REGULATORY AFFAIRS STRATEGY DOCUMENT Rapifex
Rapifex nasal spray is a prescription medicine (Brexolone) used in adults to treat Postpartum Depression
(PPD). It is the first medicine designed for the treatment of PPD in adults.
Scope
The scope of this document is to define and design a regulatory strategy for the approval
of Rapifex in the American market.
Description
Rapifex contains Brexolone that is a positive allosteric modulator of both synaptic
and extrasynaptic GABA-A receptors. It is administered via a nasal spray under the
supervision of healthcare providers in sites of care certified under the Rapifex Risk Evaluation
and Mitigation Strategy (REMS) program. The one-time spray offers the potential for rapid
resolution of depressive symptoms of PPD. PPD is a serious and debilitating condition that is
characterized by a major depressive episode temporally and patho-physiologically related to
pregnancy. It is a common complication of childbirth, is potentially life-threatening due to
risk of suicide, and can confer enormous suffering on the mother, the infant, and the entire
family. Recent estimates of PPD prevalence in the United States vary by state from 8.0% to
20.1%, with an overall average of 11.5%.
Diagrams/Photos
Indications for Use
PPD
Written description
As the first medical device developed specifically for the treatment of PPD, with positive
Phase 2 data, the Regulatory Strategy for Rapifex will be to apply for a Breakthrough
Therapy designation and design its development program for PPD in consultation with the
Food and Drug Administration (FDA) under an expedited development pathway.
The safety and efficacy of Rapifex is supported by 3 placebo-controlled, randomized, doubleblind studies in women with PPD. Each study independently demonstrated
that Rapifex provides a rapid, statistically significant, clinically meaningful, and stable
reduction in depressive symptoms with a single 60-hour infusion. The efficacy results,
combined with a clearly articulated safety profile underscore the potential for Rapifex to
change the treatment paradigm for women suffering from PPD.
Milestones: Shalaka
Booking a task and setting courses of events is the objective for us as an organization to make
progress. The task should be agreeable with every one of the guideline and every one of the
prerequisites should be satisfied. All the venture objectives should be cultivated which can be
conceivable with time the board. Arranging and execution should be finished. In the
administrative business, courses of events are vital, to appoint the undertaking in like manner.
• Pharmacokinetics of Rapifex CIV has been evaluated through double blinded
placebo study.
• By Dec 2021- According to FDA draft guidance on Lactation, Rapifex will be studied
on lactating women.
• For the individual studies, primary and secondary endpoints will be analyzed using
mixed effect models for repeated measures analysis method.
• As a required part of the New Drug Application Submission, to evaluate an
integrated summary of efficacy, the data from key study will be pooled.
• Cumulative outcome of these studies will be to establish safety and efficacy of the
drug.
• Adverse events will be observed and overviewed.
• Risk factors will be analyzed.
• Product labelling will be done to mitigate the risk of sedation related events,
excessive sedation and potential overdose.
In order to be considered for Breakthrough Therapy designation, an open mark study will be
conducted in mid 2022 to show a considerable decrease in the burdensome
manifestations in atleast 4 patients. Along these lines, the investigation will be terminated from
the get-go for starting a bigger fake treatment controlled examination. With positive outcomes
from these two examinations, Raifex holds a bright chance of bagging the Breakthrough Therapy
assignment for the treatment of Postpartum Depression. The FDA awards Breakthrough Therapy
assignment for genuine conditions where fundamental clinical information show considerable
improvement over as of now accessible treatment.
In light of this facilitated pathway, it is expected that the FDA will cooperate on the sped up
clinical program for Rapifex. Following the end of the creating program, a pre NDA (New Drug
Application) meeting will be held in next 2 months to talk about clinical, nonclinical and
administrative contemplations ahead of presenting the New Drug Application for the treatment
of Postpartum Depression.
Proposed Marketing claims
• Predicate Devices: The United States Food and Drug Administration granted approval
for Spravato (esketamine) nasal spray in combination with an oral antidepressant for the
treatment of depression in adults who have attempted but failed to benefit from other
antidepressant drugs. Spravato is only available via a limited delivery channel, under a Risk
Assessment and Reduction Plan, due to the risk of significant adverse effects from sedation
and dissociation caused by its administration, as well as the potential for exploitation and
misuse of the drug. Treatment-resistant depression is described as a patient with major
depressive disorder who has not responded to at least two antidepressant medications
administered at sufficient doses for an adequate period in the current episode.
• Describe differences with predicates: Rapifex is used for the treatment of the postpartum
depression whereas esketamine is used for depression. A black box warning on
the Spravato label advises that after taking the medication, patients can experience sedation,
trouble with concentration, judgement, and reasoning, violence and misuse, and suicidal
thoughts and behaviors. Patients must be supervised by a health care provider for at least
two hours after taking their Spravato dosage due to the risk of sedation and dissociation.
• Market Opportunity: Brexanolone is not approved are marketed in the United States. As
this is the first drug for postpartum depression, there are high chances for excellent marketing
opportunity.
• Competitive Products: There are some medications that are prescribed for postpartum
depression called selective serotonin-reuptake inhibitors. The drugs include fluoxetine,
sertraline and venlafaxine. The number of options for postpartum depression is very few, so
the competition is very low.
• Business Case (estimate of unit sales for new or modified product):
•
Target Markets (Countries): This drug is used in women. We cannot specifically indicate
the target countries. This would be a drug very useful for women suffering from postpartum
depression. 10 to 15% of the mothers are affected yearly.
• Country specific competitive issues if different from overall: There will be low competitive
issues for this drug as the number of drugs for this particular condition are very less.
• Business/clinical need:
THIS PART NEED TO BE DONE
Regulatory Analysis
• Legal Manufacturer/Manufacturing sites/ distributors/in country reps
• Classification analysis for each country
• Proposed regulatory pathway options for each country
• General Regulatory issues for the new device (if applicable for your device)
o Quality systems
o translations
o Clinical studies
o Country of Origin/GMDN Codes/UDI
o Other Depends of device and situation
Project Regulatory Timeline /Milestones
• When will submissions/clinical studies start/finish and
• how they relate to each other
Regulatory Budget Analysis
Revision History
Document Approval Section
Brexanolone Injection, IV Briefing Document
Psychopharmacologic Drug Advisory Committee and
Drug Safety and Drug Safety and Risk Management Meeting
November 2, 2018
Brexanolone Injection, for Intravenous Use
Sponsor Briefing Document
Joint Meeting of the Psychopharmacologic Drug Advisory Committee
and Drug Safety and Risk Management Advisory Committee
Meeting Date: November 2, 2018
Advisory Committee Briefing Materials:
Available for Public Release
Brexanolone Injection, IV Briefing Document
Psychopharmacologic Drug Advisory Committee and
Drug Safety and Drug Safety and Risk Management Meeting
November 2, 2018
TABLE OF CONTENTS
TABLE OF CONTENTS .................................................................................................................2
Table of Tables ................................................................................................................................6
Table of Figures ...............................................................................................................................7
LIST OF ABBREVIATIONS ..........................................................................................................9
1.
EXECUTIVE SUMMARY ........................................................................................11
1.1.
Introduction.................................................................................................................11
1.2.
Background and Unmet Need .....................................................................................11
1.3.
Product Description ....................................................................................................12
1.4.
Clinical Pharmacology................................................................................................13
1.5.
Overview of Clinical Studies ......................................................................................14
1.6.
Efficacy Findings ........................................................................................................18
1.6.1.
Primary Endpoint ........................................................................................................18
1.6.2.
Key Secondary Endpoint ............................................................................................19
1.6.3.
Additional Endpoints ..................................................................................................20
1.6.4.
Pooled Key Studies .....................................................................................................22
1.7.
Safety Findings ...........................................................................................................22
1.7.1.
Overview of Adverse Events ......................................................................................23
1.7.2.
Adverse Events of Interest ..........................................................................................24
1.7.2.1.
Events Potentially Related to GABAA Receptor Positive Modulation.......................24
1.8.
Healthcare Professional Oversight and Risk Mitigation ............................................27
1.9.
Healthcare Professional Oversight .............................................................................27
1.9.1.
Product Labeling .........................................................................................................27
1.10.
Conclusions.................................................................................................................28
2.
BACKGROUND ON POSTPARTUM DEPRESSION .............................................30
2.1.
Overview of Postpartum Depression ..........................................................................31
2.2.
Current Treatment Options .........................................................................................32
2.3.
Patient Medical Need ..................................................................................................33
3.
PRODUCT DESCRIPTION AND DEVELOPMENT HISTORY ............................34
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3.1.
Proposed Indication and Dosing .................................................................................34
3.1.1.
Proposed Indication ....................................................................................................34
3.1.2.
Dosing .........................................................................................................................34
3.2.
Product Overview and Rationale for PPD Treatment.................................................35
3.3.
Mechanism of Action .................................................................................................36
3.4.
Clinical Development Program ..................................................................................37
3.5.
Regulatory Milestones ................................................................................................39
4.
CLINICAL PHARMACOLOGY ...............................................................................40
4.1.
Pharmacokinetics ........................................................................................................40
4.1.1.
Special Populations .....................................................................................................41
4.1.2.
Drug-Drug Interactions ...............................................................................................42
4.1.3.
Lactation .....................................................................................................................43
4.2.
Pharmacodynamics .....................................................................................................43
4.3.
Human Abuse Potential ..............................................................................................44
4.4.
Dose Regimen Selection .............................................................................................44
5.
CLINICAL EFFICACY .............................................................................................46
5.1.
General Study Design – Key Studies..........................................................................47
5.1.1.
Study Differences .......................................................................................................49
5.1.2.
Dosing Regimen .........................................................................................................49
5.1.3.
Enrollment Criteria .....................................................................................................50
5.1.4.
Efficacy Endpoints......................................................................................................51
5.1.4.1.
Primary Endpoint – Change in HAM-D Total Score from Baseline at Hour
60 ................................................................................................................................51
5.1.4.2.
Key Secondary Endpoint – Change in HAM-D Total Score from Baseline at
Day 30 .........................................................................................................................51
5.1.4.3.
Additional Secondary Efficacy Endpoints..................................................................51
5.1.5.
Assessment Tools .......................................................................................................52
5.1.5.1.
17-Item Hamilton Rating Scale for Depression..........................................................52
5.1.5.2.
Clinical Global Impression - Improvement ................................................................52
5.1.5.3.
Montgomery-Åsberg Depression Rating Scale ..........................................................53
5.1.6.
Statistical Analyses .....................................................................................................53
5.1.6.1.
Analysis Populations ..................................................................................................53
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5.1.6.2.
Endpoint Analyses ......................................................................................................53
5.1.6.3.
Multiplicity .................................................................................................................54
5.1.6.4.
Determination of Sample Size ....................................................................................54
5.1.6.5.
Sensitivity Analyses....................................................................................................54
5.1.6.6.
Subgroup Analyses .....................................................................................................55
5.1.7.
Study Population .........................................................................................................55
5.1.7.1.
Patient Disposition ......................................................................................................55
5.1.7.2.
Patient Demographics and Baseline Characteristics...................................................57
5.2.
Results – Key Studies .................................................................................................61
5.2.1.
Primary Endpoint Results – Change in HAM-D Total Score from Baseline at
Hour 60 .......................................................................................................................61
5.2.1.1.
Individual Study Results .............................................................................................61
5.2.1.2.
Sensitivity Analyses....................................................................................................63
5.2.1.3.
Pooled Study Results ..................................................................................................63
5.2.2.
Key Secondary Endpoint Results – Change in HAM-D Total Score from
Baseline at Day 30 ......................................................................................................64
5.2.2.1.
Individual Study Results .............................................................................................64
5.2.2.2.
Pooled Study Results ..................................................................................................67
5.2.3.
Additional Secondary Efficacy Endpoint Results ......................................................67
5.2.3.1.
HAM-D Remission .....................................................................................................67
5.2.3.2.
HAM-D Response ......................................................................................................68
5.2.3.3.
Clinical Global Impression-Improvement (CGI-I) at Hour 60 ...................................69
5.2.3.4.
Montgomery-Åsberg Depression Rating Scale Total Score at Hour 60.....................69
5.2.3.5.
Use of Other Antidepressant Medications (Pooled Key Studies) ...............................70
5.2.3.6.
Efficacy in Subgroups (Pooled Key Studies) .............................................................70
5.2.3.7.
HAM-D Individual Item Scores from Baseline (Pooled Key Studies).......................71
5.3.
Efficacy Conclusions ..................................................................................................72
6.
CLINICAL SAFETY..................................................................................................74
6.1.
Brexanolone IV Exposure...........................................................................................75
6.2.
Approach to Summary and Discussion of Safety Data ..............................................76
6.3.
Adverse Event Overview ............................................................................................76
6.4.
Common Adverse Events ...........................................................................................77
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6.5.
Adverse Events Leading to Discontinuation of Study Drug ......................................78
6.6.
Adverse Events Leading to Dose Interruptions/Reductions .......................................79
6.7.
Adverse Events of Interest ..........................................................................................79
6.7.1.
Events Potentially Related to GABAA Receptor Positive Modulation.......................80
6.7.2.
Cardiovascular-Related Events ...................................................................................86
6.7.3.
Psychiatric Events .......................................................................................................86
6.7.4.
General Events of Interest for Investigational Drugs .................................................87
6.7.5.
Events Related to Drug Abuse or Dependence...........................................................87
6.8.
Laboratory Results ......................................................................................................88
6.9.
Vital Signs ..................................................................................................................88
6.10.
Electrocardiograms .....................................................................................................89
6.11.
Safety in Subgroups ....................................................................................................89
6.12.
Safety Conclusions .....................................................................................................89
7.
HEALTHCARE PROFESSIONAL OVERSIGHT AND RISK
MITIGATION ............................................................................................................90
7.1.
Healthcare Professional Oversight .............................................................................90
7.2.
Product Labeling .........................................................................................................90
8.
BENEFIT-RISK SUMMARY ....................................................................................92
9.
REFERENCES ...........................................................................................................94
10.
APPENDICES ..........................................................................................................100
APPENDIX A. ADDITIONAL STUDIES SUPPORTING BREXANOLONE IV FOR
PPD 101
APPENDIX B. HAMILTON RATING SCALE FOR DEPRESSION ....................................103
APPENDIX C. PATIENT NARRATIVES ..............................................................................108
Patient C (SAEs; Altered State of Consciousness, Syncope) ......................................................108
Patient D (Loss of Consciousness) ..............................................................................................109
Patient E (presyncope) .................................................................................................................110
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Table of Tables
Table 1.
Baseline Characteristics in Pooled Key Studies .........................................................18
Table 2.
Change from Baseline at Hour 60 in HAM-D Total Score Based on MMRM
for Key Studies (Full Analysis Set) ............................................................................19
Table 3:
Change from Baseline at Day 30 in HAM-D Total Score Based on MMRM
for Key Studies (Full Analysis Set) ............................................................................20
Table 4.
Overview of Adverse Events in the Pooled Key Studies ...........................................23
Table 5.
Adverse Events Reported by ≥ 3.0% of Patients in Either Group in Pooled
Key Studies .................................................................................................................24
Table 6.
Sedation-Related Events in Pooled Key Studies ........................................................25
Table 7.
Key Studies of Brexanolone IV in Postpartum Depression: Double-Blind
Placebo-Controlled .....................................................................................................38
Table 8.
Summary of Individual Predicted Brexanolone AUC and Cmax in Patients
with PPD .....................................................................................................................41
Table 9.
Demographic Characteristics for Key Studies (Full Analysis Set) ............................58
Table 10.
Baseline Characteristics for Key Studies (Full Analysis Set) ....................................60
Table 11.
Change from Baseline at Hour 60 in HAM-D Total Score Based on MMRM
for Key Studies (Full Analysis Set) ............................................................................62
Table 12.
Change from Baseline at Hour 60 in HAM-D Total Score Based on MMRM
for Pooled Key Studies (Full Analysis Set) ................................................................64
Table 13.
Change from Baseline at Day 30 in HAM-D Total Score Based on MMRM
for Key Studies (Full Analysis Set) ............................................................................65
Table 14.
Change from Baseline at Hour 60 in MADRS Total Score Based on MMRM
for Key Studies (Full Analysis Set) ............................................................................70
Table 15:
Brexanolone PPD Program Safety Exposures ............................................................75
Table 16.
Number of Patients in Pooled Key Studies.................................................................76
Table 17.
Exposure for Pooled Key Studies ...............................................................................76
Table 18.
Summary of Adverse Events in Pooled Key Studies..................................................77
Table 19.
Adverse Events Reported by ≥ 3.0% of Patients in Either Group in Pooled
Key Studies .................................................................................................................78
Table 20.
Patients in Pooled Key Studies with AEs Leading to Study Drug
Discontinuation ...........................................................................................................79
Table 21.
Sedation-Related Events in Pooled Key Studies ........................................................81
Table 22.
Listing of Moderate and Severe Sedation-Related Adverse Events ...........................82
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Table 23.
Incidence of Sedation-Related Events in Patients by Use of Concomitant
Antidepressant Medications........................................................................................85
Table 24.
Incidence of Sedation-Related Events in Patients by Use of Benzodiazepines..........85
Table 25.
Additional Studies Supporting Brexanolone IV for PPD .........................................101
Table of Figures
Figure 1.
Study Design of Key Studies ......................................................................................15
Figure 2.
Dosing Regimen in Key Studies .................................................................................15
Figure 3.
Disposition for Key Studies (Full Analysis Set).........................................................17
Figure 4.
HAM-D Remission at Hour 60 for Individual Key Studies (Full Analysis
Set) ..............................................................................................................................21
Figure 5.
HAM-D Response at Hour 60 for Individual Key Studies (Full Analysis Set)..........21
Figure 6.
CGI-I Response at Hour 60 for Individual Key Studies (Full Analysis Set)..............22
Figure 7.
Mechanism of Action of Brexanolone ........................................................................37
Figure 8.
Predicted Brexanolone Exposure AUC∞ for the 60 and 90 Dose Regimens in
Patients with PPD .......................................................................................................41
Figure 9.
Impact of Hepatic and Renal Impairment on Brexanolone Pharmacokinetics ...........42
Figure 10. Study Design of Key Studies ......................................................................................48
Figure 11. Dosing Regimen in Key Studies .................................................................................50
Figure 12. Disposition for Study 202A ........................................................................................55
Figure 13. Disposition for Study 202B ........................................................................................56
Figure 14. Disposition for Study 202C ........................................................................................56
Figure 15. Disposition for Pooled Key Studies ............................................................................57
Figure 16. Least Squares Mean Change in HAM-D Total Score Through Hour 60 for
Study 202A (Full Analysis Set) ..................................................................................62
Figure 17. Least Squares Mean Change in HAM-D Total Score Through Hour 60 for
Study 202B (Full Analysis Set) ..................................................................................63
Figure 18. Least Squares Mean Change in HAM-D Total Score Through Hour 60 for
Study 202C (Full Analysis Set) ..................................................................................63
Figure 19. Change from Baseline Through Day 30 in HAM-D Total Score for Study
202A (Full Analysis Set) ............................................................................................65
Figure 20. Change from Baseline Through Day 30 in HAM-D Total Score for Study
202B (Full Analysis Set) ............................................................................................66
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Figure 21. Change from Baseline Through Day 30 in HAM-D Total Score for Study
202C (Full Analysis Set) ............................................................................................66
Figure 22: Least Squares Mean Change in HAM-D Total Score Over Time for Pooled
Key Studies (Full Analysis Set)..................................................................................67
Figure 23. HAM-D Remission at Hour 60 for Individual Key Studies (Full Analysis
Set) ..............................................................................................................................68
Figure 24. HAM-D Response at Hour 60 for Individual Key Studies (Full Analysis Set)..........68
Figure 25. CGI-I Response at Hour 60 for Individual Key Studies (Full Analysis Set)..............69
Figure 26. Difference Between 90 Dose Regimen and Placebo for Change from
Baseline at Hour 60 in HAM-D Total Score by Subgroups for Pooled Key
Studies (Full Analysis Set) .........................................................................................71
Figure 27. Difference Between 90 Dose Regimen and Placebo for Change from
Baseline in HAM-D Individual Item Scores at Hour 60 for Pooled Key
Studies (Full Analysis Set) .........................................................................................72
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LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse event
ALT
Alanine aminotransferase
APA
American Psychiatric Association
AST
Aspartate aminotransferase
AUC
Area under the curve
AUCinf or AUC∞
Area under the curve from 0 to infinity
BMI
Body mass index
Brexanolone IV
Brexanolone injection for intravenous use
BRX60
Brexanolone 60 dose regimen
BRX90
Brexanolone 90 dose regimen
CI
Confidence interval
CLP
Clinical pharmacology
Cmax
Maximum observed concentration
CGI-I
Clinical global impression of improvement
CNS
Central nervous system
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
Cytochrome P450
DSM
Diagnostic and Statistical Manual of Mental Disorders
FDA
Food and Drug Administration
ECG
Electrocardiogram
ED
Emergency Department
eGFR
Estimated glomerular filtration rate
EPDS
Edinburgh Postnatal Depression Scale
ETD
Essential Tremor Disorder
GABA
γ-aminobutyric acid
GABAA
γ aminobutyric acid-ligand gated chloride channel
GEE
Generalized estimating equation
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
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Abbreviation
Definition
HAM-D
17-Item Hamilton Rating Scale for Depression
IV
Intravenous
LS
Least squares
MedDRA
Medical Dictionary for Regulatory Activities
MADRS
Montgomery-Åsberg Depression Rating Scale
MDD
Major depressive disorder
MMRM
Mixed effect model for repeated measures
NC
Not summarized in clinical study report
NDA
New drug application
NF
National Formulary
PD
Pharmacodynamic
PK
Pharmacokinetic
PopPK
Population pharmacokinetics
PP
Per protocol
PPD
Postpartum depression
PRAMS
Pregnancy Risk Assessment Monitoring Systems
QTcF
QT corrected according to Fridericia
RID
Relevant infant dose
SAE
Serious adverse event
SBECD
Sulfobutyl ether betacyclodextrin
SD
Standard deviation
SE
Standard error
SOC
System Organ Class
SSRI
Selective serotonin reuptake inhibitor
US
United States
USP
United States Pharmacopeia
Vss
Volume of distribution at steady state
W/in
Within
Wks
Weeks
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1.
EXECUTIVE SUMMARY
1.1.
Introduction
Brexanolone injection for intravenous use (brexanolone IV) is a novel product developed by
Sage Therapeutics for the treatment of postpartum depression (PPD), a serious and potentially
life-threatening condition, for which no current pharmacotherapies are specifically indicated.
Brexanolone is chemically identical to endogenous allopregnanolone, a positive allosteric
modulator of GABAA (γ aminobutyric acid-ligand gated chloride channel) receptors.
As the first medication developed specifically for the treatment of PPD, with positive Phase 2
data, brexanolone IV was granted Breakthrough Therapy designation, and its development
program for PPD was designed in consultation with the Food and Drug Administration (FDA)
under an expedited development pathway.
The safety and efficacy of brexanolone IV are supported by 3 placebo-controlled, randomized,
double-blind studies in women with PPD. Each study independently demonstrated that
brexanolone IV provides a rapid, statistically significant, clinically meaningful, and stable
reduction in depressive symptoms with a single 60-hour infusion. The efficacy results, combined
with a clearly articulated safety profile underscore the potential for brexanolone IV to change the
treatment paradigm for women suffering from PPD.
1.2.
Background and Unmet Need
PPD is a serious and debilitating condition that is characterized by a major depressive episode
temporally and pathophysiologically related to pregnancy. It is a common complication of
childbirth, is potentially life-threatening due to risk of suicide, and can confer enormous
suffering on the mother, the infant, and the entire family. Recent estimates of PPD prevalence in
the United States vary by state from 8.0% to 20.1%, with an overall average of 11.5% (Ko 2017).
The societal burden of PPD is significant, with contributions from maternal death from suicide
(Johannsen 2016), loss of work days due to depression, maternal morbidity, and child morbidity
associated with impaired mother-infant bonding and infant malnutrition during the first year of
life (Gavin 2005; Parsons 2012; Szegda 2014; Accortt 2015).
PPD may be triggered in susceptible women by an inability of the brain to adapt to fluctuations
in allopregnanolone that occur in the peripartum period. Plasma concentrations of
allopregnanolone increase during pregnancy and peak at the end of the third trimester before
rapidly returning to pre-pregnancy levels after childbirth (Luisi 2000; Nappi 2001). These
fluctuations in allopregnanolone have been associated with symptoms of PPD (Osborne 2017;
Deligiannidis 2016; Hellgren 2014; Schiller 2014; Bloch 2000; Amin 2006; Epperson 2006;
Nappi 2001) and may contribute to the development of changes in brain networks associated
with PPD (Deligiannidis 2013; Chase 2014). See Section 3.2 for additional details.
PPD is distinguishable from postpartum blues (baby blues) where sadness and anxiety are
milder, are time-limited (lasting for a few hours to a few days in the first week postpartum) and
have few negative sequelae (Bernard-Bonnin 2004). In contrast, PPD diagnosis requires the
persistence of depressive symptoms which result in functional impairment nearly every day for
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at least 2 weeks; the diagnosis involves an onset of symptoms during pregnancy or during the
first 4 weeks postpartum (American Psychiatric Association 2013).
PPD is characterized by significant functional impairment for the mother due to sadness and
depressed mood, loss of interest in daily activities, anxiety, changes in eating and sleeping habits,
fatigue and decreased energy, inability to concentrate, and feelings of worthlessness, shame, or
guilt, and potentially suicidal ideation.
PPD symptoms may result in substantial burden on the mother, child, and family unit (Fitelson
2011), including interfering with the mother’s ability to connect with and care for her baby
(National Institute of Mental Health 2018), breastfeeding complications, disruption of sleep
routines for the infant and mother (Eastwood 2012), increased marital discord (Kerstis 2012),
and depression in the partner (Goodman 2004). If depressive symptoms persist during the first
year postpartum, mothers with PPD are more likely to have depressive symptomatology up to 11
years after childbirth (Netsi 2018). This persistent PPD is associated with adverse sequelae in the
children such as increased risk of child behavioral disturbances at 3.5 years, lower academic
performance at 16 years, and depression in the child at 18 years (Netsi 2018).
PPD is one of the strongest predictors of suicidal ideation in new mothers (Do 2013) and carries
an increased risk for suicide (Savitz 2011, American Psychiatric Association 2013). Recent
studies suggest that postpartum suicidal ideation occurs in 19% to 30% of women with PPD
(Mauri 2012; Wisner 2013). Suicide is the leading cause of maternal death following childbirth
through 1 year postpartum in developed countries (Oates 2003; Metz 2016). According to one
case series of 211 maternal deaths in Colorado, 30% of mortalities that occurred during
pregnancy or within 1 year postpartum were attributed to self-harm; greater than 35% of these
deaths were in women who had been diagnosed with depression (Metz 2016).
There are no approved pharmacotherapies specifically indicated for the treatment of PPD. While
antidepressants approved for major depressive disorder (MDD) are the current mainstay of drug
therapy in PPD, these agents typically take approximately 6 weeks to achieve a positive response
in PPD (defined as statistically significant proportion of patients achieving 50% or more
reduction in baseline depression score compared to placebo), require chronic dosing to
demonstrate evidence of efficacy, and are not uniformly effective, requiring multiple agents to
achieve a response (Molyneaux 2014; Cox 2016; Hendrick 2000).
Given the significant effects on the mother, infant and family, there is a clear unmet need for
improved pharmacological treatment options. An effective and rapidly-acting medication would
be ideal, allowing the mother to potentially experience more positive interactions with her infant
and her family, and reduce the potential for significant morbidity and mortality.
1.3.
Product Description
Brexanolone IV is a novel product with an active pharmaceutical ingredient that is classified
from a regulatory perspective as a new molecular entity. However, brexanolone is chemically
identical to endogenous allopregnanolone. Allopregnanolone is a metabolite of progesterone that
is formed in the brain and corpus luteum, and during pregnancy in the placenta.
Allopregnanolone does not act as a sex steroid or glucocorticoid at physiological levels. It is well
Version: September 28, 2018
Available for Public Release
Page 12 of 111
Brexanolone Injection, IV Briefing Document
Psychopharmacologic Drug Advisory Committee and
Drug Safety and Drug Safety and Risk Management Meeting
November 2, 2018
established that its primary biological role is as a positive allosteric modulator of the GABAA
receptor (Reddy 2010). Additional details can be found in Section 3.2.
Brexanolone IV is supplied as a concentrated solution, prepared in the pharmacy and diluted in
an IV bag prior to dispensing. It is administered as a 60-hour continuous infusion with a
recommended maximum dose of 90 µg/kg/h. The brexanolone IV infusion consists of the
following dosing phases and is hereafter referred to as the “90 dose regimen”:
1.4.
•
Titration at 30 μg/kg/h for 4 hours followed by 60 μg/kg/h for 20 hours (Hour 0-24)
•
Maintenance at 90 μg/kg/h for 28 hours (Hour 24-52)
•
Taper at 60 μg/kg/h for 4 hours followed by 30 μg/kg/h for 4 hours (Hour 52-60)
Clinical Pharmacology
The pharmacokinetics (PK) of brexanolone IV doses from 30 to 270 μg/kg/h were evaluated
across the various clinical studies including studies in patients with PPD and in healthy lactating
women. Exposure increases in direct proportion to dose, exhibiting linear and time-independent
PK. Brexanolone IV is rapidly cleared from plasma, necessitating a continuous intravenous
infusion to maintain plasma concentrations. The rapid clearance from plasma, at approximately
0.8 L/h/kg, is independent of dose and accounts for the very rapid, biexponential decline in
plasma concentrations as doses are reduced or the infusion ends. Brexanolone exhibits biphasic
kinetics, with an initial rapid decline with an estimated half-life of approximately 40 minutes,
followed later by a terminal half-life estimated to be approximately 12 hours. The short initial
half-life is consistent with the rapid offset of sedation related events in the context of immediate
cessation of the infusion (Section 4.1).
There was no evidence of PK-related differences by age, body mass index (BMI), race, or
ethnicity. No dose adjustment is necessary for patients with hepatic or mild-to-moderate renal
impairment. In vitro, ex vivo and clinical testing confirmed that there were no significant PK
drug-drug interactions for brexanolone IV.
In keeping with the 2005 FDA Draft Guidance on Lactation, the PK of brexanolone IV was
studied in healthy lactating women (Section 4.1.3). The data demonstrated rapid equilibrium
between milk and plasma and the relationship between plasma and milk concentrations (a ratio
of 1:1.36) was linear, constant with time, and unaffected by the volume of milk expressed by the
mother. Concentrations of brexanolone in breastmilk were at low levels (< 10 ng/mL) in > 95%
of women by 36 hours after the end of the infusion of brexanolone.
Relative infant dose (RID) is the dose of a drug to which an infant is exposed if breastfed during
administration of the drug. This can be calculated as a percentage of the mother’s dose. Drugs
with an RID of
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