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Home , Asunaprevir, Danoprevir, Sovaprevir

Hepatitis C Virus

A New Era Begins HCV

• Prevalence • Clinical Issues • HCV Life Cycle • Emerging DAAs

Global HCV Prevalence

HCV Regional Prevalence

Region Anti-HCV (%) No. HCV-infected Asia 3.8% 116,000,000 China, Pakistan, Japan, Thailand

N.Africa/Middle East 3.6 15,00,000

Africa 2.5 18,000,000

Europe 2.4 20,000,000

North America 1.3 4,000,000

World Pop (2005) 2.8 >184,000,000 6.5 billion Hanafiah KM et al Hep 2013 ;57: 1333

Diagnostic Barriers USA  Only 50% had screening HCV-Ab

 50% + HCV-Ab had HCV-RNA testing

 7-11% had a liver bx or treated

 Overall SVR estimated 5-6%

Holmberg SD et al NEJM 2013 368;1859 Screening

 IOM – 75% of Americans unaware  Missed diagnosis M- ALT 30 IU/ml, F- 19 IU/ml

Ann Int Med 2002;137:1-37  Risked-based vs birth-cohort screening – >800,000 additional cases identified – Cost-saving $35,700/life-saved with DAA+PR Ann Int Med 2012;156:263  Birth-cohort screening – USP-STF – designation “B” • ACA – covers grades A, B

Clinical Spectrum

ACUTE HCV ASYMPTOMATIC

CHRONIC RESOLVES DIAGNOSIS 80-85% 15-20%

MILD/MOD CIRRHOSIS DEATH/HCC CHC

80% 20% 1-4%/yr

0 5 10 20 30 YEARS Clinical Decisions – Who To Treat

Pathology Outlines.com 2012 The HCV Life Cycle HCV Cell Cultures

1) Replicons- engineered HCV genomes  NS3-5B sufficient for replication  only intracellular steps Lohmann V et al Science 1999; 285:110

2) HCVpp- HCV E1 and E2 surrounded by a lipid membrane,  host cell binding, entry and uncoating J Exp Med 2003; 197:633

3) HCVcc- replication in-vitro and in-vivo  provides key insights into the assembly and release Kato T et al Gastroenterology 2003;125:1808 Lindenbach BD et al Science 2005, 309:623

NS3/4A protease inhibitors Drug name Lead Companies Study Phase

Simeprevir Medivir/Janssen approved ABT-450/r AbbVie NDA Bristol-Myers Squibb NDA Boehringer Ingelheim NDA /r Roche Vedroprevir Gilead Achillion MK-5172 Merck & Co.

Nature Review/Drug Discovery June/2013

NS5B polymerase inhibitors

Drug name Companies Study Phase

Nucleoside/nucleotide Gilead approved uridine nucleotide Roche Cytidine nucleoside VX-135 Vertex uridine nucleotide

Non-nucleoside AbbVie NDA BI-207127 Boehringer Ingelheim Tegobuvir Gilead ABT-072 AbbVie BMS-791325 Bristol-Myers Squibb TMC-647055 Janssen

NS5A inhibitors Drug Name Lead companies Phase

Obitasvir AbbVie NDA Bristol-Myers Squibb NDA Gilead NDA ACH-3102 Achillion GSK2336805 GlaxoSmithKline MK-8742 Merck & Co PPI-668 Presidio

NEUTRINO STUDY Sofosbuvir + Peg + Riba 12wks, n=327 naïve, GT 1, 4, 5, 6

100

99 80 99 90

60 91

40

20

Viral clearance clearance Viral 0 wk 2 wk 4 wk 12 SVR12

SVR12 80% cirrhosis n=54 ; SVR12 87% AA n=54

Lawitz E et al NEJM 2013;368:1878

FISSION STUDY Sofosbuvir + Riba 12 wks, naïve, GT 2,3

12 SVR

n=103 n=24 n=284 n=75 Jacobson IM et al NEJM 2013;368:1867 FUSION STUDY Sofosbuvir + Riba Non-responders, GT2,3 Jacobson IM et al NEJM 2013;368:1867

100 96 100 80

78

12 60 63 61 60 SOF+R 12wks 40 SOF+R 16wks

SVR 37 20 19 26 23 10 9 38 40 26 23 0 no cirrhosis cirrhosis no cirrhosis cirrhosis

Genotype 2 Genotype 3 COSMOS STUDY 12wks,GT-1, Nonresponders, F0-2

Simeprevir + Sofosbuvir + Simeprevir + Sofosbuvir Riba N=40 N=40 SVR 96% SVR 93%

Sulkowski M, et al EASL Annual Meeting April 2014 Current AASLD/IDSA Rec's

• Naive GT-1 – Sofosbuvir 400mg + Peg + Riba: 12 wks • GT1a SVR 92% • GT1b SVR 82% • Cirrhosis SVR 78%

• Ineligible for Therapy – Sofosbuvir + Simeprevir

Current AASLD/IDSA Rec's

• GT-2 (+/- cirrhosis) – Sofosbuvir 400mg + Riba for 12 wks – SVR 94% • GT-3 (without cirrhosis) – Sofosbuvir + Riba for 24 wks – SVR 93% naive, 77% tx-experienced

Interferon-Free Trials For GT-1

Study NS3/4a PI NS5B – NI NS5B - NNI NS5A

Abbvie ABT-450/r Dasabuvir Obitasvir +/-

Gilead Sofosbuvir Ledipasvir yes

Sofosbuvir Daclatasvir +/-

Sofosbuvir yes

BMS Asunaprevir BMS791325 Daclatasvir

Asunaprevir Daclatasvir +/-

Vertex Teleprevir VX-222 yes

ION-I Ledipasvir and Sofosbuvir Naive HCV GT 1 +/- cirrhosis

12 wk 12 wk 24 wk 24 wk LDV/SOF + R LDV/SOF LDV/SOF + R LDV/SOF n=214 n=217 n=217 n=217 SVR 211 SVR 211 SVR 212 SVR 215 (99%) (97%) (98%) (99%)

GT 1a > 97%, > 94% cirrhosis, > 91% AA AE: Fatigue, HA, Nausea, Insomnia 8-25%, 0 discontinuation 12wk arms

Afdhal N et al: N Engl J Med 2014;370:1889-98

ION-II Ledipasvir and Sofosbuvir for Previously Treated HCV Genotype 1, +/- Cirrhosis

12 wks 12 wks 24 wks 24 wks LDV/SOF LDV/SOF+R LDV/SOF LDV/SOF+R N=109 N=111 N=109 N=111

SVR 102 SVR 107 SVR 108 SVR 110 (94%) (96%) (99%) (99%)

Afdhal N et al. N Engl J Med 2014; 370:1483-1493

ION-III Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis

8 wks 8 wks 12 wks LDV/SOF LDV/SOF + Riba LDV/SOF n=215 n=216 n=216 SVR 202 SVR 201 SVR 206 (94%) (93%) (95%)

Kowdley K et al N Engl J Med 2014;370:1879-88

Abbvie Pharmaceutical non-interferon based clinical trials: 3DAAs +/- Ribavirin

• ABT-450/r Protease inhibitor

• NS5a

• Dasabuvir NS5b (bid)

PEARL-III Naïve GT1b PEARL IV Naïve GT 1a No Cirrhosis

GT 1b GT 1b GT 1a GT 1a 3 DAAs + R 3DAAs no R 3 DAAs + R 3DAAs no R 12 wks 12 wks 12 wks 12 wks N=210 N=209 N=100 N=205

SVR 209 SVR 207 SVR 97 SVR 185 (99.5%) (99%) (97%) (90.2%) F/R 1/0 F/R 0/2 F/R 1/2 F/R 6/10

Ferenci P et al. N Engl J Med 2014;370:1983-1992. SAPPHIRE-II Previously Treated GT1 GT 1a GT 1b 3DAAs + R 3 DAAs + R N=173 N=123 SVR 166 SVR 119 (96%) (96.7%) F/R 0/3 F/R 0/4

Prior Relapse, Partial Responders or Null Responders: SVR 95%, 100%, 95%, respectively

Zeuzem S et al. N Engl J Med 2014;370:1604-1614. TURQUOISE-II 3 DAAs + Riba HCV with Cirrhosis- Naïve and Failed Therapy

Poordad F et al. N Engl J Med 2014;370:1973-1982. Milestones of HCV Therapy 1989-98 1998-01 2001-11 2011-13 2013-14 2015 100 95 90 80 80 70 70 60

50 45 SVR 40 30 30 20 20 10 0 IFN mono IFN/RIBA PEG/Riba PEG/R/PI PEG/R/NS5b NS5b/NS5a Kabiri M, et al Ann Int Med 2014;161:170-180 Final Thoughts Diagnosis Oral Regimen Pill burden Effective Safety Cost

? Treating mild HCV