during Brexanolone maintenance. After 4 days, the Brexanolone dose was tapered. Safety and functional status were assessed over 3 weeks of follow-up. Results Twenty-five patients received open-label study drug. No serious adverse events (SAEs) were attributable to study drug, as determined by the Safety Review Committee. Sixteen patients (64%) experienced ≥1 SAE. Six patient deaths occurred, all deemed related to underlying medical conditions. Twenty-two patients underwent ≥1 TLA wean attempt. Seventeen (77%) met the response endpoint of weaning successfully off TLAs before tapering Brexanolone. Sixteen (73%) were successfully weaned off TLAs within 5 days of initiating Brexanolone infusion without anesthetic agent reinstatement in the following 24 hours. Interpretation In an open-label cohort of limited size, Brexanolone demonstrated tolerability among SRSE patients of heterogeneous etiologies and was associated with a high rate of successful TLA weaning. The results suggest the possible development of Brexanolone as an adjunctive therapy for SRSE requiring pharmacological coma for seizure control. Ann Neurol 2017;82:342–352
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Brexanolone sage 547 injection in post partum depression a randomised controlled trial
The Lancet, 2017Co-Authors: Stephen Kanes, Shane Raines, Helen Colquhoun, James J Doherty, H Gunduzbruce, Ryan Arnold, Amy Schacterle, Neill C Epperson, Kristina M Deligiannidis, Robert RiesenbergAbstract:Summary Background Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated Brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid (GABA A ) receptors, for the treatment of post-partum depression. Methods For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (≤6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression [HAM-D] total score ≥26) in four hospitals in the USA. Eligible women were randomly assigned (1:1), via a computer-generated randomisation program, to receive either a single, continuous intravenous dose of Brexanolone or placebo for 60 h. Patients and investigators were masked to treatment assignments. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all randomised patients who started infusion of study drug or placebo and who had a completed baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Patients were followed up until day 30. This trial is registered with ClinicalTrials.gov, number NCT02614547. Findings This trial was done between Dec 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). 21 women were randomly assigned to the Brexanolone (n=10) and placebo (n=11) groups. At 60 h, mean reduction in HAM-D total score from baseline was 21·0 points (SE 2·9) in the Brexanolone group compared with 8·8 points (SE 2·8) in the placebo group (difference −12·2, 95% CI −20·77 to −3·67; p=0·0075; effect size 1·2). No deaths, serious adverse events, or discontinuations because of adverse events were reported in either group. Four of ten patients in the Brexanolone group had adverse events compared with eight of 11 in the placebo group. The most frequently reported adverse events in the Brexanolone group were dizziness (two patients in the Brexanolone group vs three patients in the placebo group) and somnolence (two vs none). Moderate treatment-emergent adverse events were reported in two patients in the Brexanolone group (sinus tachycardia, n=1; somnolence, n=1) and in two patients in the placebo group (infusion site pain, n=1; tension headache, n=1); one patient in the placebo group had a severe treatment-emergent adverse event (insomnia). Interpretation In women with severe post-partum depression, infusion of Brexanolone resulted in a significant and clinically meaningful reduction in HAM-D total score, compared with placebo. Our results support the rationale for targeting synaptic and extrasynaptic GABA A receptors in the development of therapies for patients with post-partum depression. A pivotal clinical programme for the investigation of Brexanolone in patients with post-partum depression is in progress. Funding Sage Therapeutics, Inc.
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open label proof of concept study of Brexanolone in the treatment of severe postpartum depression
Human Psychopharmacology-clinical and Experimental, 2017Co-Authors: Stephen Kanes, Shane Raines, Ethan Hoffmann, Helen Colquhoun, James J Doherty, David R Rubinow, Samantha MeltzerbrodyAbstract:Objective Preclinical evidence indicates that rapid changes in levels of allopregnanolone, the predominant metabolite of progesterone, confer dramatic behavioral changes and may trigger postpartum depression (PPD) in some women. Considering the pathophysiology of PPD (i.e., triggered by reproductive steroids), the need for fast-acting, efficacious treatments and the negative consequences of untreated PPD, there is an increasing focus on developing PPD therapies. Brexanolone (USAN; formerly SAGE-547 Injection), a proprietary injectable allopregnanolone formulation, was evaluated as a treatment for severe PPD in a proof-of-concept, open-label study. Methods Four women with severe PPD, defined as a baseline 17-item Hamilton Rating Scale for Depression (HAMD) score of ≥20, received Brexanolone, titrated to a dose reflecting third-trimester allopregnanolone levels. After a 36-hour maintenance infusion, tapering occurred over 12 hours. Primary outcomes were measures of safety. Secondary outcomes were assessments of efficacy, including HAMD. Results All enrolled patients completed the study. Fourteen adverse events were reported, of which none was severe. Starting at the first measure after infusion initiation and continuing through Hour 84, mean HAMD total scores were reduced to levels consistent with remission of symptoms. All other efficacy assessments showed similar improvements. Conclusions Brexanolone was well tolerated and demonstrated activity in severe PPD. Larger, double-blind trials are needed for further evaluation.
Helen Colquhoun - One of the best experts on this subject based on the ideXlab platform.
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steroides neuroactifs modulateurs allosteriques positifs du recepteur gabaa la Brexanolone brx et sage 217 dans le traitement des troubles depressifs
French Journal of Psychiatry, 2019Co-Authors: F Gressier, Helen Colquhoun, H Gunduzbruce, Samantha Meltzerbrody, Abdul J Sankoh, Robert Lasser, K M Deligiannidis, Brian Werneburg, S KanesAbstract:La Brexanolone (BRX) et SAGE-217 sont des steroides neuroactifs modulateurs allosteriques positifs du recepteur GABAA, evalues dans des essais randomises, en double aveugle versus placebo (RCT) dans la depression du post-partum (PPD) et le trouble depressif majeur (MDD). Trois RCT ont evalue l’efficacite et la tolerance de la BRX : perfusion de 60 h de BRX 90 μg/kg/h (BRX90), BRX 60 μg/kg/h (1 seule etude), ou placebo chez des femmes avec PPD moderee-severe (HAM-D ≥ 20). Deux RCT ont evalue la prise orale de SAGE-217 30 mg 1×/j pendant 14 j versus placebo dans le traitement du MDD modere-severe (HAM-D ≥ 22) et chez des femmes avec PPD severe (HAM-D ≥ 26). L’analyse groupee des etudes sur la BRX90 a montre une reduction des scores moyens a l’HAM-D superieure au placebo a la 60e heure (H60) (p
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Brexanolone injection in post partum depression two multicentre double blind randomised placebo controlled phase 3 trials
The Lancet, 2018Co-Authors: Samantha Meltzerbrody, Helen Colquhoun, Amy Schacterle, Neill C Epperson, Kristina M Deligiannidis, Robert Riesenberg, David R Rubinow, Abdul J Sankoh, Christine Clemson, Jeffrey JonasAbstract:Summary Background Post-partum depression is associated with substantial morbidity, and improved pharmacological treatment options are urgently needed. We assessed Brexanolone injection (formerly SAGE-547 injection), a positive allosteric modulator of γ-aminobutyric-acid type A (GABA A ) receptors, for the treatment of moderate to severe post-partum depression. Methods We did two double-blind, randomised, placebo-controlled, phase 3 trials, at 30 clinical research centres and specialised psychiatric units in the USA. Eligible women were aged 18–45 years, 6 months post partum or less at screening, with post-partum depression and a qualifying 17-item Hamilton Rating Scale for Depression (HAM-D) score (≥26 for study 1; 20–25 for study 2). Women with renal failure requiring dialysis, anaemia, known allergy to allopregnanolone or to progesterone, or medical history of schizophrenia, bipolar disorder, or schizoaffective disorder were excluded. Patients were randomly assigned (1:1:1) to receive a single intravenous injection of either Brexanolone 90 μg/kg per h (BRX90), Brexanolone 60 μg/kg per h (BRX60), or matching placebo for 60 h in study 1, or (1:1) BRX90 or matching placebo for 60 h in study 2. Patients, the study team, site staff, and the principal investigator were masked to treatment allocation. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all patients who started infusion of study drug or placebo, had a valid HAM-D baseline assessment, and had at least one post-baseline HAM-D assessment. The safety population included all randomised patients who started infusion of study drug or placebo. Patients were followed up until day 30. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT02942004 (study 1) and NCT02942017 (study 2). Findings Participants were enrolled between Aug 1, 2016, and Oct 19, 2017, in study 1, and between July 25, 2016, and Oct 11, 2017, in study 2. We screened 375 women simultaneously across both studies, of whom 138 were randomly assigned to receive either BRX90 (n=45), BRX60 (n=47), or placebo (n=46) in study 1, and 108 were randomly assigned to receive BRX90 (n=54) or placebo (n=54) in study 2. In study 1, at 60 h, the least-squares (LS) mean reduction in HAM-D total score from baseline was 19·5 points (SE 1·2) in the BRX60 group and 17·7 points (1·2) in the BRX90 group compared with 14·0 points (1·1) in the placebo group (difference −5·5 [95% CI −8·8 to −2·2], p=0·0013 for the BRX60 group; −3·7 [95% CI −6·9 to −0·5], p=0·0252 for the BRX90 group). In study 2, at 60 h, the LS mean reduction in HAM-D total score from baseline was 14·6 points (SE 0·8) in the BRX90 group compared with 12·1 points (SE 0·8) for the placebo group (difference −2·5 [95% CI −4·5 to −0·5], p=0·0160). In study 1, 19 patients in the BRX60 group and 22 patients in the BRX90 group had adverse events compared with 22 patients in the placebo group. In study 2, 25 patients in the BRX90 group had adverse events compared with 24 patients in the placebo group. The most common treatment-emergent adverse events in the Brexanolone groups were headache (n=7 BRX60 group and n=6 BRX90 group vs n=7 placebo group for study 1; n=9 BRX90 group vs n=6 placebo group for study 2), dizziness (n=6 BRX60 group and n=6 BRX90 group vs n=1 placebo group for study 1; n=5 BRX90 group vs n=4 placebo group for study 2), and somnolence (n=7 BRX60 group and n=2 BRX90 group vs n=3 placebo group for study 1; n=4 BRX90 group vs n=2 placebo group for study 2). In study 1, one patient in the BRX60 group had two serious adverse events (suicidal ideation and intentional overdose attempt during follow-up). In study 2, one patient in the BRX90 group had two serious adverse events (altered state of consciousness and syncope), which were considered to be treatment related. Interpretation Administration of Brexanolone injection for post-partum depression resulted in significant and clinically meaningful reductions in HAM-D total score at 60 h compared with placebo, with rapid onset of action and durable treatment response during the study period. Our results suggest that Brexanolone injection is a novel therapeutic drug for post-partum depression that has the potential to improve treatment options for women with this disorder. Funding Sage Therapeutics, Inc.
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Brexanolone as adjunctive therapy in super refractory status epilepticus
Annals of Neurology, 2017Co-Authors: Eric Rosenthal, Jan Claassen, Mark S Wainwright, Aatif M Husain, Henrikas Vaitkevicius, Shane Raines, Ethan Hoffmann, Helen Colquhoun, James J Doherty, Stephen KanesAbstract:Objective Super-refractory status epilepticus (SRSE) is a life-threatening form of status epilepticus that continues or recurs despite 24 hours or more of anesthetic treatment. We conducted a multicenter, phase 1/2 study in SRSE patients to evaluate the safety and tolerability of Brexanolone (USAN; formerly SAGE-547 Injection), a proprietary, aqueous formulation of the neuroactive steroid, allopregnanolone. Secondary objectives included pharmacokinetic assessment and open-label evaluation of Brexanolone response during and after anesthetic third-line agent (TLA) weaning. Methods Patients receiving TLAs for SRSE control were eligible for open-label, 1-hour Brexanolone loading infusions, followed by maintenance infusion. After 48 hours of Brexanolone infusion, TLAs were weaned during Brexanolone maintenance. After 4 days, the Brexanolone dose was tapered. Safety and functional status were assessed over 3 weeks of follow-up. Results Twenty-five patients received open-label study drug. No serious adverse events (SAEs) were attributable to study drug, as determined by the Safety Review Committee. Sixteen patients (64%) experienced ≥1 SAE. Six patient deaths occurred, all deemed related to underlying medical conditions. Twenty-two patients underwent ≥1 TLA wean attempt. Seventeen (77%) met the response endpoint of weaning successfully off TLAs before tapering Brexanolone. Sixteen (73%) were successfully weaned off TLAs within 5 days of initiating Brexanolone infusion without anesthetic agent reinstatement in the following 24 hours. Interpretation In an open-label cohort of limited size, Brexanolone demonstrated tolerability among SRSE patients of heterogeneous etiologies and was associated with a high rate of successful TLA weaning. The results suggest the possible development of Brexanolone as an adjunctive therapy for SRSE requiring pharmacological coma for seizure control. Ann Neurol 2017;82:342–352
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Brexanolone sage 547 injection in post partum depression a randomised controlled trial
The Lancet, 2017Co-Authors: Stephen Kanes, Shane Raines, Helen Colquhoun, James J Doherty, H Gunduzbruce, Ryan Arnold, Amy Schacterle, Neill C Epperson, Kristina M Deligiannidis, Robert RiesenbergAbstract:Summary Background Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated Brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid (GABA A ) receptors, for the treatment of post-partum depression. Methods For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (≤6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression [HAM-D] total score ≥26) in four hospitals in the USA. Eligible women were randomly assigned (1:1), via a computer-generated randomisation program, to receive either a single, continuous intravenous dose of Brexanolone or placebo for 60 h. Patients and investigators were masked to treatment assignments. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all randomised patients who started infusion of study drug or placebo and who had a completed baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Patients were followed up until day 30. This trial is registered with ClinicalTrials.gov, number NCT02614547. Findings This trial was done between Dec 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). 21 women were randomly assigned to the Brexanolone (n=10) and placebo (n=11) groups. At 60 h, mean reduction in HAM-D total score from baseline was 21·0 points (SE 2·9) in the Brexanolone group compared with 8·8 points (SE 2·8) in the placebo group (difference −12·2, 95% CI −20·77 to −3·67; p=0·0075; effect size 1·2). No deaths, serious adverse events, or discontinuations because of adverse events were reported in either group. Four of ten patients in the Brexanolone group had adverse events compared with eight of 11 in the placebo group. The most frequently reported adverse events in the Brexanolone group were dizziness (two patients in the Brexanolone group vs three patients in the placebo group) and somnolence (two vs none). Moderate treatment-emergent adverse events were reported in two patients in the Brexanolone group (sinus tachycardia, n=1; somnolence, n=1) and in two patients in the placebo group (infusion site pain, n=1; tension headache, n=1); one patient in the placebo group had a severe treatment-emergent adverse event (insomnia). Interpretation In women with severe post-partum depression, infusion of Brexanolone resulted in a significant and clinically meaningful reduction in HAM-D total score, compared with placebo. Our results support the rationale for targeting synaptic and extrasynaptic GABA A receptors in the development of therapies for patients with post-partum depression. A pivotal clinical programme for the investigation of Brexanolone in patients with post-partum depression is in progress. Funding Sage Therapeutics, Inc.
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open label proof of concept study of Brexanolone in the treatment of severe postpartum depression
Human Psychopharmacology-clinical and Experimental, 2017Co-Authors: Stephen Kanes, Shane Raines, Ethan Hoffmann, Helen Colquhoun, James J Doherty, David R Rubinow, Samantha MeltzerbrodyAbstract:Objective Preclinical evidence indicates that rapid changes in levels of allopregnanolone, the predominant metabolite of progesterone, confer dramatic behavioral changes and may trigger postpartum depression (PPD) in some women. Considering the pathophysiology of PPD (i.e., triggered by reproductive steroids), the need for fast-acting, efficacious treatments and the negative consequences of untreated PPD, there is an increasing focus on developing PPD therapies. Brexanolone (USAN; formerly SAGE-547 Injection), a proprietary injectable allopregnanolone formulation, was evaluated as a treatment for severe PPD in a proof-of-concept, open-label study. Methods Four women with severe PPD, defined as a baseline 17-item Hamilton Rating Scale for Depression (HAMD) score of ≥20, received Brexanolone, titrated to a dose reflecting third-trimester allopregnanolone levels. After a 36-hour maintenance infusion, tapering occurred over 12 hours. Primary outcomes were measures of safety. Secondary outcomes were assessments of efficacy, including HAMD. Results All enrolled patients completed the study. Fourteen adverse events were reported, of which none was severe. Starting at the first measure after infusion initiation and continuing through Hour 84, mean HAMD total scores were reduced to levels consistent with remission of symptoms. All other efficacy assessments showed similar improvements. Conclusions Brexanolone was well tolerated and demonstrated activity in severe PPD. Larger, double-blind trials are needed for further evaluation.
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Brexanolone in postpartum depression post hoc analyses to help inform clinical decision making
Journal of Womens Health, 2021Co-Authors: Margaret E Gerbasi, Stephen Kanes, Paul Hodgkins, Samantha Meltzerbrody, Sarah Acaster, Moshe Fridman, Vijayveer Bonthapally, Adi EldarlissaiAbstract:Background: Brexanolone (BRX) injection was approved by the United States Food and Drug Administration in 2019 for the treatment of adults with postpartum depression (PPD) based on two Phase 3 clin...
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cost effectiveness of Brexanolone versus selective serotonin reuptake inhibitors for the treatment of postpartum depression in the united states
Journal of managed care & specialty pharmacy, 2020Co-Authors: Adi Eldarlissai, Paul Hodgkins, Joshua T Cohen, Samantha Meltzerbrody, Margaret E Gerbasi, Elizabeth Chertavian, Julia C Bond, Scott J JohnsonAbstract:BACKGROUND: Brexanolone injection (BRX) was approved by the FDA in 2019 for the treatment of adult patients with postpartum depression (PPD), but its cost-effectiveness has not yet been evaluated. ...
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using matching adjusted indirect comparisons and network meta analyses to compare efficacy of Brexanolone injection with selective serotonin reuptake inhibitors for treating postpartum depression
CNS Drugs, 2019Co-Authors: Miranda C Cooper, Hannah S Kilvert, Paul Hodgkins, Neil Roskell, Adi EldarlissaiAbstract:Brexanolone injection, the first therapy approved by the US FDA for the treatment of postpartum depression (PPD) in adults, has been shown to produce a significantly greater decrease in the Hamilton Rating Scale for Depression (HAM-D) total score than placebo in randomised controlled trials (RCTs) of women with PPD. Given the rapid effect of Brexanolone injection (within 60 h) sustained throughout the length of the trials (30 days), we sought to compare its efficacy data against selective serotonin reuptake inhibitors (SSRIs), the class of antidepressants most commonly prescribed for PPD, using HAM-D and Edinburgh Postnatal Depression Scale (EPDS) outcomes from currently available RCTs. We extracted data from 26 studies identified in a systematic literature review of pharmacological and pharmacological/nonpharmacological combination therapies in PPD. Six studies were suitable to form evidence networks through which to perform indirect treatment comparisons (ITCs) of HAM-D and EPDS outcomes between Brexanolone and SSRIs. Having assessed the comparability and suitability of the available evidence for analysis, we discovered significant heterogeneity in the study designs, most notably in the placebo arms of the trials. We therefore conducted matching-adjusted indirect comparisons (MAICs) between Brexanolone and the placebo arms of comparator studies, subsequently using the MAIC results of Brexanolone versus placebo, and results for SSRIs versus placebo, to form ITCs of Brexanolone versus SSRIs at three separate time points—day 3, week 4 and last observation. ITCs were calculated as the differences in change from baseline (CFB) in HAM-D and, separately, CFB in EPDS, between treatments, and reported with 95% confidence intervals (CIs). For all time points, MAICs showed larger differences in CFB for Brexanolone compared with SSRIs. Differences (95% CIs) between Brexanolone and SSRIs were 12.79 (8.04–17.53) [day 3], 5.87 (− 1.62 to 13.37) [week 4] and 0.97 (− 6.35 to 8.30) [last observation] for the HAM-D. For the EPDS, the differences in CFB were 7.98 (5.32–10.64) [day 3], 6.35 (3.13–9.57) [week 4] and 4.05 (0.79–7.31) [last observation]. Other analytical approaches are also presented to demonstrate the similarity of results, using a network meta-analysis approach, and the importance of using the MAIC method to control for the important heterogeneity between placebo arms. Acknowledging the limitations of ITCs and this evidence base, when compared with SSRIs, these analyses suggest that Brexanolone demonstrated larger differences in CFB for both patient- and clinician-reported PPD outcomes and at all investigated time points after adjusting for differences between placebos in the included studies.