#AIDS2016 Innovations in HCV treatment: what the future holds Jürgen Kurt Rockstroh Department of Medicine I, University Hospital Bonn, Bonn, Germany 21 st International AIDS Conference, Session: Synergistic Epidemics: New drugs, New challenges, Tuesday 20 th July 2016, Durban, South Africa

#AIDS2016 Jürgen Rockstroh has received: Honoraria for lectures and/or consultancies from Abbott, AbbVie, Bionor, BMS, Cipla, Gilead, Janssen, Merck and ViiV. Research grants from Dt. Leberstiftung, DZIF, NEAT ID. Conflict of Interest

#AIDS2016 Genotype Map HCV a global epidemic

#AIDS % ? FDA approves RBV to combine with IFN FDA approves IFN as the first therapy Discovery of HCV New Era of HCV Therapy

#AIDS2016 Treatment Options 2015/2016 Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir (± RBV) Sofosbuvir + Simeprevir (± RBV) Sofosbuvir + Daclatasvir (± RBV) Ombitasvir/Paritaprevir/Ritonavir (± RBV) PegIFN  + RBV + sofosbuvir PegIFN  + RBV + simeprevir Sofosbuvir + RBV Sofosbuvir/Ledipasvir (± RBV) IFN-free regimens IFN-containing regimens GT 1 1, 4 All 4 1, 4 2, 3 1, 4, 5, 6 All (J-M Pawlotsky, ILC2015, Vienna, Austria, April 24, EASL Recommendations on Treatment of Hepatitis C 2015)

#AIDS2016 Summary of EASL 2014 SVR24 rate (%) % J-M Pawlotsky Perfectovir

#AIDS2016 Any difficult-to-treat populations left? Patients with inherited blood disorders Patients after kidney +/- liver transplantion Patients with chronic renal insufficiency Patients with ongoing substance abuse Patients with HIV coinfection Patients with……………………..

#AIDS2016 What are the remaining challenges? Cost, cost and cost Access and implementation of HCV therapy To minimize pre-diagnostic requirements Virological failure in patient with 2K/1B Chimeras after receiving SOF + RBV Broad pangenotypic activity in particular also for genotype 3 Lack of data in genotype 5 and 6 for some DAA combinations To develop DAAs which can be used in advanced cirrhosis and have low risk for drug-drug interactions

#AIDS2016 ALLY-3+: Results HCV RNA < LLOQ TD/TND (%) Overall12 Weeks 16 Weeks Treatment-Experienced Cirrhotic Patients HCV RNA < LLOQ TD/TND (%) Treatment History All Patients SVR12 (ITT) by Prior Treatment Leroy V, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-3.

#AIDS2016 SVR > 95% No Toxicity Excellent Tolerability Must haves Short duration One size fits all: pangenotypic High barrier to resistance Helpful No drug–drug interactions Low pill burden Nice bonus Requirements for HCV Therapy

#AIDS2016 Present and Future Major DAAs

#AIDS2016 Double blind, placebo controlled Broad inclusion criteria 5:1 randomization to SOF/VEL or placebo – Stratified by HCV genotype and cirrhosis (presence/absence) – GT 5 patients not randomized Conducted at 81 sites in US, Canada, UK, Germany, France, Italy, Belgium, and Hong Kong ASTRAL-1: Study Design Week 0Week 12Week 24 Placebo SVR12 SOF/VEL n=500 n=100 Feld J, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-2

#AIDS2016 ASTRAL-1: SVR12 by HCV Genotype Feld J, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB relapse 2 lost to follow-up 1 withdrew consent 1 relapse1 death

#AIDS2016 Open-label, active-comparator trial in GT2 patients Broad Inclusion criteria 1:1 randomization to SOF/VEL or SOF + RBV – Stratified by prior treatment (TN/TE) and cirrhosis (presence/absence) Conducted at 51 sites in US ASTRAL-2: Study Design Week 0Week 12Week 24 SOF + RBV SVR12 SOF/VEL n=120 Sulkowski M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 205.

#AIDS2016 ASTRAL-2: SVR12 by Treatment 133/134124/132 SOF/VELSOF + RBV p= LTFU 6 Relapse 2 LTFU 9994 Sulkowski M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 205.

#AIDS2016 ASTRAL-3: SOF/VEL FDC Daily for 12 Weeks Versus SOF/RBV for 24 Weeks in Patients with HCV Genotype 3 Infection relapses 2 other 16 relapses 8 other 4 relapses 2 other 15 relapses 13 other 22 relapses 6 other 7 relapses 1 non-response 23 relapses 2 other Mangia A, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 249.

#AIDS2016 Open-label, randomized (1:1:1) US study GT 1-6 treatment-naïve or -experienced patients with CPT B cirrhosis Eligibility criteria: CrCL >50 mL/min, platelets >30,000 x 103/μL; no HCC or liver transplant Weight-based RBV dosing (1000 or 1200 mg/day) Study Design ASTRAL-4 Wk 0Wk 12Wk 24 SOF/VEL SVR12 Wk 36 SOF/VEL + RBV SVR12 SOF/VEL SVR12 n=75 Charlton M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-13.

#AIDS2016 P-value < for comparison of SVR12 rate to 1% for each treatment group Results: Overall SVR12 ASTRAL-4 SVR12 (%) SOF/VEL+ RBV 12 week SOF/VEL 24 week SOF/VEL 12 week 75 —— —— —— 90 Charlton M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-13.

#AIDS2016 ABT ABT-530 in G1 and G2 Poordad F, et al. 51 st EASL; Barcelona, Spain; April 13-17, Abst. SAT-157. P/R. pegIFN/RBv; pegIFN, pegylated interferon; RBV, ribavirin. SURVERYOR-1 and –II Study Design 8-week Treatment Arms Only SURVEYOR-I: 71% G1a, 85% TN, 71% F0-F1 SURVEYOR-II: 70% G2b, 87% TN, 82% F0-F1 SURVERYOR-I G1 without cirrhosis Open-label study Treatment-naïve or P/R experienced 0824 ABT-493 (300 mg) + ABT-530 (120 mg) ABT-493 (300 mg) + ABT-530 (120 mg) SURVERYOR-II G2 without cirrhosis Open-label study Treatment-naïve or P/R experienced SVR12 Week N=34 N=54

#AIDS2016 Results SVR Rates after 8 weeks of Treatment Poordad F, et al. 51 st EASL; Barcelona, Spain; April 13-17, Abst. SAT-157. Error bars represent 2-sided 95% confidence intervals (Cis) calculated using the Wilson score method. ITT rates are presented ont eh left for all treated subjects. mITT rates are presented on the right for all treated subjects excluding non-virologic failures ABT-493 (300mg) + ABT-530 (120mg) 8weeks ABT-493 (300mg) + ABT-530 (120mg) 8weeks ITT mITT

#AIDS2016 ABT-493 and ABT-530 Co-Administered for 8 Weeks Results SVR Rate – G3 Non-cirrhotics Muir AJ, et al. 51 st EASL; Barcelona, Spain; April 13-17, Abst. PS098. mITT SVR12 rate excludes non-virologic failures SVR12mITT SVR12 SVR12, % Patients 28 / / 28 No virologic failures 1 patient withdrew consent after treatment week 6 due to intolerance of blood draws and had an undetectable HCV RNA at the time of discontinuation Safe and well tolerated

#AIDS2016 Kwo P, et al. 51 st EASL; Barcelona, Spain; April 13-17, Abst. LB01. ABT-493 and ABT-530 +/- RBV in GT3 with Cirrhosis Results: SVR12 by ITT Analysis ABT ABT-530 ABT ABT RBV SVR12, % Patients 24 / / 24

#AIDS2016

PYRAMID-1 study-Egypt: Phase 3 registrational trial in Egyptian HCV gt-4 patients, Esmat AASLD 2015 and CROI 2016

#AIDS2016 DNDi/Pharco: Sofosbuvir + ravidasvir Goal: short, pangenotypic, easy to use, high efficacy, safe, all oral. Phase II/III Malaysia Thailand started, n=750. – Possible partnership with South Africa, Vietnam. Price <300 $ per course of 12 weeks License territories: include Asia, Latin America, Eastern Europe. Possibility to negotiate a license that covers Europe from Slide courtesy from Isabelle Andrieux-Meyer

#AIDS2016 Hot topic: Generics 26 Freemen J et al. EASL 2015 At the end of treatment 99.6% of patients were <LLOQ – One virological breakthrough reduced the result of LDV The overall SVR4 rate was 94.2% Looking at GT1 only the results of LDV and DCV were similar, with the LDV result again suffering from that breakthrough patient (S282T RAV) Redemption-1 HCV RNA <LLOQ at EOT and SVR4 GLOBAL ACCESS TO DAA THERAPY

#AIDS2016 SVR > 95% No Toxicity Excellent Tolerability Must haves Short duration One size fits all: pangenotypic High barrier to resistance Helpful No drug–drug interactions???? Low pill burden Nice bonus Innovation in HCV Treatment: what the future holds