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Brexanolone Injection for Postpartum Depression

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Brexanolone Injection for Postpartum Depression Out of the Pipeline Brexanolone injection for postpartum depression Samantha Meltzer-Brody, MD, Kristina M. Deligiannidis, MD, Helen Colquhoun, MD, and Stephen J. Kanes, MD, PhD ostpartum depression (PPD) is one partners experiencing depression.6 Current First-in-class of the most prevalent complications PPD management strategies include the neuroactive associated with pregnancy and child- use of psychotherapy and pharmacologic P steroid was birth in the United States, affecting more interventions for major depressive disorder than 400,000 women annually.1 Postpartum that may take up to 4 to 6 weeks for some recently FDA- depression is most commonly treated patients, and may not achieve remission approved for with psychotherapy and antidepres- for all patients.7-9 treating adults sants approved for the treatment of major Brexanolone injection is a first-in-class with PPD depressive disorder. Until recently, there medication with a novel mechanism of was no pharmacologic therapy approved action. In clinical studies, it achieved rapid by the FDA specifically for the treatment (by Hour 60) and sustained (through Day of PPD. Considering the adverse outcomes 30) reductions in depressive symptoms and associated with untreated or inadequately could provide a meaningful new treatment treated PPD, and the limitations of existing option for adult women with PPD.10,11 therapies, there is a significant unmet need for pharmacologic treatment options for How it works PPD.2 To help address this need, the FDA Animal and human studies have established recently approved brexanolone injection the relevance of GABAergic signaling in (brand name: ZULRESSO™) (Table 1,3 page the etiology and symptoms of depression, 44) as a first-in-class therapy for the treat- and supported the investigation of gamma- 3 ment of adults with PPD. aminobutyric acid A receptor (GABAAR) positive allosteric modulators (PAMs)—and Clinical implications Postpartum depression can result in Dr. Meltzer-Brody is the Ray M. Hayworth Distinguished Professor, Department of Psychiatry, University of North Carolina School of adverse outcomes for the patient, baby, Medicine, Chapel Hill, North Carolina. Dr. Deligiannidis is Associate and family when under- or untreated, and Professor, Department of Psychiatry, Zucker Hillside Hospital and the need for rapid resolution of symptoms Feinstein Institute for Medical Research, Glen Oaks, New York. Dr. Colquhoun is VP Medical Science, Sage Therapeutics, Inc., 2 cannot be overstated. Suicide is strongly Cambridge, Massachusetts. Dr. Kanes is Chief Medical Officer, Sage associated with depression and is a lead- Therapeutics, Inc., Cambridge, Massachusetts. ing cause of pregnancy-related deaths.4 Disclosures Dr. Meltzer-Brody receives personal fees from Medscape and received Additionally, PPD can impact the health, grants from Sage Therapeutics, Inc., awarded to the University of safety, and well-being of the child, with Carolina during the conduct of the brexanolone injection clinical trials, and grants from Janssen, Patient-Centered Outcomes Research both short- and long-term consequences, Institute, and the National Institutes of Health (NIH) outside the including greater rates of psychological or submitted work. Dr. Deligiannidis serves as a consultant to Sage Therapeutics, Inc., receives National Institute of Mental Health support behavioral difficulties among children of and royalties from an NIH employee invention, and received grants patients with PPD.5 Postpartum depres- from Sage Therapeutics, Inc., awarded to the Zucker Hillside Hospital during the conduct of the brexanolone injection and SAGE-217 sion can also have negative effects on clinical trials. Dr. Colquhoun and Dr. Kanes are employees of Sage Current Psychiatry the patient’s partner, with 24% to 50% of Therapeutics, Inc., with stock/stock options. Vol. 18, No. 9 43 Out of the Pipeline Table 1 GABAARs in mammalian cells expressing Fast facts about brexanolone α1β2γ2 receptor subunits, α4β3δ receptor 3 injection subunits, and α6β3δ receptor subunits. Positive allosteric modulation of both Brand name: ZULRESSO™ synaptic and extrasynaptic GABAARs dif- Class: Neuroactive steroid gamma- ferentiates brexanolone from other GABAAR aminobutyric acid (GABA) A receptor positive 10,11 allosteric modulator modulators, such as benzodiazepines. Brexanolone’s mechanism of action in the Indication: Postpartum depression in adults treatment of PPD is not fully understood, Approval date: March 19, 2019 but it is thought to be related to GABAAR Availability date: June 30, 2019 PAM activity.3 Manufacturer: Sage Therapeutics Inc., Clinical Point Cambridge, Mass. Supporting evidence Dosing forms: 100 mg/20 mL (5 mg/mL) The FDA approval of brexanolone injec- In 2 studies, titration single-dose vial, dilution required prior to tion was based on the efficacy dem- to 90 µg/kg/hour administration Recommended dosage: Administered as a onstrated in 2 Phase III multicenter, of brexanolone was continuous IV infusion over 60 hours (2.5 days) randomized, double-blind, placebo-con- superior to placebo as follows: trolled studies in adult women (age 18 to • 0 to 4 hours: Initiate with a dosage 45) with PPD (defined by DSM-IV crite- in improvement of 30 μg/kg/hour ria for a major depressive episode, with of depressive • 4 to 24 hours: Increase dosage to onset of symptoms in the third trimester 60 μg/kg/hour symptoms or within 4 weeks of delivery). Exclusion • 24 to 52 hours: Increase dosage to 90 μg/kg/hour (alternatively, consider a criteria included the presence of bipo- dosage of 60 μg/kg/hour for those who do lar disorder or psychosis. In these stud- not tolerate 90 μg/kg/hour) ies, 60-hour continuous IV infusions of • 52 to 56 hours: Decrease dosage to brexanolone or placebo were given, fol- 60 μg/kg/hour lowed by 4 weeks of observation. Study 1 • 56 to 60 hours: Decrease dosage to 30 μg/kg/hour (202B) enrolled patients with severe PPD Source: Reference 3 (Hamilton Rating Scale for Depression [HAM-D] total score ≥26), and Study 2 (202C) enrolled patients with moderate PPD (HAM-D score 20 to 25). A titration to the recommended target dosage of particularly neuroactive steroids, such as 90 μg/kg/hour was evaluated in both brexanolone—as potential therapeutics in studies. BRX90 patients received 30 μg/ PPD (Table 2,12-14 page 45). Through preg- kg/hour for 4 hours, 60 μg/kg/hour for nancy, the levels of allopregnanolone, a 20 hours, 90 μg/kg/hour for 28 hours, fol- neuroactive steroid metabolite of proges- lowed by a taper to 60 μg/kg/hour for 4 terone, rise in concert with progesterone, hours and then 30 μg/kg/hour for 4 hours. before a precipitous decrease at childbirth. The primary endpoint in both studies was This fluctuation, as well as other pertur- the mean change from baseline in depres- Discuss this article at bations of GABAergic signaling in the sive symptoms as measured by HAM-D www.facebook.com/ peripartum period, may contribute to the total score at the end of the 60-hour infu- MDedgePsychiatry development of PPD.12-15 sion. A pre-specified secondary efficacy Brexanolone is a neuroactive steroid endpoint was the mean change from base- that is chemically identical to endogenous line in HAM-D total score at Day 30. allopregnanolone produced in the CNS. Efficacy. In both placebo-controlled Brexanolone potentiates GABA-mediated studies, titration to a target dose of brex- Current Psychiatry 44 September 2019 currents from recombinant human anolone 90 μg/kg/hour was superior to Out of the Pipeline placebo in improvement of depressive Table 2 symptoms (Table 3,3 page 46). Key facts: Neuroactive steroids and GABA Pharmacological profile Neuroactive steroids are metabolites of Brexanolone exposure-response relation- cholesterol-derived steroid hormones made in ships and the time course of pharmacody- the CNS and periphery namic response are unknown.3 Neuroactive steroids are positive allosteric modulators of GABA synaptic and Adverse reactions. Safety was evaluated A extrasynaptic receptors, facilitating phasic and from all patients receiving brexanolone injec- tonic inhibition at the postsynaptic membrane tion, regardless of dosing regimen (N = 140, Neuroactive steroids have distinct including patients from a Phase IIb study, pharmacology compared with other GABAergic 202A).3,11 agents (ie, benzodiazepines) The most common adverse reactions GABAergic system dysregulation is thought Clinical Point (incidence ≥5% and at least twice the to contribute to the etiology and symptoms of depression The most common rate of placebo) were sedation/somno- GABA : gamma-aminobutyric acid A lence, dry mouth, loss of consciousness, A adverse reactions Source: References 12-14 and flushing/hot flush.3 The incidence of were sedation/ patients discontinuing due to any adverse somnolence, dry reaction was 2% for brexanolone vs 1% mouth, loss of for placebo.3 Pharmacokinetics consciousness, and Sedation, somnolence, and loss of In clinical trials, brexanolone exhibited dose- consciousness. In clinical studies, brex- proportional pharmacokinetics, and the flushing/hot flush anolone caused sedation and somno- terminal half-life is approximately 9 hours lence that required dose interruption (Table 4,3 page 47). Brexanolone is metabo- or reduction in some patients during lized by non-cytochrome P450 (CYP)- the infusion (5% of brexanolone-treated based pathways, including keto-reduction, patients compared with 0% of placebo- glucuronidation, and sulfation.3 No clini- treated patients).3 Some patients were also cally significant
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