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 differences in the pharma- reported to have loss of consciousness cokinetics of brexanolone were observed or altered state of consciousness during based on renal or hepatic impairment, and the brexanolone infusion (4% of patients no studies were conducted to evaluate the treated with brexanolone compared with effects of other drugs on brexanolone.3 0% of patients treated with placebo).3 All Lactation. A population pharmacokinet- patients with loss of or altered state of con- ics model constructed from studies in the sciousness recovered fully 15 to 60 min- clinical development program calculated utes after dose interruption.3 There was no the maximum relative infant dose for brex- clear association between loss or alteration anolone during infusion as 1.3%.3 Given of consciousness and pattern or timing the low oral bioavailability of brexanolone of dose, and not all patients who experi- (<5%) in adults, the potential for breastfed enced a loss or alteration of consciousness infant exposure is considered low.3 reported sedation or somnolence before the episode. Clinical considerations Suicidality. The risk of developing sui- Risk Evaluation and Mitigation Strategies cidal thoughts and behaviors with brex- (REMS) requirements. Brexanolone injec- anolone is unknown, due to the relatively tion is a Schedule IV controlled substance. It low number of exposures to brexanolone has a “black-box” warning regarding exces- injection during clinical development and sive sedation and sudden loss of conscious- a mechanism of action distinct from that of ness, which has been taken into account Current Psychiatry existing antidepressant medications.3 within the REMS drug safety program. Vol. 18, No. 9 45 continued Out of the Pipeline

Table 3 Results for the primary endpoint—HAM-D total score (Studies 1 and 2) Treatment LS mean change Placebo-subtracted group (# ITT Mean baseline from baseline difference (95% CI) Study participants) score (SD) (SE) Unadjusted P value 1 BRX90 28.4 (2.5) −17.7 (1.2) −3.7 (−6.9, −0.5) (n = 41) P = .0252a Placebo 28.6 (2.5) −14.0 (1.1) (n = 43) BRX60 29.0 (2.7) −19.5 (1.2) −5.5 (−8.8, −2.2) (n = 38) P = .0013a Placebo 28.6 (2.5) −14.0 (1.1) Clinical Point (n = 43) 2 BRX90 22.6 (1.6) −14.6 (0.8) −2.5 (−4.5, −0.5) Brexanolone (n = 51) P = .0160a injection should Placebo 22.7 (1.6) −12.1 (0.8) (n = 53) be administered in aStatistically significant after multiplicity adjustments a REMS-certified CI: confidence interval; HAM-D: Hamilton Depression Rating Scale; ITT: intention to treat; LS: least squares; SD: standard deviation; SE: standard error health care setting to Source: Reference 3 allow for continous monitoring Health care facilities and pharmacies must supportive measures initiated as necessary. enroll in the REMS program and ensure that Patients must not be the primary caregiver of brexanolone is administered only to patients dependents, and must be accompanied dur- who are enrolled in the REMS program. Staff ing interactions with their child(ren). must be trained on the processes and pro- Contraindications. There are no contra- cedures to administer brexanolone, and the indications for the use of brexanolone in facility must have a fall precautions protocol adults with PPD. in place and be equipped with a program- End-stage renal disease (ESRD). Avoid mable peristaltic IV infusion pump and using brexanolone in patients with ESRD continuous pulse oximetry with alarms.3 because of the potential accumulation of Monitoring. A REMS-trained clinician the solubilizing agent, betadex sulfobutyl must be available continuously on-site to ether sodium. oversee each patient for the duration of Pregnancy. Brexanolone has not been the continuous IV infusion, which lasts 60 studied in pregnant patients. Pregnant hours (2.5 days) and should be initiated women and women of reproductive age early enough in the day to allow for recog- should be informed of the potential risk to nition of excessive sedation. Patients must a fetus based on data from other drugs that be monitored for hypoxia using continuous enhance GABAergic inhibition. pulse oximetry equipped with an alarm and Breastfeeding. There are no data on the should also be assessed for excessive seda- effects of brexanolone on a breastfed infant. tion every 2 hours during planned, non- Breastfeeding should be a discussion of risk sleep periods. If excessive sedation occurs, and benefit between the patient and her doc- the infusion should be stopped until symp- tor. The developmental and health benefits toms resolve, after which the infusion may be of breastfeeding should be considered, along resumed at the same or a lower dose as clini- with the mother’s clinical need for brexano- cally appropriate. In case of overdosage, the lone and any potential adverse effects on the Current Psychiatry 46 September 2019 infusion should be stopped immediately and breastfed child from brexanolone or from the Out of the Pipeline

underlying maternal condition. However, Table 4 based on the low relative infant dose (<2%) Pharmacokinetic highlights and the low oral bioavailability in adults, the of brexanolone injection risk to breastfed infants is thought to be low.16 Potential for abuse. Brexanolone injec- Volume of distribution: ~3 L/kg (suggesting tion is a Schedule IV controlled substance. extensive distribution into tissues) Although it was not possible to assess Plasma protein binding: >99% (independent physical dependency in the registrational of plasma concentrations) trials due to dose tapering at the end of Terminal half-life: ~9 hours treatment, clinicians should advise patients Total plasma clearance: ~1 L/h/kg about the theoretical possibility for brex- anolone to be abused or lead to dependence Metabolism: primarily metabolized by non- cytochrome P450 (CYP)-based pathways based on other medications with similar Clinical Point primary pharmacology. Excretion: 47% feces (primarily as metabolites) and 42% in urine (with <1% as unchanged There are no Concomitant medications. Caution brexanolone) contraindications patients that taking opioids or other CNS Maximum relative infant dose during infusion depressants, such as benzodiazepines, in for the use of (modeled): 1.3% combination with brexanolone may increase brexanolone in Source: Reference 3 the severity of sedative effects. adults with PPD continued Out of the Pipeline

. Advise 5. Netsi E, Pearson RM, Murray L, et al. Association Suicidal thoughts and behaviors of persistent and severe postnatal depression with patients and caregivers to look for the emer- child outcomes. JAMA Psychiatry. 2018;75(3):247-253. gence of suicidal thoughts and behavior and 6. Goodman JH. Paternal postpartum depression, its relationship to maternal postpartum depression, and instruct them to report such symptoms to implications for family health. J Adv Nurs. 2004;45(1): their clinician. Consider changing the thera- 26-35. 7. Gelenberg AJ, Freeman MP, Markowitz JC, et al; American peutic regimen, including discontinuing Psychiatric Association Work Group on Major Depressive Disorder. Practice guidelines for the treatment of patients brexanolone, in patients whose depression with major depressive disorder. 3rd ed. Washington, DC: becomes worse or who experience emergent American Psychiatric Association; 2010. suicidal thoughts and behaviors. 8. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Why Rx? Psychiatry. 2006;163(11):1905-1917. 9. Molyneaux E, Telesia LA, Henshaw C, et al. Antidepressants Postpartum depression is a common and for preventing postnatal depression. Cochrane Database Clinical Point often devastating medical complication Syst Rev. 2018;4:CD004363. 10. Kanes S, Colquhoun H, Gunduz-Bruce H, et al. Brexanolone The risk of of childbirth that can result in adverse (SAGE-547 injection) in post-partum depression: a outcomes for the patient, baby, and fam- randomised controlled trial. Lancet. 2017;390(10093):480-489. brexanolone to 11. Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. ily when left undertreated or untreated. Brexanolone injection in post-partum depression: two breastfed infants There is a great need to identify and treat multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet. 2018;392(10152):1058-1070. is thought women who develop PPD. Rapid and sus- 12. Melon LC, Hooper A, Yang X, et al. Inability to suppress tained resolution of symptoms in women the stress-induced activation of the HPA axis during the to be low peripartum period engenders deficits in postpartum who experience PPD should be the goal of behaviors in mice. Psychoneuroendocrinology. 2018;90: treatment, and consequently, brexanolone 182-193. 13. Deligiannidis KM, Fales CL, Kroll-Desrosiers AR, et al. injection presents an important new tool in Resting-state functional connectivity, cortical GABA, available treatment options for PPD. and neuroactive steroids in peripartum and peripartum depressed women: a functional magnetic resonance imaging and spectroscopy study. Neuropsychopharmacology. 2019; References 44(3):546-554. 1. Ko JY, Rockhill KM, Tong VT, et al. Trends in postpartum 14. Licheri V, Talani G, Gorule AA, et al. Plasticity of GABAA depressive symptoms - 27 states, 2004, 2008, and receptors during pregnancy and postpartum period: from 2012. MMWR Morb Mortal Wkly Rep. 2017;66(6): gene to function. Neural Plast. 2015;2015:170435. doi: 153-158. 10.1155/2015/170435. 2. Frieder A, Fersh M, Hainline R, et al. Pharmacotherapy 15. Luisi S, Petraglia F, Benedetto C, et al. Serum of postpartum depression: current approaches and allopregnanolone levels in pregnant women: changes novel drug development. CNS Drugs. 2019;33(3):265-282. during pregnancy, at delivery, and in hypertensive patients. 3. Brexanolone injection [package insert]. Cambridge, MA: J Clin Endocrinol Metab. 2000;85(7):2429-2433. Sage Therapeutics, Inc.; 2019. 16. Hoffmann E, Wald J, Dray D, et al. Brexanolone 4. Bodnar-Deren S, Klipstein K, Fersh M, et al. Suicidal injection administration to lactating women: breast milk ideation during the postpartum period. J Womens Health allopregnanolone levels [30J]. Obstetrics & Gynecology. (Larchmt). 2016;25(12):1219-1224. 2019;133:115S.

Bottom Line Brexanolone injection is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive allosteric modulator that’s been FDA-approved for the treatment of postpartum depression (PPD). It is administered as a continuous IV infusion over 60 hours. The rapid and sustained improvement of PPD observed in clinical trials with brexanolone injection may support a new treatment paradigm for women Current Psychiatry 48 September 2019 with PPD.