NYU Brexanolone Injection for Intravenous Use Research Paper

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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 Version: September 28, 2018 Available for Public Release Page 2 of 111 Brexanolone Injection, IV Briefing Document Psychopharmacologic Drug Advisory Committee and Drug Safety and Drug Safety and Risk Management Meeting November 2, 2018 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 Version: September 28, 2018 Available for Public Release Page 3 of 111 Brexanolone Injection, IV Briefing Document Psychopharmacologic Drug Advisory Committee and Drug Safety and Drug Safety and Risk Management Meeting November 2, 2018 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 Version: September 28, 2018 Available for Public Release Page 4 of 111 Brexanolone Injection, IV Briefing Document Psychopharmacologic Drug Advisory Committee and Drug Safety and Drug Safety and Risk Management Meeting November 2, 2018 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 Version: September 28, 2018 Available for Public Release Page 5 of 111 Brexanolone Injection, IV Briefing Document Psychopharmacologic Drug Advisory Committee and Drug Safety and Drug Safety and Risk Management Meeting November 2, 2018 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 Version: September 28, 2018 Available for Public Release Page 6 of 111 Brexanolone Injection, IV Briefing Document Psychopharmacologic Drug Advisory Committee and Drug Safety and Drug Safety and Risk Management Meeting November 2, 2018 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 Version: September 28, 2018 Available for Public Release Page 7 of 111 Brexanolone Injection, IV Briefing Document Psychopharmacologic Drug Advisory Committee and Drug Safety and Drug Safety and Risk Management Meeting November 2, 2018 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 Version: September 28, 2018 Available for Public Release Page 8 of 111 Brexanolone Injection, IV Briefing Document Psychopharmacologic Drug Advisory Committee and Drug Safety and Drug Safety and Risk Management Meeting November 2, 2018 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 Version: September 28, 2018 Available for Public Release Page 9 of 111 Brexanolone Injection, IV Briefing Document Psychopharmacologic Drug Advisory Committee and Drug Safety and Drug Safety and Risk Management Meeting November 2, 2018 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 Version: September 28, 2018 Available for Public Release Page 10 of 111 Brexanolone Injection, IV Briefing Document Psychopharmacologic Drug Advisory Committee and Drug Safety and Drug Safety and Risk Management Meeting November 2, 2018 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 Version: September 28, 2018 Available for Public Release Page 11 of 111 Brexanolone Injection, IV Briefing Document Psychopharmacologic Drug Advisory Committee and Drug Safety and Drug Safety and Risk Management Meeting November 2, 2018 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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REGULATORY AFFAIRS STRATEGY DOCUMENT Rapifexâ

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Table of Contents
REGULATORY AFFAIRS STRATEGY DOCUMENT Rapifexâ ................................... 3
Scope ................................................................................................................................... 3
Description .......................................................................................................................... 3
Diagrams/Photos ................................................................................................................. 4
Indications for Use .............................................................................................................. 4
Written description.............................................................................................................. 4
Milestones: Shalaka ............................................................................................................ 5
Regulatory Analysis ............................................................................................................ 8
Manufacturing ..................................................................................................................... 8
Classification....................................................................................................................... 8
United States ....................................................................................................................... 8
France ................................................................................................................................. 8
India .................................................................................................................................... 8
Mexico ................................................................................................................................. 8
Brazil ................................................................................................................................... 8
Proposed regulatory pathway options for each country ...................................................... 9
United States ....................................................................................................................... 9
France ................................................................................................................................. 9
India .................................................................................................................................... 9
Mexico ............................................................................................................................... 10
Brazil ................................................................................................................................. 10
Labeling ............................................................................................................................ 11
Regulatory milestone ........................................................................................................ 11
Regulatory budget analysis ............................................................................................... 13
Revision history ................................................................................................................ 14
Expected profit .................................................................................................................. 14
References ......................................................................................................................... 15

3
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Anonymous
Awesome! Perfect study aid.

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