CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`209195Orig1s000
`
`CLINICAL REVIEW(S)
`
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`
`
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`
`
`
`

`

`Clinical Review
`Kirk Chan-Tack, MD
`NDA 209195
`Vosevi (sofosbuvir and velpatasvir and voxilaprevir)
`CLINICAL REVIEW
`Application Type New Drug Application
`Application Number(s) 209195
`Priority or Standard Priority
`Submit Date(s) December 8, 2016
`Received Date(s) December 8, 2016
`PDUFA Goal Date August 8, 2017
`Division/Office Division of Antiviral Products/Office of Antimicrobial Products
`Reviewer Name(s) Kirk Chan-Tack, MD
`Review Completion Date May 5, 2017
`Established Name sofosbuvir and velpatasvir and voxilaprevir
`(Proposed) Trade Name Vosevi®
`Applicant Gilead Sciences, Inc.
`Formulation(s) Fixed dose combination tablet containing 400 mg sofosbuvir and
`100 mg velpatasvir and 100 mg voxilaprevir
`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: 4094448
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`

`

`Clinical Review
`Kirk Chan-Tack, MD
`NDA 209195
`Vosevi (sofosbuvir and velpatasvir and voxilaprevir)
`Table of Contents
`
`Glossary ..........................................................................................................................................7
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Executive Summary.................................................................................................................9
`1.1.
`Product Introduction........................................................................................................9
`1.2.
`Conclusions on the Substantial Evidence of Effectiveness...............................................9
`1.3.
`Benefit-Risk Assessment ..................................................................................................9
`
`Therapeutic Context..............................................................................................................16
`2.1. Analysis of Condition......................................................................................................16
`2.2. Analysis of Current Treatment Options .........................................................................17
`
`Regulatory Background .........................................................................................................18
`3.1. U.S. Regulatory Actions and Marketing History.............................................................18
`3.2.
`Summary of Presubmission/Submission Regulatory Activity ........................................19
`3.3.
`Foreign Regulatory Actions and Marketing History .......................................................19
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety ................................................................................................................20
`4.1. Office of Scientific Investigations (OSI) ..........................................................................20
`4.2.
`Clinical Microbiology......................................................................................................20
`4.3.
`Product Quality ..............................................................................................................21
`4.4. Nonclinical Pharmacology/Toxicology ...........................................................................22
`4.5.
`Clinical Pharmacology ....................................................................................................23
`4.5.1. Mechanism of Action..............................................................................................23
`4.5.2. Pharmacodynamics.................................................................................................23
`4.5.3. Pharmacokinetics....................................................................................................24
`4.6. Devices and Companion Diagnostic Issues ....................................................................27
`4.7.
`Consumer Study Reviews...............................................................................................27
`
`Sources of Clinical Data and Review Strategy .......................................................................27
`5.1.
`Table of Clinical Studies .................................................................................................27
`5.2.
`Review Strategy .............................................................................................................30
`
`Review of Relevant Individual Trials Used to Support Efficacy .............................................30
`6.1.
`POLARIS-1 ......................................................................................................................31
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`Reference ID: 4094448
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`

`Clinical Review
`Kirk Chan-Tack, MD
`NDA 209195
`Vosevi (sofosbuvir and velpatasvir and voxilaprevir)
`6.1.1. Study Design ...........................................................................................................31
`6.1.2. Study Results ..........................................................................................................33
`POLARIS-4 ......................................................................................................................40
`6.2.1. Study Design ...........................................................................................................40
`6.2.2. Study Results ..........................................................................................................41
`
`6.2.
`
`7
`
`8
`
`Integrated Review of Effectiveness.......................................................................................53
`7.1. Assessment of Efficacy Across Trials..............................................................................53
`7.1.1. Primary Endpoints ..................................................................................................53
`7.1.2. Subpopulations.......................................................................................................53
`7.1.3. Dose and Dose-Response .......................................................................................53
`7.1.4. Onset, Duration, and Durability of Efficacy Effects.................................................54
`7.2. Additional Efficacy Considerations.................................................................................54
`7.2.1. Considerations on Benefit in the Postmarket Setting.............................................54
`7.2.2. Other Relevant Benefits..........................................................................................54
`Integrated Assessment of Effectiveness ........................................................................54
`
`7.3.
`
`Review of Safety....................................................................................................................55
`8.1.
`Safety Review Approach ................................................................................................55
`8.2.
`Review of the Safety Database ......................................................................................56
`8.2.1. Overall Exposure.....................................................................................................57
`8.2.2. Relevant characteristics of the safety population ..................................................57
`8.2.3. Adequacy of the safety database ...........................................................................57
`8.3. Adequacy of Applicant’s Clinical Safety Assessments....................................................57
`8.3.1. Issues Regarding Data Integrity and Submission Quality........................................57
`8.3.2. Categorization of Adverse Events...........................................................................58
`8.3.3. Routine Clinical Tests..............................................................................................58
`Safety Results.................................................................................................................58
`8.4.1. Deaths.....................................................................................................................59
`8.4.2. Serious Adverse Events...........................................................................................61
`8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects....................................64
`8.4.4. Significant Adverse Events......................................................................................65
`8.4.5. Treatment Emergent Adverse Events and Adverse Reactions ...............................67
`
`8.4.
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`Reference ID: 4094448
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`Clinical Review
`Kirk Chan-Tack, MD
`NDA 209195
`Vosevi (sofosbuvir and velpatasvir and voxilaprevir)
`8.4.6. Laboratory Findings ................................................................................................69
`8.4.7. Vital Signs................................................................................................................73
`8.4.8. Electrocardiograms (ECGs) .....................................................................................74
`8.4.9. QT ...........................................................................................................................74
`8.4.10.
`Immunogenicity...............................................................................................75
`8.5. Analysis of Submission-Specific Safety Issues ................................................................75
`8.5.1. Hepatotoxicity ........................................................................................................75
`8.5.2. Cardiac Disorders....................................................................................................81
`8.5.3. Neuropsychiatric Disorders ....................................................................................83
`8.5.4. Rash ........................................................................................................................84
`8.5.5. Rhabdomyolysis......................................................................................................84
`8.5.6. Pancreatitis .............................................................................................................85
`8.5.7. Pancytopenia ..........................................................................................................85
`8.5.8. Safety Profile Among Subjects with Baseline CPT A Cirrhosis ................................85
`Safety Analyses by Demographic Subgroups .................................................................86
`8.6.
`Specific Safety Studies/Clinical Trials .............................................................................88
`8.7.
`8.8. Additional Safety Explorations.......................................................................................88
`8.8.1. Human Carcinogenicity or Tumor Development ....................................................88
`8.8.2. Human Reproduction and Pregnancy.....................................................................89
`8.8.3. Pediatrics and Assessment of Effects on Growth ...................................................89
`8.8.4. Overdose, Drug Abuse Potential, Withdrawal, and Rebound.................................90
`Safety in the Postmarket Setting ...................................................................................91
`8.9.1. Safety Concerns Identified Through Postmarket Experience .................................91
`8.9.2. Expectations on Safety in the Postmarket Setting..................................................92
`8.10.
`Additional Safety Issues From Other Disciplines ........................................................92
`8.11.
`Integrated Assessment of Safety................................................................................92
`
`8.9.
`
`9
`
`Advisory Committee Meeting and Other External Consultations .........................................92
`
`10 Labeling Recommendations ..................................................................................................92
`10.1.
`Prescribing Information..............................................................................................92
`10.2.
`Patient Labeling..........................................................................................................95
`
`11 Risk Evaluation and Mitigation Strategies (REMS) ................................................................96
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`Reference ID: 4094448
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`

`Clinical Review
`Kirk Chan-Tack, MD
`NDA 209195
`Vosevi (sofosbuvir and velpatasvir and voxilaprevir)
`12 Postmarketing Requirements and Commitments.................................................................96
`
`13 Appendices............................................................................................................................96
`13.1.
`References..................................................................................................................96
`13.2.
`Financial Disclosure ....................................................................................................98
`13.3.
`Supplemental Tables ..................................................................................................99
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`Reference ID: 4094448
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`Clinical Review
`Kirk Chan-Tack, MD
`NDA 209195
`Vosevi (sofosbuvir and velpatasvir and voxilaprevir)
`Table of Tables
`Table 1. Summary of Currently Approved Interferon-Free Treatment for Chronic HCV Infection
`......................................................................................................................................................17
`Table 2. Summary of Relevant Clinical Trials................................................................................28
`Table 3. POLARIS-1 Baseline Demographic Characteristics, FAS ..................................................34
`Table 4. POLARIS-1 Baseline HCV Disease Characteristics............................................................35
`Table 5. POLARIS-1 Primary Efficacy Results, SOF/VEL/VOX Subjects..........................................36
`Table 6. POLARIS-1 Subgroup Analysis: SVR12 by selected baseline disease characteristics,
`SOF/VEL/VOX Subjects .................................................................................................................38
`Table 7. POLARIS-1 Subgroup Analysis: SVR12 by Baseline Demographic Characteristics...........39
`Table 8. POLARIS-4 Baseline Demographic Characteristics ..........................................................42
`Table 9. POLARIS-4 Baseline HCV Disease Characteristics............................................................43
`Table 10. POLARIS-4 Overall Primary Efficacy Results and Subgroup Analysis of Virologic
`Outcomes at Post-Treatment Week 12 by HCV Genotype...........................................................44
`Table 11: POLARIS-4 Subgroup Analysis: SVR12 by selected baseline disease characteristics.....48
`Table 12: POLARIS-4 Subgroup Analysis: SVR12 by Baseline Demographic Characteristics.........49
`Table 13. SVR12 rates by HCV genotype and cirrhosis status among subjects with 1 or 2 negative
`host factors in POLARIS-4 .............................................................................................................51
`Table 14. SVR12 rates by HCV genotype and cirrhosis status among subjects with 3, 4 or 5
`negative host factors in POLARIS-4 ..............................................................................................52
`Table 15. POLARIS-1: SVR12 by HCV GT Among Subjects Treated with SOF/VEL/VOX n (%) .......53
`Table 16. POLARIS-4: SVR12 by Treatment Arm and HCV GT n (%)..............................................53
`Table 17. Safety Population, Size and Denominators...................................................................57
`Table 18. Overview of Adverse Events, POLARIS-1 and POLARIS-4..............................................59
`Table 19. Treatment-emergent SAEs by SOC, POLARIS-1 and POLARIS-4 ....................................62
`Table 20. Adverse Events Leading to Study Drug Discontinuation, POLARIS-1 and POLARIS-4....65
`Table 21. Grade 3 and 4 AEs, POLARIS-1 and POLARIS-4..............................................................66
`Table 22. Treatment-emergent AEs Reported in ≥ 5% of SOF/VEL/VOX Subjects, All Grade and
`All Causality, POLARIS-1 and POLARIS-4.......................................................................................67
`Table 23. Treatment-emergent ADRs Reported in ≥ 2% of SOF/VEL/VOX Subjects, All Grade,
`POLARIS-1 and POLARIS-4 ............................................................................................................68
`Table 24. Treatment-emergent ADRs Reported in ≥ 2% of SOF/VEL/VOX Subjects, All Grade,
`POLARIS-1 and POLARIS-4 ............................................................................................................69
`Table 25. Liver Function Tests and Other Chemistry Lab Results, All Grade, POLARIS-1 and
`POLARIS-4 .....................................................................................................................................70
`Table 26. Hematology Laboratory Results, All Grade, POLARIS-1 and POLARIS-4........................72
`Table 27. Laboratory abnormalities, All Grade, reported with ≥2% risk difference between
`SOF/VEL/VOX 8 Week versus 12 Week (ISS) ................................................................................73
`Table 28: On-treatment Hepatic Lab Abnormalities, Integrated Phase 3 and Phase 2 Safety
`Population ....................................................................................................................................79
`Table 29: Cardiac Events, All Cause, All Grade, POLARIS-1 and POLARIS-4 ..................................81
`Table 30. POLARIS-4: SVR12 rates by genotype and regimen (SOF-containing vs. non-SOF
`containing)....................................................................................................................................95
`
`Reference ID: 4094448
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`

`

`Clinical Review
`Kirk Chan-Tack, MD
`NDA 209195
`Vosevi (sofosbuvir and velpatasvir and voxilaprevir)
`
`Glossary
`
`AE
`APRI
`AUC
`BRF
`CDER
`CFR
`CHC
`CK
`CMC
`CPT
`CSR
`CYP
`DAA
`DAIDS
`DMC
`DDI
`DILI
`ECG
`ECI
`eCTD
`eGFR
`FAS
`FDA
`FDC
`FU
`GT
`HCV
`IAC
`ICH
`IND
`IFN
`ITG
`ISE
`ISS
`ITT
`MedDRA
`MELD
`NC
`
`adverse event
`aspartate aminotransferase: platelet ratio index
`area under the concentration-time curve
`Benefit Risk Framework
`Center for Drug Evaluation and Research
`Code of Federal Regulations
`Chronic Hepatitis C
`creatine kinase
`chemistry, manufacturing, and controls
`Child-Pugh-Turcotte score
`clinical study report
`cytochrome P450
`direct acting antiviral
`Division of AIDS
`data monitoring committee
`drug-drug interaction
`drug-induced liver injury
`electrocardiogram
`event of clinical interest
`electronic common technical document
`estimated glomerular filtration rate
`full analysis set
`Food and Drug Administration
`fixed-dose combination
`follow up
`genotype
`hepatitis C virus
`Independent Adjudication Committee
`International Conference on Harmonization
`Investigational New Drug
`interferon alfa
`immediate treatment group
`integrated summary of effectiveness
`integrated summary of safety
`intent to treat
`Medical Dictionary for Regulatory Activities
`Model for End-Stage Liver Disease score
`noncirrhotic
`
`Reference ID: 4094448
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`

`Clinical Review
`Kirk Chan-Tack, MD
`NDA 209195
`Vosevi (sofosbuvir and velpatasvir and voxilaprevir)
`NDA
`new drug application
`NME
`new molecular entity
`OSI
`Office of Scientific Investigation
`PBO
`placebo
`PD
`pharmacodynamics
`PI
`protease inhibitor
`PK
`pharmacokinetics
`PMC
`postmarketing commitment
`PMR
`postmarketing requirement
`PPI
`patient package insert
`PR
`pegylated interferon alfa and ribavirin
`PREA
`Pediatric Research Equity Act
`PT
`Preferred Term (aka Dictionary Derived Term)
`RAP
`resistance associated polymorphism
`RAS
`resistance associated substitution
`RBV
`ribavirin
`REMS
`risk evaluation and mitigation strategy
`SAE
`serious adverse event
`SAP
`statistical analysis plan
`SOC
`system organ class
`SOF
`sofosbuvir
`SVR
`sustained virologic response
`TE
`treatment experienced
`TEAE
`treatment emergent adverse event
`TN
`treatment naïve
`TW
`treatment week
`VEL
`velpatasvir
`VOX
`voxilaprevir
`US
`United States
`
`Reference ID: 4094448
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`

`Clinical Review
`Kirk Chan-Tack, MD
`NDA 209195
`Vosevi (sofosbuvir and velpatasvir and voxilaprevir)
`1 Executive Summary
`
`Product Introduction
`
`1.1.
`
`Vosevi® (SOF/VEL/VOX) is a fixed dose combination (FDC) tablet containing three direct acting
`antiviral (DAA) agents that interfere with critical steps in the replication cycle of hepatitis C virus
`(HCV). Sofosbuvir (SOF) is a nucleotide analog inhibitor of HCV nonstructural protein 5B (NS5B)
`polymerase, which is essential for viral replication. SOF is currently approved for use in
`combination with other agents for the treatment of chronic HCV infection in adults and is
`commercially available as a single entity (tradename Sovaldi®; NDA 204671) and in combination
`with ledipasvir (LDV) in an FDC tablet (LDV/SOF, tradename Harvoni®; NDA 205834) and in
`combination with velpatasvir (VEL) in an FDC tablet (SOF/VEL, tradename Epclusa®; NDA
`208341). Velpatasvir (VEL) inhibits activity of the HCV NS5A protein, which is essential for both
`RNA replication and the assembly of HCV virions. VEL is commercially available as Epclusa.
`Voxilaprevir (VOX) is an HCV NS3/4A protease inhibitor (PI). VOX is a new molecular entity
`(NME) that will be available only in the FDC product currently under review.
`
`The Applicant’s proposed indication is treatment of patients with chronic HCV infection
` The Applicant’s recommended dosage for noncirrhotic
`subjects and subjects with compensated cirrhosis is one tablet by mouth once daily for 12
`weeks. The Applicant has not proposed a different dose or duration based on HCV genotype
`
`
`
`(GT). 1.2.
`
`Conclusions on the Substantial Evidence of Effectiveness
`
`Data from the POLARIS-1 and POLARIS-4 Phase 3 trials included in this application provide
`substantial evidence of effectiveness as required by law 21 CFR 314.126(a)(b) to support
`approval of SOF/VEL/VOX x 12 weeks for treatment of chronic HCV infection without cirrhosis
`or with compensated cirrhosis (Child Pugh Turcotte [CPT] A) in the following populations:
` Genotype 1, 2, 3, 4, 5, or 6 in NS5A inhibitor treatment-experienced adults
` Genotype 1a or 3 in nucleotide analog NS5B polymerase inhibitor treatment-experienced
`adults who are NS5A inhibitor treatment-naïve
`The overall sustained virologic response rates at post-treatment week 12 (SVR12), considered a
`virologic cure, were 96% among subjects treated with SOF/VEL/VOX for 12 weeks in POLARIS-1;
`and 97% for subjects treated with SOF/VEL/VOX for 12 weeks in POLARIS-4.
`
` Benefit-Risk Assessment
`
`1.3.
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`Reference ID: 4094448
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`(b) (4)
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`

`

`Clinical Review
`Kirk Chan-Tack, MD
`NDA 209195
`Vosevi (sofosbuvir and velpatasvir and voxilaprevir)
`
`Benefit-Risk Summary and Assessment
`
`Sofosbuvir (SOF) is a hepatitis C virus (HCV) NS5B inhibitor, velpatasvir (VEL) is an HCV NS5A inhibitor, and voxilaprevir (VOX) is an HCV NS3/4A
`protease inhibitor. SOF/VEL/VOX is a fixed-dose combination tablet with a proposed indication for treatment of patients with chronic HCV
`infection
` Intended subpopulations include DAA-experienced patients with compensated liver disease,
`defined as the absence of cirrhosis or with compensated (Child Pugh Turcotte [CPT] A) cirrhosis.
`
`HCV infection is a serious disease, affecting an estimated 3-5 million people in the US and 130-150 million people worldwide. Although often
`asymptomatic in early stages, if untreated, chronic HCV can lead to debilitating and life-threatening liver problems, including hepatocellular
`carcinoma, liver failure, and death. Treatment options for chronic hepatitis C (CHC) have changed dramatically over the past 5 years as oral
`direct-acting antiviral (DAAs) agents have replaced interferon-based regimens, resulting in markedly improved efficacy rates. The standard
`measure of efficacy is the absence of detectable HCV RNA, termed sustained virologic response (SVR), documented 12 weeks after the end of
`treatment (SVR12); SVR12 is considered a virologic cure. Several DAA regimens have been approved that confer SVR12 rates greater than 93%
`for HCV GT 1, 2, 3, 4, 5, or 6-infected patients (TN, IFN/RBV-experienced, or NS3/4A PI-experienced) with compensated liver disease.
`
`While great progress has been made in improving SVR12 rates among TN, IFN/RBV-experienced patients, and NS3/4A PI-experienced patients,
`treatment options are needed for patients who have failed DAA-only treatment, such as NS5A inhibitor-containing regimens or NS5B
`polymerase inhibitor-containing regimens. In NS5A inhibitor treatment-experienced adults, SOF/VEL/VOX demonstrated SVR12 rates ranging
`from 91-100% depending on the HCV GT. In NS5B polymerase inhibitor treatment-experienced and NS5A inhibitor treatment-naïve adults,
`SOF/VEL/VOX demonstrated SVR12 rates ranging from 94-98% in HCV GT1a and GT3; these SVR12 rates were numerically higher than SOF/VEL
`SVR12 rates in HCVT GT1a and GT3. For these DAA-experienced patients with compensated liver disease, SOF/VEL/VOX is a highly effective,
`RBV-free, single tablet, once daily treatment option.
`
`No major safety issues unique to SOF/VEL/VOX were identified in this review. The most frequent adverse drug reactions were headache,
`fatigue, and diarrhea. SOF has been associated with serious bradycardia when co-administered with amiodarone; amiodarone treatment was
`prohibited in the phase 3 trials, and no cases of serious bradycardia were observed. Current SOF-containing labels include a Boxed Warning and
`a Warning and Precaution regarding the risk of hepatitis B virus (HBV) reactivation, resulting in fulminant hepatitis, hepatic failure and death in
`HCV/HBV coinfected patients who received treatment with DAA drugs for CHC coinfection. HBV coinfection was prohibited in the phase 3 trials
`and therefore no cases of HBV reactivation were observed.
`Approval of SOF/VEL/VOX for treatment of adult patients with CHC infection is fully supported by the available evidence of efficacy and safety.
`
`Reference ID: 4094448
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`10
`
`(b) (4)
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`

`

`Clinical Review
`Kirk Chan-Tack, MD
`NDA 209195
`Vosevi (sofosbuvir and velpatasvir and voxilaprevir)
`Based on thorough analysis of efficacy, safety, and virology data overall, and in each subpopulation, SOF/VEL/VOX for 12 weeks recommended
`for the following patient populations:
`(1) Genotype 1, 2, 3, 4, 5, or 6 in NS5A inhibitor treatment-experienced adults
`(2) Genotype 1a or 3 in nucleotide analog NS5B polymerase inhibitor treatment-experienced adults who are NS5A inhibitor treatment-
`naïve
`
`Dimension
`
`Evidence and Uncertainties
`
` Chronic infection with hepatitis C virus (HCV) causes inflammation of the liver that can
`lead to long-term health problems or death.
` Globally, it is estimated that over 130 million people are infected with HCV, including
`approximately 3 million people in the United States (US).
` There are at least seven distinct HCV genotypes (GTs). GT 1 is the most common among
`US patients (72%), followed by GT 2 (11%), GT 3 (9%), and GT 4 (6%). GTs 5 and 6
`occur uncommonly (< 1%) in the US but may predominate in other parts of the world.
` HCV infection is typically asymptomatic in its early stages. However, if left
`untreated, HCV infection can lead to cirrhosis, hepatocellular carcinoma, liver
`failure, and death. HCV infection is a leading cause of chronic liver disease in the
`US
` Once cirrhosis is established, complications such as jaundice, ascites, variceal
`hemorrhage, and encephalopathy may develop which defines decompensated
`cirrhosis, or end-stage liver disease. In patients with decompensated cirrhosis,
`the 5-year survival rate is approximately 50%.
` The current standard-of-care treatments for CHC are interferon-free, all-oral DAA
`regimens. Treatment options vary based on HCV GT:
`o GT1: ledipasvir/sofosbuvir; elbasvir/grazoprevir;
`paritaprevir/ombitasvir/ritonavir + dasabuvir; daclatasvir (in combination with
`sofosbuvir); simeprevir (in combination with sofosbuvir);
`sofosbuvir/velpatasvir (+ ribavirin in CPT B and C)
`
`Analysis of
`Condition
`
`Current
`Treatment
`Options
`
`Conclusions and Reasons
`
`HCV infection is a significant and
`growing public health concern. If
`untreated, chronic HCV infection
`is a life-threatening condition,
`one that affects a large
`population in the US and
`worldwide. Patients can
`experience symptoms that are
`severe and debilitating.
`
`Patients with chronic HCV
`infection would greatly benefit
`from new therapeutic options
`that are well tolerated and
`equally or more efficacious than
`current interferon-free DAA
`
`11
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`Reference ID: 4094448
`
`

`

`Clinical Review
`Kirk Chan-Tack, MD
`NDA 209195
`Vosevi (sofosbuvir and velpatasvir and voxilaprevir)
`
`Dimension
`
`Benefit
`
`Reference ID: 4094448
`
`Evidence and Uncertainties
`o GT2: sofosbuvir + ribavirin; sofosbuvir/velpatasvir (+ ribavirin in CPT B and C)
`o GT3: daclatasvir + sofosbuvir; sofosbuvir + ribavirin; sofosbuvir/velpatasvir (+
`ribavirin in CPT B and C)
`o GT4: ledipasvir/sofosbuvir; elbasvir/grazoprevir; ombitasvir/
`paritaprevir/ritonavir with ribavirin; sofosbuvir/velpatasvir (+ ribavirin in CPT B
`and C)
`o GT5: ledipasvir/sofosbuvir; sofosbuvir/velpatasvir (+ ribavirin in CPT B and C)
`o GT6: ledipasvir/sofosbuvir; sofosbuvir/velpatasvir (+ ribavirin in CPT B and C)
` Treatment with DAAs in TN, IFN/RBV-experienced patients, and NS3/4A PI-experienced
`patients can result in sustained virologic response determined 12 weeks after the end of
`treatment (SVR12), considered a virologic cure, in > 93% of CHC patients with
`compensated liver disease. However, SVR12 rates were lower for certain
`subpopulations, and some of these regimens require the addition of RBV or longer
`treatment durations for subjects with cirrhosis and/or prior treatment failure.
` At the time of this review, no DAA regimens are approved for patients who have failed
`DAA-only treatment. For treatment-experienced patient populations, such as NS5A
`inhibitor treatment-experienced patients (evaluated in POLARIS-1), as well as nucleotide
`analog NS5B polymerase inhibitor treatment-experienced patients who are NS5A
`inhibitor treatment-naïve (evaluated in POLARIS-4), a limited amount of data exists
`about options not currently in approved labels and strategies that failed. Most of these
`other options are 24 week, RBV-containing regimens with a wide range of SVR12 rates
`(70-97% in GT1; 93% in GT2; 76% in GT3) and SVR12 rates are impacted by baseline RAS.
`
`The efficacy of SOF/VEL/VOX was established in two Phase 3 clinical trials
`which cumulatively evaluated 445 subjects in the SOF/VEL/VOX treatment
`arms. The trial populations varied based on DAA experience.
`o POLARIS-1: DAA-experienced subjects who have previously received
`NS5A inhibitors with compensated liver disease and HCV GT 1, 2, 3, 4, 5,
`or 6. Subjects received SOF/VEL/VOX x 12 weeks or placebo x 12 weeks.
`
`Conclusions and Reasons
`
`options.
`
`RBV-free regimens with shorter
`treatment durations (< 16 weeks)
`are needed for populations that
`are traditionally harder to treat;
`such regimens may improve
`treatment adherence and
`minimize safety and tolerability
`issues associated with RBV.
`
`A specific unmet medical need
`exists for highly effective DAA
`regimens for subjects who have
`failed prior DAA treatment
`because no approved regimens
`are available.
`
`Two clinical trials provide
`substantial evidence of
`effectiveness of SOF/VEL/VOX x
`12 weeks in subjects with
`compensated liver disease for
`treatment of the following
`
`12
`
`

`

`Clinical Review
`Kirk Chan-Tack, MD
`NDA 209195
`Vosevi (sofosbuvir and velpatasvir and voxilaprevir)
`
`Dimension
`
`Evidence and Uncertainties
`o POLARIS-4: DAA-experienced subjects who have not previously
`received NS5A inhibitors with compensated liver disease and HCV GT 1,
`2, 3, 4, 5, or 6. Subjects received SOF/VEL/VOX x 12 weeks or SOF/VEL x
`12 weeks.
`The primary efficacy endpoint was SVR12, or virologic cure. As displayed in the
`tables below, SVR12 results overall ranged from 91-100% depending on the HCV GT.
`
`
`
`POLARIS-1: SVR12 by HCV GT Among Subjects Treated with SOF/VEL/VOX n (%)
`GT1
`GT2
`GT3
`GT4
`GT5
`GT6
`Total
`146/150
`5/5
`74/78
`20/22
`1/1
`6/6
`253/263
`(97%)
`(100%)
`(95%)
`(91%)
`(100%)
`(100%)
`(96%)
`
`GT4
`
`Total
`
`POLARIS-4: SVR12 by