Updates on the AASLD/IDSA HCV Guidance

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Updates on the AASLD/IDSA HCV Guidance Susanna Naggie, MD, MHS Associate Professor of Medicine Duke University School of Medicine Durham, North Carolina Learning Objectives After attending this

1 Updates on the AASLD/IDSA HCV Guidance Susanna Naggie, MD, MHS Associate Professor of Medicine Duke University School of Medicine Durham, North Carolina Learning Objectives After attending this presentation, learners will be able to: List the pending changes to guidance Describe the data supporting the FDA approvals of recently approved regimens List populations who may need off-label use of recently approved regimens Slide 4 of 31

2 Slide 5 of 31 HCV in Children HCV testing in perinatally exposed children Counseling regarding transmission Monitoring and medical management Treatment Slide 6 of 31 HCV in Pregnancy HCV testing in pregnant women Treatment Monitoring during pregnancy Postpartum issues Slide 7 of 31 HCV Resistance Primer Background Terminology and Assays Resistance testing in clinical practice Who to test, who not to test Characterizing risk of relapse Regimen specific recommendations

Slide 8 of 31 Recommended regimens for treatment-naïve or PEG/RBV experienced patients with HCV genotype 1 7 FDA approved regimens Daclatasvir+sofosbuvir (12)* 5 come as fixed-dose combinations

3 Slide 8 of 31 Recommended regimens for treatment-naïve or PEG/RBV experienced patients with HCV genotype 1 7 FDA approved regimens Daclatasvir+sofosbuvir (12)* 5 come as fixed-dose combinations Elbasvir/grazoprevir (12)* (3 single tablet) Glecaprevir/pibrentasvir (8-12) 2 have 8 week options in patients Ledipasvir/sofosbuvir (8-12 ± RBV) without (one is universal, in P/R failure and pangenotypic) PrOD (12 ± RBV) 1 requires RBV and 1 may require Simeprevir+sofosbuvir (12) RBV based on NS5A testing in 1a* Sofosbuvir/velpatasvir (12) 4 have 12 week options in patients with, although 1 requires RBV for PEG/RBV failures Approach to retreatment for DAA experienced patients with HCV genotype 1 Slide 9 of 31 Ledipasvir/sofosbuvir (RBV, 24) Sofosbuvir/velpatasvir Daclatasvir + sofosbuvir (24,?RBV) Elbasvir/grazoprevir (RBV, 16) 1 st gen PI + P/R Non-NS5A, SOFcontaining Ledipasvir/sofosbuvir (RBV, 24) RAS testing 24 + RBV Triple NS5A Inhibitor Experienced weeks regardless of, no RBV Which statement regarding FDA approval of glecaprevir/pibrentasvir is true? 1. It is an 8 week regimen only in patients without 2. It is a 12 week regimen regardless of presence of 3. It is an 8 week regimen only in treatment naïve patients 4. It is a 16 week regimen in patients with prior treatment experience to DAA 5. It is a single daily dosed pill It is a 12 week regimen regardl... It is an 8 week regimen only in... 20%20% 20%20% 20% It is an 8 week regimen only in... It is a 16 week regimen in patie... It is a single daily dosed pill Slide 11 of 31 10

4 Slide 12 of 31 Glecaprevir (NS3)/pibrentasvir (NS5A) Co-formulated 3 pills once daily Pangenotypic Next generation Active vs NS3 RAS at 80, 155, 168 and NS5A RAS at 28, Q30, 31, 93 A30K associated with failure in GT3 infection Negligible renal excretion Contains a protease inhibitor Has interaction with acid suppressing meds Glecaprevir/pibrentasvir Slide 13 of 31 Non-salvage (TN, PEG/RBV, SOF) & special pops ENDURANCE (Phase 3) GT 1 no (8 vs 12W) GT 2 no (12W) GT 3 no (8 and 12W) GT 4-6 (12W) EXPEDITION (Phase 3) GT 1, 2, 4-6 GT 1-6 HIV GT 1-6 Renal impairment SURVEYOR (Phase 2) GT 2, 4-6 no 8 weeks GT 3 /TE 12 vs 16 W Salvage MAGELLAN (Phase 2) GT 1, 4-6 prior DAA failures 12 vs 16 W (GT 1-6 renal and liver transplant, no ) NOT SALVAGE Slide 14 of 31 Glecaprevir/pibrentasvir: no 8 (N=828) vs 12 (N=1076) weeks TN and TE PEG, RBV, SOF No DAA otherwise Relapse <1% Tx emergent RAS TN GT3 may need 12W TE GT3 may need 16 weeks Puoti et al. EASL weeks 12 weeks All GT 1 GT 2 GT 3 GT 4 GT 5 GT 6

Slide 15 of 31 Glecaprevir/pibrentasvir in GT3 Treatment naïve without Non-inferiority 12W vs DAC/SOF X12W 12W vs 8W Viral Failure

failures with A30K BL A30K+Y93 (69-fold R) Foster et al.

52-55% NS5A 9-11% NS3+NS5A Overall SVR 89% vs 91% 12 weeks higher relapse with NS5A RAS Dual NS3/NS5A 55% SVR Poordad et al.

5 Slide 15 of 31 Glecaprevir/pibrentasvir in GT3 Treatment naïve without Non-inferiority 12W vs DAC/SOF X12W 12W vs 8W Viral Failure 3% G/P 4 in 12W (3 relapse, 1 VBT) 1 in DAC/SOF 6 in 8W (5 relapse, 1 VBT) BL dual NS3/NS5A 71-86% SVR Tx emergent RAS 50% failures with A30K BL A30K+Y93 (69-fold R) Foster et al. EASL 2017 Slide 16 of 31 Glecaprevir/pibrentasvir: DAA failures 12 (N=44) vs 16 (N=47) weeks in GT 1, % Baseline RAS 52-55% NS5A 9-11% NS3+NS5A Overall SVR 89% vs 91% 12 weeks higher relapse with NS5A RAS Dual NS3/NS5A 55% SVR Poordad et al. EASL 2017 Slide 17 of 31 Glecaprevir/pibrentasvir: Cirrhosis 12 weeks in N=146 Compensated TN or TE (25%) with IFN, P/R or SOF+P/R GT1a 33%, GT1b 27%, GT2 23%, GT4 11%, GT5 1%, GT6 5% 1 relapse- GT1a Forns et al. EASL 2017

Slide 18 of 31 Glecaprevir/pibrentasvir: Renal Impairment GT 1-6 for 12 weeks Stage 4 or 5 CKD GFR<30 including HD 82% on HD TN or TE (42%) with IFN, P/R or SOF+P/R Including compensated (19%) GT1a

EASL 2017 Slide 19 of 31 Glecaprevir/pibrentasvir: HIV GT 1-6 Primarily an 8 week study 12 weeks in 16 patients with TN or TE (19%) with IFN, P/R or SOF+P/R VBT on treatment GT3 with 100 90 80 70 60

6 Slide 18 of 31 Glecaprevir/pibrentasvir: Renal Impairment GT 1-6 for 12 weeks Stage 4 or 5 CKD GFR<30 including HD 82% on HD TN or TE (42%) with IFN, P/R or SOF+P/R Including compensated (19%) GT1a 22%, GT1b 28%, GT2 16%, GT3 11%, GT4 19%, GT5 1, GT6 1 Gane et al. EASL 2017 Slide 19 of 31 Glecaprevir/pibrentasvir: HIV GT 1-6 Primarily an 8 week study 12 weeks in 16 patients with TN or TE (19%) with IFN, P/R or SOF+P/R VBT on treatment GT3 with /136 14/15 8 week no 12 week cirhosis Rocksroh et al. EASL 2017 Slide 20 of 31 Glecaprevir/pibrentasvir DDI with ARV Allowed vs enrolled need clinical data to support safety Enrolled- Raltegravir- 45 Dolutegravir - 67 Rilpivirine - 32 PI/r none ELV/cobi - 1 Rockstroh et al. EASL 2017, Kosloski et al. CROI 2017

Slide 21 of 31 Glecaprevir/pibrentasvir safety 1977 patients w/o 288 patients with 24% with plat<100,000 2 patients with G3 ALT No DILI 6 patients without with G3 tbili Event No N=1977 Cirrhosis

7 Slide 21 of 31 Glecaprevir/pibrentasvir safety 1977 patients w/o 288 patients with 24% with plat<100,000 2 patients with G3 ALT No DILI 6 patients without with G3 tbili Event No N=1977 Cirrhosis N=288 Any AE, n(%) 1316 (67) 213 (74) AE 10% -Headache -Fatigue 363 (18) 272 (14) 47 (16) 58 (20) Any SAE 31 (2) 17 (6) DAA-related SAE 1 (<0.1) 0 AE leading to d/c 8 (0.4) 0 DAA-AE G3 4 (0.2) 0 Fatal AE 2 (0.1) 0 Death 5 (0.3) 1 (0.3) Slide 22 of 31 Glecaprevir/Pibrentasvir 8 weeks in treatment naïve or P/R failures without 12 weeks if Except GT3 P/R failure 16 weeks Retreatment of SOF or PI/P/R failures- less data 12 weeks of less concern than 8 Again in GT3 SOF/RBV failures 16 weeks Salvage (NS5A) only phase 2 data- but need in CKD/ESRD Length of therapy not clear 16 most studied in the phase 2 FDA limited to those receiving NS5A with NS5B (SOF), not with NS3/4A Which statement regarding FDA approval of sofosbuvir/velpatasvir/voxilaprevir is true? 1. It is an 8 week regimen only in patients without 2. It is a 12 week regimen regardless of presence of 3. It is an 8 week regimen regardless of prior treatment experience to DAA 4. It is approved for all genotypes across all DAA failures It is an 8 week regimen only in... 25% 25% 25% 25% It is a 12 week regimen regardl... It is an 8 week regimen regardle.. It is approved for all genotypes... Slide 24 of 31 10

8 Slide 25 of 31 Sofosbuvir/velpatasvir/voxilaprevir (NS3) Single fixed dose combination daily pill Pangenotypic Next generation? Active vs NS3 RAS at 80, 155, 168 and NS5A RAS at 28, Q30, 31 Contains a protease inhibitor Sofosbuvir still with limited renal data Velpatasvir still with acid suppressing issue Slide 26 of 31 Sofosbuvir/velpatasvir/voxilaprevir Non-salvage (TN, PEG/RBV, SOF) & special pops POLARIS-2 POLARIS-3 Salvage POLARIS-1 POLARIS-4 8 vs 12 weeks of SOF/VEL POLARIS 2 GT 1-6 w/ and w/o POLARIS 3 GT 3 with 2 relapses Pooled analysis N=611 8 weeks of therapy failed non-inferiority in POLARIS-2 3.8% relapse 14 GT1a (regardless of ) a 1b Genotype Roberts et al. EASL 2017; Jacobson et al. Gastro 2017 Slide 27 of 31

Slide 28 of 31 non-ns5a Inhibitor DAA-Experienced POLARIS 4 GT 1-6 (no 5 or 6 enrolled) 12 weeks of

SOF/VEL failures had Y93 H/C Bourliere et al.

therapy vs placebo Including compensated (46%) 2.

9 Slide 28 of 31 non-ns5a Inhibitor DAA-Experienced POLARIS 4 GT 1-6 (no 5 or 6 enrolled) 12 weeks of therapy vs 12 weeks SOF/VEL Including compensated (46%) 1 relapse No treatment emergent RAS 10/15 SOF/VEL failures had Y93 H/C Bourliere et al. NEJM 2017 NS5A Inhibitor DAA-Experienced Slide 29 of 31 POLARIS 1 GT 1-6 (30% GT3) 12 weeks of therapy vs placebo Including compensated (46%) 2.2% relapse 4 GT 3 relapse all 3a and ¾ had BL NS5A RAS No treatment emergent RAS all VF had (6 R, 1 VBT) Bourliere et al. NEJM 2017 Special Populations Slide 30 of 31 No data Transplant Decompensation HIV CKD/ESRD

Slide 31 of 31 ARV DDI Healthy volunteer study included DRV/r + TDF/FTC EVG/cobi/TAF/FTC BIC/TAF/FTC RPV/TAF/FTC Remember no EFV/ETR allowed due to VEL Garrison et al.

Event All combined N=1056 Cirrhosis N=405 Any AE, n(%) 790 (75) 308 (76) AE 10% -Headache -Fatigue -Diarrhea -Nausea 277 (26) 233 (22) 188 (18) 162 (15) -- -- -- --

2) Slide 33 of 31 Sofosbuvir/velpatasvir/voxilaprevir Only 12 week length of therapy No indication in treatment naïve or P/R +/- PI failures No 8 week therapy?

10 Slide 31 of 31 ARV DDI Healthy volunteer study included DRV/r + TDF/FTC EVG/cobi/TAF/FTC BIC/TAF/FTC RPV/TAF/FTC Remember no EFV/ETR allowed due to VEL Garrison et al. Clin Pharm 2017 Safety Slide 32 of patients w/o 405 patients with No G3 or 4 GI AE, no discontinuation 1 patient with G3 ALT No DILI 1 patient with G3 tbili Event All combined N=1056 Cirrhosis N=405 Any AE, n(%) 790 (75) 308 (76) AE 10% -Headache -Fatigue -Diarrhea -Nausea 277 (26) 233 (22) 188 (18) 162 (15) Any SAE 26 (2.5) 7 (0.7) DAA-related SAE 0 0 AE leading to d/c 1 (0.1) 1 (0.2) AE G3 21 (2) 8 (0.7) Death 2 (0.2) 1 (0.2) Slide 33 of 31 Sofosbuvir/velpatasvir/voxilaprevir Only 12 week length of therapy No indication in treatment naïve or P/R +/- PI failures No 8 week therapy? Exception GT3 where P/R failures require RAS testing (?Y93) and those with require RBV G/P is 16 weeks Retreatment of Non-NS5A, SOF failures- specific to 1a and 3 Salvage (NS5A) Primary approval 12 weeks across board What about GT3?

11 Slide 34 of 31 Summary G/P SOF/VEL/VOX Remaining challenges GT3 to some extent Patients with combination baseline features PPI, CKD, decomp, transplant, incompatible ARV Access due to cost? Questions Slide 35 of 31

Treating Hepatitis C Virus (HCV) Infection

Slide 1 of 42 Treating Hepatitis C Virus (HCV) Infection Susanna Naggie, MD, MHS Associate Professor of Medicine Duke Clinical Research Institute Durham, North Carolina Slide 3 of 42 Learning Objectives