Genotype 1 HCV in 2016 Clinical Decision Making

Genotype 1 HCV in 2016: Clinical Decision Making in a Time of Plenty Ira M. Jacobson, MD Chair, Department of Medicine Mount Sinai Beth Israel Senior Faculty and Vice-Chair, Department of Medicine Icahn School of Medicine at Mount Sinai New York, New York Supported by educational grants from Abb. Vie, Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, Merck, and Vii. V Healthcare.

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Disclosures Ira. M. Jacobson, MD, has disclosed that he has received funds for research support from Abb. Vie, Bristol -Myers Squibb, Gilead Sciences, Janssen, and Merck; has served on speaker bureaus for Abb. Vie, Bristol. Myers Squibb, Gilead Sciences, and Janssen; and has received consulting fees from Abb. Vie, Bristol-Myers Squibb, Gilead Sciences, Intercept, Janssen, Merck, and Trek.

New Regimens and Data for Genotype 1 HCV Infection AASLD Guidance Updated February 24, 2016 § AASLD guidance stratifies regimens as “recommended” and “alternative” AASLD/IDSA. HCV guidelines. April 2016. Slide credit: clinicaloptions. com

AASLD: Recommended and Alternative Regimens for GT 1 Without Cirrhosis Nucleotide Population No nucleotide LDV/SOF DCV + SOF SMV + SOF GZR/EBR OBV/PTV/RTV + DSV GT 1 a 12 wks 16 wks + RBV† 12 wks + RBV GT 1 b 12 wks 12 wks †If NS 5 A RAVs present. AASLD/IDSA. HCV guidelines. April 2016. Recommended Alternative Slide credit: clinicaloptions. com

AASLD: Recommended and Alternative Regimens for GT 1 With Compensated Cirrhosis Nucleotide Population GT 1 a §Naive §PR exp GT 1 b §Naive §PR exp No nucleotide LDV/SOF DCV + SOF SMV + SOF GZR/EBR OBV/PTV/RTV + DSV 12 wks 24 wks ± RBV* 12 wks 16 wks + RBV† 24 wks + RBV 24 wks ± RBV 12 wks 12 wks + RBV or 24 wks *Not with Q 80 K. †If NS 5 A RAVs present. AASLD/IDSA. HCV guidelines. April 2016. Recommended 24 wks + RBV Alternative Slide credit: clinicaloptions. com

Grazoprevir/Elbasvir: Approved Jan 2016 § Genotype 1 a, with/without compensated cirrhosis, treatment naive or treatment experienced – Without NS 5 A RAVs: GZR/EBR, 12 wks – With NS 5 A RAVs: GZR/EBR + RBV, 16 wks* – RAVs at positions 28, 30, 31, 93 § Genotype 1 b, with/without compensated cirrhosis, treatment naive or treatment experienced – GZR/EBR, 12 wks – RAV testing not indicated *Listed as “alternative” regimen. AASLD/IDSA. HCV guidelines. April 2016. Slide credit: clinicaloptions. com

C-EDGE TN: 12 Wks of GZR/EBR in Genotype 1, 4, or 6 97 231/ 246 68/ 70 99 100 80 60 nc ir 3 1 9 18/ 18 8/ 10 GT 4 GT 6 1 b 129/ 131 GT 144/ 157 GT 1 a ot No Ci rrh s rh o l P 0 299/ 316 tic 20 ics 40 Al § 92 80 ts SVR 12 (%) n/N = 94 95 100 1 0 0 0 2 Non-VF Breakthrough Relapse Good safety and tolerability profile – No drug-related serious AEs; 2 deaths unrelated to drug – No concurrent ALT/bilirubin increase § Lower SVR 12 rates in pts with BL NS 5 A RAVs (2/9, 22%); associated with > 5 -fold loss of EBR susceptibility § Virologic failure only if baseline HCV RNA > 800, 000 IU/m. L Zeuzem S, et al. Ann Intern Med. 2015; 163: 1 -13. Slide credit: clinicaloptions. com

C-EDGE TE: 12 or 16 Wks of GZR/EBR ± RBV in Treatment-Experienced GT 1, 4, or 6 n/N = SVR 12 (%, 95% CI) 100 92 94 92 97 80 12 wks 60 16 wks 40 20 0 Breakthrough Rebound Relapse LTFU/early d/c 97/ 105 98/ 104 97/ 105 103/ 106 No RBV + RBV 0 0 6 2 0 0 60 1 2 41 0 0 03 *ITT population. § Virologic failures driven by RAVs § Analysis from AASLD 2015 shows that presence of baseline NS 5 A RAVs by population sequencing or next-generation sequencing (with 10% to 20% cutoff) is predictive of failure Kwo P, et al. EASL 2015. Abstract P 0886. Jacobson I, et al. AASLD 2015. Abstract LB 22. Slide credit: clinicaloptions. com

C-EDGE TE: Efficacy of 12 Wks of GZR/EBR ± RBV by Baseline RAVs SVR 12, n/N (%) Total GT 1 a GT 1 b NS 3 RAVs ≤ 5 -Fold Shift NS 3 RAVs > 5 -Fold Shift 95% 99% 107/112 (96) 133/135 (99) 104/111 (94) 9/9 (100) 0 1/1 (100%) NS 5 A Variants Not Detectable GT 1 a GT 1 b NS 3 Variants Not Detectable NS 5 A RAVs ≤ 5 -Fold Shift NS 5 A RAVs > 5 -Fold Shift 190/192 (99) 127/127 (100) 10/10 (100) 0 11/21 (52) 16/18 (89) 95% 99% § Should baseline RAV testing be done with this regimen? – The NS 5 A RAVs that matter are in the 28, 30, 31, and 93 positions Kwo P, et al. EASL 2015. Abstract P 0886. Slide credit: clinicaloptions. com

C-SURFER: Grazoprevir/Elbasvir in Pts With GT 1 HCV and Stage 4/5 CKD Treatment Wk 12 Follow-up Wk 4 Follow-up Wk 16 Randomized period GT 1 HCV–infected pts with stage 4/5 CKD (n = 224) Grazoprevir/Elbasvir (n = 111) Placebo (n = 113) SVR 12* Open-label period Grazoprevir/Elbasvir (n = 113) 99% 98% Grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily. This study also included a pharmacokinetic analysis (n = 11) in which pts were treated as in the randomized grazoprevir/elbasvir study group. § 76% on dialysis § 34% with diabetes § 52% GT 1 a, 48% GT 1 b § *Modified full analysis set population. 6% cirrhosis Roth D, et al. Lancet. 2015; 386: 1537 -1545 Roth D, et al. Kidney Week 2015. Abstract SA-PO 1100. Slide credit: clinicaloptions. com

Daclatasvir + Sofosbuvir § Genotype 1 a or 1 b, treatment naive or experienced, without cirrhosis – DCV + SOF, 12 wks § Genotype 1 a or 1 b, treatment naive or experienced, with compensated cirrhosis – DCV + SOF ± RBV, 24 wks* *Listed as “alternative” regimen AASLD/IDSA. HCV guidelines. April 2016. Slide credit: clinicaloptions. com

DCV + SOF ± RBV for 24 Wks in GT 1 Pts With Advanced Liver Disease SVR 12 by Genotype 100 SVR 12 (%) 80 98 98 92 91 98 100 96 96 97 97 89 90 60 40 20 0 All GT 1 a GT 1 b As observed DCV + SOF + RBV m. ITT DCV + SOF + RBV Welzel T, et al. EASL 2016. Abstract SAT-275. Slide credit: clinicaloptions. com

Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir § Genotype 1 a, treatment naive or experienced – No cirrhosis: OBV/PTV/RTV + DSV + RBV, 12 wks – With compensated cirrhosis: OBV/PTV/RTV + DSV + RBV, 24 wks* – RAV testing not indicated § Genotype 1 b, with/without compensated cirrhosis, treatment naive or experienced – OBV/PTV/RTV + DSV, 12 wks – RAV testing not indicated *Listed as “alternative” regimen. AASLD/IDSA. HCV guidelines. April 2016. Slide credit: clinicaloptions. com

TURQUOISE III: 12 Wks of OBV/PTV/RTV + DSV Without RBV in Cirrhotic GT 1 b Pts Virologic Response 100 100 100 60/60 RVR EOTR SVR 4 SVR 12 Pts (%) 80 60 40 20 n/N = 0 AASLD guidance now recommends OBV/PTV/RTV + DSV 12 wks without RBV for GT 1 b cirrhotics Still need 24 wks + RBV for GT 1 a cirrhotics, naive or experienced Poordad F, et al. AASLD 2015. Abstract 1051. AASLD/IDSA. HCV Guidance. April 2016. Slide credit: clinicaloptions. com

Real-World Efficacy of OBV/PTV/RTV ± DSV ± RBV: German HCV Registry Cohort § Efficacy population (complete follow-up): n = 543; safety population (initiated treatment): n = 1017 – GT 1: 88%; GT 4: 12%; cirrhosis: 22% (CTP B/C: 7%); tx experienced: 59% 97 96 97 100 95 93 96 100 96 98 96 80 *Includes 13 pts with mixed or unknown GT 1 subgenotype infection, all of whom achieved SVR. 60 Hinrichsen H, et al. EASL 2016. Abstract GS 07. g)I ive FN ± TV RBV peg R/B IFN OC +R + BV With Cirrhosis 200/ 268/ 46/ 208 274 48 Na 4 2/ 2 (pe Without Cirrhosis 121/ 26/ 93/ 127 28 97 GT 0 4 n/N = 365/ 108/ 246/ 51/ 378 113 254 51 GT 20 G To T 1 tal* GT 1 a GT 1 b 40 G To T 1 tal* GT 1 a GT 1 b SVR 24 (%) 100 Slide credit: clinicaloptions. com

Real-World Efficacy of OBV/PTV/RTV ± DSV ± RBV: Israeli Cohort § Efficacy population (complete follow-up): n = 432; safety population (initiated treatment): n = 661 Pts With Undetectable HCV RNA (%) – GT 1: 100%; cirrhosis: 62% (CTP A/B: 98. 5%/1. 5%); tx exp’d: 62% 100 99 99 80 No cirrhosis Cirrhosis 60 40 20 n/N = – Post LT: n = 22 0 161/ 163 251/ 253 SVR 12 (m. ITT*) *Excludes pts who did not achieve SVR 12 for reasons other than virologic failure. – SVR 12 m. ITT/overall: 82%/86%; 4 discontinued due to serious AEs, one of which achieved SVR Zuckerman E, et al. EASL 2016. Abstract PS 004. Slide credit: clinicaloptions. com

Real-World Safety of OBV/PTV/RTV ± DSV ± RBV: German and Israeli Cohorts § Most common AEs across both cohorts[1, 2]: fatigue, pruritus, headache, insomnia, nausea, diarrhea (Israeli), anemia (German) – Serious AE: 2. 1% to 3. 8% – D/c for AE: 1. 5% to 3. 0% – 3 deaths deemed unrelated to HCV therapy: stroke, MI, multiple organ failure § In Israeli cohort, 20 pts discontinued for AEs[2] § In Israeli cohort, several factors identified as significant predictors of hepatic decompensation[2] Factor P Value Age older than 75 yrs . 005 Platelets < 90, 000/m. L . 03 Albumin < 3. 5 g/d. L . 048 CTP score ≥ 7 . 07 MELD score > 10 . 01 Previous decompensation <. 001 – Serious AE: n = 12 – Decompensation: n = 8 1. Hinrichsen H, et al. EASL 2016. Abstract GS 07. 2. Zuckerman E, et al. EASL 2016. Abstract PS 004. Slide credit: clinicaloptions. com

Ledipasvir/Sofosbuvir for GT 1 Tx-Naive Noncirrhotics With HCV RNA < 6 M IU/m. L: Are 8 wks sufficient? Or are 12 wks better? § Established by retrospective analysis of ION-3 § Many clinicians were initially uncomfortable § What do “real-world” data show? Slide credit: clinicaloptions. com

8 vs 12 Wks of LDV/SOF in Pts With GT 1 HCV: HCV-TARGET and TRIO Network § Treatment-naive, noncirrhotic pts with GT 1 HCV – HCV RNA < 6 M IU/m. L in HCV-TARGET[1] 97 97 80 60 40 20 n/N = 0 100 SVR 12 (%) 100 TRIO Network[2] 127/131 187/192 8 Wks 1. Terrault N, et al. AASLD 2015. Abstract 94. 2. Curry M, et al. AASLD 2015. Abstract 1046. 95 96 251/263 604/632 80 60 40 20 0 8 Wks 12 Wks Slide credit: clinicaloptions. com

8 Wks of LDV/SOF in Pts With GT 1 HCV: German Real-World Single-Center Study § Pts noncirrhotic (100%) and primarily treatment naive (97%), GT 1 (98%), and HCV RNA < 6 M IU/m. L (96%) 99 SVR 12 (%) 100 80 60 40 20 n/N = 127/128 0 Buggisch P et al, EASL 2016. Abstract SAT-242. 8 Wks Slide credit: clinicaloptions. com

LDV/SOF: SVR 12 by Treatment Regimen and Duration in Pts Without Cirrhosis § Pooled data from multiple trials, HCV RNA < 6 M IU/m. L in 8 -wk arm With RAVs 98 99 30/32 100 107/108 No RAVs 99 99 SVR 12 (%) 80 60 40 20 n/N = 0 8 Wks Zeuzem S, et al. AASLD 2015. Abstract 91. 187/189 504/509 12 Wks Slide credit: clinicaloptions. com

PPIs and Ledipasvir: Does Acid Suppression Matter?

HCV-TARGET: Effect of PPI Use? § Virologic outcome known for 1074 pts SVR 12 According to Baseline PPI Use PPI: No 100 93 28/ 30 456/ 464 60 40 20 n/N = 0 Terrault N, et al. AASLD 2015. Abstract 94. 98 PPI: Yes 98 93 80 SVR 12 (%) § Pts treated according to local standards of care at 44 academic/ 17 community medical centers in North America/Europe 122/ 124 151/ 163 8 -Wk LDV/SOF 12 -Wk LDV/SOF Slide credit: clinicaloptions. com

TRIO Network: No Effect of PPI Use? § Real-world data from 2034 pts with GT 1 HCV receiving LDV/SOF § A per protocol analysis (n = 1979) showed no effect of PPIs on SVR 12 According to Baseline PPI Use 98 100 98 97 99 97 SVR 12 (%) PPI: No PPI: Yes n/N = 230/ 234 41/ 41 8 Wks Afdhal N, et al. EASL 2016. Abstract LBP 519. 1024/ 1045 287/ 297 12 Wks 243/ 246 113/ 116 24 Wks Slide credit: clinicaloptions. com

TRIO Network: Predictors of Response to LDV/SOF by PPI Usage § Per protocol analysis (n = 1979) 97% n = 454 PPI drug Dexlansoprazole (n = 10) Esomeprazole (n = 48) Lansoprazole (n = 26) P =. 799 Omeprazole (n = 288) Pantoprazole (n = 77) “Caution with use of high dose PPIs with LDV/SOF” Rabeprazole (n = 5) PPI dose Low (n = 282) P =. 965 High (n = 172) PPI frequency Once daily (n = 420) P =. 030 Twice daily (n = 34) 80% Afdhal N, et al. EASL 2016. Abstract LBP 519. 90% 100% Slide credit: clinicaloptions. com

New Regimens

ASTRAL-1: VEL/SOF FDC for 12 Wks in GT 1/2/4/5/6 With and Without Cirrhosis § Velpatasvir (GS-5816): pangenotypic HCV NS 5 A inhibitor § GT 3 pts evaluated in separate study § 19% cirrhosis, 32% treatment experienced SVR 12* (%) 99 98 99 618/624 100 206/210 117/118 Overall GT 1 a GT 1 b 75 50 25 n/N = 0 *HCV RNA < 15 IU/m. L Feld JJ, et al. AASLD 2015. Abstract LB-2. Slide credit: clinicaloptions. com

ASTRAL-4: VEL/SOF FDC for HCV in Pts With Decompensated Liver Disease § Treatment-naive or treatment-experienced pts with GT 1 -6 HCV infection and CTP B cirrhosis (N = 267) – 55% treatment experienced; 95% MELD < 15; 75% to 83% ascites; 58% to 66% encephalopathy – GT 1: 78%; GT 3: 15%, GT 2/4/6: 8% Wk 0 Wk 12 n = 90 VEL/SOF* n = 87 VEL/SOF* + RBV n = 90 VEL/SOF* Wk 24 Wk 36 SVR 12 *100 mg/400 mg Charlton MR, et al. AASLD 2015. Abstract LB-13. Slide credit: clinicaloptions. com

ASTRAL-4: VEL/SOF FDC for HCV in Pts With Decompensated Liver Disease SOF/VEL 12 wks SVR 12 (%) 100 n/N = 83 94 SOF/VEL + RBV 12 wks 86 88 77/90 60/68 SOF/VEL 24 wks 96 92 65/68 65/71 80 60 40 20 0 75/90 Breakthrough, n Relapse, n 11 LTFU, n 1 Death, n 3 82/87 Overall 1 2 2 Genotype 1 1 7 3 2 § D/c due to AE: 3% (n = 9) § Death due to AE: 3% (n = 9) § Fatigue (29%); nausea (23%); HA (22%); anemia (13%; 31% in RBV arm) § AE more frequent with RBV Charlton MR, et al. AASLD 2015. Abstract LB-13 5 1 2 3 3 - § RBV arm: Hb < 10 mg/d. L, 23%; Hb < 8. 5 mg/d. L, 7% § RBV decreased in 37% and d/c in 17% Slide credit: clinicaloptions. com

ASTRAL-5: VEL/SOF FDC for 12 Wks in Pts Coinfected With HCV and HIV-1 N = 106 SVR 12 VEL/SOF Wk 0 SVR 12 (%) 100 95 12 24 100 95 92 2 relapse 1 LTFU 99/ 104 62/ 65 11/ 12 11/ 11 11/ 12 4/ 4 Total GT 1 a GT 1 b GT 2 GT 3 GT 4 92 80 60 1 withdrew consent 40 20 n/N = 0 Wyles D, et al. EASL 2016. Abstract PS 104. Slide credit: clinicaloptions. com

VEL/SOF + GS-9857 for 6 or 8 Wks in Treatment-Naive Pts With GT 1 -6 HCV Genotype 1 Genotypes 1 -6 100 96 100 79 60 40 20 n/N = § 53/67 0 Cirrhosis 94 71 81 80 SVR (%) 80 No Cirrhosis 100 95/99 No RBV 6 Wks No RBV 8 Wks 60 40 20 25/35 0 36/36 31/33 25/31 No RBV 6 Wks No RBV 8 Wks 8 wks of VEL/SOF + GS 9857 highly effective including pts with RAVs and cirrhosis – Single tablet QD in phase III – 6 wks had high relapse § § No benefit of RBV with 8 wks Will the triplet be used as primary first-line treatment or as salvage treatment for persons who fail current DAAs? Gane EJ, et al. EASL 2016. Abstract SAT-138. Slide credit: clinicaloptions. com

VEL/SOF + GS-9857 for 12 Wks in Treatment-Experienced GT 1 -6 HCV Cirrhosis, n (%) Mean HCV RNA, log 10 IU/m. L (range) VEL/SOF + GS-9857 61 (48) 6. 3 (3. 8 -8. 1) HCV genotype, n (%) § 1 § 2 § 3 § 4/6 63 (49) 21 (16) 35 (27) 9 (7) DAA experience, n (%) § None (GT 2 -6 only) § 1 DAA class § ≥ 2 DAA classes 27 (21) 36 (28) 65 (51) Lawitz E, et al. EASL 2016. Abstract PS 008. 100 99 100 127/128 63/63 Overall GT 1 80 SVR 12 (%) BL Characteristics (N = 128) 60 40 20 n/N = 0 § 1 pt relapsed at posttreatment Wk 8 Slide credit: clinicaloptions. com

SURVEYOR-I/II: ABT-493 + ABT-530 for 8 or 12 Wks in Pts With GT 1 or 2 HCV § Open-label, treatment naive or peg. IFN/RBV experienced SVR 12 in Pts With GT 1 HCV 8 wks 97 100 80 60 40 20 n/N = 0 100 SVR 12 (%) 100 12 wks 33/34 33/33 ITT m. ITT No Cirrhosis[1] 1. Poordad F, et al. EASL 2016. Abstract SAT-157. 2. Gane EJ, et al. EASL 2016. Abstract SAT-135. 96 80 60 40 20 0 26/27 Cirrhosis[2] Slide credit: clinicaloptions. com

C-CREST 1 and 2: MK-3682/GZR/MK-8408 for 8 Wks in Tx-Naive Noncirrhotic Pts § GT 1, 2, or 3 without cirrhosis (N = 240) 100 87 80 60 40 20 n/N = 0 MK-3682 (300 mg) + GZR + MK-8408 MK-3682 (450 mg) + GZR + MK-8408 24/24 20/23 Genotype 1 § In GT 1 arm, no impact of baseline NS 5 A, NS 3, or NS 5 B RAVs on SVR 12 Gane EJ, et al. EASL 2016. Abstract 139. Slide credit: clinicaloptions. com

Conclusions § 5 highly effective regimens approved for GT 1 HCV – Newest is GZR/EBR, which requires RAV testing in GT 1 a § Need for extended therapy and/or RBV in cirrhotics depending on regimen, GT 1 subtype, and prior treatment status § Real-world data reflect efficacy in clinical trials § Data support 8 wks of LDV/SOF in GT 1 treatment-naive noncirrhotics with HCV RNA < 6 M IU/m. L § High-dose PPIs should be avoided with LDV (same likely to be the case with VEL based on clinical trial designs) Slide credit: clinicaloptions. com

New Regimens in Development § Promising regimens – VEL/SOF (likely to be approved in June 2016) – Second-generation 2 -drug regimen of ABT-493/ ABT-530 – Triplet regimens of PI/NS 5 A/Nuc § New regimens may offer 8 -week option for noncirrhotics § High SVR rates in DAA failures Slide credit: clinicaloptions. com

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