Viva La Revolución: Options to Combat Hepatitis C

Viva La Revolución: Options to Combat Hepatitis C David L. Wyles, MD Professor of Medicine University of Colorado Chief, Division of Infectious Disease Denver Health Learning Objectives After attending this presentation, learners will be able to: List the available drugs and regimens for treating hepatitis C and their viral targets Describe the efficacy of treatments, by virus genotype, for initial therapy and retreatment Slide 2 of 33 SVR (%) 2 Slide 3 of 33 HCV Therapeutics Timeline You are here BILN-261 BoceprevirTelaprevir Phase 1b SOF/LDV Consensus IFN In vitro PrO-D EBR/GZR GLE/PIB Peg-IFNa-2bHCV replication 1989 HCV Vaccine?? identified 211 213 214 1995 2 25 21 215 216217218 IFN a-2b Sofosbuvir IFN a-2a HCV replicons Peg-IFNa-2a Simeprevir Daclatasvir (US) IFN a-2b + RBV Peg-IFNa-2ain HCV/HIVDaclatasvir (EU) 1 8 6 4 Relative misery

Overview of HCV life-cycle and antiviral targets NS5A Inhib NS3 Inhib NS5B Inhib Slide 4 of 33 Georgel et al. Trends in Molecular Medicine 16(21) 277-286. Moradpour D. Nat Rev 27. Approved HCV antiviral drugs/regimens Approved in 217 SOF/ VEL/VO X G/P Slide 5 of 33 SOF / LDV SOF / VEL SOF DC V IFN-free Treatment Options pre-217 SOF SM V EBR/ GZR OBV/ RBV PTV/r DSV SOF RBV Characteristics of Direct Acting Antivirals (DAAs) Simeprevir Paritaprevir Drug Class Activity Potency GT 1, 4 Resistance Barrier Low (1a<1b) Slide 6 of 33 Grazoprevir Voxilaprevir Glecaprevir Daclatasvir NS3 PI GT 1, 4 & 6 (3) GT 1-6 GT 1-6 Ledipasvir GT 1, 4 & 6 Ombitasvir NS5A Elbasvir GT 1,4 & 6 Velpatasvir Pibrentasvir Sofosbuvir NS5B Nucleotide GT 1-6 GT 1-6 High High High Moderate High Low (1a<1b) Moderate Very high Very High

In vitro activity: old vs. new NS3 PI (nm) GT1a GT1b GT2a GT3a GT4a GT6a Paritaprevir 1..21 5.3 a 19.9.68 Simeprevir 13 9.4 15 472 NA NA Asunaprevir 4. 1.2 23 1162 NA NA Grazoprevir.38.87 1.3 36 1.2.89 Glecaprevir.85.94 2.7 a 1.6 2.8.86 Voxilaprevir 3.9 3.3 3.7 6.1 2.9 1.5 NS5A (pm) GT1a GT1b GT2a GT2b GT3a GT4a GT5a GT6a Ombitasvir 14 5 12 4 19 2 3 366 Daclatasvir 22 3 13, NA 53 13 5 74 Ledipasvir 31 4 21, 16, 168, 39 15 11 Elbasvir 4 3 3 3 2 3 1 3 Velpatasvir 12 15 9 8 12 9 75 6 Pibrentasvir 2 4 2 2 2 2 1 3 Ruzasvir 1 2 1 4 2 2 1 4 Slide 7 of 33 NS5B nucleoside polymerase inhibitors have consistent pangenotypic acitivity (sofosbuvir, uprifosbuvir) New approval in 217: Glecaprevir/Pibrentasivr Slide 8 of 33 1. What: NS3 protease inhibitor plus NS5A inhibitor 2. Pangenotypic and activity against RASs 8 week option for non-cirrhotic patients (all GT1, 2, 4-6; GT3 only naïve) High efficacy in GT3 12 week treatment duration with cirrhosis 16 weeks if treatment experienced 3. Genotyping still required for treatment experienced 4. Drug-interaction potential Statins- atorvastatin not recommended Acid reducing agents lower exposure; NO clear impact on outcomes 5. Caution: Safety unknown in decompensated cirrhosis (CTP-B/C). Till data available, should be avoided as with all PI-containing HCV regimens New approval in 217: Sofosbuvir/velpatasvir/voxilaprevir Slide 9 of 33 1. What: NS5B nucleoside plus NS5A inhibitor plus NS3 protease inhibitor 2. Pangenotypic and activity against RASs 8 weeks did not meet non-inferiority criteria compared to SOF/VEL for 12 weeks Driven by lower response in GT1a High efficacy in GT3 8 week treatment duration possible with cirrhosis 3. May require genotyping to optimize management 4. Primary role likely in DAA failures- high efficacy, no demonstrable impact of resistance 5. Caution: Safety unknown in decompensated cirrhosis (VOX; CTP-B/C). SOF metabolite accumulation in ESRD (egfr <3ml/min) Till data available, should be avoided as with all PI-containing HCV regimens Caution in severe renal impairment

ARS Question 1: Eight weeks of LDV/SOF is not recommended for which patient population with GT1 and an HCV RNA <6 million? (AASLD/IDSA Guidelines) 1. Patients without cirrhosis 2. Black patients 3. Female patients 4. Male patients 5. Genotype 1a subtype Slide 1 of 33 SOF/LDV: 8 vs. 12 weeks for treatment naïve GT1 N=216 N=215 N=216 SOF/LDV SOF/LDV SOF/LDV/r 8 Weeks Cirrhosis excluded Relapses 4-5% in 8 week arms 2/23 in 8 week arms 1% in 12 week arm Post-hoc analyses HCV RNA <6 million 2% relapse in 8 and 12 weeks arms 99% SVR women 91% SVR Black 12 ION-3 1 8 6 4 2 95 94 93 12wk 8wk HCV Guidelines 8 week recommendation Non-black HIV uninfected HCV RNA <6 million Slide 11 of 33 Impact of Baseline NS5A RAVs in Pts With GT1a HCV Treated With EBR/GZR Analysis of pts with GT1a HCV treated with GZP/EBR in phase II/III trials (naive/relapsers) Population Sequencing Next-Generation Sequencing (1% Level) EBR RAVs NS5A Class RAVs EBR RAVs NS5A Class RAVs No RAVS: 414/438 (95%) No RAVS: No RAVS: No RAVS: 5% 432/438 2% 396/439 1% 289/439 35% (8%) (9%) (65%) Slide 12 of 33 98 98 98 98 1 86 91 72 8 58 Patients without 6 RAVs Patients with RAVs 4 2 45/ 14/ 345/ 74/ 389/ 31/ 284/ 136/ 414 24 352 86 396 43 289 15 EBR RAVs NS5A RAVs EBR RAVs NS5A RAVs Population Sequencing Next Generation Sequencing Jacobson I, et al. AASLD 215. Abstract LB-22.

GZR/EBR Efficacy in GT1a HCV: Resistance is all that matters! Analysis of PEP* of TN pts with GT1a HCV treated with GZP/EBR in phase II/III trials Multivariable logistic regression model eor (95% CI) P value *PEP = pooled efficacy population. Slide 13 of 33 Zeuzem S, et al. AASLD 215. Abstract 7. Integrated analysis of G/P in non-cirrhotics ITT Pooled analysis across phase 2/3 studies G/P 8 wk vs 12 wk Non-cirrhotic GT3 were also treatment naïve mitt (exclude non-virologic failures) 1/13 virologic failures were GT3.6% discontinued prematurely (same in 8 and 12 wk arms) Slide 14 of 33 Pol S. SAT-233. EASL 217. EXPEDITION-I: GT1, 2, 4-6 with cirrhosis 25% Treatment experienced 8% SOF experienced 2% with PLT <1, Slide 15 of 33 1 VF: Y93N at baseline Y93N + Q3R + H58D

ASTRAL-1: SOF/VEL for 12 weeks 1 8 6 4 2 Slide 16 of 33 99 98 99 1 1 97 1 618 624 12 weeks of SOF/VEL 26 21 117 118 14 14 116 116 1a 1b 2 4 5 6 Genotype 34 35 2 virologic failures: 1a, TN, NC, IL28 CT with Q3R 1b, TE, Cirr, IL28 TT with Q3R/L31M SVR with baseline NS5A RASs*: 99% (255/257) *RASs at >1%, all genotypes 32% treatment experienced (99% SVR12); 19% cirrhosis (99% SVR12) 41 41 Slide 17 of 33 Genotype 1 treatment naïve Recommended vs Alternative Treatment naïve 1a 1b LDV/SOF GLE/PIB EBR/GZR SOF/VEL PTV/r/OBV +DSV 8 $ - 8WKS Cirrhosis * RASs: 16WKS+R * RASs: 16WKS+R +R 24WKS+R 8WKS Cirrhosis $- additional criteria apply R=weight-based Ribavirin *RAS testing recommended-rass= EBR specific NS5A RAVs (28, 3, 31, 93) Slide 18 of 33 Genotype 1 treatment experienced Recommended vs Alternative Interferon+RBV LDV/SOF GLE/PIB EBR/GZR SOF/VEL 1a 1b Cirrhosis Cirrhosis +R # 24WKS # 8WKS * RASs: 16WKS+R * RASs: 16WKS+R PTV/r/OBV +DSV +R 24WKS+R 8WKS +R 24WKS # Consider RAS testing. *RAS testing recommended-rass= EBR specific NS5A RAVs (28, 3, 31, 93)

ARS Question 2: NS5A resistance testing should be considered in which population infected with GT3 HCV prior to use of SOF/VEL? 1. Treatment experienced (IFN) patients without cirrhosis 2. Treatment naïve patients without cirrhosis 3. SOF/DCV experienced patients 4. Treatment experienced (IFN) patients with cirrhosis Slide 19 of 33 G/P in GT3 treatment naïve patients without cirrhosis ENDURANCE-3 Slide 2 of 33 2% VF 4% VF Integrated analysis of 8 vs. 12 weeks in GT3 8 weeks N=28 12 weeks N=294 Slide 21 of 33

Genotype 2/3 treatment naïve Recommended Treatment naïve 2 SOF /VEL GLE /PIB 8WKS Cirrhosis 3 Cirrhosis # 8WKS Slide 22 of 33 R=weight-based Ribavirin # Consider RAS testing ASTRAL-3: SOF/VEL for genotype 3 infection Wk Wk 12 Wk 24 N = 277 N = 275 SOF/VEL SOF + RBV SVR12 SVR12 Treatment Experienced Slide 23 of 33 1 91 89 9 8 71 7 58 6 5 4 3 2 1 34 31 37 38 TE Cirrhotic TE Cirr SOF/VEL SOF/RBV Foster GR, et al. N Engl J Med. 215;373:268-2617. G/P in treatment experienced GT3 42 (46%) of TE were SOF experienced Slide 24 of 33

C-ISLE: SOF + EBR/GZR for GT3 with cirrhosis naïve experienced 68% male Mean TE: 25.4 kpa 24% PLT <1, Slide 25 of 33 Slide 26 of 33 IFN+RBV (+/- SOF) Genotype 2/3 TE Recommended vs Alternative GLE/ PIB SOF/ VEL EBR/ GZR + SOF SOF/VEL /VOX 2 NC 8WKS -- -- (12 if SOF) Cirr -- -- 3 NC 16WKS # (not if SOF exposed) -- (if Y93H) Cirr 16WKS +R R=weight-based Ribavirin # Consider RAS testing Triple DAA therapy for re-treatment 1 Regimen: SOF/VEL/VOX for 12 weeks POLARIS-1 (n=263) POLARIS-4 (n=182) NS5A experienced 46% cirrhosis 96 99 93 NO NS5A exposure 46% cirrhosis 97% SVR vs 9% SOF/VEL 8 6 4 4/11 GT1a non-svr 2 LTFU 1 relapse 1 BT (non-compliance) 2 All No Cirrhosis Cirrhosis SVR12: 96% GT1a; 1% GT1b; 95% GT3 Slide 27 of 33 No cirrhosis Cirrhosis SOF/VEL/VOX: 98% GT1a; 96% GT1b; 94% GT3 Bourliere M. NEJM 217. SOF/VEL: 89% GT1a; 95% GT1b; 85% GT3

GLE/PIB for DAA experienced patients: MAGELLAN-I (parts 1 and 2) Part 1: 12 weeks GLE/PIB 86% (19/22) SVR12; 95% (19/2) SVR mitt 1 VF: PrOD experience with NS3 (Y56H, D168A/T) and NS5A (M28V, Q3R, H58C)RASs Part 2: 12 vs. 16 wks GLE/PIB PI NS5A both NS3 RASs NS5A RASs NS3+5A RASs GT1 and 4 DAA experienced PI: 3% NS5A: 37% PI+NS5A: 29% 3% cirrhosis Slide 28 of 33 PoordadF. Hepatology 217. PoordadF. PS-156. EASL 217 DAA experienced: What do the labels say? Prior treatment SOF/VEL/VOX GLE/PIB GT1 NS5A (+/- SOF) 12 (also 2-6) 16 GT1 NS3 (+/- SOF) 12 (1a only) 12 GT1-6 NS3+NS5A 12 NR GT3 SOF (no NS5A) 12 16 AASLD/IDSA Guidelines: GT3 NS5A-experienced with compensated cirrhosis Slide 29 of 33 Reminder: HCV PIs (including VOX and GLE) are either not recommended or contraindicated in CTP B/C cirrhosis Options for patients with end-stage renal disease 1 GT1: EBR/GZR 12 weeks 99 99 1 1 99 99 1 1 GT 1-6: G/P 12 wks 42% TE, 2% F4 98 8 8 per protocol 6 4 ITT 6 4 2 Overall No Yes 4 5 No Yes (n=116) (n=11) (n=6) (n=22) (n=94) (n=29) (n=87) Cirrhosis CKD Stage Dialysis 94% SVR12 in ITT analysis Slide 3 of 33 2 12/14 CKD 4/5 1% SVR mitt

Treatment of HCV in HIV/HCV Coinfection Same Regimens, Same Efficacy as in HCV Monoinfection Patients With SVR12, % 1 9 8 7 6 5 4 3 2 1 98 1 97 99 95 95 95 96 1 2 3 4 SOF/VEL ELB/GRZ LDV/SOF GLE/PIB HIV/HCV HCV Slide 31 of 33 Slide 32 of 33 Take home points Tremendous advances in antiviral treatment of HCV have been realized in the last 5 years SVR >95% is attainable in all populations with 8-12 weeks of therapy From a treatment efficacy standpoint there are no more special populations There is a very limited role for resistance testing or the use of ribavirin Diagnosis, access and coverage limitations are now the most significant barriers to HCV cure Question-and-Answer Remember to raise your hand and wait until you have the microphone before you ask your question we are recording! Slide 33 of 33