CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`208341Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`Clinical Review Addendum
`
`Prabha Viswanathan, MD
`Sarah Connelly, MD
`NDA 208341
`
`Epclusa (sofosbuvir and velpatasvir)
`
`CLINICAL REVIEW ADDENDUM
`
`
`June 1, 2016
`
`Prabha Viswanathan, MD
`
`Sarah Connelly, MD
`Clinical Review Addendum
`Subject
`208341
`NDA/BLA #
`Gilead Sciences
`Applicant
`
`Date of Submission
`October 28, 2015
`
`PDUFA Goal Date
`June 28, 2016
`
`Proprietary Name I
`Non-Proprietary Name
`
`Epclusa
`
`sofosbuvir and velpatasvir (SOF/VEL)
`Fixed dose combination tablet containing 400 mg sofosbuvir
`Dosage form(s) / Strength(s)
`
`and 100 mg velpatasvir
`
`Indication(s)/Population(s) SOFIVEL: Treatment of adult patients with chronic hepatitis C
`
`Applicant Proposed
`
`Indication(s)/Population(s)
`
`Treatment of adult patients with chronic hepatitis C virus
`infection
`
`Approval
`Recommendation on Regulatory
`
`Action
`
`Recommended
`
`virus genotype 1, 2, 3, 4, 5 and 6 infection without cirrhosis or
`
`with compensated cirrhosis
`
`SOFIVEI. with ribavirin: Treatment of adult patients with
`chronic hepatitis C virus genotype 1, 2, 3, 4, 5 and 6 infection
`
`with decompensated cirrhosis
`
`The purpose of this addendum is to address two major review issues that were under
`
`consideration at the time the clinical review was finalized: treatment optimization for HCV
`
`genotype 3 (GT3) subjects and labeling of HIV antiretroviral drugs. This document will
`summarize the ultimate conclusions of the clinical review team.
`
`1. Treatment Optimization for GT3 Subjects Without Cirrhosis or with Compensated
`Cirrhosis
`
`As discussed in the clinical review, GT3 subjects treated with 12 weeks of sofosbuvir/velpatasvir
`
`(SOF/VEL) in ASTRAL—3 experienced higher rates of relapse compared to subjects infected with
`
`GT 1, 2, 4, 5, or 6 in ASTRAL-1 or ASTRAL-Z. A key review issue was whether or not the addition
`
`of ribavirin (RBV) would prevent relapse and/or emergence of NS5A RAPs, particularly among
`
`subjects with cirrhosis. At the time the clinical review was finalized, the primary clinical team
`
`concluded that there are insufficient data to support the addition of RBV for GT3 cirrhotic
`
`subjects.
`
`Reference ID: 3939699
`
`

`

`Clinical Review Addendum
`Prabha Viswanathan, MD
`Sarah Connelly, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`At the Late Cycle Meeting on April 19, 2016, the Division queried the Applicant about their
`perspective on the addition of RBV for GT3 cirrhotics,
`
`
`
`
`
`
` The results of this study will be
`
`submitted in response to a post-marketing requirement.
`
`
`
`
`
`
`
`
`
`Reviewer Comment: Based on the currently available data, the clinical review team and the
`Applicant agree that SOF/VEL for 12 weeks, without ribavirin, is the most appropriate regimen
`for all GT3 infected subjects without cirrhosis or with compensated cirrhosis. Once data from
`the SOF/VEL versus SOF/VEL + RBV trial are available, the optimal regimen for GT3 cirrhotics can
`be reevaluated.
`
`2. Co-administration of SOF/VEL with HIV Antiretroviral Agents (ARVs)
`
`Phase 1 drug-drug interaction trials form the basis of the information presented in Sections 7
`and 12 of the proposed label, supported by preliminary safety results from Trial GS-US-342-
`1202 (ASTRAL-5), a Phase 3, open-label study evaluating the safety and efficacy of SOF/VEL for
`12 weeks in subjects with HIV/HCV co-infection. Interim safety results from ASTRAL-5 were
`included in the 90 day Safety Update Report, and follow-up summaries through the SVR4
`datacut were provided for subjects receiving tenofovir disoproxil fumarate (TDF)-containing
`ARV regimens as well as subjects on atazanavir-based regimens who developed hepatic
`laboratory abnormalities.
`
`Summary of ASTRAL-5
`A total of 106 subjects with HIV/HCV coinfection and suppressed HIV viral load at study entry
`were enrolled and treated in ASTRAL-5. At the SVR4 datacut, 102 subjects had completed 12
`weeks of SOF/VEL and 4 subjects had prematurely discontinued treatment: two discontinued
`due to adverse events (AEs) and two were lost to follow-up. Ninety-one subjects (86%)
`received TDF-containing regimens, of which 56 (53%) received ritonavir or cobicistat (“boosted
`TDF” regimens). Fifty subjects (47%) were on protease inhibitor (PI) - based regimens, 36
`(34%) were on integrase inhibitor (INSTI)-based regimens, and the remaining 20 subjects were
`on non-nucleoside reverse transcriptase inhibitor (NNRTI) or INSTI+PI-based regimens.
`
`Reference ID: 3939699
`
`2
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review Addendum
`Prabha Viswanathan, MD
`Sarah Connelly, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`No deaths have occurred in this study. Two subjects (2%) had SAEs that were considered
`unrelated to study medication: 1 subject had Grade 2 radial nerve palsy, and 1 subject had
`localized infection, sepsis, and urinary tract infection (all Grade 3). Two subjects (2%)
`prematurely discontinued SOF/VEL due to AEs: 1 subject who received lamivudine, abacavir,
`and ritonavir-boosted atazanavir (ATV/r) discontinued on study Day 4 due to Grade 1 vomiting;
`1 subject who was receiving emtricitabine (FTC), TDF, and ATV/r discontinued on study Day 41
`due to Grade 3 increased hepatic enzymes (see clinical review for additional details). A total of
`75 subjects (71%) experienced at least 1 AE; 9 subjects (9%) had Grade 3 AEs and no Grade 4
`AEs have been reported. The most commonly reported AEs were fatigue (25%), headache
`(13%), and arthralgia (9%).
`
`Subjects Receiving Tenofovir-containing ARV Regimens
`Phase 1 drug-drug interaction studies demonstrated higher TDF exposures when TDF is
`coadministered with SOF and VEL. Notable adverse drug reactions associated with TDF
`exposure include decreased bone mineral density and nephrotoxicity. Given the short duration
`of therapy for SOF/VEL, bone toxicity is not a great concern; in contrast, renal insufficiency can
`occur acutely and, if significant, may require modifications to ARV and/or SOF/VEL dosing.
`Hence, the Division requested the Applicant to assess renal AEs and renal laboratory
`abnormalities among TDF-treated subjects in ASTRAL-5 to help inform dosing recommendations
`for TDF with SOF/VEL.
`
`Four subjects (4%) had an AE under the Renal and Urinary Disorders system organ class,
`including pollakiuria, glycosuria, and proteinuria. Of these, 2 subjects were receiving boosted
`TDF regimens and 2 subjects were receiving non-boosted TDF-containing regimens. All events
`were Grade 1 or 2 in severity. A total of 5 subjects experienced a change in serum Cr ≥ 0.4
`mg/dL, creatinine clearance (CrCl) < 50 ml/min or normoglycemic glycosuria. Of these, 4 were
`receiving boosted TDF regimens and 1 subject was receiving a non-boosted TDF-containing
`regimen. These abnormalities were transient and asymptomatic in 4 of the 5 subjects; one
`subject on a boosted TDF regimen (FTC/TDF/ATV/r) with a history of chronic kidney disease
`developed 3+ proteinuria, normoglycemic glycosuria, elevated creatinine (3.3 mg/dL at Week 4,
`up from 1.4 mg/dL at baseline), and decreased CrCl following an episode of acute
`gastroenteritis with dehydration at Week 4, and his creatinine remained elevated at
`subsequent visits (2-2.7 mg/dL). No changes were made in ART in any of the five subjects and
`all completed 12 weeks of SOF/VEL.
`
`Reviewer Comment: Preliminary safety data from ASTRAL-5 are adequate to support labeling for
`co-administration of SOF/VEL with TDF-containing ARV regimens.
`
`Reference ID: 3939699
`
`3
`
`

`

`Clinical Review Addendum
`Prabha Viswanathan, MD
`Sarah Connelly, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`Subjects Receiving ATV/r-Based ARV Regimens
`Phase 1 drug-drug interaction studies demonstrated no significant changes in ATV, SOF, or VEL
`exposure when ATV is coadministered with SOF and VEL, and therefore no unique safety
`considerations are anticipated. However, review of the Safety Update Report revealed that a
`significant proportion of subjects on ATV/r-based regimens had elevated bilirubin (in excess of
`baseline elevations due to ATV/r), and additional information was requested from the
`Applicant.
`
`A total of 20 subjects received ATV/r-based regimens. By the SVR4 datacut, 13/20 subjects
`(65%) had symptomatic elevations of total bilirubin > 2 x ULN. Twelve of the 13 subjects had
`increases of ≥ 0.5 mg/dL and 9/13 had increases of ≥ 1 mg/dL from baseline total bilirubin; the
`maximum increase was 3.2 mg/dL from baseline. The elevations peaked by Week 6 of SOF/VEL
`in 12/13 subjects, and the majority of subjects (9/13) had total bilirubin values that were less
`than or equal to their baseline value at Week 12 of SOF/VEL. All elevations in total bilirubin
`were attributed to increases in indirect bilirubin only; there were no significant concomitant
`increases in ALT, AST, alkaline phosphatase, or total bilirubin in any of the 13 subjects. The
`increased bilirubin values were not associated with clinical AEs and did not lead to treatment
`interruption or dosage adjustment of SOF/VEL or ARVs for any of the 13 subjects.
`
`Reviewer Comment: Co-administration of SOF/VEL with ATV/r may result in increases in indirect
`bilirubin that are not associated with clinical adverse events or other hepatic laboratory
`abnormalities. The mechanism for this observation is unclear. Based on currently available
`information, no specific laboratory monitoring is required. The clinical review team has
`proposed inclusion of the following language to Section 6.1 of product labeling to inform
`prescribers of this observation:
`
`Indirect Bilirubin: Increases in indirect bilirubin up to 3 mg/dL above baseline were noted
`among HIV-HCV co-infected subjects treated with EPCLUSA and an atazanavir/ritonavir-
`based antiretroviral regimen. The elevated indirect bilirubin values were not associated
`with clinical adverse events and all subjects completed 12 weeks of EPLCUSA without
`dose adjustment or treatment interruption of either EPCLUSA or HIV antiretroviral
`agents.
`
`In conclusion, the preliminary safety data from ASTRAL-5 are adequate to support labeling for
`SOF/VEL co-administration with ARVs. Labeling negotiations are ongoing at this time. A PMR
`will be issued to request formal submission of the final data once with trial has been
`completed. These data will be used to further characterize the safety and efficacy of SOF/VEL
`in HIV/HCV co-infected subjects, and to support the clinical pharmacology information
`contained product labeling.
`
`Reference ID: 3939699
`
`4
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`PRABHA VISWANATHAN
`06/01/2016
`
`KIMBERLY A STRUBLE
`06/01/2016
`
`Reference ID: 3939699
`
`

`

`Clinical Review
`Prabha Viswanathan, MD
`Sarah Connelly, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`
`
`CLINICAL REVIEW
`Application Type New Drug Application
`Application Number(s) 208341
`Priority or Standard Priority
`Submit Date(s) October 28, 2015
`Received Date(s) October 28, 2015
`PDUFA Goal Date
`June 28, 2016
`Division/Office Division of Antiviral Products/Office of Antimicrobial Products
`Reviewer Name(s) Prabha Viswanathan, MD
`Sarah Connelly, MD
`Review Completion Date March 29, 2016
`Established Name sofosbuvir and velpatasvir
`(Proposed) Trade Name Epclusa®
`Applicant Gilead Sciences, Inc.
`Formulation(s) Fixed dose combination tablet containing 400 mg sofosbuvir and
`100 mg velpatasvir
`Dosing Regimen One tablet orally once daily
`Applicant Proposed
`Treatment of adult patients with chronic hepatitis C virus
`Indication(s)/Population(s)
`infection
`Recommendation on
`Approval
`Regulatory Action
`Recommended
`Indication(s)/Population(s)
`(if applicable)
`
`Treatment of adult patients with chronic hepatitis C virus
`infection
`
`Reference ID: 3909326
`
`1
`
`

`

`Clinical Review
`Prabha Viswanathan, MD
`Sarah Connelly, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`
`
`Table of Contents
`
`Glossary ........................................................................................................................................... 9
`
`1
`
`Executive Summary ............................................................................................................... 11
`
`
`
` Product Introduction ...................................................................................................... 11 1.1.
`
`
`
` Conclusions on the Substantial Evidence of Effectiveness ............................................ 11 1.2.
`
`
`
` Benefit-Risk Assessment ................................................................................................ 11 1.3.
`
`2
`
`Therapeutic Context .............................................................................................................. 18
`
`
`
` Analysis of Condition ...................................................................................................... 18 2.1.
`
`
`
` Analysis of Current Treatment Options ......................................................................... 19 2.2.
`
`3
`
`Regulatory Background ......................................................................................................... 21
`
`
`
` U.S. Regulatory Actions and Marketing History ............................................................. 21 3.1.
`
`3.2.
`
`
`Summary of Presubmission/Submission Regulatory Activity ........................................ 21
`
`3.3.
`
`
`Foreign Regulatory Actions and Marketing History ....................................................... 22
`
`4
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety................................................................................................................. 22
`
`
`
` Office of Scientific Investigations (OSI) .......................................................................... 22 4.1.
`
`
`
` Product Quality .............................................................................................................. 23 4.2.
`
`
`
` Clinical Microbiology ...................................................................................................... 23 4.3.
`
`
`
` Nonclinical Pharmacology/Toxicology ........................................................................... 24 4.4.
`
`
`
` Clinical Pharmacology .................................................................................................... 25 4.5.
`
`4.5.1.
`
` Mechanism of Action .............................................................................................. 25
`
`4.5.2.
`
` Pharmacodynamics ................................................................................................. 26
`
`4.5.3.
`
` Pharmacokinetics .................................................................................................... 27
`
`4.6.
` Devices and Companion Diagnostic Issues .................................................................... 29
`
`
`
` Consumer Study Reviews ............................................................................................... 30 4.7.
`
`5
`
`Sources of Clinical Data and Review Strategy ....................................................................... 30
`
`
`
` Table of Clinical Studies .................................................................................................. 30 5.1.
`
`
`
` Review Strategy .............................................................................................................. 33 5.2.
`
`Reference ID: 3909326
`
`2
`
`

`

`Clinical Review
`Prabha Viswanathan, MD
`Sarah Connelly, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`
`6
`
`Review of Relevant Individual Trials Used to Support Efficacy ............................................. 34
`
`
`
` ASTRAL-1 ........................................................................................................................ 34 6.1.
`
`6.1.1.
`
` Study Design............................................................................................................ 34
`
`6.1.2.
`
` Study Results ........................................................................................................... 36
`
`
`
` ASTRAL-2 ........................................................................................................................ 43 6.2.
`
`6.2.1.
`
` Study Design............................................................................................................ 43
`
`6.2.2.
` Study Results ........................................................................................................... 44
`
`
`
` ASTRAL-3 ........................................................................................................................ 48 6.3.
`
`6.3.1.
`
` Study Design............................................................................................................ 48
`
`6.3.2.
`
` Study Results ........................................................................................................... 49
`
`
`
` ASTRAL-4 ........................................................................................................................ 61 6.4.
`
`6.4.1.
`
` Study Design............................................................................................................ 61
`
`6.4.2.
`
` Study Results ........................................................................................................... 63
`
`7
`
`Integrated Review of Effectiveness ....................................................................................... 79
`
`
`
` Assessment of Efficacy Across Trials .............................................................................. 79 7.1.
`
`7.1.1.
` Primary Endpoints ................................................................................................... 79
`
`7.1.2.
`
` Subpopulations ....................................................................................................... 80
`
`7.1.3.
`
` Dose and Dose-Response........................................................................................ 80
`
`7.1.4.
`
` Onset, Duration, and Durability of Efficacy Effects ................................................ 80
`
`
`
` Additional Efficacy Considerations ................................................................................. 80 7.2.
`
`7.2.1.
`
` Considerations on Benefit in the Postmarket Setting ............................................ 80
`
`7.2.2.
`
` Other Relevant Benefits .......................................................................................... 81
`
`7.3.
`
`
`Integrated Assessment of Effectiveness ........................................................................ 81
`
`8
`
`Review of Safety .................................................................................................................... 81
`
`8.1.
`
`
`Safety Review Approach ................................................................................................ 81
`
`
`
` Review of the Safety Database ...................................................................................... 83 8.2.
`
`8.2.1.
`
` Overall Exposure ..................................................................................................... 83
`
`8.2.2.
`
` Relevant characteristics of the safety population: ................................................. 83
`
`8.2.3.
`
` Adequacy of the safety database: .......................................................................... 85
`
`
`
` Adequacy of Applicant’s Clinical Safety Assessments .................................................... 86 8.3.
`
`Reference ID: 3909326
`
`3
`
`

`

`Clinical Review
`Prabha Viswanathan, MD
`Sarah Connelly, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`
`
`8.3.1.
`
` Issues Regarding Data Integrity and Submission Quality ....................................... 86
`
`8.3.2.
`
` Categorization of Adverse Events ........................................................................... 86
`
`8.3.3.
`
` Routine Clinical Tests .............................................................................................. 86
`
`8.4.
`
`
`Safety Results ................................................................................................................. 86
`
`8.4.1.
`
` Deaths ..................................................................................................................... 88
`
`8.4.2.
`
` Serious Adverse Events ........................................................................................... 94
`
`8.4.3.
` Dropouts and/or Discontinuations Due to Adverse Effects ................................... 98
`
`8.4.4.
`
` Significant Adverse Events .................................................................................... 101
`
`8.4.5.
`
` Treatment Emergent Adverse Events and Adverse Reactions ............................. 103
`
`8.4.6.
`
` Laboratory Findings .............................................................................................. 108
`
`8.4.7.
`
` Vital Signs .............................................................................................................. 115
`
`8.4.8.
`
` Electrocardiograms (ECGs) .................................................................................... 115
`
`8.4.9.
`
` QT .......................................................................................................................... 116
`
`8.4.10.
`
`
`Immunogenicity ............................................................................................. 117
`
`
`
` Analysis of Submission-Specific Safety Issues .............................................................. 117 8.5.
`
`8.5.1.
`
` Hepatotoxicity ....................................................................................................... 118
`
`8.5.2.
`
` Cardiac Disorders .................................................................................................. 132
`
`8.5.3.
`
` Neuropsychiatric Disorders .................................................................................. 136
`
`8.5.4.
`
` Rash ....................................................................................................................... 139
`
`8.5.5.
`
` Rhabdomyolysis .................................................................................................... 141
`
`8.5.6.
`
` Pancreatitis ........................................................................................................... 143
`
`8.5.7.
`
` Pancytopenia ........................................................................................................ 144
`
`8.5.8.
`
` Safety Profile Among Subjects with Baseline CPT A, B or C Cirrhosis .................. 145
`
`8.6.
`
`
`Safety Analyses by Demographic Subgroups ............................................................... 146
`
`8.7.
`
`
`Specific Safety Studies/Clinical Trials ........................................................................... 151
`
`
`
` Additional Safety Explorations ..................................................................................... 151 8.8.
`
`8.8.1.
`
` Human Carcinogenicity or Tumor Development .................................................. 151
`
`8.8.2.
`
` Human Reproduction and Pregnancy ................................................................... 152
`
`8.8.3.
`
` Pediatrics and Assessment of Effects on Growth ................................................. 153
`
`8.8.4.
`
` Overdose, Drug Abuse Potential, Withdrawal, and Rebound .............................. 153
`
`Reference ID: 3909326
`
`4
`
`

`

`Clinical Review
`Prabha Viswanathan, MD
`Sarah Connelly, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`
`
`8.9.
`
`
`Safety in the Postmarket Setting.................................................................................. 154
`
`8.9.1.
`
` Safety Concerns Identified Through Postmarket Experience ............................... 154
`
`8.9.2.
`
` Expectations on Safety in the Postmarket Setting ............................................... 154
`
`8.10.
`
`
`
`Additional Safety Issues From Other Disciplines ...................................................... 155
`
`8.11.
`
`
`
`Integrated Assessment of Safety .............................................................................. 155
`
`9 Advisory Committee Meeting and Other External Consultations ....................................... 155
`
`10 Labeling Recommendations ................................................................................................ 155
`
`10.1.
`
`
`Prescribing Information ............................................................................................ 155
`
`10.2.
`
`
`Patient Labeling ........................................................................................................ 157
`
`11 Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 157
`
`12 Postmarketing Requirements and Commitments ............................................................... 157
`
`13 Appendices .......................................................................................................................... 158
`
`13.1.
`
`
`References ................................................................................................................ 158
`
`13.2.
`
`
`Financial Disclosure .................................................................................................. 160
`
`13.3.
`
`
`Supplemental Tables ................................................................................................ 162
`
`
`
`Reference ID: 3909326
`
`5
`
`

`

`Clinical Review
`Prabha Viswanathan, MD
`Sarah Connelly, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`
`
`Table of Tables
`
`
`Table 1. Summary of Currently Approved Interferon-Free Treatment for Chronic HCV Infection
`....................................................................................................................................................... 20
`Table 2. Summary of Relevant Clinical Trials ................................................................................ 31
`Table 3. ASTRAL-1 Baseline Demographic Characteristics, FAS ................................................... 37
`Table 4. ASTRAL-1 Baseline HCV Disease Characteristics ............................................................. 38
`Table 5. ASTRAL-1 Primary Efficacy Results .................................................................................. 39
`Table 6. ASTRAL-1 Subgroup Analysis: SVR12 by HCV GT, SOF/VEL Subjects .............................. 41
`Table 7. ASTRAL-1 Subgroup Analysis: SVR12 by Baseline Demographic Characteristics ............ 42
`Table 8. ASTRAL-2 Baseline Demographic Characteristics ........................................................... 45
`Table 9. ASTRAL-2 Baseline HCV Disease Characteristics ............................................................. 46
`Table 10. ASTRAL-2 Primary Efficacy Results ................................................................................ 47
`Table 11. ASTRAL-3 Baseline Demographic Characteristics ......................................................... 50
`Table 12. ASTRAL-3 Baseline HCV Disease Characteristics ........................................................... 51
`Table 13. ASTRAL-3 Primary Efficacy Results ................................................................................ 52
`Table 14. Baseline Disease Characteristics of ASTRAL-3 Relapsers .............................................. 53
`Table 15. ASTRAL-3 Subgroup Analysis of the Primary Endpoint: Baseline Demographic
`Characteristics. .............................................................................................................................. 54
`Table 16. ASTRAL-3 Selected Subgroup Analysis of the Primary Endpoint: Baseline Disease
`Characteristics ............................................................................................................................... 55
`Table 17. ASTRAL-3 Subgroup Analysis of Impact of Cirrhosis and Prior HCV Treatment on SVR12
`Rates.............................................................................................................................................. 56
`Table 18. SVR12 Rates Among TE GT3 Cirrhotics, Trial 342-0109 Groups 7 and 8 ...................... 57
`Table 19. Subject Disposition in ASTRAL-4 ................................................................................... 63
`Table 20. Demographics and Baseline Characteristics, ASTRAL-4 ................................................ 65
`Table 21. Selected Baseline Disease Characteristics, ASTRAL-4 ................................................... 66
`Table 22. ASTRAL-4 Primary Efficacy Results ................................................................................ 68
`Table 23. ASTRAL-4 Efficacy Results, By HCV Genotype ............................................................... 69
`Table 24. SVR12 Rates by Baseline Demographics in ASTRAL-4 (All Treated) .............................. 74
`Table 25. SVR12 Rates by Selected Baseline Disease Characteristics in ASTRAL-4 (All Treated) . 74
`Table 26. SVR12 Rates by Baseline CPT Class in ASTRAL-4 (All Treated) ...................................... 75
`Table 27. Ribavirin Dosing and SVR12 Rates in ASTRAL-4 ............................................................ 79
`Table 28: Percentage of Subjects Achieving SVR12, Pooled Analysis of ASTRAL 1-3 Subjects
`Treated with SOF/VEL 12 Weeks .................................................................................................. 80
`Table 29: Safety Population, Size and Denominators ................................................................... 83
`Table 30. Summary of Demographic Characteristics, ISS Population .......................................... 84
`Table 31. Summary of Baseline HCV Disease Characteristics, ISS Population.............................. 85
`Table 32. Overview of Adverse Events, ISS Population ................................................................ 87
`Table 33. Overview of Adverse Events, ASTRAL-4 ........................................................................ 88
`
`Reference ID: 3909326
`
`6
`
`

`

`Clinical Review
`Prabha Viswanathan, MD
`Sarah Connelly, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`
`Table 34. Treatment-Emergent and Nontreatment-Emergent Deaths, ASTRAL-4 ...................... 92
`Table 35: Treatment-emergent SAEs by SOC, ISS Population ...................................................... 94
`Table 36. Treatment Emergent SAEs by SOC, ASTRAL-4 .............................................................. 96
`Table 37. Treatment Emergent SAEs in SOF/VEL+RBV 12 Week Group, ASTRAL-4 ..................... 97
`Table 38. Adverse Events Leading to Discontinuation from Study Drug, ASTRAL-4 .................. 100
`Table 39. Grade 3 and 4 AEs Reported in 2 or More Subjects, ISS Population .......................... 102
`Table 40. Treatment-emergent AEs Reported in ≥ 5% of SOF/VEL Subjects, All Grade and All
`Causality, ISS Population ............................................................................................................. 103
`Table 41. Treatment-emergent ADRs Reported in ≥ 2% of SOF/VEL Subjects, All Grade, ISS
`Population ................................................................................................................................... 104
`Table 42. Treatment-Emergent AEs Reported in ≥5% of Subjects in Any Treatment Group, All
`Grade and All Cause by Preferred Term, ASTRAL-4 .................................................................... 106
`Table 43. Treatment-Emergent ADRs Reported in ≥5% of Subjects in Any Treatment Group, All
`Grade by Preferred Term, ASTRAL-4 .......................................................................................... 107
`Table 44. Liver Function Tests and Other Chemistry Lab Results, All Grade, ISS Population ..... 108
`Table 45. Hematology Laboratory Results, All Grade, ISS Population ........................................ 110
`Table 46. Grade 3 or 4 Laboratory Data, ASTRAL-4 .................................................................... 111
`Table 47. On-treatment Hepatic Lab Abnormalities, Integrated Phase 3 and Phase 2 Safety
`Population ................................................................................................................................... 123
`Table 48. ASTRAL-4 Subjects Meeting