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Home , Asunaprevir

HCV: Has the future arrived?

Paul Y Kwo, MD Professor of Medicine Medical Director, Liver Transplantation Gastroenterology/Hepatology Division Indiana University School of Medicine 975 W. Walnut, IB 327 Indianapolis, IN 46202-5121 phone 317-274-3090 fax 317-274-3106 email [email protected]

How will we know the future has arrived?

. All HCV infected individuals are candidates for therapy . Therapy side effects are minimal . All HCV infected individuals have access to therapy . There are no special populations left

2 Antiviral Therapies for Genotype 1 Currently Available in US and Europe

Regimen DAA Class PEG + RBV None PEG + RBV + Protease Inhibitor PEG + RBV + Protease Inhibitor PEG + RBV + Protease Inhibitor PEG + RBV + Nucleotide Analogue NS5B Polymerase Inhibitor RBV + sofosbuvir* Nucleotide Analogue (Extended duration) NS5B Polymerase Inhibitor Sofosbuvir + simeprevir NUC + PI (Off-label)

*Sofosbuvir + for 24 weeks can be considered in patients with genotype 1 HCV who are ineligible for . AASLD/IDSA Treatment Recommendations www.hcvguidelines.org, accessed 4/24/2014 Multiple Classes of Direct Acting Antiviral Agents

5’UTR Core E1 E2 NS2 NS3 NS4B NS5A NS5B 3’UTR p7

Protease Polymerase

NS3 NS5A NS5B NS5B Ribavirin protease Replication NUC Non-NUC inhibitors Complex Inhibitors Inhibitors Inhibitors Telaprevir Sofosbuvir Boceprevir VX-135 BMS-791325 Simeprevir IDX20963 PPI-383 Asunaprevir MK-8742 ACH-3422 GS-9669 ABT-450 GS-5885 TMC647055 MK-5172 GS-5816 ACH-3102 PPI-668 ACH-2684 GSK2336805 *representative list. May not be fully inclusive. Side effects of new agents

. NS5b: minimal . NS5a: minimal . NS3: Rash, elevated bilirubin due to transporter inhibition . Non-nucleoside polymerase: minimal . Ribavirin : anemia . Interferon: flu-like symptoms, cytopenias, decompensation in advanced liver disease

5 The components of SVR in HCV

PEG IFN RBV NS3 NS5b NS5a NS5b NNI

6 The Current Standard of Care in Korea

PEG IFN/RBV with no DAA

RBV PEG

IFN percent

7 The current standard of care in US: Genotype 1 Treatment-Naive Patients

. Patients who are eligible to receive IFN: • Sofosbuvir (400 mg) and weight-based RBV (1000-1200 mg) plus weekly PEG for 12 weeks regardless of subtype (1a or 1b)

. Patients who are NOT eligible to receive IFN: • Sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based RBV (1000-1200 mg) for 12 weeks regardless of subtype (1a or 1b)

8 Neutrino:SOF 400 mg QD + Peg-IFN-alfa-2a 180 µg/week + RBV 1000‒1200 mg/day for 12 weeks (no response-guided therapy)

Week 0 12 24 SOF + Peg-IFN + RBV, SVR12 n=327

. Open label PEG IFN • SOF 400 mg QD + Peg-IFN-alfa-2a 180 µg/week + RBV 1000‒1200 mg/day NS5b for 12 weeks (no response-guided therapy) . Treatment-naïve, genotype 1, 4, 5, and 6 HCV-infected patients RBV • Targeted 20% enrollment of patients with cirrhosis . Broad inclusion criteria • No upper limit to age or BMI • Opiate replacement therapy permitted • Platelets ≥90,000/mm3, neutrophils ≥1500/mm3 or 1000/mm3 (blacks)

9 SVR12 Rates in GT 1, 4–6 (NEUTRINO) by Fibrosis

10 Patel K, et al. AASLD 2013. Washington, DC. #1093 NS3 NS5b RBV

11 The current standard of care: Genotypes 2/3

. HCV genotype 2, regardless of eligibility for IFN therapy or treatment failure with PEG/RBV : Sofosbuvir (400 mg) and weight-based RBV (1000- 1200 mg) for 12 weeks • cirrhotics may benefit from extension to 16 weeks . HCV genotype 3, regardless of eligibility for IFN therapy or treatment failure with PEG/RBV : Sofosbuvir (400 mg) and weight-based RBV (1000- 1200 mg) for 24 weeks

12 FISSION Study: Treatment-Naïve, Genotype 2 or 3 Patients

Week 0 12 24 36 SVR SOF + RBV*, n=256 12 SVR PegIFN + RBV* (SOC), n=243 12

PEG IFN RBV NS5b versus NS5b RBV

*RBV dose 1,000-1,200 mg/day for SOF + RBV and 800 mg/day for PegIFN + RBV

Gane E, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 5. Results: SVR12 by Genotype and

Cirrhosis

SVR12 SVR12 (%)

58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37

No cirrhosis Cirrhosis No cirrhosis Cirrhosis GT 2 GT 3

Error bars represent 95% confidence intervals. 14 FISSION: Better Tolerability Profile With Sofosbuvir/RBV vs PegIFN/RBV

. Grade ≥ 3 AEs: 7% with SOF/RBV vs 19% for pegIFN/RBV . Discontinuations due to AEs: 1% for SOF/RBV vs 11% for pegIFN/RBV

GT 2/3 Pts, AEs Occurring in SOF/RBV PegIFN/RBV P Value ≥ 15% in Either Arm, % (n = 256) (n = 243) Fatigue 36 55 < .0001 Headache 25 44 < .0001 Nausea 18 29 .0057 Insomnia 12 29 < .0001 Rash 9 17 .0052 Diarrhea 9 17 .0075 Irritability 10 17 .0328 Decreased appetite 7 18 .0001 Myalgia 8 17 .0060 Pruritus 7 17 .0009 Influenzalike symptoms 3 18 < .0001 Chills 3 18 < .0001

Gane E, et al. EASL 2013. Abstract 5. SVR12 in GT 3 Patients Treated for 24 Weeks Sofosbuvir/RBV

Zeuzem et al. AALSD 2013 LB-28 16 Direct-Acting Antiviral Agents (DAAs) - Key Characteristics

NS3 /4A Inhibitors (Protease inhibitor PI) NS5B Nucleos(t)ide Inhibitors (NI) High potency Intermediate potency Limited genotypic coverage Pan genotypic coverage Low barrier to resistance High barrier to resistance

NS5A Inhibitors NS5B Non Nucleoside Inhibitors (NNI) High potency Intermediate potency Multi-genotypic coverage Limited genotypic coverage Low barrier to resistance Low barrier to resistance Interferon-Free, All Oral Regimens Treatment Naïve Study M11-646 (SAPPHIRE-I): AbbVie 3D Regimen + RBV in HCV Genotype 1

Phase 3 Study

Double-Blind Double-Blind ABT-450/r/ABT-267 qd + ABT-333 bid + RBV bid Key eligibility criteria (n=473) Open-Label • HCV genotype 1 ABT-450/r/ABT-267 qd + • Placebo* Treatment-naïve (n=158) ABT-333 bid + RBV bid • No cirrhosis (n=158) • No HIV or HBV 0 12 24 Week

ABT-450/r (150/100 mg) co-formulated with ABT-267 (25 mg) and administered once-daily. ABT-333 (250 mg) + RBV (weight-based dosing) administered twice-daily. *After week 12, placebo patients received open-label ABT-450/r/ABT-267 + ABT-333 + RBV for 12 weeks. Gastroenterologist Regional Primary outcome: SVR12. Advisory Board | Date 03.24.14 | Company Confidential ©

Feld J, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O60. 19 2014 High SVR rates for Genotype 1 with ABT- 450/r, ombitasvir, and dasabuvir +/- RBV for 12 weeks

NS5b NNI NS3 NS5a

RBV

20 SAPPHIRE-I: Adverse Events Occurring in >10% of Patients in Either Group 3D + RBV Placebo Event, n (%) (N=473) (N=158) P Value Any AE 414 (87.5) 116 (73.4) <0.05 Fatigue 164 (34.7) 45 (28.5) NS Headache 156 (33.0) 42 (26.6) NS Nausea 112 (23.7) 21 (13.3) <0.05 Pruritus 80 (16.9) 6 (3.8) <0.05 Insomnia 66 (14.0) 12 (7.6) <0.05 Diarrhea 65 (13.7) 11 (7.0) <0.05 Asthenia 57 (12.1) 6 (3.8) <0.05 Rash 51 (10.8) 9 (5.7) NS

AEs were generally mild. Genotype 1b achieves High rate of SVR with ABT 450/r/Ombitasvir Daabuvir with No RBV

NS5b NNI NS3 NS5a

22 Daclatasvir plus Asunaprevir for 24 weeks in

HCV Genotype 1b: SVR24 (%)

NS5a

NS3

HCV RNA

118/135 70/87 188/222 High rates of SVR24 were achieved in patient populations typically associated with poor responses to other therapies or with limited therapeutic options *mITT: modified intent-to-treat, all treated subjects

Chayama K et al. Presidential Plenary Oral 211. 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. 23 Study Design GT 1 Treatment-Naïve (ION-1)

Wk 0 Wk 12 Wk 24 Wk 36

LDV/SOF SVR12 NS5a LDV/SOF + RBV NS5b LDV/SOF LDV/SOF + RBV

. GT 1 HCV treatment-naïve patients in Europe and USA . Broad inclusion criteria • Targeted 20% enrollment of patients with cirrhosis • No upper age or BMI limit • Platelet count ≥50,000/mm3, no neutrophil minimum . 865 patients randomized 1:1:1:1 across four arms . Stratified by HCV subtype (1a or 1b) and cirrhosis Mangia A, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O164. SVR12: Absence of Cirrhosis vs Cirrhosis GT 1 Treatment-Naïve (ION-1): RBV not required

Absence of Cirrhosis Cirrhosis

SVR

179/180 32/34 178/184 33/33 181/184 31/33 179/181 36/36 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Error bars represent 95% confidence intervals.

Mangia A, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O164. Interferon-Free, All Oral Regimens Other populations Genotype 1 . Equally high SVR rates in • Treatment experienced populations • HIV/HCV coinfected populations • Cirrhosis patients • Post-transplant patients

26 Populations that still require additional study . Dialysis patients . Decompensated cirrhosis . Hepatoceullar carcinoma patients . Acute . Pre-Liver transplant patients • suppress prior to transplant or treat to SVR after transplant

27 The Ideal Therapy

. Pangenotypic . Minimal side effects . Minimal drug-drug interactions . Short duration . Minimal pill burden

28 NS5b

SVR 12 (%) Sofosbuvir/GS5816 (NS5a) no ribavirin : NS5a

26/27 GT 1

SOF + GS + SOF

28/28

- 5816 25 mg 5816 SVR12 10/11 GT 2

10/10

SOF + GS + SOF

25/27 - 5816 100 mg 5816 GT 3

25/27

29

Sofosbuvir + Daclatasvir ± RBV For Genotypes 1-3

NS5a _ NS5b

Sulkowski NEJM 2014 30 Has the future arrived?

. Yes for genotype 1 treatment naïve and experienced populations by end of 2014 • Sofosbuvir/ledipasvir • ABT 450/Ombitasvir/dasabuvir/±RBV • Sofosbuvir/simeprevir currently used, not licensed together • In Korea (genotype 1b, near 100% SVR) without RBV

Not quite for Genotype 2/3

. Genotype 2: future has arrived for majority of patients: • RBV toxicity will become more apparent with sofosbuvir/RBV in anemic, elderly, chronic kidney disease . Genotype 3 with cirrhosis is now the most problematic to treat . 24 weeks of sofosbuvir/RBV for all G3 . 12 weeks sofosbuvir + PEG IFN/RBV gives best SVR for G3 cirrhosis who have failed therapy . Sofosbuvir/ledipasvir +RBV . Sofosbuvir/GS 5816 . Sofosbuvir/daclatasvir

32 Summary: To be continued . Special populations are becoming not so special • HCC patients awaiting OLT, HIV/HCV patients, Post OLT patients all solved • Dialysis, advanced cirrhosis patients still need data

. Expect > 95% SVR, 12 week duration . Cirrhotics: Some may require 24 weeks? . Salvage therapies for the few failures will be required

. Access to therapy will be important • Collaboration between physicians, HCV drug developers, payors, governments, and patients

33 Hepatitis C Therapy Will Parallel Helicobacter pylori Therapy

H pylori HCV

All Oral Therapy Duration 8-24 weeks

Polymerase Inhibitor All Oral Therapy, ± single tablet Protease Inhibitor ±

NS5a ±

Non-nucleoside Inhibitor ±

ribavirin