CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`205834Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`

`

`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`DIVISION OF ANTIVIRAL PRODUCTS
`
`DATE:
`September 25, 2014
`TO:
`NDA 205834 SDN 32, received August 7, 2014
`FROM:
`Medical Officer, Division of Antiviral Products
`SUBJECT: GS-US-337-0115 and NIAID-13-I-0159 Summary Interim Safety Data
`GS-US-337-0115, A Phase 3, Multicenter, Open-Label Study to
`Investigate the Safety and Efficacy of Sofosbuvir/Ledipasvir Fixed-Dose
`Combination for 12 Weeks in Subjects with Chronic Genotype 1 or 4
`Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV)-1 Co
`Infections
`NIAID-13-I-0159, An Open Label Trial to Assess Safety, Tolerability, and
`Efficacy of the Fixed Dose Combination of GS-5885 and GS-7977 in HCV
`Genotype 1 Subjects Coinfected with HIV
`
`Summary interim safety data are available from approximately 175 subjects who
`received LDV/SOF plus Atripla (or its components) within the GS-US-337-0115 and
`NIAID-13-I-0159 trials, including approximately 94 subjects receiving a 12 week
`treatment duration. No subject discontinued LDV/SOF and a single subject changed
`their antiretroviral regimen from Atripla to EFV/RAL/FTC based upon laboratory
`evidence of renal dysfunction. Graded creatinine increases from GS-US-337-0115 were
`low (approximately 2.5%) and all were ≤Grade 2. One subject from the NIAID trial with
`baseline eGFR of 52.5 mL/min experienced treatment-emergent eGFR <50 and
`normoglycemic glycosuria. The eGFR improved to 52.2 mL/min by Week 12 and
`normoglycemic glucosuria was no longer detectable at post-treatment Week 2.
`
`In summary, although LDV/SOF and Atripla coadministration increased tenofovir
`exposures by up to ~2-fold in the phase 1 DDI trial GS-US-337-0127, preliminary safety
`data from the GS-US-337-0115 and NIAID trials are determined to be adequate to
`support labeling for LDV/SOF and Atripla coadministration.
`
` Labeling
`regarding LDV/SOF and Atripla coadministration will refer to the respective tenofovir
`labels to inform providers of the need for close renal monitoring: please refer to Dr.
`Jenny Zheng’s clinical pharmacology review for further details. Submission of the GS-
`US-337-0115 final clinical study report and datasets is an agreed upon postmarketing
`requirement.
`
`Reference ID: 3634380
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SARAH M CONNELLY
`09/25/2014
`
`KIMBERLY A STRUBLE
`09/25/2014
`
`Reference ID: 3634380
`
`

`

`CLINICAL REVIEW
`
`Application Type New Drug Application (NDA)
`Application Number(s) 205834
`Priority or Standard Priority
`
`Submit Date(s) February 8, 2014
`Received Date(s) February 10, 2014
`PDUFA Goal Date October 10, 2014
`Division / Office Division of Antiviral
`Products/Office of
`Antimicrobial Products
`
`Reviewer Name(s) Sarah M. Connelly, MD
`Review Completion Date July 10, 2014
`
`Established Name Ledipasvir (GS-5885) 90
`mg/Sofosbuvir (GS-7977) 400
`mg Fixed Dose Combination
`
`(Proposed) Trade Name
`Therapeutic Class Hepatitis C virus NS5A
`inhibitor/Hepatitis C virus
`NS5B polymerase inhibitor
`Applicant Gilead Sciences, Inc.
`
`Formulation(s) Tablets for oral use
`Dosing Regimen
`Indication(s) Treatment of chronic hepatitis
`C
`Intended Population(s) Adult patients (18 years and
`
`Reference ID: 3540289
`
`

`

`older) with chronic hepatitis C
`
`Template Version: March 6, 2009
`
`Reference ID: 3540289
`
`

`

`Clinical Review
`Sarah M. Connelly, MD
`NDA 205834
`Ledipasvir/Sofosbuvir Fixed-Dose Combination
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT....................................... 11
`1.1 Recommendation on Regulatory Action ........................................................... 11
`1.2 Risk Benefit Assessment.................................................................................. 12
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 14
`1.4 Recommendations for Postmarket Requirements and Commitments .............. 14
`INTRODUCTION AND REGULATORY BACKGROUND ...................................... 15
`2.1 Product Information .......................................................................................... 15
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 16
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 17
`2.4
`Important Safety Issues With Consideration to Related Drugs......................... 17
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 18
`2.6 Other Relevant Background Information .......................................................... 20
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 20
`3.1 Submission Quality and Integrity ...................................................................... 20
`3.2 Compliance with Good Clinical Practices ......................................................... 21
`3.3 Financial Disclosures........................................................................................ 21
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 21
`4.1 Chemistry Manufacturing and Controls ............................................................ 21
`4.2 Clinical Microbiology......................................................................................... 22
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 24
`4.4 Clinical Pharmacology...................................................................................... 26
`4.4.1 Mechanism of Action.................................................................................. 26
`4.4.2 Pharmacodynamics.................................................................................... 26
`4.4.3 Pharmacokinetics....................................................................................... 27
`5 SOURCES OF CLINICAL DATA............................................................................ 30
`5.1 Tables of Studies/Clinical Trials ....................................................................... 31
`5.2 Review Strategy ............................................................................................... 34
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 35
`6 REVIEW OF EFFICACY......................................................................................... 54
`Efficacy Summary...................................................................................................... 54
`6.1
`Indication .......................................................................................................... 58
`6.1.1 Methods ..................................................................................................... 58
`6.1.2 Demographics............................................................................................ 60
`6.1.3 Subject Disposition .................................................................................... 66
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 69
`6.1.5 Analysis of Secondary Endpoints(s)........................................................... 72
`
`Reference ID: 3540289
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`Clinical Review
`Sarah M. Connelly, MD
`NDA 205834
`Ledipasvir/Sofosbuvir Fixed-Dose Combination
`
`6.1.6 Other Endpoints ......................................................................................... 82
`6.1.7 Subpopulations .......................................................................................... 82
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 85
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 85
`6.1.10 Additional Efficacy Issues/Analyses........................................................... 86
`7 REVIEW OF SAFETY............................................................................................. 86
`7.1 Methods............................................................................................................ 88
`7.1.1 Clinical Trials Used to Evaluate Safety ...................................................... 88
`7.1.2 Categorization of Adverse Events.............................................................. 90
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 91
`7.2 Adequacy of Safety Assessments .................................................................... 91
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 91
`7.2.2 Explorations for Dose Response................................................................ 93
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 94
`7.2.4 Routine Clinical Testing ............................................................................. 94
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 95
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 95
`7.3 Major Safety Results ...................................................................................... 103
`7.3.1 Deaths...................................................................................................... 103
`7.3.2 Nonfatal Serious Adverse Events ............................................................ 104
`7.3.3 Dropouts and/or Discontinuations ............................................................ 108
`7.3.4 Significant Adverse Events ...................................................................... 109
`7.3.5 Submission Specific Primary Safety Concerns ........................................ 117
`7.4 Supportive Safety Results .............................................................................. 154
`7.4.1 Common Adverse Events ........................................................................ 154
`7.4.2
`Laboratory Findings ................................................................................. 164
`7.4.3 Vital Signs................................................................................................ 173
`7.4.4 Electrocardiograms (ECGs) ..................................................................... 174
`7.4.5 Special Safety Studies/Clinical Trials....................................................... 176
`7.4.6
`Immunogenicity........................................................................................ 180
`7.5 Other Safety Explorations............................................................................... 180
`7.5.1 Dose Dependency for Adverse Events .................................................... 180
`7.5.2 Time Dependency for Adverse Events..................................................... 181
`7.5.3 Drug-Demographic Interactions ............................................................... 181
`7.5.4 Drug-Disease Interactions........................................................................ 183
`7.5.5 Drug-Drug Interactions............................................................................. 184
`7.6.1 Human Carcinogenicity............................................................................ 186
`7.6.2 Human Reproduction and Pregnancy Data.............................................. 187
`7.6.3 Pediatrics and Assessment of Effects on Growth .................................... 188
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound.................... 189
`7.7 Additional Submissions / Safety Issues.......................................................... 189
`
`Reference ID: 3540289
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`

`

`Clinical Review
`Sarah M. Connelly, MD
`NDA 205834
`Ledipasvir/Sofosbuvir Fixed-Dose Combination
`
`8 POSTMARKET EXPERIENCE............................................................................. 194
`9 APPENDICES ...................................................................................................... 195
`9.1
`Literature Review/References ........................................................................ 195
`9.2
`Labeling Recommendations ........................................................................... 196
`9.3 Advisory Committee Meeting.......................................................................... 198
`
`Reference ID: 3540289
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`5
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`

`

`Clinical Review
`Sarah M. Connelly, MD
`NDA 205834
`Ledipasvir/Sofosbuvir Fixed-Dose Combination
`
`Table of Tables
`
`Table 1 Currently US Approved Agents for Treatment of Chronic HCV Genotype 1
`Infection ......................................................................................................... 17
`Table 2 Phase 2 LDV-Containing Trials ........................................................................ 31
`Table 3 Overview of Phase 2 and Pivotal Phase 3 LDV/SOF Trials ............................. 33
`Table 4 Methods of Cirrhosis Determination in Phase 3 Trials...................................... 34
`Table 5 GS-US-248-0120: Adverse Events in at Least 10% of Subjects in Any
`Treatment Group............................................................................................ 37
`Table 6 Response Rates in Selected ELECTRON HCV Genotype 1 LDV+SOF- and
`LDV/SOF-Containing Treatment Groups ....................................................... 39
`Table 7 GS-US-337-0118: Sustained Virologic Response Rate at Posttreatment Follow-
`Up Week 12 (Full Analysis Set) ..................................................................... 41
`Table 8 GS-US-337-0122: Proportion of Subjects with HCV Genotype 3 Infection
`Achieving SVR12 (Full Analysis Set) ............................................................. 42
`Table 9 Overall Summary of Adverse Events in ION-1 (GS-US-337-0102: Safety
`Analysis Set).................................................................................................. 46
`Table 10 Discontinuation of LDV/SOF due to Adverse Events, ION-1 (GS-US-337-0102:
`Safety Analysis Set)....................................................................................... 47
`Table 11 Serious Adverse Events in ION-1 (GS-US-337-0102: Safety Analysis Set) ... 48
`Table 12 Overall Summary of Adverse Events in ION-3 (GS-US-337-0108: Safety
`Analysis Set).................................................................................................. 50
`Table 13 Discontinuation of LDV/SOF due to Adverse Event, ION-3 (GS-US-337-0108:
`Safety Analysis Set)....................................................................................... 51
`Table 14 Serious Adverse Events in ION-3 (GS-US-337-0108: Safety Analysis Set) ... 51
`Table 15 Overall Summary of Adverse Events in ION-2 (GS-US-337-0109: Safety
`Analysis Set).................................................................................................. 53
`Table 16 Serious Adverse Events in ION-2 (GS-US-337-0109: Safety Analysis Set) ... 54
`Table 17 Demographics and Baseline Characteristics, ION-1 (GS-US-337-0102: Safety
`Analysis Set).................................................................................................. 61
`Table 18 Selected Baseline Disease Characteristics, ION-1 (GS-US-337-0102: Safety
`Analysis Set).................................................................................................. 62
`Table 19 Demographics and Baseline Characteristics, ION-3 (GS-US-337-0108: Safety
`Analysis Set).................................................................................................. 63
`Table 20 Selected Baseline Disease Characteristics, ION-3 (GS-US-337-0108: Safety
`Analysis Set).................................................................................................. 64
`Table 21 Demographics and Baseline Characteristics, ION-2 (GS-US-337-0109: Safety
`Analysis Set).................................................................................................. 65
`Table 22 Selected Baseline Disease Characteristics, ION-2 (GS-US-337-0109: Safety
`Analysis Set).................................................................................................. 66
`Table 23 Subject Disposition in ION-1 (GS-US-337-0102)............................................ 67
`Table 24 Subject Disposition in ION-3 (GS-US-337-0108)............................................ 68
`Table 25 Subject Disposition in ION-2 (GS-US-337-0109)............................................ 69
`Table 26 Primary Efficacy Results and Relapse Rates in ION-1 (All Treated) .............. 70
`
`Reference ID: 3540289
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`6
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`

`Clinical Review
`Sarah M. Connelly, MD
`NDA 205834
`Ledipasvir/Sofosbuvir Fixed-Dose Combination
`
`Table 27 Primary Efficacy Results and Relapse Rates in ION-3 (All Treated) .............. 71
`Table 28 Inter Group Comparison of SVR12 Rates in ION-3 (All Treated) ................... 71
`Table 29 Primary Efficacy Results and Relapse Rates in ION-2 (All Treated) .............. 72
`Table 30 Relapse Rates in ION-1 and ION-3 (All Treated) ........................................... 73
`Table 31 Comparison of Relapse Rates Between Different Treatment Durations in ION-
`3 (All Treated) ................................................................................................ 74
`Table 32 Relapse Rates by Baseline Viral Load for 8-Week and 12-Week Regimens in
`ION-3 (All Treated)......................................................................................... 75
`Table 33 Selected Subgroup Relapse Rates for LDV/SOF 8 Week and 12 Week
`Regimens in ION-3 (All Treated).................................................................... 76
`Table 34 Relapse Rates in ION-2 (All Treated)............................................................. 77
`Table 35 Response and Relapse Rates in Subjects with Cirrhosis, ION-2 ................... 78
`Table 36 Results for Selected Subgroup Relapse Rates for 12-Week and 24-Week
`Regimens in ION-2 (All Treated).................................................................... 79
`Table 37 Relapse by Baseline NS5A Resistance Associated Polymorphisms, IL28B,
`Age, Non-Cirrhotic Population, ION-2 (Limited to LDV/SOF±RBV 12 Week
`and LDV/SOF 24 Week arms) ....................................................................... 80
`Table 38 Response and Relapse Rates in Subjects with Cirrhosis, ION-1 ................... 83
`Table 39 SVR12 Based on HCV Genotype 1 Subtype (ION-1, ION-2, ION-3).............. 84
`Table 40 Response Rates in Subjects Based on Prior HCV Treatment History (ION-2)85
`Table 41 ION-1, ION-2, ION-3: Subject Disposition for LDV/SOF Phase 3 Integrated
`Safety Population........................................................................................... 93
`Table 42 Cardiac Disorder System Organ Class Treatment-Emergent Adverse Events,
`All Cause, All Grade, LDV/SOF Phase 3 Integrated Safety Population ......... 97
`Table 43 Events of Cardiomyopathy or Cardiac Failure in the Sofosbuvir Clinical
`Development Program................................................................................... 98
`Table 44 Events of Cardiomyopathy or Cardiac Failure in the LDV/SOF Clinical
`Development Program................................................................................. 100
`Table 45 Treatment-Emergent Serious Adverse Events by System Organ Class and
`Preferred Term, LDV/SOF Phase 3 Integrated Safety Population ............... 104
`Table 46 Adverse Events Leading to Discontinuation from Study Drug, LDV/SOF Phase
`3 Integrated Safety Population..................................................................... 109
`Table 47 Overall Summary of Adverse Events in the Phase 3 LDV/SOF Trials
`(Integrated Safety Population) ..................................................................... 110
`Table 48 Overall Summary of ≥Grade 3 Clinical AEs in the Phase 3 LDV/SOF Trials,
`Reported in Two or More Subjects (Integrated Data)................................... 111
`Table 49 Lipase Elevations in the LDV/SOF Phase 3 Integrated Safety Population ... 113
`Table 50 Depression and Suicidal Events, Treatment-Emergent, LDV/SOF Phase 3
`Integrated Safety Population........................................................................ 115
`Table 51 Treatment-Emergent ≥Grade 3 and/or SAEs within the Gastrointestinal
`System Organ Class, LDV/SOF Phase 3 Integrated Safety Population....... 122
`Table 52 Treatment-Emergent Adverse Events within the Hepatic and Hepatobiliary
`High Level Group Term, All Grade, LDV/SOF Phase 3 Integrated Safety
`Population.................................................................................................... 127
`
`Reference ID: 3540289
`
`7
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`

`Clinical Review
`Sarah M. Connelly, MD
`NDA 205834
`Ledipasvir/Sofosbuvir Fixed-Dose Combination
`
`Table 53 Summary of Liver Tests for Subject 71474 in ION-1 .................................... 128
`Table 54 Laboratory Data in Phase 3 LDV/SOF Integrated Safety Population, Liver
`Laboratories................................................................................................. 129
`Table 55 Selected Laboratory Tests for Subject #7832-1020 ..................................... 132
`Table 56 Subjects with Myocardial Ischemia Events in LDV/SOF Trials..................... 143
`Table 57 Pooled Rash Events, Treatment-Emergent, LDV/SOF Phase 3 Integrated
`Safety Population......................................................................................... 147
`Table 58 Treatment-Emergent Adverse Events, All Cause, All Grade, by Preferred Term
`(≥5% of subjects in any treatment group), LDV/SOF Phase 3 Integrated Safety
`Population.................................................................................................... 155
`Table 59 Treatment-Emergent, Treatment-Related Adverse Events, All Grade, by
`Preferred Term (≥5% of subjects in any treatment group), LDV/SOF Phase 3
`Integrated Safety Population........................................................................ 156
`Table 60 Treatment-Emergent, Treatment-Related Adverse Events, All Grade, by
`Preferred Term (≥5% of subjects in any treatment group), LDV/SOF Phase 3
`Integrated Safety Population: Pooled LDV/SOF+RBV versus LDV/SOF Arms
`..................................................................................................................... 157
`Table 61 Overall Summary of Adverse Events in the HCV Genotype 1 Treatment-Naïve,
`Non-Cirrhotic Population, LDV/SOF Arms (ION-1 and ION-3 Integrated Safety
`Population)................................................................................................... 158
`Table 62 Treatment-Emergent, Treatment-Related Adverse Events, All Grade ≥5% in
`the HCV Genotype 1 Treatment-Naïve, Non-Cirrhotic Population, LDV/SOF
`Arms (ION-1 and ION-3 Integrated Safety Population)................................ 159
`Table 63 Pooled ION-1 and ION-3 LDV/SOF 8 and 12 Week Arms: Treatment-
`Emergent, Treatment-Related Adverse Events, All Grade ≥5% in the HCV
`Genotype 1 Treatment-Naïve, Non-Cirrhotic Population (ION-1 and ION-3
`Integrated Safety Population) 1 .................................................................... 160
`Table 64 Overall Summary of Adverse Events in the HCV Genotype 1 Cirrhotic and
`Non-Cirrhotic Population, LDV/SOF Arms (ION-1 and ION-2 Integrated Safety
`Population)................................................................................................... 161
`Table 65 Treatment-Emergent, Treatment-Related Adverse Events, All Grade ≥5% in
`the HCV Genotype 1 Cirrhotic and Non-Cirrhotic Populations, LDV/SOF Arms
`(ION-1 and ION-2 Integrated Safety Population) ......................................... 162
`Table 66 Pooled ION-1 and ION-2 LDV/SOF 12 and 24 week arms: Treatment-
`Emergent, Treatment-Related Adverse Events, All Grade ≥5% in the HCV
`Genotype 1 Cirrhotic and Non-Cirrhotic Population, LDV/SOF Arms (ION-1
`and ION-2 Integrated Safety Population) 1................................................... 163
`Table 67 Hemoglobin Laboratories <10 and <8.5 g/dL, LDV/SOF Phase 3 Integrated
`Safety Population......................................................................................... 164
`Table 68 Hematology Laboratory Data, LDV/SOF Phase 3 Integrated Safety Population
`..................................................................................................................... 165
`Table 69 Additional Laboratories with ≥Grade 3 Event in >1 Subject, LDV/SOF Phase 3
`Integrated Safety Population........................................................................ 169
`
`Reference ID: 3540289
`
`8
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`

`

`Clinical Review
`Sarah M. Connelly, MD
`NDA 205834
`Ledipasvir/Sofosbuvir Fixed-Dose Combination
`
`Table 70 Creatinine Laboratory Data, LDV/SOF Phase 3 Integrated Safety Population
`..................................................................................................................... 169
`Table 71 Cases of Renal Failure Reported in the Safety Update Report .................... 171
`Table 72 The Point Estimates and the 90% CIs Corresponding to the Largest Upper
`Bounds for Ledipasvir 120 mg BID and the Largest Lower Bound for
`Moxifloxacin (FDA Analysis) ........................................................................ 174
`
`Reference ID: 3540289
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`9
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`

`

`Clinical Review
`Sarah M. Connelly, MD
`NDA 205834
`Ledipasvir/Sofosbuvir Fixed-Dose Combination
`
`Table of Figures
`
`Figure 1 Trial Schematic of Pivotal Phase 3 Trials........................................................ 44
`Figure 2 On-Treatment Virologic Response by Treatment Groups in ION-1 and ION-3
`(All Treated, NC=F)........................................................................................ 81
`Figure 3 On-Treatment Virologic Response by Treatment Groups in ION-2 (All Treated,
`NC=F) ............................................................................................................ 82
`Figure 4 Subject #4238-71160 Laboratory Data ......................................................... 131
`Figure 5 Subject #6833-79354 Laboratory Data ......................................................... 138
`Figure 6 Subject #3054-79014 Laboratory Data ......................................................... 139
`Figure 7 Subject #4007-71021 Laboratory Data ......................................................... 168
`
`Reference ID: 3540289
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`10
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`

`Clinical Review
`Sarah M. Connelly, MD
`NDA 205834
`Ledipasvir/Sofosbuvir Fixed-Dose Combination
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1
`
`Recommendation on Regulatory Action
`
`I recommend approval of ledipasvir (LDV)/sofosbuvir (SOF) fixed dose combination
`(FDC) for use in adults with chronic genotype 1 (GT 1) hepatitis C virus (HCV) infection.
`This recommendation is based on data contained in the NDA submission 205834. The
`efficacy and safety of LDV/SOF is demonstrated in the three pivotal phase 3 trials, GS-
`US-337-0102 (ION-1), GS-US-337-0108 (ION-3), GS-US-337-0109 (ION-2). The
`currently available data supports a favorable risk benefit assessment for the use of
`LDV/SOF in treatment-naïve and treatment-experienced patients with chronic HCV GT
`1 infection.
`
`Efficacy
`
`The efficacy of LDV/SOF in subjects with chronic HCV GT 1 infection is demonstrated
`in three pivotal phase 3 trials (ION-1, ION-2, ION-3). The primary efficacy endpoint is
`sustained virologic response, defined as HCV RNA less than the lower limit of
`quantification (LLOQ) 12 weeks after discontinuation of treatment (SVR12). Overall
`phase 3 efficacy results are summarized here and details are further discussed in
`Section 6 (Review of Efficacy).
` The efficacy and safety of LDV/SOF with or without (±) ribavirin (RBV) for 12
`weeks was evaluated in HCV treatment-naïve subjects with HCV GT 1 infection,
`including 16% with compensated cirrhosis (ION-1). A statistically significant
`proportion of subjects (p<0.001) in each treatment group achieved SVR12 (99%
`LDV/SOF 12 Week, 97% LDV/SOF+RBV 12 Week) compared to a prespecified
`historical control rate of 60%. Relapse rates are 0.5% in the LDV/SOF 12 Week
`arm and 0% in the LDV/SOF+RBV 12 Week arm.
`
` The efficacy and safety of LDV/SOF±RBV for 8 or 12 weeks was evaluated in
`HCV treatment-naïve subjects with HCV GT 1 infection and without cirrhosis
`(ION-3). A statistically significant proportion of subjects (p<0.001) in each
`treatment group achieved SVR12 (94% LDV/SOF 8 Week, 93% LDV/SOF+RBV
`8 Week, 96% LDV/SOF 12 Week) compared to a prespecified historical control
`rate of 60%. Relapse rates are 5.1% in the LDV/SOF 8 Week arm, 4.2% in the
`LDV/SOF+RBV 8 Week arm, and 1.4% in the LDV/SOF 24 Week arm.
`
` The efficacy and safety of LDV/SOF±RBV for 12 or 24 weeks was evaluated in
`HCV treatment-experienced subjects with HCV GT 1 infection, including 20%
`with compensated cirrhosis and 53% prior HCV NS3/4A protease inhibitor (PI)-
`containing treatment failures (ION-2). A statistically significant proportion of
`
`Reference ID: 3540289
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`11
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`

`Clinical Review
`Sarah M. Connelly, MD
`NDA 205834
`Ledipasvir/Sofosbuvir Fixed-Dose Combination
`
`subjects (p<0.001) in each treatment group achieved SVR12 (94% LDV/SOF 12
`Week, 96% LDV/SOF+RBV 12 Week, 99% LDV/SOF 24 Week, 99%
`LDV/SOF+RBV 24 Week) compared to a prespecified historical control rate of
`25%. Relapse rates are 6.5% in the LDV/SOF 12 Week arm, 3.6% in the
`LDV/SOF+RBV 12 Week arm and 0% in each of the LDV/SOF±RBV 24 Week
`arms.
`
`In summary, two phase 3 trials demonstrate efficacy in HCV GT 1 treatment-naive
`subjects: ION-1 demonstrates the efficacy of LDV/SOF±RBV for 12 weeks, and ION-3
`demonstrates the efficacy of LDV/SOF±RBV for 8 weeks and LDV/SOF for 12 weeks
`in non-cirrhotic subjects. One phase 3 trial (ION-2) demonstrates the efficacy of
`LDV/SOF±RBV for 12 or 24 weeks in HCV GT 1 treatment-experienced subjects. ION-
`1 and ION-2 include a subset of subjects with compensated cirrhosis which represents
`a harder to treat subgroup.
`
`Safety
`
`The observed safety profile of LDV/SOF-containing treatment is favorable. No safety
`event warrants Warnings and Precautions labeling consideration at this time. No on-
`treatment deaths occur in the phase 3 program. The overall percentage of serious
`adverse events (SAE) and discontinuations due to adverse events (AE) is low. A
`LDV/SOF regimen has an improved safety profile compared with a LDV/SOF+RBV
`regimen with a lower incidence of treatment-emergent AEs, Grade 3 or higher AEs,
`and AEs leading to dose modification or interruption. No safety signal is identified
`precluding administration of LDV/SOF treatment duration up to 24 weeks. LDV/SOF
`treatment durations of 8 and 12 weeks have similar safety profiles in treatment-naïve,
`non-cirrhotic subjects. LDV/SOF treatment durations of 12 and 24 weeks have similar
`safety profiles overall and in cirrhotic subjects. No unique safety concerns are
`identified based on analyses of sex, race and age.
`
`In summary, LDV/SOF provides an all-oral treatment option for patients with chronic
`HCV GT 1 infection. A LDV/SOF regimen offers an improved safety profile compared to
`known toxicities associated with both interferon-based and RBV-based regimens, and
`provides a therapeutic option for patients who cannot take interferon and/or RBV,
`addressing an unmet need in this population.
`
`No deficiencies in the submitted data preclude recommendation for approval of
`LDV/SOF at this time.
`
`1.2
`
`Risk Benefit Assessment
`
`The overall risk benefit assessment is highly favorable for LDV/SOF. This assessment
`is based upon the demonstrated efficacy results, observed safety profile and interferon-
`
`Reference ID: 3540289
`
`12
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`

`

`Clinical Review
`Sarah M. Connelly, MD
`NDA 205834
`Ledipasvir/Sofosbuvir Fixed-Dose Combination
`
`free, once daily, simpler treatment regimen compared to currently available therapeutic
`regimens for the treatment of chronic HCV GT 1 infection.
`
`Benefit
`
`LDV/SOF is a once daily tablet, interferon-free regimen for the treatment of HCV GT
`1 infection. The addition of RBV