209195Orig1s000

Home , Asunaprevir, Beclabuvir, Danoprevir, Deleobuvir, Filibuvir, Samatasvir

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

209195Orig1s000

STATISTICAL REVIEW(S)

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Translational Sciences Office of Biostatistics

A d d e n d u m S TATISTICAL R E V I E W A N D E VALUATION

CLINICAL STUDIES

NDA/BLA #: 209195 Drug Name: Sofosbuvir 400 mg / Velpatasvir 100 mg / Voxilaprevir 100 mg fixed dose combination Indication(s): Treatment of adult subjects infected with chronic HCV infection (b) (4)

Applicant: Gilead Sciences, Inc. Date(s): Original NDA submitted date: 12/08/2016 Additional data submitted date: 06/09/2017 PDUFA date: 08/08/2017 Review Priority: Priority

Biometrics Division: DB4 Statistical Reviewer: Karen Qi, Ph.D. Concurring Reviewers: Dionne Price, Ph.D. Medical Division: Division of Antiviral Products Clinical Team: Kirk Tack-Chan, MD, Clinical Reviewer Project Manager: Andrew Gentles, PharmD, BCPS AQ-ID

Reference ID: 4112714 This is an addendum to the statistical review of NDA 209195. In the original NDA submission dated December 08, 2016, Subject 05969-27808, a participant with HCV GT3 infection and cirrhosis in POLARIS-4, did not have an HCV RNA assessment for post- treatment Week 12. The subject therefore was considered as not achieving SVR12 and the reason was classified as “Other”. However, the applicant provided updated SVR24 data for the subject on June 9, 2017 which was stored in \\CDSESUB1\evsprod\NDA209195\0019. According to the applicant, the subject returned for the post-treatment Week 24 study visit and had no HCV RNA detected. Therefore, the subject has now been imputed as having achieved SVR12. The review team agreed with the applicant’s revision. The change of the SVR12 status for the subject did not impact the conclusion that the contribution of VOX in SOF/VEL/VOX regimen was more apparent in NS5A inhibitor DAA-naïve and sofosbuvir- experienced subjects with HCV GT1a or 3 infection as compared to subjects with GT1b or 2 infection. However, the revision resulted in some numerical changes for the primary efficacy analysis as well as subgroup and exploratory analyses of POLARIS-4 and impacted Tables 12, 16, 23, 24, 25, 27 and 28 in the statistical review of the original NDA. This addendum includes the revised tables based on the updated SVR24 data.

Table 12: Reviewer’s Results for Virologic Outcomes at Post-Treatment Week 12 in POLARIS-4 (All Treated)

SOF/VEL/VOX 12 Weeks SOF/VEL 12 Weeks (N=182) (N=151)

SVR12 rate 97.8% 90.1% (number of responders/N) (178/182) (136/151) [95% CI]1 [94.5%, 99.4%] [84.1%, 94.3%] P-value2 <0.001 0.092 Not achieving SVR12 On-treatment virologic failure 0% (0/182) 0.7% (1/151) Relapse 0.5% (1/182) 8.7% (13/150) Other 1.6% (3/182) 0.7% (1/151) 1based on Clopper-Pearson method 2 based on a comparison to the 85% threshold

Reference ID: 4112714 Table 16: Reviewer’s Results of SVR12 Rates by HCV Genotype and Baseline Cirrhotic Status among Subjects with 3, 4, or 5 Negative Host Factors in POLARIS-4 SOF/VEL/VOX SOF/VEL 12 Weeks 12 Weeks GT1a Cirrhosis No 100% (27/27) 92.9% (13/14) Yes 93.8% (15/16) 81.3% (13/16) GT1b Cirrhosis No 100% (5/5) 100% (5/5) Yes 100% (10/10) 100% (7/7) GT2 Cirrhosis No 100% (10/10) 90% (9/10) Yes 100% (12/12) 100% (15/15) GT3 Cirrhosis No 93.3% (14/15) 92.3% (12/13) Yes 100% (28/28) 76.7% (23/30) GT4 Cirrhosis No 100% (5/5) n/a Yes 100% (11/11) n/a

Reference ID: 4112714 Table 23: SVR12 Rate by Demographics in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL Diff in SVR12 rate btw 12 weeks 12 weeks SOF/VEL/VOX 12 weeks (N=182) (N=151) and SOF/VEL 12 weeks (95% CI)2 Age at baseline (years) < 65 years 97.3% (145/149) 88.9% (120/135) 8.4% (2.7%, 15.5%) [95% CI]1 [93.3%, 99.3%] [82.3%, 93.6%]

≥ 65 years 100% (33/33) 100% (16/16) 0% (-11.1%, 21.9%) [95% CI]1 [89.4%, 100.0%] [79.4%, 100.0%] Sex at birth Male 97.2% (139/143) 89.5% (102/114) 7.7% (1.8%, 15.2%) [95% CI]1 [93.0%, 99.2%] [82.3%, 94.4%]

Female 100% (39/39) 91.9% (34/37) 8.1% (-1.5%, 21.7%) [95% CI]1 [91.0%, 100.0%] [78.1%, 98.3%] Race Black or African American 93.8% (15/16) 69.2% (9/13) 24.5% (-5.3%, 55.3%) [95% CI]1 [69.8%, 99.8%] [38.6%, 90.9%]

Non Black or African American 98.2% (163/166) 92.0% (127/138) 6.2% (1.5%, 12.4%) [95% CI]1 [94.8%, 99.6%] [86.2%, 96.0%] Ethnicity Hispanic or Latino 100% (19/19) 75.0% (6/8) 25% (3.0%, 62.6%) [95% CI]1 [82.4%, 100.0%] [34.9%, 96.8%]

Not Hispanic or Latino 97.6% (159/163) 90.9% (130/143) 6.6% (1.5%, 12.8%) [95% CI]1 [93.8%, 99.3%] [85.0%, 95.1%] Region US 99.0% (100/101) 87.4% (76/87) 11.7% (5.1%, 20.6%) [95% CI]1 [94.6%, 100%] [78.5%, 93.5%]

Non-US 96.3% (78/81) 93.8% (60/64) 2.5% (-5.1%, 12.1%) [95% CI]1 [89.6%, 99.2%] [84.8%, 98.3%] Body mass index (kg/m2) at baseline < 30 kg/m2 96.7% (116/120) 92.9% (91/98) 3.8% (-2.6%, 11.2%) [95% CI]1 [91.7%, 99.1%] [85.8%, 97.1%]

≥ 30 kg/m2 100% (62/62) 84.9% (45/53) 15.1% (7.5%, 27.4%) [95% CI]1 [94.2%, 100.0%] [72.4%, 93.3%] Source: Tables 9-4 and 9-5 in POLARIS-4 Interim Clinical Study Report 1based on the Clopper-Pearson method 2The differences in SVR 12 rate between the two treatment arms in the subgroups and the corresponding exact 95% CIs based on inverting a two-sided test were calculated by the statistical reviewer.

Reference ID: 4112714 Table 24: SVR12 Rate by Selected Baseline Disease Characteristics in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL Diff in SVR12 rate btw 12 weeks 12 weeks SOF/VEL/VOX 12 weeks and (N=182) (N=151) SOF/VEL 12 weeks (95% CI)2 Genotype GT1 97.4% (76/78) 90.9% (60/66) 6.5% (-1.2%, 16.6%) [95% CI] [91.0%, 99.7%] [81.3%, 96.6%]

GT1a 98.1% (53/54) 88.6% (39/44) 5.7% (-0.4%, 23.3%) [95% CI] [90.1%, 100%] [75.4%, 96.2%]

GT1b 95.8% (23/24) 95.5% (21/22) 0.4% (-17.6%, 19.3%) [95% CI] [78.9%, 99.9%] [77.2%, 99.9%]

GT2 100% (31/31) 97.0% (32/33) 3.0% (-8.3%, 16.5%) [95% CI] [88.8%, 100.0%] [84.2%, 99.9%]

GT3 96.3% (52/54) 84.6% (44/52) 11.7% (0.5%, 24.8%) [95% CI] [87.3%, 99.6%] [71.9%, 93.1%]

GT4 100% (19/19) n/a n/a [95% CI] [82.4%, 100.0%] Cirrhosis Yes 97.6% (82/84) 85.5% (59/69) 12.1% (3.5%, 22.9%) [95% CI] [91.7%, 99.7%] [75.0%, 92.8%]

No 98.0% (96/98) 93.9% (77/82) 4.1% (-2.1%, 11.9%) [95% CI] [92.8%, 99.8%] [86.3%, 98.0%] IL28B CC 97.0% (32/33) 86.2% (25/29) 10.8% (-4.2%, 29.1%) [95% CI] [84.2%, 99.9%] [68.3%, 96.1%]

Non-CC 98.0% (146/149) 91.0% (111/122) 7.0% (1.7%, 13.8%) [95% CI] [94.2%, 99.6%] [84.4%, 95.4%]

CT [95% CI] 97.2% (104/107) 91.6% (87/95) 5.6% (-0.8%, 13.8%) [92.0%, 99.4%] [84.1%, 96.3%] TT [95% CI] 100% (42/42) 88.9% (24/27) 11.1% (1.8%, 29.7%) [91.6%, 100%] [70.8%, 97.6%] Baseline HCV RNA < 800,000 IU/mL 95.7% (44/46) 92.1% (35/38) 3.6% (-8.0%, 17.4%) [95% CI] [85.2%, 99.5%] [78.6%, 98.3%]

≥ 800,000 IU/mL 98.5%% (134/136) 89.4% (101/113) 9.1% (3.5%, 16.5%) [95% CI] [94.8%, 99.8%] [82.2%, 94.4%] Baseline ALT ≤ 1.5 x ULN 100% (88/88) 91.7% (66/72) 8.3% (3.4%, 17.4%) [95% CI] [95.9%, 100.0%] [82.7%, 96.9%]

> 1.5 x ULN 95.7% (90/94) 88.6% (70/79) 7.1% (-0.9%, 16.8%) [95% CI] [89.5%, 98.8%] [79.5%, 94.7%] Prior HCV trt history NS5B Only 97.8% (131/134) 90.8% (99/109) 6.9% (1.2%, 14.3%) [95% CI] [93.6%, 99.5%] [83.8%, 95.5%]

NS5B + NS3 97.8% (45/46) 86.8% (33/38) 11.0% (-0.3%, 25.6%) [95% CI] [88.5%, 99.9%] [71.9%, 95.6%] Source: Table 9-5 in POLARIS-4 Interim Clinical Study Report 1based on the Clopper-Pearson method 2The differences in SVR 12 rate between the two treatment arms in the subgroups and the corresponding exact 95% CIs based on inverting a two- sided test were calculated by the statistical reviewer. 5

Reference ID: 4112714 Table 25: Reviewer’s Results for Virologic Outcomes at Post-Treatment Week 12 by HCV Genotype in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL 12 Weeks 12 Weeks GT1 SVR12 rate 97.4% (76/78) 90.9% (60/66) Not achieving SVR12 On-treatment virologic failure 0% (0/78) 0% (0/66) Relapse1 1.3% (1/78) 7.6% (5/66) Other2 1.3% (1/78) 1.5% (1/66) GT1a SVR12 rate 98.1% (53/54) 88.6% (39/44) Not achieving SVR12 On-treatment virologic failure 0% (0/54) 0% (0/44) Relapse1 1.9% (1/54) 11.4% (5/44) Other2 0% (0/54) 0% (0/44) GT1b SVR12 rate 95.8% (23/24) 95.5% (21/22) Not achieving SVR12 On-treatment virologic failure 0% (0/24) 0% (0/22) Relapse1 0% (0/24) 0% (0/22) Other2 4.2% (1/24) 4.6% (1/22) GT2 SVR12 rate 100% (31/31) 97.0% (32/33) Not achieving SVR12 On-treatment virologic failure 0% (0/31) 3.0% (1/33) Relapse1 0% (0/31) 0% (0/32) Other2 0% (0/31) 0% (0/33) GT3 SVR12 rate 96.3% (52/54) 84.6% (44/52) Not achieving SVR12 On-treatment virologic failure 0% (0/54) 0% (0/52) Relapse1 0% (0/54) 15.4% (8/52) Other2 3.7% (2/54) 0% (0/52) GT4 SVR12 rate 100% (19/19) n/a Not achieving SVR12 On-treatment virologic failure 0% (0/19) Relapse1 0% (0/19) Other2 0% (0/19) 1The denominator for relapse is the number of subjects with HCV RNA

Reference ID: 4112714 Table 26: Reviewer’s Results for SVR12 Rate by Genotype and Cirrhosis in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL Diff in SVR12 rate btw 12 Weeks 12 Weeks SOF/VEL/VOX 12 weeks and SOF/VEL 12 weeks (95% CI)1 GT1 Cirrhosis No 98.0% (49/50) 93.0% (40/43) 5.0% (-4.8%, 17.0%) [95% CI] [89.4%, 100.0%] [80.9%, 98,5%]

Yes 96.4% (27/28) 87.0% (20/23) 9.5% (-7.0%, 29.5%) [95% CI] [81.7%, 99.9%] [66.4%, 97.2%] GT1a Cirrhosis No 100% (37/37) 92.9% (26/28) 7.1% (-3.1%, 23.5%) [95% CI] [90.5%, 100%] [76.5%, 99.1%]

Yes 94.1% (16/17) 81.3% (13/16) 12.9% (-12.1%, 39.4%) [95% CI] [71.3%, 99.9%] [54.4%, 96.0%] GT1b Cirrhosis No 92.3% (12/13) 93.3% (14/15) -1.0% (-29.6%, 24.6%) [95% CI] [64.0%, 99.8%] [68.1%, 99.8%]

Yes 100% (11/11) 100% (7/7) 0% (-28.8%, 37.7%) [95% CI] [71.5%, 100%] [59.0%, 100%] GT2 Cirrhosis No 100% (18/18) 94.1% (16/17) 5.9% (-12.7%, 28.9%) [95% CI] [81.5%, 100%] [71.3%, 99.9%]

Yes 100% (13/13) 100% (16/16) 0% (-23.0%, 20.8%) [95% CI] [75.3%, 100%] [79.4%, 100%] GT3 Cirrhosis No 95.7% (22/23) 95.5% (21/22) 0.2% (-17.5%, 18.9%) [95% CI] [78/1%, 99.9%] [77.2%, 99.9%]

Yes 96.8% (30/31) 76.7% (23/30) 20.1% (3.3%, 39.3%) [95% CI] [83.3%, 99.9%] [57.7%, 90.1%] GT4 Cirrhosis No 100% (7/7) [95% CI] [59.0%, 100%] n/a n/a

Yes 100% (12/12) [95% CI] [73.5%, 100%] 1The exact 95% CIs were based on inverting a two-sided test.

Reference ID: 4112714 Table 27: Reviewer’s Results for SVR12 Rates by Genotype and Prior Exposure to SOF-Containing Regimen in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL Diff in SVR12 rate btw 12 weeks 12 weeks SOF/VEL/VOX 12 weeks and SOF/VEL 12 weeks (95% CI)1 GT1a SOF-containing regimen 97.2% (35/36) 82.1% (23/28) 15.1% (0.6%, 34.0%) Non SOF-containing regimen 100% (18/18) 100% (16/16) 0% (-18.8%, 20.9%) GT1b SOF-containing regimen 94.4% (17/18) 91.7% (11/12) 2.8% (-19.4%, 31.6%) Non SOF-containing regimen 100% (6/6) 100% (10/10) 0% (-41.5%, 29.9%) GT2 SOF-containing regimen 100% (31/31) 97.0% (32/33) 3.0% (-8.3%, 16.5%) Non SOF-containing regimen n/a n/a n/a GT3 SOF-containing regimen 96.3% (52/54) 84.6% (44/52) 11.7% (0.5%, 24.8%) Non SOF-containing regimen n/a n/a n/a GT4 SOF-containing regimen 100% (18/18) n/a n/a Non SOF-containing regimen 100% (1/1) n/a n/a 1The 95% exact CIs were based on inverting a two-sided test.

Reference ID: 4112714 Table 28: Reviewer’s Results for Virologic Outcome at Post-Treatment Week 12 by Genotype among Subjects with Prior Exposure to SOF-Containing Regimen in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL 12 Weeks 12 Weeks (N=139) (N=125) Genotype 1 SVR12 96.3% (52/54) 85.0% (34/40) Not achieving SVR12 On-treatment virologic failure 0% (0/54) 0% (0/40) Relapse1 1.9% (1/54) 12.5% (5/40) Other2 1.9% (1/54) 2.5% (1/40) Genotype 1a SVR12 97.2% (35/36) 82.1% (23/28) Not achieving SVR12 On-treatment virologic failure 0% (0/36) 0% (0/28) Relapse1 2.8% (1/36) 17.9% (5/28) Other2 0% (0/36) 0% (0/28) Genotype 1b SVR12 94.4% (17/18) 91.7% (11/12) Not achieving SVR12 On-treatment virologic failure 0% (0/18) 0% (0/12) Relapse1 0% (0/18) 0% (0/12) Other2 5.6% (1/18) 8.3% (1/12) Genotype 2 SVR12 100% (31/31) 97.0% (32/33) Not achieving SVR12 On-treatment virologic failure 0% (0/31) 3.0% (1/33) Relapse1 0% (0/31) 0% (0/32) Other2 0% (0/31) 0% (0/33) Genotype 3 SVR12 96.3% (52/54) 84.6% (44/52) Not achieving SVR12 On-treatment virologic failure 0% (0/54) 0% (0/52) Relapse1 0% (0/54) 15.4% (8/52) Other2 3.7% (2/54) 0% (0/52) Genotype 4 SVR12 100% (18/18) n/a Not achieving SVR12 On-treatment virologic failure 0% (0/18) Relapse1 0% (0/18) Other2 0% (0/18) 1The denominator for relapse is the number of subjects with HCV RNA

Reference ID: 4112714 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------XIAOJING K QI 06/16/2017

DIONNE L PRICE 06/16/2017 Concur

Reference ID: 4112714 U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Translational Sciences Office of Biostatistics

S TATISTICAL R E V I E W A N D E VALUATION

CLINICAL STUDIES

NDA #: 209195 Drug Name: Sofosbuvir 400 mg / Velpatasvir 100 mg / Voxilaprevir 100 mg fixed dose combination Indication(s): Treatment of adult subjects infected with chronic HCV infection (b) (4)

Applicant: Gilead Sciences, Inc. Date(s): Submitted date: 12/08/2016 PDUFA date: 08/08/2017 Review Priority: Priority

Biometrics Division: Division of Biometrics IV Statistical Reviewer: Karen Qi, Ph.D. Concurring Reviewers: Thamban Valappil, Ph.D., Biometrics IV Team Leader

Medical Division: Division of Antiviral Products Clinical Team: Kirk Tack-Chan, MD, Clinical Reviewer Project Manager: Andrew Gentles, PharmD, BCPS AQ-ID

Keywords: Clinical trials, Clopper –Pearson method, non-inferiority, closed testing procedure, Cochran-Mantel-Haenszel test, HCV, compensated cirrhosis, decompensated cirrhosis, Sofosbuvir, Velpatasvir

Reference ID: 4095069 Table of Contents 1. EXECUTIVE SUMMARY...... 5

2. INTRODUCTION...... 6

2.1 OVERVIEW ...... 6 2.2 DATA SOURCES...... 8 3. STATISTICAL EVALUATION...... 9

3.1 DATA AND ANALYSIS QUALITY...... 9 3.2 EVALUATION OF EFFICACY...... 9 3.2.1 Efficacy Endpoints and Statistical Methods Common to Both Studies Reviewed...... 9 3.2.2 POLARIS-1...... 11 3.2.3 POLARIS-4...... 16 4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ...... 21 4.1 POLARIS-1...... 21 4.2 POLARIS-4...... 21 5. SUMMARY AND CONCLUSIONS...... 22

5.1 STATISTICAL ISSUES ...... 22 5.2 COLLECTIVE EVIDENCE ...... 22 5.3 CONCLUSIONS AND RECOMMENDATIONS ...... 23 5.4 LABELING RECOMMENDATIONS...... 24 6. APPENDIX ...... 29 6.1 POLARIS-1...... 29 6.2 POLARIS-4...... 32

Reference ID: 4095069 LIST OF TABLES

Table 1: Approved IFN-Free DAA-Based HCV Regimens in US by 2016 ...... 7 Table 2: List of Phase 3 Studies Included in Review...... 8 Table 3: Applicant’s Results for Patient Disposition in POLARIS-1...... 12 Table 4: Applicant’s Results for Patient Demographics and Selected Baseline Characteristics in POLARIS-1 (All Treated)...... 13 Table 5: Applicant’s Results for Selected Baseline Disease Characteristics in POLARIS-1 (All Treated)....14 Table 6: Reviewer’s Results for Use of prior NS5A Inhibitors for Subjects in 12-Week SOF/VEL/VOX Group in POLARIS-1 (All Treated)...... 15 Table 7: Applicant’s Results for Virologic Outcomes at Post-Treatment Week 12 in POLARIS-1 (All Treated) ...... 15 Table 8: Applicant’s Results for Observed Proportion of Subjects with HCV RNA < LLOQ While on Active Treatment by Visit in POLARIS-1 (All Treated)...... 16 Table 9: Applicant’s Results for Patient Disposition in POLARIS-4...... 17 Table 10: Applicant’s Results for Patient Demographics and Baseline Characteristics in POLARIS-4 (All Treated) ...... 17 Table 11: Applicant’s Results for Selected Baseline Disease Characteristics in POLARIS-4 (All Treated)..18 Table 12: Reviewer’s Results for Virologic Outcomes at Post-Treatment Week 12 in POLARIS-4 ...... 20 Table 13: Applicant’s Results for SVR4 Rate in POLARIS-4 (All Treated) ...... 20 Table 14: Applicant’s Results for Observed Proportion of Subjects with HCV RNA < LLOQ While on Active Treatment by Visit in POLARIS-4 (All Treated)...... 20 Table 15: Reviewer’s Results of SVR12 rates by HCV Genotype and Baseline Cirrhotic Status among Subjects with 1 or 2 Negative Host Factors in POLARIS-4 ...... 27 Table 16: Reviwewer’s Results of SVR12 Rates by HCV Genotype and Baseline Cirrhotic Status among Subjects with 3, 4, or 5 Negative Host Factors in POLARIS-4 ...... 28 Table 17: Reviewer’s Results of Prior HCV DAAs for Subjects in 12-Week SOF/VEL/VOX in POLARIS-1 (All Treated)...... 29 Table 18: Applicant’s Results of SVR12 Rates by Demographics in POLARIS-1 (All Treated)...... 30 Table 19: Applicant’s Results of SVR12 Rates by Selected Baseline Disease Characteristics in POLARIS-1 (All Treated)...... 31 Table 20: Applicant’s Results of Prior HCV DAA(s) by Genotype in POLARIS-4 (All Treated)...... 32 Table 21: Reviewer’s Results for Prior Exposure to SOF-Containing Regimen by Genotype in POLARIS-4 (All Treated)...... 33 Table 22: Reviewer’s Results of Prior HCV DAA(s) and PegIFN/RBV Treatment History in POLARIS-4 (All Treated)...... 33 Table 23: SVR12 Rate by Demographics in POLARIS-4 (All Treated) ...... 34 Table 24: SVR12 Rate by Selected Baseline Disease Characteristics in POLARIS-4 (All Treated)...... 35 Table 25: Reviewer’s Results for Virologic Outcomes at Post-Treatment Week 12 by HCV Genotype in POLARIS-4 (All Treated)...... 36 Table 26: Reviewer’s Results for SVR12 Rate by Genotype and Cirrhosis in POLARIS-4 (All Treated).....37 Table 27: Reviewer’s Results for SVR12 Rates by Genotype and Prior Exposure to SOF-Containing Regimen in POLARIS-4 (All Treated) ...... 38 Table 28: Reviewer’s Results for Virologic Outcome at Post-Treatment Week 12 by Genotype among Subjects with Prior Exposure to SOF-Containing Regimen in POLARIS-4 (All Treated) ...... 39

Reference ID: 4095069 LIST OF FIGURES Figure 1: Applicant’s Results of Percent of Subjects with Cumulative Negative Host Factors (POLARIS-2, POLARIS-3 and POLARIS-4; SOF/VEL Groups Only)...... 25 Figure 2: Applicant’s Results of SVR12 Rates by Cumulative Negative Host Factors (POLARIS-4, SOF/VEL/VOX and SOF/VEL groups)...... 26

APPEARS THIS WAY ON ORIGINAL

Reference ID: 4095069 1. EXECUTIVE SUMMARY

Gilead has submitted New Drug Application 209195 to support the approval of a fixed dose combination (FDC) of three direct-acting antiviral (DAA) agents, Sofosbuvir (SOF) 400 mg, Velpatasvir (VEL) 100 mg and Voxilaprevir (VOX) 100 mg, for the treatment of adult patients with HCV infection. The proposed treatment regimens are SOF/VEL/VOX FDC once daily for 12 weeks in DAA-experienced subjects with hepatitis C virus (HCV) infection, without cirrhosis or with compensated cirrhosis, (b) (4)

The application included interim clinical study reports for two Phase 3, randomized, multi-center studies referred to as POLARIS-1 and POLARIS-4. The studies assessed efficacy via the sustained virologic response (SVR12) rate defined as the proportion of subjects who had HCV RNA below the lower limit of quantitation (LLOQ) 12 weeks after the end of treatment. The patient population in POLARIS-1 included nonstructural (NS)5A inhibitor DAA-experienced subjects with chronic HCV infection who had previously received 5A inhibitor(s). In the study, subjects with HCV GT1 infection were randomized to receive either 12 weeks of SOF/VEL/VOX or placebo. Subjects infected with other HCV genotypes were not randomized and only received 12 weeks of SOF/VEL/VOX, with exception of two GT6 subjects receiving placebo. Although a placebo arm was included in the study, the primary efficacy objective was to demonstrate the SVR12 rate for 12 weeks of SOF/VEL/VOX was higher than the clinical threshold of 85%. The placebo arm was included for the purpose of evaluating comparative safety only.

POLARIS-4 was conducted in non-NS5A inhibitor DAA-experienced subjects with chronic HCV infection previously treated with non-NS5A inhibitor(s). Subjects who had DAA exposure to a NS3/4A protease inhibitor (PI) only were excluded. The study consisted of two treatment arms: 12 weeks of SOF/VEL/VOX and 12 weeks of SOF/VEL. Subjects infected with HCV GT1, 2 or 3 were randomized to the two treatment groups, stratified by genotype. Subjects infected with HCV GT4 were enrolled to receive only 12 weeks of SOF/VEL/VOX. The primary efficacy goal was to show that the SVR12 rate in each arm was greater than 85%, a pre-specified threshold.

In POLARIS-1, the SVR12 rate for SOF/VEL/VOX was approximately 96.2% in the NS5A inhibitor DAA-experienced subjects which was significantly higher than the pre- specified threshold of 85% (Table 7). The pre-specified subgroup analysis demonstrated that the SVR12 rates were above 90% in all genotypes. However, the majority of the subjects had HCV GT1 (57.0%) or GT3 (29.7%) infection. There were a limited number of subjects infected with GT2, 4, 5 or 6 HCV. Specifically, the study only included five subjects with GT2 infection, 22 subjects with GT4 infection, one subject with GT5 infection, and one subject with GT6 infection. Subjects with HCV GT3 infection and cirrhosis are generally considered the most difficult to treat with DAA regimens. The 12 weeks of SOF/VEL/VOX resulted in a SVR12 rate as high as 92.9% in these patients. Therefore; the clinical team postulated that subjects with GT2, 4, 5, or 6 infections would 5

Reference ID: 4095069 benefit from treatment of 12-week SOF/VEL/VOX even though the study did not provide any direct evidence.

In POLARIS-4, the overall SVR12 rate for SOF/VEL/VOX was statistically significantly higher than the 85% performance goal, but the rate for the SOF/VEL arm was not significantly higher than the threshold. Findings from POLARIS-4 also revealed that the 12-week SOF/VEL/VOX regimen had a numerically higher SVR12 rate (97.3%) as compared to the 12-week SOF/VEL regimen (90.1%) (Table 12), and the reviewer’s exploratory analysis further suggested the overall superiority of the SOF/VEL/VOX regimen to the SOF/VEL regimen (p=0.006 based on Chi-square test).

Since SOF is the only approved NS5B inhibitor for treatment of HCV thus far, the majority of subjects had prior exposure in POLARIS-4. Approximately 65.3% GT1 subjects had prior exposure to a SOF-containing regimen, and with the exception of one subject, all GT2, GT3 and GT4 subjects had previously received a SOF-containing regimen. Further subgroup analyses demonstrated that all subjects who had not previously received a SOF-containing regimen achieved SVR12 in both groups (Table 27). Among the subjects who had received a SVR-containing regimen, the contribution of VOX in the SOF/VEL/VOX regimen was more apparent in subjects with HCV GT1a or 3 infection compared to the subjects with HCV GT1b or GT2 infection (Table 27 and Table 28). In POLARIS-4, all subjects with GT4 infection received 12 weeks of SOF/VEL/VOX, and therefore the additional contribution of VOX to the SOF/VEL/VOX regimen could not be (b) assessed. Finally, the study did not enroll any subjects with GT5 or 6 infections. (4) (b) (4)

2. INTRODUCTION

2.1 Overview

HCV infection is one of major causes of cirrhosis and other liver diseases. According to the World Health Organization (WHO), 130 to 150 million people are infected with HCV worldwide and 500,000 die from hepatitis C related liver disease every year. There are six major HCV genotypes (1-6) and subgenotypes (a, b, c, etc.). The most prevalent genotype is HCV GT1 (46%), followed by HCV GT3 (30%), GT2 (9%), GT4 (8%), GT5 (<1%). In most countries, GT1 is the most common genotype. Meanwhile, GT2 dominates in West African, GT3 in South Asian and parts of Scandinavia, GT4 in central and North Africa, GT5 in South Africa, and GT6 in Southeast Asian (Messina JP, Hematology 2014).

Treatment of HCV has been changing rapidly in recent years. HCV treatment contained interferon (IFN) and ribavirin (RBV) before the year 2013. Since then, several IFN-free DAA-based regimens have been approved for HCV infection. There are four classes of DAAs defined by their mechanism of action and therapeutic target. These four classes are 6

Reference ID: 4095069 nonstructural proteins 3/4A (NS3/4A) protease inhibitors (PIs), NS5B nucleoside polymerase inhibitors (NPIs), NS5B non-nucleoside polymerase inhibitors (NNPIs), and NS5A inhibitors. The approved DAA-based regimens and their drug classes are displayed in Table 1. Compared with the IFN-containing treatments, the IFN-free DAA-based therapies have much higher SVR12 rates. However, there is a medical need to treat the growing population of patients who failed IFN-free DAA-based regimens. No therapies have been approved for this patient population so far. Additionally, the applicant’s literature review suggested that the re-treatment options with currently available DAA therapies were limited for these subjects, in particular for those who previously had been treated with regimen(s) containing NS5A inhibitor(s). Treatment of FDC of SOF/VEL (EPCLUSA®) for 12 weeks was approved in treatment of subjects with HCV GT1, 2, 3, 4, 5, or 6 infections without decompensated cirrhosis in 2016. The applicant claimed that their Phase 2 studies demonstrated that the addition of VOX to SOF/VEL for 12 weeks resulted in high SVR rates (b) (4) in DAA-experienced subjects. Therefore, they conducted two phase 3 trials, POLARIS-1 and POLARIS-4, to evaluate efficacy and safety of SOF/VEL/VOX for 12 weeks in NS5A inhibitor DAA-experienced and non-NS5A inhibitor DAA-experienced subjects, respectively. Both of the trials are ongoing. This NDA included the interim clinical study reports for the two studies. The interim clinical study reports consisted of the efficacy and safety analyses conducted when all subjects had completed the post-treatment Week 12 visit or had prematurely discontinued from the study. The statistical reviewer evaluated the efficacy results presented in the interim clinical study reports. The summaries of the key elements of the study designs are displayed in Table 2.

Table 1: Approved IFN-Free DAA-Based HCV Regimens in US by 2016 Name Drug classes Genotype Year of approval EPCLUSA® NS5B NPI, NS5A GT1, 2, 3, 4, 5, 6 2016 (sofosbuvir / velpatasvir) inhibitor ZEPATIER® NS5A inhibitor, NS3/4A GT1 or 4 2016 (elbasvir / grazoprevir) PI TECHNIVIE® NS5A inhibitor, NS3/4A GT4 2015 (paritaprevir / ombitasvir / ritonavir) PI, PK enhancer DAKLINZA® NS5A inhibitor GT1, 3 2015 (daclatasvir) HARVONI® NS5A inhibitor, NS5B GT1, 4, 5, 6 2014 (ledipasvir/sofosbuvir) NPI VIEKIRA PAK® NS5B NNPI, NS5A GT1 2014 (paritaprevir/ombitasvir/ritonavir inhibitor, NS3/4A PI and dasabuvir) SOVALDI® NS5B NPI GT2, 3 2013 (sofosbuvir) OLYSIO® NS3/4 PI GT1 2013 (simeprevir) Note: The reviewer generated this table based on labels for EPCLUSA®, ZEPATIER®, TECHNIVIE®, DAKLINZA®, HARVONI®, VIEKIRA PAK®, SOVALDI® and OLYSIO®.

Reference ID: 4095069 Table 2: List of Phase 3 Studies Included in Review Study Design Study Randomization and Primary Efficacy Population Treatment Arm Hypothesis POLARIS-1 randomized, NS5A inhibitor Three hundred subjects The SVR12 rate of (GS-US-367- double-blind, DAA- infected with GT1 HCV were the 12-week 1171) placebo- experienced randomized in a 1:1 ratio to SOF/VEL/VOX controlled, subjects the following two arms, regimen was higher multicenter, stratified by cirrhotic status at than 85% international screening. performance goal.

Group 1: SOF/VEL/VOX 12 weeks (n=150) Group 2: placebo (n=150)

One hundred and thirteen subjects with other GTs were enrolled in Group 1. Two subjects with GT6 were enrolled in placebo group. POLARIS-4 randomized, Non-NS5A Three hundred and fourteen The SVR12 rate in (GS-US-367- open-label, inhibitor DAA- subjects infected with GT1, 2 each arm was 1170) multicenter, experienced or 3 HCV were randomized in higher than 85% international subjects a 1:1 ratio to the following performance goal. two arms, stratified by HCV GT and cirrhotic status at screening.

Group 1: SOF/VEL/VOX 12 weeks (n=163) Group 2: SOF/RBV 12 weeks (n=151)

Nineteen GT4 subjects were enrolled in Group 1. Note: The reviewer generated this table.

2.2 Data Sources

The original submitted data for the NDA were located in \\CDSESUB1\evsprod\NDA209195\0000\m5\datasets.

During the mid-cycle communication with the applicant, the review team expressed concern that the additional benefit of VOX was not obvious in NS5A inhibitor – naïve and NS5B inhibitor– experienced subjects infected with GT1b, 2, 4, 5 or 6 subjects based on POLARIS-4 results. The applicant’s responses were located in \\CDSESUB1\evsprod\NDA209195\0010.

Reference ID: 4095069 3. STATISTICAL EVALUATION

3.1 Data and Analysis Quality

The quality of the data in this NDA is good, and the reviewer did not have any concerns.

3.2 Evaluation of Efficacy

The two studies had the same efficacy endpoints and similar statistical methodologies which are summarized in Section 3.2.1. Each study is evaluated individually in Sections 3.2.2 and 3.2.3, respectively.

3.2.1 Efficacy Endpoints and Statistical Methods Common to Both Studies Reviewed

3.2.1.1 Efficacy Endpoints

For POLARIS-1 and POLARIS-4, the primary efficacy endpoint was the proportion of subjects that achieved SVR12 defined as HCV RNA < LLOQ 12 weeks after cessation of study treatment. In addition to the primary efficacy endpoint, the secondary efficacy endpoints included in both studies were:

1) percentage of subjects with sustained virologic response at 4 weeks and 24 weeks after cessation of treatment (SVR4 and SVR24)

2) proportion of subjects with HCV RNA < LLOQ while on study by study visit

3) HCV RNA (log10 IU/mL) and change from baseline in HCV RNA through end of treatment

4) percentage of subjects with virologic virologic failure as the following:

 on-treatment virologic failure:

− HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ, while on treatment, confirmed with 2 consecutive values (note, second confirmation value can be post-treatment), or last available on-treatment measurement with no subsequent follow up values (ie, breakthrough)

− >1 log10IU/mL increase in HCV RNA from nadir while on treatment, confirmed with 2 consecutive values (note, second confirmation value can be post-treatment), or last available on-treatment measurement with no subsequent follow up values (i.e., rebound)

Reference ID: 4095069 − HCV RNA persistently ≥ LLOQ through 8 weeks of treatment (i.e. , nonresponse)

 relapse:

− HCV RNA ≥ LLOQ during the post-treatment period having achieved HCV RNA < LLOQ at the end of treatment, confirmed with consecutive values or last available post-treatment measurement

5) characterization of HCV drug resistance substitutions at baseline, during, and after study therapy

3.2.1.2 Statistical Methods

The statistical methods that the applicant used in both studies were very similar and will be summarized in this section.

A. Efficacy Population and Subgroup Analyses

In both studies, the efficacy analysis population included subjects who received at least one dose of study drugs. The applicant referred to the analysis set as the full analysis set, while the reviewer referred to the analysis population as all treated. Also, subgroup analyses to assess the relationship between different subgroups defined by patient demographics and baseline characteristics were performed in both studies.

B. Efficacy Analysis

In POLARIS-1, the SVR12 rate for the 12-week SOF/VEL/VOX regimen was compared to the 85% benchmark using a two-sided exact one-sample binomial test. The two-sided 95% exact confidence interval (CI) based on the Clopper-Pearson method was used to calculate the SVR12 rate.

POLARIS-4 had two primary efficacy tests: the SVR12 rates for the12-week SOF/VEL/VOX and 12-week SOF/VEL regimens were compared to the performance goal of 85% separately. To control the overall Type I error, each primary efficacy test was tested at the significance level of 0.025 using a Bonferroni adjustment. The primary analysis was based on the same exact test and the 95% CI based on the Clopper-Pearson method as what were used in POLARIS-1study.

C. Visit Windows

The baseline value was the last nonmissing value on or prior to the first dose date of study drug. The visit windows were pre-specified for all scheduled visits. A visit window was defined as half of the duration of time between the two consecutive study visits. The on- 10

Reference ID: 4095069 treatment visit windows were calculated from the first dose of study drug (i.e., study day = collection date – date of the first dose; +1 if the result is ≥0), while the post-treatment visit windows were from the last study drug dosing date (i.e., follow-up day = collection data – last dose date). HCV RNA, viral signs, and safety laboratory data collected up to the last dose date + 3 days were considered to be on-treatment data; and the data collected after the last dose date + 3 days were regarded as post-treatment data.

D. Handling Missing Data

In the analysis of the primary efficacy endpoint, all subjects who did not have HCV RNA below LLOQ 12 weeks after the end of treatment were considered as not achieving SVR12. When calculating the proportion of subjects with HCV RNA < LLOQ while on treatment by study visit, the applicant excluded the subjects who discontinued from the study and considered the subjects who were still on study but had missing HCV RNA as failures. Meanwhile, subjects categorized as successes for SVR12 who had no further HCV RNA measurements collected were counted as successes for SVR24 due to the potential high correlation between these 2 endpoints.

3.2.2 POLARIS-1

3.2.2.1 Study Design

POLARIS -1 was a phase 3, randomized, double-blind, placebo-controlled, multicenter study conducted in the United States, Canada, Europe, Australia and New Zealand. The primary objective was to evaluate efficacy, safety and tolerability of SOF/VEL/VOX for 12 weeks in NS5A inhibitor DAA-experienced subjects with chronic HCV infection. Subjects with HCV GT1were randomized in a 1:1 ratio into one of the following two treatment groups stratified by presence or absence of cirrhosis at screening:

Group 1: SOF/VEL/VOX FDC (400/100/100 mg) tablet once daily (QD) with food for 12 weeks Group 2: SOF/VEL/VOX placebo tablet QD with food for 12 weeks

Subjects with GT2, 3, 4, 5, or 6 HCV infections were not randomized but enrolled directly into the SOF/VEL/VOX 12 week arm.

Subjects in the 12-week SOF/VEL/VOX group were to complete the post-treatment assessments during the Week 4 and 12 visits. If the subjects achieved SVR12, then they completed the post-treatment assessment at the Week 24 visit. Subjects in the placebo arm who completed treatment and the post-treatment Week 4 visit were not required to complete post-treatment assessments at the Week 12 and 24 visits. The placebo subjects were offered the option of SOF/VEL/VOX for 12 weeks in a deferred treatment study. The HCV RNA measurements were assessed at screening, baseline, on-treatment Weeks 1, 2, 4, 8, 12 visits, and at post-treatment Weeks 4, 12 and 24 visits (if applicable). 11

Reference ID: 4095069 Although a placebo-arm was included for comparative safety, the design was essentially the same as a single-arm study for the evaluation of efficacy. The primary efficacy hypothesis was that the SVR12 rate for 12-week SOF/VEL/VOX was significantly higher than the pre-specified clinical threshold of 85%. Possible reasons for this single arm design included the lack of approved regimens in this patient population (preventing an active control) and historical data indicating that placebo subjects would be not achieve SVR12. The review team also had suggested a study design with a superiority comparison of 12-week SOF/VEL/VOX against 12-week SOF/VEL in order to evaluate the additional benefit of VOX over the SOF/VEL regimen at the time of review of the study protocol.

3.2.2.2 Patient Disposition, Demographic and Baseline Characteristics

Table 3 shows the patient disposition. Two hundred and sixty-four subjects were randomized to or enrolled in the 12-week SOF/VEL/VOX arm and 116 subjects were randomized to the placebo group. With the exception of one subject, all randomized or enrolled subjects in the 12-week SOF/VEL/VOX group took at least one dose of the assigned medication. Also, among the randomized and treated subjects, the majority completed the study treatment. Two treated subjects in the 12-week SOF/VEL/VOX group discontinued the study treatment: one was due to adverse event (AE) and another was due to lack of efficacy. Three placebo subjects discontinued the study drugs prematurely due to AE.

Table 3: Applicant’s Results for Patient Disposition in POLARIS-1 SOF/VEL/VOX 12 weeks Placebo Randomized/Enrolled 264 152 Treated 263 (100%) 152 (100%) Completed study treatment 261 (99.2%) 149 (98.0%) Not completed study treatment 2 (0.8%) 3 (2.0%) Adverse event 1 (0.4%) 3 (2.0%) Lost to follow-up 1 (0.4%) 0 Source: Table 8-2 in POLARIS-1 Interim Clinical Study Report

Table 4 and Table 5 display patient demographic and selected baseline disease characteristics in both groups, and Table 6 summarizes the prior HS5A inhibitors for the subjects in 12-week SOF/VEL/VOX. The more detailed prior HCV DAAs treatment history for the subjects in 12-week SOF/VEL/VOX is shown in Table 17 in Appendix (Section 6). Among all randomized and treated subjects, the average age (standard deviation [SD]) was 58 (8.3) years. The majority of the subjects were male (77.3%), white (80.7%), recruited in US sites (56.9%) and had baseline BMI < 30 kg/m2 (67.2%).

In the 12-week SOF/VEL/VOX treatment arm, most of the subjects had HCV GT1 (57.0%) or GT3 (29.7%) infection and there were a few subjects infected with HCV GT2 (1.9%), GT4 (8.4%), GT5 (0.4%) or GT6 (2.3%). Approximately 46.0% of the subjects in the group had cirrhosis at baseline. Also, the majority of the subjects in the arm had CT IL28B allele (62.7%), baseline HCV RNA ≥ 800,000 IU/mL (72.2%), and DAA-

Reference ID: 4095069 experience with NS5A + NS5B (61.2%). The most common NS5A inhibitor the subjects had previously received was Ledipasvir (50.6%), followed by Daclatasvir (26.6%), Ombitasvir (11.4%), and Velpatasvir (7.2%).

Table 4: Applicant’s Results for Patient Demographics and Selected Baseline Characteristics in POLARIS-1 (All Treated) SOF/VEL/VOX 12 Weeks Placebo Total (N=263) (N=152) (N=415) Age Mean (SD) 58 (8.5) 59 (8.0) 58 (8.3) Median 59 60 59 Q1, Q3 54, 63 55, 64 54, 63 Min, Max 27, 84 29, 80 27, 84

< 65 years 222 (84.4%) 121 (79.6%) 343 (82.7%) ≥ 65 years 41 (15.6%) 31 (20.4%) 72 (17.3%) Gender Male 200 (76.0%) 121 (79.6%) 321 (77.3%) Female 63 (24.0%) 31 (20.4%) 94 (22.7%) Race White 211 (80.2%) 124 (80.2%) 335 (80.7%) Black/African American 38 (14.4%) 22 (14.5%) 60 (14.5%) Asian 8 (3.0%) 6 (3.9%) 14 (3.4%) American Indian or Alaska Native 3 (1.1%) 0 3 (0.7%) Native Hawaiian or Pacific Islander 1 (0.4%) 0 1 (0.2%) Not disclosed 1 (0.4%) 0 1 (0.2%) Other 1 (0.4%) 0 1 (0.2%) Ethnicity Hispanic/Latino Yes 15 (5.7%) 10 (6.6%) 25 (6.0%) No 247 (93.9%) 142 (93.4%) 389 (93.7%) Not disclosed 1 (0.4%) 0 1 (0.2%) Region US 135 (51.3%) 101 (66.4%) 236 (56.9%) Non-US 128 (48.7%) 51 (33.6%) 179 (43.1%) Canada1 28 (10.7%) 14 (9.2%) 42 (10.1%) Europe1 80 (30.4%) 24 (15.8%) 104 (25.1%) Australia / New Zealand1 20 (7.6%) 13 (8.6%) 33 (8.0%) BMI2 (kg/m2) Mean (SD) 28.8 (5.5) 28.5 (5.8) 28.7 (5.6) Median 27.8 27.9 27.8 Q1, Q3 25.4, 31.3 25.0, 31.2 25.3, 31.3 Min, Max 18.4, 66.7 18.0, 61.2 18.0, 66.7

< 30 kg/m2 179 (68.1%) 100 (65.8%) 279 (67.2%) ≥ 30 kg/m2 84 (31.9%) 52 (34.2%) 136 (32.8%) Source: Tables 8-5 and 8-6 in POLARIS-1 Interim Clinical Study Report 1summarized by the statistical reviewer 2body mass index

Reference ID: 4095069 Table 5: Applicant’s Results for Selected Baseline Disease Characteristics in POLARIS-1 (All Treated) SOF/VEL/VOX 12 Weeks Placebo Total (N=263) (N=152) (N=415) Genotype1 GT1 150 (57.0%) 150 (98.7%) 300 (72.3%) GT1a 101 (38.4%) 117 (77.0%) 218 (52.5%) GT1b 45 (17.1%) 31 (20.4%) 76 (18.3%) GT1 other 4 (1.5%) 2 (1.3%) 6 (1.4%) GT2 5 (1.9%) 0 5 (1.2%) GT3 78 (29.7%) 0 78 (18.8%) GT4 22 (8.4%) 0 22 (5.3%) GT5 1 (0.4%) 0 1 (0.2%) GT6 6 (2.3%) 2 (1.3%) 8 (1.9%) Unknown 1 (0.4%) 0 1 (0.2%) Cirrhosis Yes 121 (46.0%) 51 (33.6%) 172 (41.4%) No 142 (54.0%) 101 (66.4%) 243 (58.6%) IL28B CC 47 (17.9%) 27 (17.8%) 74 (17.8%) Non-CC 216 (82.1%) 125 (82.2%) 341 (82.2%) CT 165 (62.7%) 93 (61.2%) 258 (62.2%) TT 51 (19.4%) 32 (21.1%) 83 (20.0%) Baseline HCV RNA (log10IU/mL) Mean (SD) 6.3 (0.68) 6.3 (0.63) 6.3 (0.66) Median 6.3 6.4 6.3 Q1, Q3 5.8, 6.7 5.9, 6.7 5.9, 6.7 Min, Max 1.6, 7.7 3.7, 7.6 1.6, 7.7

< 800,000 IU/mL 73 (27.8%) 36 (23.7%) 100 (26.3%) ≥ 800,000 IU/mL 190 (72.2%) 116 (76.3%) 306 (73.7%) Baseline ALT ≤ 1.5 x ULN 120 (45.6%) 93 (61.2%) 213 (51.3%) > 1.5 x ULN 143 (54.4%) 59 (38.8%) 202 (48.7%) Prior DAA(s) history NS5A + NS5B 161 (61.2%) 81 (53.3%) 242 (58.3%) NS5A + NS3 ± NS5B 83 (31.6%) 61 (40.1%) 144 (34.7%) NS5A ± Other(s) 18 (6.8%) 9 (5.9%) 27 (6.5%) Other(s) 1 (0.4%) 1 (0.7%) 2 (0.5%) Source: Tables 8-4 and 8-5 in POLARIS-1 Interim Clinical Study Report 1determined by sequencing-based BLAST analysis

Reference ID: 4095069 Table 6: Reviewer’s Results for Use of prior NS5A Inhibitors for Subjects in 12-Week SOF/VEL/VOX Group in POLARIS-1 (All Treated) Prior NS5A inhibitor SOF/VEL/VOX 12 Weeks (n=263) Daclatasvir 70 (26.6%) Elbasvir 7 (2.7%) Ledipasvir 133 (50.6%) Ombitasvir 30 (11.4%) Pibrentasvir 2 (0.8%) Samatasvir 4 (1.5%) Velpatasvir 19 (7.2%) Note: This table was generated by the statistical reviewer.

3.2.2.3 Results and Conclusions

As shown in Table 7, the applicant’s analysis demonstrated that treatment with SOF/VEL/VOL for 12 weeks resulted in a 96.2% SVR12 rate with 95% CI of (93.1%, 98.2%). The reviewer agrees with the applicant’s results. Among the subjects who experienced relapse, three of them relapsed by post-treatment Week 4 and three relapsed between post-treatment Weeks 4 and 8. Meanwhile, among the subjects who did not meet virologic failure criteria and were categorized as “other” in Table 7, one of them discontinued study treatment on Day 12 due to AE, one was lost follow-up at post- treatment Week 4 visit, and one withdrew consent before the post-treatment Week 12 visit.

Table 7: Applicant’s Results for Virologic Outcomes at Post-Treatment Week 12 in POLARIS-1 (All Treated) SOF/VEL/VOX 12 Weeks (N=263) SVR12 rate 96.2% (253/263) [95% CI]1 [93.1%, 98.2%] p-value (compared to 85%) <0.001 Not achieving SVR12 On-treatment virologic failure 0.4% (1/263) Relapse 2.3% (6/261) Other 1.1% (3/263) Sources: Tables 9-1 and 9-2 in POLARIS-1 Interim Clinical Study Report 1based on Clopper-Pearson method

The secondary efficacy endpoint of SVR4 rate was 97.7% (257/263) with 95% CI of (95.1%, 99.2%). The SVR4 was similar to the SVR12 rate with the difference only in four subjects who either relapsed or withdrew consent between post-treatment Week 4 and Week 12 visits. Additionally, the applicant did not summarize the SVR24 rate in this interim clinical study report and plan to provide complete SVR24 data in the final clinical study report.

Table 8 shows the applicant’s observed proportion of subjects with HCV RNA below LLOQ at each on-treatment visit. The applicant excluded the subjects who discontinued the study by Week 12 from their analyses. More than 90% of subjects achieved HCV 15

Reference ID: 4095069 RNA viral suppression 4 weeks after receiving SOF/VEL, and the high response rate was maintained through the end of treatment.

Table 8: Applicant’s Results for Observed Proportion of Subjects with HCV RNA < LLOQ While on Active Treatment by Visit in POLARIS-1 (All Treated) Visit SOF/VEL/VOX 12 Weeks (N=263) Week 1 15.6% (41/263) Week 2 56.7% (149/263) Week 4 92.7% (243/262) Week 8 100% 262/262 Week 12 99.6% (260/261) Source: Table 9-6 in POLARIS-1 Interim Clinical Study Report

3.2.3 POLARIS-4

3.2.3.1 Study Design and Endpoints

POLARIS-4 was a phase 3, randomized, open-label, multicenter study conducted in the US, Canada, Europe, Australia and New Zealand. The primary efficacy objective was to determine the efficacy and safety of treatment with SOF/VEL/VOX FDC for 12 weeks and SOF/VEL for 12 weeks in non-NS5A inhibitor DAA-experienced subjects with HCV infection. Subjects who had DAA exposure to a NS3/4A PI only were excluded. Subjects infected with HCV GT1, 2 or 3 were randomized using a 1:1 ratio to one of the following two groups, stratified by HCV GT (1, 2, or 3) and cirrhotic status at screening (present vs. absent).

Group 1: SOF/VEL/VOX (400/100/100 mg) FDC once daily with food for 12 weeks Group 2: SOF/VEL (400/100 mg) FDC without regard to food for 12 weeks

All subjects with GT4 infection were to enroll in 12-week SOF/VEL/VOX group.

All subjects were to complete the post-treatment Week 4 and 12 visit assessments. Subjects who achieved SVR12 were to complete the post-treatment Week 24 visit. Subjects achieving SVR were eligible to enroll into an SVR registry study or an SVR cirrhosis registry study; otherwise, they would enroll into a sequence registry study. The HCV RNA measurements were assessed at screening, baseline, on-treatment Weeks 1, 2, 4, 8, 12 visits, and at post-treatment Weeks 4, 12 and 24 visits

3.2.3.2 Patient Disposition, Demographic and Baseline Characteristics

Table 9 shows patient disposition in POLARIS-4. All randomized or enrolled subjects received at least one dose of the assigned study drug. With the exception of two subjects in the SOF/VEL arm, all subjects completed study treatment. Of the two subjects who discontinued study drug prematurely, one discontinued due to AE and the other due to lack of efficacy.

Reference ID: 4095069 Table 9: Applicant’s Results for Patient Disposition in POLARIS-4 SOF/VEL/VOX 12 weeks SOF/VEL 12 weeks Randomized / enrolled 182 151 Treated 182 (100%) 151 (100%) Completed study treatment 182 (100%) 149 (98.7%) Not completed study treatment Adverse event 0 1 (0.7%) Lack of efficacy 0 1 (0.7%) Source: Table 8-2 in POLARIS-2 Interim Clinical Study Report

Patient demographics and selected characteristics were similar between the two groups (Table 10). Among all randomized and treated subjects, the mean age (SD) was 57 (8) years. The majority of subjects were male (77.2%) and white (87.4%). Approximately 56.5% of subjects were recruited in US sites.

Table 10: Applicant’s Results for Patient Demographics and Baseline Characteristics in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL 12 weeks 12 weeks Total (N=182) (N=151) (N=333) Age at baseline (years) Mean (SD) 57 (9.0) 57 (7.3) 57 (8.3) Median 58 58 58 Q1, Q3 54, 62 52, 62 53, 62 Min, Max 24, 85 24, 80 24, 85 Sex at birth Male 143 (78.6%) 114 (75.5%) 257 (77.2%) Female 39 (21.4% 37 (24.5%) 76 (22.8%) Race White 160 (87.9%) 131 (86.8%) 291 (87.4%) Black or African American 16 (8.8%) 13 (8.6%) 29 (8.7%) Asian 2 (1.1%) 4 (2.6%) 6 (1.8%) American Indian or Alaska Native 2 (1.1%) 0 2 (0.6%) Native Hawaiian or Pacific Islander 0 2 (1.3%) 2 (0.6%) Other 2 (1.1%) 1 (0.7%) 3 (0.9%) Ethnicity Hispanic or Latino 19 (10.4%) 8 (5.3%) 27 (8.1%) Not Hispanic or Latino 163 (89.6%) 143 (94.7%) 306 (91.9%) Region US 101 (55.5%) 87 (57.6%) 188 (56.5%) Non-US 81 (44.5%) 64 (42.4%) 145 (43.5%) Body mass index (kg/m2) at baseline Mean (SD) 29 (5.6) 29 (5.8) 29 (5.7) Median 28 28 28 Q1, Q3 25, 32 25, 32 25, 32 Min, Max 18, 45 18, 53 18, 53

< 30 kg/m2 120 (65.9%) 98 (64.9%) 218 (65.5%) ≥ 30 kg/m2 62 (34.1%) 53 (35.1%) 115 (34.5%) Source: Table 8-4 in POLARIS-4 Interim Clinical Study Report

Reference ID: 4095069 Table 11 displays the selected disease characteristics at baseline. Table 20 to Table 22 in Section 6 summarize the prior HCV treatments the subjects received. Overall, most subjects had HCV GT1 (43.2%) or GT3 (31.8%) infection. Approximately 45.9% of subjects had cirrhosis at baseline and 60.7% had CT IL28B allele. The mean (SD) HCV RNA at baseline was 6.3 (0.6) log10 IU/mL. The majority of subjects were treatment- experienced with NS5B inhibitor alone (73.0%) and had received SOF-containing regimens previously (84.7%). Approximately 65.3% of subjects infected with HCV GT1 received a SOF-containing regimen previously, and all subjects with HCV GT2, 3 or 4 infection except for one GT4 subject had prior exposure to SOF (Table 21).

Table 11: Applicant’s Results for Selected Baseline Disease Characteristics in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL 12 weeks 12 weeks Total (N=182) (N=151) (N=333) HCV genotype GT1 78 (42.9%) 66 (43.7%) 144 (43.2%) GT1a 54 (29.7%) 44 (29.1%) 98 (29.4%) GT1b 24 (13.2%) 22 (14.6%) 46 (13.8%) GT2 31 (17.0%) 33 (21.9%) 64 (19.2%) GT3 54 (29.7%) 52 (34.4%) 106 (31.8%) GT4 19 (10.4%) 0 19 (5.7%) Cirrhosis Yes 84 (46.2%) 69 (45.7%) 153 (45.9%) No 98 (53.8%) 82 (54.3%) 180 (54.1%) IL28B CC 33 (18.1%) 29 (19.2%) 62 (18.6%) Non-CC 149 (81.9%) 122 (80.8%) 271 (81.4%) CT 107 (58.8%) 95 (62.9%) 202 (60.7%) TT 42 (23.1%) 27 (17.9%) 69 (20.7%) HCV RNA at baseline (log10 IU/mL) Mean (SD) 6.3 (0.56) 6.3 (0.66) 6.3 (0.61) Median 6.4 6.4 6.4 Q1, Q3 5.9, 6.7 5.9, 6.7 5.9, 6.7 Min, Max 5.0, 7.5 3.6, 7.3 3.6, 7.5

< 800,000 IU/mL 46 (25.3%) 38 (25.2%) 84 (25.2%) ≥ 800,000 IU/mL 136 (74.7%) 113 (78.4%) 249 (74.8%) ALT at baseline (U/L) Mean (SD) 84 (65.0) 85 (67.7) 84 (66.1) Median 65 64 65 Q1, Q3 42, 101 33, 108 39, 105 Min, Max 13, 417 9, 384 9, 417

≤ 1.5 x ULN 88 (48.4%) 72 (47.7%) 160 (48.0%) > 1.5 x ULN 94 (51.6%) 79 (52.3%) 173 (52.0%) Source: Tables 8-5, 8-6 and Adhoc Table 22 in POLARIS-4 Interim Clinical Study Report 1summarized by the statistical reviewer (to be continued)

Reference ID: 4095069 Table 11: Applicant’s Results for Selected Baseline Disease Characteristics in POLARIS-4 (All Treated) (Continued) SOF/VEL/VOX SOF/VEL 12 weeks 12 weeks Total (N=182) (N=151) (N=333) Prior DAA treatment history DAA-naïve 0 1 (0.7%) 1 (0.3%) DAA-experienced 182 (100%) 150 (99.3%) 332 (99.7%) NS5B only 134 (73.6%) 109 (72.2%) 243 (73.0%) NS5B + NS3 46 (25.3%) 38 (25.2%) 84 (25.2%) NS3 only 2 (1.1%) 3 (2.0%) 5 (1.5%)

Sofosbuvir-experienced Yes 157 (86.3%) 125 (82.8%) 282 (84.7%) Sofosbuvir only 127 (69.8%) 104 (68.9%) 231 (69.4%) Sofosbuvir + NS3 28 (15.4%) 21 (13.1%) 49 (14.7%) Sofosbuvir + other investigational agents 2 (1.1%) 0 2 (0.6%) No 25 (13.7%) 26 (17.2%) 51 (15.3%) NS3 only 2 (1.1%) 3 (2.0%) 5 (1.5%) NS3 + investigational agents 3 (1.7%) 3 (2.0%) 6 (1.8%) Investigational agents only 20 (11.0%) 19 (12.6%) 39 (11.7%) DAA-naïve 0 (0%) 1 (0.7%) 1 (0.3%) Source: Tables 8-5, 8-6 and Adhoc Table 22 in POLARIS-4 Interim Clinical Study Report

3.2.3.3 Results and Conclusions

Subjects treated with SOF/VEL/VOX for 12 weeks had a 97.3% SVR12 rate which was statistically significantly higher than the pre-specified 85% performance goal (Table 12). Treatment of SOF/VEL for 12 weeks resulted in a 90.1% SVR12 rate which was not statistically significantly higher than the pre-specified criteria. The reviewer agrees with applicant’s results regarding SVR12. The reviewer conducted a post-hoc analysis to compare the overall SVR12 rate between the two groups. The results demonstrated the treatment difference was 7% in favor of 12-week SOF/VEL/VOX regimen (95% CI of [1.9%, 12.5%], and p = 0.006 based on Chi-square test).

With respect to relapse, the review team disagreed with the applicant’s classification of Subject GS-US-367-1170-00407-27557 as a relapser. This subject discontinued the study drug prematurely due to an AE (headache) on Day 56 (Week 8). The last HCV RNA measurement before discontinuation was below <15 IU/mL at Week 4. The HCV RNA was 2,050,000 IU/mL approximately 12 weeks after the treatment. The applicant classified this subject as having relapsed. However, in the review team’s opinion, the subject should be classified as “other” since the subject did not complete the full course of 12 weeks of study treatment. Nevertheless, a lower relapse rate was observed in the SOF/VEL/VOX group as compared to the SOF/VEL group. Only one subjects relapsed in the 12-week SOF/VEL/VOX group, whereas 13 subjects experienced relapse by post- treatment Week 12 visit in the SOF/VEL group.

Reference ID: 4095069 Table 12: Reviewer’s Results for Virologic Outcomes at Post-Treatment Week 12 in POLARIS-4 (All Treated)

SOF/VEL/VOX 12 Weeks SOF/VEL 12 Weeks (N=182) (N=151)

SVR12 rate 97.3% 90.1% (number of responders/N) (177/182) (136/151) [95% CI]1 [93.7%, 99.1%] [84.1%, 94.3%] P-value (compared to 85%) <0.001 0.092 Not achieving SVR12 On-treatment virologic failure 0% (0/182) 0.7% (1/151) Relapse 0.5% (1/182) 8.7% (13/150) Other 2.2% (4/182) 0.7% (1/151) 1based on Clopper-Pearson method

The secondary efficacy endpoint of SVR4 rate was similar to SVR12 rate in each arm (Table 13). Most of relapses occurred by post-treatment Week 4. In the 12-week SOF/VEL/VOX group, one subject relapsed by post-treatment Week 4, but none relapsed between post-treatment Week 4 and 12 visits. In the 12-week SOF/VEL group, 12 of 13 relapses occurred by post-treatment Week 4, and one of 13 relapses occurred between post-treatment Week 4 and 12. Like POLARIS-1, the SVR24 data was not submitted in this interim clinical study report and will be provided in the final clinical study report.

Table 13: Applicant’s Results for SVR4 Rate in POLARIS-4 (All Treated)

SOF/VEL/VOX 12 Weeks SOF/VEL 12 Weeks (N=182) (N=151)

SVR4 rate 97.8% 91.4% (number of responders/N) (178/182) (138/151) [95% CI]1 [94.5%, 99.4%] [85.7, 95.3%] Sources: Table 9-3 in POLARIS-4 Interim Clinical Study Report 1based on Clopper-Pearson method

The applicant’s observed proportion of subjects with HCV RNA below LLOQ during on- treatment visits are shown in Table 14 below. Approximately 90% of the subjects in both arms achieved HCV RNA < LLOQ four weeks after taking study medicine. The response rates were above 95% in both arms by Week 8 and the high response rates were maintained thereafter up to the end of the 12-week treatment course.

Table 14: Applicant’s Results for Observed Proportion of Subjects with HCV RNA < LLOQ While on Active Treatment by Visit in POLARIS-4 (All Treated) Visit SOF/VEL/VOX 12 Weeks (N=182) SOF/VEL 12 Weeks (N=151) Week 1 15.9% (29/182) 17.2% (26/151) Week 2 62.6% (114/182) 56.3% (85/151) Week 4 88.5% (161/182) 90.7% (137/151) Week 8 100% (182/182) 98.7% (149/151) Week 12 98.9% (180/182) 99.3% (149/150) Sources: Table 9-6 in POLARIS-4 Interim Clinical Study Report

Reference ID: 4095069 4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS

This section summarizes the subgroup analyses for the SVR12 rate in each study. The results of the subgroup analyses should be interpreted with caution because of multiple comparisons with no adjustments applied, small sample sizes in some of the subgroups, and lack of an active control in POLARIS-1.

4.1 POLARIS-1

The SVR12 rate was 96.2% in the 12-week SOF/VEL group in POLARIS-1. The SVR12 rates were high for all subgroups by patient demographics and baseline disease characteristics (Table 18 and Table 19). As the applicant mentioned, the SVR12 rates were in slightly lower in subjects with BMI ≥ 30 kg/m2 (92.9% [78/84]) and in Black/African Americans (92.1% [35/38]). However, the sample sizes in these subgroups were too small to make a reliable conclusion.

The SVR12 rate was 97.3% in subjects with HCV GT1 infection and 94.9% in subjects with HCV GT3 infection. As mentioned in the previous section, there was very limited data for subjects with HCV GT2, 4, 5 or 6 infection. Specifically, the study only enrolled five HCV GT2 subjects, 22 HCV GT4 subjects, one HCV GT5 subject and one HCV GT6 subject. Therefore, the study did not provide sufficient evidence to support SOF/VEL/VOX 12 weeks in treatment of these genotypes. However, subjects with HCV GT3 infection and cirrhosis are generally regarded as the most difficult to treat with DAA regimens, and the 12-week SOF/VEL/VOX resulted in a 92.9% (52/56) SVR12 rate in this subgroup. Therefore, it is hypothesized that the 12-week SOF/VEL/VOX could lead to high SVR12 rate in subjects infected with HCV GT2, 4, 5, or 6.

4.2 POLARIS-4

In POLARIS-4, the applicant performed the pre-specified subgroup analyses defined by patient demographics and selected baseline characteristics in each treatment arm. To explore the contribution of VOX in the 12-week SOF/VEL/VOX regimen, the reviewer further conducted exploratory analyses to calculate the differences in the SVR12 rate between the two treatment arms and the corresponding 95% CIs. The results of these analyses are displayed in Table 23 and Table 24. Overall SOF/VEL/VOX resulted in numerically higher SVR12 rates in most of the subgroups compared to SOF/VEL. The trends were more apparent among the Black/African American and Hispanic subpopulations. However, the numbers among these two subpopulations were too small to be conclusive.

HCV genotype was the randomization stratifier in subjects infected with HCV GT1, 2 and 3 infections. In additional to comparing the SVR12 rate between the two treatment groups by HCV genotype as shown Table 24, the reviewer also summarized the virologic outcomes at post-treatment Week 12 by genotype in Table 25. The differences in SVR12

Reference ID: 4095069 and relapse rates between the two treatment groups were more obvious in HCV GT1a or GT3 subjects as compared to GT1b or GT2 subjects. The virologic outcome for the two treatments was similar in GT1b subjects. Among the HCV GT2-infected subjects, the two regimens had almost identical SVR12 rates. Specifically, the SOF/VEL/VOX regimen had a 100% SVR12 rate, while the SOF/VEL treatment had a 97% SVR12 rate with only one subject not achieving SVR12 because of on-treatment virologic failure. Also, none of the subjects infected with HCV GT2 experienced relapse. As mentioned in the previous section, all GT4 subjects received SOF/VEL/VOX for 12 weeks, and therefore the contribution of VOX could not be assessed in the GT4 subjects. Finally, the study did not include any subjects with HCV GT5 or 6. Thus, there is no evidence to support either regimen in treatment of HCV GT5 or 6 infection.

Baseline cirrhotic status was expected to affect the SVR12 rate. The difference in SVR12 rate between the two regimens was more apparent in cirrhotic subjects as compared to non-cirrhotic subjects. The trend was most obvious in subjects with HCV GT3 infection and cirrhosis Table 26. Among these subjects, the SVR12 rate was approximately 93.6% for the SOF/VEL/VOX regimen and only 76.7% for the SOF/VEL treatment.

SOF is the only approved NS5B inhibitor for the treatment of HCV. In POLARIS-4, approximately 65.3% of GT1 subjects had prior exposure to SOF while all GT2, 3 and 4 subjects, with the exception of one GT4 subject, received a SOF-containing regimen previously. It was of clinical interest to explore whether the SVR12 rate was different between subjects with and without exposure to a SOF-containing regimen in each genotype and subgenotype of GT1 in order to more precisely describe the patient population in the label. Therefore, the additional subgroup analyses defined by genotype and whether the subjects had failed a SOF-containing regimen were conducted. As shown in Table 27, all subjects without prior exposure to a SOF-containing regimen achieved SVR12 in both treatment groups. The analyses also suggested that, among subjects with prior receiving a SOF-containing regimen, the treatment difference between SOF/VEL/VOX and SOF/VEL tended to be numerically larger in HCV GT1a and GT3 subjects as compared to GT1b and GT2 subjects (Table 27 and Table 28).

5. SUMMARY AND CONCLUSIONS

5.1 Statistical Issues

There are no statistical issues.

5.2 Collective Evidence

The NDA included interim clinical study reports for POLARIS-1 and POLARIS-4 for the evaluation of safety and efficacy of 12 weeks of SOF/VEL/VOX in subjects who previously failed DAA regimens. Both studies assessed efficacy based on the SVR rate. SVR12 was evaluated in NS5A inhibitor DAA-experienced subjects with chronic HCV 22

Reference ID: 4095069 infection in POLARIS-1 and in NS5A DAA-naïve subjects with chronic HCV infection in POLARIS-4. Although a placebo arm was included for safety in POLARIS-1, both studies evaluated efficacy based on a pre-specified clinical threshold of 85%. POLARIS-4 additionally included and evaluated a SOF/VEL treatment arm.

In POLARIS-1, the SVR12 rate for 12 weeks of SOF/VEL was approximately 96% which was significantly higher than the pre-specified threshold of 85%. However, the majority of the subjects in the study had HCV GT1 or GT3 infection. There was limited number of subjects infected with GT2, 4, 5 or 6 HCV. Specifically, the study only included five subjects with GT2 infection, 22 subjects with GT4 infection, one subject with GT5 infection, and one subject with GT6 infection.

In POLARIS-4, the SVR12 rate for SOF/VEL/VOX was significantly higher than the 85% threshold, but the SVR rate for the SOF/VEL group was not significantly higher. Moreover, the regimen of SOF/VEL/VOX had numerically higher SVR12 rate (97%) as compared to the treatment of SOF/VEL for 12 weeks (90%). The reviewer’s exploratory analyses demonstrated that SOF/VEL/VOX had a nominally significantly higher SVR12 rate than 12-week SOF/VEL (p=0.006). POLARIS-4 only included subjects infected with HCV GT1, 2, 3 or 4. Further exploratory subgroup analyses suggested that all of the limited subjects without exposure to a SOF-containing regimen achieved SVR12 in both groups. The analyses also suggested that among the subjects who had received a SOF- containing regimen previously, the contribution of VOX in the SOF/VEL/VOX regimen was more apparent in the subjects with GT1a or 3 infection compared to the subjects with GT1b and GT2 infection. In the study, all subjects with GT4 infection received 12 weeks of SOF/VEL/VOX, and therefore the additional contribution of VOX to the SOF/VEL/VOX regimen could not be assessed. Finally, the study did not enroll any subjects with GT5 or 6 infection.

5.3 Conclusions and Recommendations

The results from POLARIS-1 indicated that the 12-week SOF/VEL/VOX regimen was effective in treatment of NS5A inhibitor DAA-experienced subjects with HCV GT1 or 3 infections and without decompensated cirrhosis. (b) (4) (b) (4)

The results from POLARIS-4 indicated that the 12-week SOF/VEL/VOX regimen was effective in treating NS5A inhibitor DAA-naïve and SOF-experienced subjects with HCV GT1a or 3 infections and without decompensated cirrhosis (b) (4) (b) (4)

(b) (4) In addition, all subjects infected with HCV 23

Reference ID: 4095069

Figure 1: Applicant’s Results of Percent of Subjects with Cumulative Negative Host Factors (POLARIS-2, POLARIS-3 and POLARIS-4; SOF/VEL Groups Only)

The applicant then compared the SVR12 rates between the two treatment arms in POLARIS-4 within each number of negative host factors (i.e., 1, 2, 3, 4, and 5) (Figure 2). The results revealed that cumulative negative host factors led to lower response rates in the 12-week SOF/VEL group as compared to the 12-week SOF/VEL/VOX arm. The applicant further generated a linear regression model for each treatment group where they modeled SVR12 rate as a function of number of negative host factors. The results of their regression analyses confirmed that there was a strong linear relationship between the SVR12 rate and number of negative host factors in the SOF/VEL group, but not in the SOF/VEL/VEL group. Based on the results of these analyses, the applicant concluded that “the contribution of VOX in POLARIS-4 is not genotype specific, but rather host specific with failure to a prior DAA regimen enriching for patients who are intrinsically more difficult to cure.”

Reference ID: 4095069 Figure 2: Applicant’s Results of SVR12 Rates by Cumulative Negative Host Factors (POLARIS-4, SOF/VEL/VOX and SOF/VEL groups)

The review team had several concerns about the applicant’s analyses. First, the analyses were post-hoc. Also, the applicant did not specify how they identified the five negative host factors. They assumed these factors were “historically” associated with a poor response to HCV treatment. Per the clinical team, these five factors may be historically correlated with lower response rates for the interferon based regimens but did not appear to be prognostic factors for virologic outcomes for the approved non-interferon DAA- containing regimens. The baseline cirrhotic status has been predictive for negative virologic outcomes and was included in labeling for the approved DAAs.

Furthermore, based on the applicant’s results, the additional benefit of VOX over SOF/VEL was not obvious among subjects with 1 or 2 negative host factors and therefore SOF/VEL was considered sufficient for these subjects. However, this subset also included some cirrhotic subjects, including subjects with HCV GT3 infection and cirrhosis who are generally considered the most difficult to treat with DAA regimen (Table 15).

Reference ID: 4095069 Table 15: Reviewer’s Results of SVR12 rates by HCV Genotype and Baseline Cirrhotic Status among Subjects with 1 or 2 Negative Host Factors in POLARIS-4 SOF/VEL/VOX SOF/VEL 12 Weeks 12 Weeks GT1a Cirrhosis No 100% (10/10) 92.9% (13/14) Yes 100% (1/1) n/a GT1b Cirrhosis No 87.5% (7/8) 90.0% (9/10) Yes 100% (1/1) n/a GT2 Cirrhosis No 100% (8/8) 100% (7/7) Yes 100% (1/1) n/a GT3 Cirrhosis No 100% (8/8) 100% (9/9) Yes 66.7% (2/3) n/a GT4 Cirrhosis No 100% (2/2) n/a Yes 100% (1/1) n/a

Meanwhile, the applicant’s analyses indicated the contribution of VAX was more evident in subjects with 3, 4 or 5 negative host factors. However, among these subjects, the difference between treatment groups were primarily driven by GT1a and GT3 subjects (Table 16).

Reference ID: 4095069 Table 16: Reviwewer’s Results of SVR12 Rates by HCV Genotype and Baseline Cirrhotic Status among Subjects with 3, 4, or 5 Negative Host Factors in POLARIS-4 SOF/VEL/VOX SOF/VEL 12 Weeks 12 Weeks GT1a Cirrhosis No 100% (27/27) 92.9% (13/14) Yes 93.8% (15/16) 81.3% (13/16) GT1b Cirrhosis No 100% (5/5) 100% (5/5) Yes 100% (10/10) 100% (7/7) GT2 Cirrhosis No 100% (10/10) 90% (9/10) Yes 100% (10/10) 100% (15/15) GT3 Cirrhosis No 93.3% (14/15) 92.3% (12/13) Yes 96.4% (27/28) 76.7% (23/30) GT4 Cirrhosis No 100% (5/5) n/a Yes 100% (11/11) n/a

With respect to the 10 GT2 subjects on the non-IND Study GS-US-342-3921, the sample size was too small to make reliable conclusion. Also, the applicant did not submit the data for full assessment. In summary, the review team did not agree with the applicant’s conclusion that the contribution of VOX was not genotype specific.

Additionally, as mentioned in the previous sections, SOF is the only approved NS5B inhibitor. The subgroup analyses revealed that all subjects without prior exposure to a SOF-containing regimen achieved SVR12 in both groups. Furthermore, among the subjects who previously received a SOF-experienced regimen, the additional benefit of VOX in the SOF/VEL/VOX regimen in HCV GT1a and GT3 subjects tended to be more evident in comparison to HCV GT1b and GT2 subjects (Table 27 and Table 28). Therefore, the review team concluded that the POLARIS-4 patient population in the proposed label should be the NS5A inhibitor-naïve and SOF-experienced subjects infected with HCV GT1a and GT3 only.

Reference ID: 4095069 6. Appendix

This section includes the summary tables of prior HCV treatment history and subgroup analyses by patient demographics and selected baseline disease characteristics in each study.

6.1 POLARIS-1

Table 17: Reviewer’s Results of Prior HCV DAAs for Subjects in 12-Week SOF/VEL/VOX in POLARIS-1 (All Treated) SOF/VEL/VOX 12 Weeks Prior HCV DAAs (N=263) Daclatasvir 70 (26.6%) Daclatasvir only 17 (6.5%) Daclatasvir + Asunaprevir 6 (2.3%) Daclatasvir + Asunaprevir + Beclabuvir 3 (1.1%) Daclatasvir + Simeprevir 3 (1.1%) Daclatasvir + Simeprevir + Sofosbuvir 1 (0.4%) Daclatasvir + Sofosbuvir 35 (13.3%) Daclatasvir + Sofosbuvir + Telaprevir 1 (0.4%) Daclatasvir + Telaprevir 1 (0.4%) Daclatasvir + Ledipasvir/Sofosbuvir 1 (0.4%) Daclatasvir + Ledipasvir/Sofosbuvir + Sofosbuvir 2 (0.8%) Elbasvir 7 (2.7%) Elbasvir + Grazoprevir 7 (2.7%) Ledipasvir 133 (50.6%) Ledipasvir only 1 (0.4%) Ledipasvir/ Sofosbuvir + Tegobuvir + Vedroprevir 1 (0.4%) Ledipasvir /Sofosbuvir + Vedroprevir 1 (0.4%) Ledipasvir + Tegobuvir + Vedroprevir 4 (1.5%) Ledipasvir/Sofosbuvir 110 (41.8%) Ledipasvir/Sofosbuvir + Boceprevir 1 (0.4%) Ledipasvir/Sofosbuvir + Grazoprevir 1 (0.4%) Ledipasvir/Sofosbuvir + Simeprevir 2 (0.8%) Ledipasvir/Sofosbuvir + Simeprevir + Sofosbuvir 2 (0.8%) Ledipasvir/Sofosbuvir + Sofosbuvir 3 (1.1%) Ledipasvir/Sofosbuvir + Telaprevir 4 (1.5%) Daclatasvir + Ledipasvir/Sofosbuvir 1 (0.4%) Daclatasvir + Ledipasvir/Sofosbuvir + Sofosbuvir 2 (0.8%) Ombitasvir 30 (11.4%) Ombitasvir/Paritaprevir/Ritonavir 6 (2.3%) Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir 19 (11.7%) Ombitasvir/Paritaprevir/Ritonavir + Sofosbuvir 1 (0.4%) Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir + Boceprevir 1 (0.4%) Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir + Simeprevir + Sofosbuvir 1 (0.4%) Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir + Telaprevir 2 (0.8%) Pibrentasvir (ABT-530) 2 (0.8%) Pibrentasvir + ABT-493 2 (0.8%) Samatasvir 4 (1.5%) Samatasvir + Simeprevir 4 (1.5%) Velpatasvir 19 (7.2%) Velpatasvir/Sofosbuvir 10 (3.8%) Velpatasvir /Sofosbuvir + GS-9857 9 (3.4%) 29

Reference ID: 4095069 Table 18: Applicant’s Results of SVR12 Rates by Demographics in POLARIS-1 (All Treated) SOF/VEL/VOX 12 Weeks 95% CI1 (N=263) Age < 65 years 95.9% (213/222) 92.4%, 98.1% ≥ 65 years 97.6% (40/41) 87.1%, 99.9% Gender Male 96.0% (192/200) 92.3%, 98.3% Female 96.8% (61/63) 89.0%, 99.6% Race Black/African American 92.1% (35/38) 78.6%, 98.3% Non Black/African American 96.9% (217/224) 93.7%, 98.7% Ethnicity Hispanic or Latino 100% (15/15) 78.2%, 100.0% Not Hispanic or Latino 96.0% (237/247) 92.7%, 98.0% Region US 96.3% (130/135) 91.6%, 98.8% Non-US 96.1% (123/128) 91.1%, 98.7% Baseline BMI < 30 kg/m2 97.8% (175/179) 94.4%, 99.4% ≥ 30 kg/m2 92.9% (78/84) 85.1%, 97.3% Source: Tables 9-4 and 9-5 in POLARIS-1 Interim Clinical Study Report 1based on Clopper-Pearson method

Reference ID: 4095069 Table 19: Applicant’s Results of SVR12 Rates by Selected Baseline Disease Characteristics in POLARIS-1 (All Treated) SOF/VEL 12 Weeks 95% CI1 (N=263) Genotype GT1 97.3% (146/150) 93.3%, 99.3% GT1a 96.0% (97/101) 90.2%, 98.9% GT1b 100% (45/45) 92.1%, 100.0% GT2 100% (5/5) 47.8%, 100.0% GT3 94.9% (74/78) 87.4%, 98.6% GT4 90.9% (20/22) 70.8%, 98.9% GT5 100% (1/1) 2.5%, 100.0% GT6 100% (6/6) 54.1%, 100.0% Cirrhosis No 98.6% (140/142) 95.0%, 99.8% Yes 93.4% (113/121) 87.4%, 97.1% IL28B CC 97.9% (46/47) 88.7%, 99.9% Non-CC 95.8% (207/216) 92.2%, 98.1% CT 96.4% (159/165) 92.3%, 98.7% TT 94.1% (48/51) 83.8%, 98.8% Baseline HCV RNA < 800,000 IU/mL 94.5% (69/73) 86.6%, 98.5% ≥ 800,000 IU/mL 96.8% (184/190) 93.3%, 98.8% Baseline ALT ≤ 1.5 x ULN 97.5% (117/120) 92.9%, 99.5% > 1.5 x ULN 95.1% (136/143) 90.2%, 98.0% Prior HCV DAAs treatment history NS5A + NS5B 93.8% (151/161) 88.9%, 97.0% NS5A + NS3/4A ± NS5B 100% (83/83) 95.7%, 100% NS5A + Other(s) 100% (18/18) 81.5%, 100% Source: Table 9-5 in POLARIS-1 Interim Clinical Study Report 1based on Clopper-Pearson method

Reference ID: 4095069 6.2 POLARIS-4

Table 20: Applicant’s Results of Prior HCV DAA(s) by Genotype in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL 12 weeks 12 weeks Total (N=182) (N=151) (N=333) Prior HCV DAA(s) treatment by GT GT1 n=78 n=66 n=144 NS5B only Sofosbuvir 32/78 (41.0%) 19/66 (28.8%) 51/144 (35.4%) Mercitabine 4/78 (5.1%) 3/66 (4.5%) 7/144 (4.9%) Tegobuvir 1/78 (1.3%) 1/66 (1.5%) 2/144 (1.4%) Valopicitabine 1/78 (1.3%) 0/66 (0%) 1/144 (0.7%) Filibuvir 0/78 (0%) 1/66 (1.5%) 1/144 (0.7%) NS5B + NS3/4A Sofosbuvir + Simeprevir 16/78 (20.5%) 14/66 (21.2%) 30/144 (20.8%) Sofosbuvir + Telaprevir 3/78 (3.9%) 3/66 (4.6%) 6/144 (4/2%) Sofosbuvir + Boceprevir 1/78 (1.3%) 0/66 (0%) 1/144 (0.7%) Sofosbuvir + GS-9256 1/78 (1.3%) 0/66 (0%) 1/144 (0.7%) Sofosbuvir + Simeprevir + Telaprevir 1/78 (1.3%) 1/66 (1.5%) 2/144 (1.4%) Sofosbuvir + Boceprevir + Telaprevir 0/78 (0%) 2/66 (3.0%) 2/144 (1.4%) Sofosbuvir + Danoprevir + Mercitabine + Simeprevir 0/78 (0%) 1/66 (1.5%) 1/144 (0.7%) Mercitabine + Danoprevir 7/78 (9.0%) 1/66 (1.5%) 8/144 (5.6%) Deleobuvir + Faldaprevir 5/78 (6.4%) 9/66 (13.6%) 14/144 (9.7%) Mercitabine + Telaprevir 3/78 (3.9%) 1/66 (1.5%) 4/144 (2.8%) Danoprevir + Mercitabine + Setrobuvir 2/78 (2.6%) 1/66 (1.5%) 3/144 (2.1%) ABT-072 + Paritaprevir 0/78 (0%) 1/66 (1.5%) 1/144 (0.7%) Danoprevir + Mercitabine + Telaprevir 0/78 (0%) 1/66 (1.5%) 1/144 (0.7%) Danoprevir + Mercitabine 0/78 (0%) 1/66 (1.5%) 1/144 (0.7%) Danoprevir + Setrobuvir 0/78 (0%) 1/66 (1.5%) 1/144 (0.7%) Dasabuvir + Paritaprevir 0/78 (0%) 1/66 (1.5%) 1/144 (0.7%) Lomibuvir + Telaprevir 0/78 (0%) 1/66 (1.5%) 1/144 (0.7%) NS3/4A only Telaprevir 1/78 (1.3%) 2/66 (3.0%) 3/144 (2.1%) Boceprevir 0/78 (0%) 1/66 (1.5%) 1/144 (0.7%)

GT2 n=31 n=33 n=64 Sofosbuvir 30/31 (96.8%) 33/33 (100%) 63/64 (98.4%) Sofosbuvir + IDX-08189 1/31 (3.2%) 0/33 (0%) 1/64 (1.6%)

GT3 n=54 n=52 n=106 Sofosbuvir 53/54 (98.1%) 52/52 (100%) 99.1% (105/106) Sofosbuvir + Simeprevir 1/54 (1.9%) 0/52 (0%) 0.9% (1/106)

GT4 n=19 n/a n=19 Sofosbuvir 12/19 (63.2%) 12/19 (63.2%) Sofosbuvir + Simeprevir 6/19 (31.6%) 6/19 (31.6%) Telaprevir 1/19 (5.3%) 1/19 (5.3%) Note: Adhoc Table 22 in POLARIS-4 interim Clinical Study Report.

Reference ID: 4095069 Table 21: Reviewer’s Results for Prior Exposure to SOF-Containing Regimen by Genotype in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL Total 12 weeks 12 weeks (N=333) (N=182) (N=151) GT1 SOF-containing regimen 69.2% (54/78) 60.6% (40/66) 65.3% (94/144) Non SOF-containing regimen 30.8% (24/78) 39.4% (26/66) 34.7% (50/144) GT1a SOF-containing regimen 66.7% (36/54) 63.6% (28/44) 65.3% (64/98) Non SOF-containing regimen 33.3% (18/54) 36.4% (16/44) 34.7% (34/98) GT1b SOF-containing regimen 75.0% (18/24) 54.5% (12/22) 65.2% (30/44) Non SOF-containing regimen 25.0% (6/24) 45.5% (10/22) 34.8% (16/44) GT2 SOF-containing regimen 100% (31/31) 100% (33/33) 100% (64/64) Non SOF-containing regimen n/a n/a n/a GT3 SOF-containing regimen 100% (54/54) 100% (52/52) 100% (106/106) Non SOF-containing regimen n/a n/a n/a GT4 SOF-containing regimen 94.7% (18/19) n/a 94.7% (18/19) Non SOF-containing regimen 5.3% (1/19) 5.3(1/19)

Table 22: Reviewer’s Results of Prior HCV DAA(s) and PegIFN/RBV Treatment History in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL Total 12 weeks 12 weeks (N=333) (N=182) (N=151) Sofosbuvir only PegIFN/RBV – experienced 54 (29.7%) 49 (32.5%) 103 (30.9%) Non PegIFN/RBV – experienced 73 (40.1%) 55 (36.4%) 128 (38.4%) Sofosbuvir + NS3/4A PegIFN/RBV – experienced 18 (9.9%) 12 (8.0%) 30 (9.0%) Non PegIFN/RBV – experienced 10 (5.5%) 9 (6.0%) 19 (5.7%) Sofosbuvir + Investigational agent(s) PegIFN/RBV – experienced 2 (1.1%) 0 (0%) 2 (0.6%) Non PegIFN/RBV – experienced 0 (0%) 0 (0%) 0 (0%) NS3/4A only PegIFN/RBV – experienced 2 (1.1%) 3 (2.0%) 5 (1.5%) Non PegIFN/RBV – experienced 0 (0%) 0 (0%) 1 (0.3%) NS3/4A + Investigational DAA(s) PegIFN/RBV – experienced 3 (1.7%) 2 (1.3%) 5 (1.5%) Non PegIFN/RBV – experienced 0 (0%) 1 (0.7%) 1 (0.3%) Investigational agent(s) only PegIFN/RBV – experienced 10 (5.5%) 7 (4.6%) 17 (5.1%) Non PegIFN/RBV – experienced 10 (5.5%) 12 (10.0%) 22 (6.6%) PegIFN/RBV – experienced only 0 (0%) 1 (0.7%) 1 (0.3%)

Reference ID: 4095069 Table 23: SVR12 Rate by Demographics in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL Diff in SVR12 rate btw 12 weeks 12 weeks SOF/VEL/VOX 12 weeks (N=182) (N=151) and SOF/VEL 12 weeks (95% CI)2 Age at baseline (years) < 65 years 96.6% (144/149) 88.9% (120/135) 7.8% (1.9%, 14.7%) [95% CI]1 [92.3%, 98.9%] [82.3%, 93.6%]

≥ 65 years 100% (33/33) 100% (16/16) 0% (-11.1%, 21.9%) [95% CI]1 [89.4%, 100.0%] [79.4%, 100.0%] Sex at birth Male 96.5% (138/143) 89.5% (102/114) 7.0% (0.9%, 14.6%) [95% CI]1 [92.0%, 98.9%] [82.3%, 94.4%]

Non Black or African American 97.6% (162/166) 92.0% (127/138) 5.6% (0.7%, 11.7%) [95% CI]1 [93.9%, 99.3%] [86.2%, 96.0%] Ethnicity Hispanic or Latino 100% (19/19) 75.0% (6/8) 25% (3.0%, 62.6%) [95% CI]1 [82.4%, 100.0%] [34.9%, 96.8%]

Not Hispanic or Latino 96.9% (158/163) 90.9% (130/143) 6.0% (0.7%, 12.3%) [95% CI]1 [93.0%, 99.0%] [85.0%, 95.1%] Region US 98.0% (99/101) 87.4% (76/87) 10.7% (3.5%, 19.6%) [95% CI]1 [93.0%, 99.8%] [78.5%, 93.5%]

Non-US 96.3% (78/81) 93.8% (60/64) 2.5% (-5.1%, 12.1%) [95% CI]1 [89.6%, 99.2%] [84.8%, 98.3%] Body mass index (kg/m2) at baseline < 30 kg/m2 95.8% (115/120) 92.9% (91/98) 2.9% (-3.5%, 10.4%) [95% CI]1 [90.5%, 98.6%] [85.8%, 97.1%]

Reference ID: 4095069 Table 24: SVR12 Rate by Selected Baseline Disease Characteristics in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL Diff in SVR12 rate btw 12 weeks 12 weeks SOF/VEL/VOX 12 weeks and (N=182) (N=151) SOF/VEL 12 weeks (95% CI)2 Genotype GT1 97.4% (76/78) 90.9% (60/66) 6.5% (-1.2%, 16.6%) [95% CI] [91.0%, 99.7%] [81.3%, 96.6%]

GT1a 98.1% (53/54) 88.6% (39/44) 5.7% (-0.4%, 23.3%) [95% CI] [90.1%, 100%] [75.4%, 96.2%]

GT1b 95.8% (23/24) 95.5% (21/22) 0.4% (-17.6%, 19.3%) [95% CI] [78.9%, 99.9%] [77.2%, 99.9%]

GT2 100% (31/31) 97.0% (32/33) 3.0% (-8.3%, 16.5%) [95% CI] [88.8%, 100.0%] [84.2%, 99.9%]

GT3 94.4% (51/54) 84.6% (44/52) 9.8% (-2.3%, 23.1%) [95% CI] [84.6%, 98.8%] [71.9%, 93.1%]

GT4 100% (19/19) n/a n/a [95% CI] [82.4%, 100.0%] Cirrhosis Yes 96.4% (81/84) 85.5% (59/69) 10.9% (1.9%, 21.9%) [95% CI] [89.9%, 99.3%] [75.0%, 92.8%]

No 98.0% (96/98) 93.9% (77/82) 4.1% (-2.1%, 11.9%) [95% CI] [92.8%, 99.8%] [86.3%, 98.0%] IL28B CC 93.9% (31/33) 86.2% (25/29) 7.7% (-8.6%, 26.2%) [95% CI] [79.8%, 99.3%] [68.3%, 96.1%]

Non-CC 98.0% (146/149) 91.0% (111/122) 7.0% (1.7%, 13.8%) [95% CI] [94.2%, 99.6%] [84.4%, 95.4%]

≥ 800,000 IU/mL 97.8% (133/136) 89.4% (101/113) 8.4% (2.5%, 16.0%) [95% CI] [93.7%, 99.5%] [82.2%, 94.4%] Baseline ALT ≤ 1.5 x ULN 100% (88/88) 91.7% (66/72) 8.3% (3.4%, 17.4%) [95% CI] [95.9%, 100.0%] [82.7%, 96.9%]

> 1.5 x ULN 94.7% (89/94) 88.6% (70/79) 6.1% (-2.3%, 15.9%) [95% CI] [88.0%, 98.3%] [79.5%, 94.7%] Prior HCV trt history NS5B Only 97.0% (130/134) 90.8% (99/109) 6.2% (2.8%, 13.6%) [95% CI] [92.5%, 99.2%] [83.8%, 95.5%]

Reference ID: 4095069 Table 25: Reviewer’s Results for Virologic Outcomes at Post-Treatment Week 12 by HCV Genotype in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL 12 Weeks 12 Weeks GT1 SVR12 rate 97.4% (76/78) 90.9% (60/66) Not achieving SVR12 On-treatment virologic failure 0% (0/78) 0% (0/66) Relapse1 1.3% (1/78) 9.1% (6/66) Other2 1.3% (1/78) 0% (0/66) GT1a SVR12 rate 98.1% (53/54) 88.6% (39/44) Not achieving SVR12 On-treatment virologic failure 0% (0/54) 0% (0/44) Relapse1 1.9% (1/54) 11.4% (5/44) Other2 0% (0/54) 0% (0/44) GT1b SVR12 rate 95.8% (23/24) 95.5% (21/22) Not achieving SVR12 On-treatment virologic failure 0% (0/24) 0% (0/22) Relapse1 0% (0/24) 0% (0/22) Other2 4.2% (1/24) 4.6% (1/22) GT2 SVR12 rate 100% (31/31) 97.0% (32/33) Not achieving SVR12 On-treatment virologic failure 0% (0/31) 3.0% (1/33) Relapse1 0% (0/31) 0% (0/32) Other2 0% (0/31) 0% (0/33) GT3 SVR12 rate 94.4% (51/54) 84.6% (44/52) Not achieving SVR12 On-treatment virologic failure 0% (0/54) 0% (0/52) Relapse1 0% (0/54) 15.4% (8/52) Other2 5.6% (3/54) 0% (0/52) GT4 SVR12 rate 100% (19/19) n/a Not achieving SVR12 On-treatment virologic failure 0% (0/19) Relapse1 0% (0/19) Other2 0% (0/19) 1The denominator for relapse is the number of subjects with HCV RNA

Reference ID: 4095069 Table 26: Reviewer’s Results for SVR12 Rate by Genotype and Cirrhosis in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL Diff in SVR12 rate btw 12 Weeks 12 Weeks SOF/VEL/VOX 12 weeks and SOF/VEL 12 weeks (95% CI)1 GT1 Cirrhosis No 98.0% (49/50) 93.0% (40/43) 5.0% (-4.8%, 17.0%) [95% CI] [89.4%, 100.0%] [80.9%, 98,5%]

Yes 96.4% (27/28) 87.0% (20/23) 9.5% (-7.0%, 29.5%) [95% CI] [81.7%, 99.9%] [66.4%, 97.2%] GT1a Cirrhosis No 100% (37/37) 92.9% (26/28) 7.1% (-3.1%, 23.5%) [95% CI] [90.5%, 100%] [76.5%, 99.1%]

Yes 94.1% (16/17) 81.3% (13/16) 12.9% (-12.1%, 39.4%) [95% CI] [71.3%, 99.9%] [54.4%, 96.0%] GT1b Cirrhosis No 92.3% (12/13) 93.3% (14/15) -1.0% (-29.6%, 24.6%) [95% CI] [64.0%, 99.8%] [68.1%, 99.8%]

Yes 100% (11/11) 100% (7/7) 0% (-28.8%, 37.7%) [95% CI] [71.5%, 100%] [59.0%, 100%] GT2 Cirrhosis No 100% (18/18) 94.1% (16/17) 5.9% (-12.7%, 28.9%) [95% CI] [81.5%, 100%] [71.3%, 99.9%]

Yes 100% (13/13) 100% (16/16) 0% (-23.0%, 20.8%) [95% CI] [75.3%, 100%] [79.4%, 100%] GT3 Cirrhosis No 95.7% (22/23) 95.5% (21/22) 0.2% (-17.5%, 18.9%) [95% CI] [78/1%, 99.9%] [77.2%, 99.9%]

Yes 93.6% (29/31) 76.7% (23/30) 16.9% (-1.8%, 36.5%) [95% CI] [78.6%, 99.2%] [57.7%, 90.1%] GT4 Cirrhosis No 100% (7/7) [95% CI] [59.0%, 100%] n/a n/a

Yes 100% (12/12) [95% CI] [73.5%, 100%] 1The exact 95% CIs were based on inverting a two-sided test.

Reference ID: 4095069 Table 27: Reviewer’s Results for SVR12 Rates by Genotype and Prior Exposure to SOF-Containing Regimen in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL Diff in SVR12 rate btw 12 weeks 12 weeks SOF/VEL/VOX 12 weeks and SOF/VEL 12 weeks (95% CI)1 GT1a SOF-containing regimen 97.2% (35/36) 82.1% (23/28) 15.1% (0.6%, 34.0%) Non SOF-containing regimen 100% (18/18) 100% (16/16) 0% (-18.8%, 20.9%) GT1b SOF-containing regimen 94.4% (17/18) 91.7% (11/12) 2.8% (-19.4%, 31.6%) Non SOF-containing regimen 100% (6/6) 100% (10/10) 0% (-41.5%, 29.9%) GT2 SOF-containing regimen 100% (31/31) 97.0% (32/33) 3.0% (-8.3%, 16.5%) Non SOF-containing regimen n/a n/a n/a GT3 SOF-containing regimen 94.4% (51/54) 84.6% (44/52) 9.8% (-2.3%, 23.1%) Non SOF-containing regimen n/a n/a n/a GT4 SOF-containing regimen 100% (18/18) n/a n/a Non SOF-containing regimen 100% (1/1) n/a n/a 1The 95% exact CIs were based on inverting a two-sided test.

Reference ID: 4095069 Table 28: Reviewer’s Results for Virologic Outcome at Post-Treatment Week 12 by Genotype among Subjects with Prior Exposure to SOF-Containing Regimen in POLARIS-4 (All Treated) SOF/VEL/VOX SOF/VEL 12 Weeks 12 Weeks (N=139) (N=125) Genotype 1 SVR12 96% (52/54) 85% (34/40) Not achieving SVR12 On-treatment virologic failure 0% (0/54) 0% (0/40) Relapse1 2% (1/54) 12.5% (5/40) Other2 2% (1/54) 2.5% (1/40) Genotype 1a SVR12 97% (35/36) 82% (23/28) Not achieving SVR12 On-treatment virologic failure 0% (0/36) 0% (0/28) Relapse1 3% (1/36) 18% (5/28) Other2 0% (0/36) 0% (0/28) Genotype 1b SVR12 94.4% (17/18) 91.7% (11/12) Not achieving SVR12 On-treatment virologic failure 0% (0/18) 0% (0/12) Relapse1 0% (0/18) 0% (0/12) Other2 5.6% (1/18) 8.3% (1/12) Genotype 2 SVR12 100% (31/31) 97.0% (32/33) Not achieving SVR12 On-treatment virologic failure 0% (0/31) 3% (1/33) Relapse1 0% (0/31) 0% (0/32) Other2 0% (0/31) 0% (0/33) Genotype 3 SVR12 94.4% (51/54) 84.6% (44/52) Not achieving SVR12 On-treatment virologic failure 0% (0/54) 0% (0/52) Relapse1 0% (0/54) 15% (8/52) Other2 6% (3/54) 0% (0/52) Genotype 4 SVR12 100% (18/18) n/a Not achieving SVR12 On-treatment virologic failure 0% (0/18) Relapse1 0% (0/18) Other2 0% (0/18) 1The denominator for relapse is the number of subjects with HCV RNA

Reference ID: 4095069 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------XIAOJING K QI 05/08/2017

THAMBAN I VALAPPIL 05/08/2017

Reference ID: 4095069