Introduction

Eugene R. Schiff, MD

Chief, Division of Hepatology Director, Center for Liver Diseases University of Miami School of Medicine Miami, Florida

Change… It’s Inevitable



Anticipate



Monitor



Adapt



Move



Be ready to do it again

Johnson, S.

Who Moved My Cheese?

New York: G. P. Putnam’s Sons, 1998.

The Handwriting on the Wall

The Increasing Challenge of HCV Disease Burden

Hepatocellular carcinoma (HCC) End-stage liver disease HCV-related cirrhosis

Reality Check

Assessing the Present to Anticipate the Future

Present

  

Parameters for success

– Virologic – Histologic

Speed of response

– Weeks, months

PEG IFN / RBV

Future

   

Parameters for success

– Sustained viral response

Speed of response

– Days?

Synergistic combination of old and new?

– PEG IFN / RBV plus STAT-C

Synergistic combination of STAT-Cs

Finding Our Way in the Maze

Changing Direction Toward More Effective Treatment

Think more like virologists than hepatologists or gastroenterologists

Let’s Talk

What Are the Key Questions for the Future?

The Handwriting on the Wall: The Increasing Challenge of HCV Disease Burden

Hashem B. El-Serag, MD, MPH

Associate Professor of Medicine Department of Medicine Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, Texas

Age-Adjusted Incidence Rates for Hepatocellular Carcinoma (HCC)

3.5

3 2.5

2

1.8

2.0

2.3

2.7

3.1

3.3

1.6

1.5

1.4

1.4

1 0.5

0 76 –78 79–81 82–84 85–87 88–90 91–93 94–96 97–99 2000–02

Year

Analysis of SEER data, courtesy of Dr. H.B. El-Serag.

Liver Cancer Has the Fastest Growing Death Rate in the United States Trends in US Cancer Mortality Rates All Other Cancers (Average) Corpus & Uterus, NOS Testis Lung & Bronchus (Female) Esophagus Thyroid Liver

-2 -1.5

-1 -0.5

0 0.5

1

Annual Percent Change (1994 –2003)

1.5

2 National Cancer Institute. Seer Summary Figures and Tables. Available at: http://seer.cancer.gov/csr/1975_2003/results_merged/topic_graph_trends.pdf. Accessed on April 17, 2007.

Racial Incidence Rates for HCC In the United States

9 8 7 6 5 4 3 2 1 0

1 2.5

6 White 2.5

1.1

5.2

Black 2.6

1.1

6.3

2.9

1.3

Other (Asian) 6.6

1.4

3.4

7.2

3.7

1.7

7.2

3.9

1.9

8.4

4.6

2.3

7.9

2.5

5 8

76 –78 79 –81 82 –84 85–87 88–90 91–93 94–96 97–99 2000–02

Year

Analysis of SEER data, courtesy of Dr. H.B. El-Serag.

Temporal Trends in the Age Distribution of HCC

20 18 16 14 12 10 8 6 4 2 0

1982 1991 2000 –84 –93 –02

20 –24 30 25 –29 –34 35 40 –39 –44 45 50 –49 –54 55 60 –59 –64 65 70 –69 –74 75 80 –79 –84 85+

Age (years)

Analysis of SEER data, courtesy of Dr. H.B. El-Serag.

HCV Cirrhosis and HCC

Multiple small foci of HCC Graphic courtesy of Dr. H.B. El-Serag.

Outlook for Those with Compensated Cirrhosis

Number Follow-up (y) Decompensation (%/y) Study A 1 384 5.0 3.9

HCC (%/y) 5-year survival (%) 1.4

91 Study B 2 Study C 3 112 103 4.5

3.3

4.4

2.3

83 5.0

3.3

84 (at 4 y) 1. Fattovich G, et al.

Gastroenterology.

3. Serfaty L, et al.

Hepatology.

1997;112:463. 2. Hu K, et al. 1998;27:1435.

Hepatology.

1999;29:1311.

Clinical Complications and Mortality Developing in HCV Patients with Compensated Cirrhosis 214 HCV RNA-seropositive patients with Child-Pugh class A cirrhosis, no evidence of HCC at enrollment, and no history of previous clinical decompensation followed for 114 months Complication

Ascites Jaundice Upper GI Bleeding

% Developing

23 17 6 Encephalopathy HCC Death 1 32 35 Sangiovanni A, et al.

Hepatology.

2006;43:1303.

Risk Factors for HCC

   – – – – –

Cirrhosis from any cause

– –

HCV HBV 1,2 1,2

– –

HBV 1,2 Inherited metabolic diseases

–

Heavy alcohol consumption 1,2 Nonalcoholic fatty liver disease 1 Hemochromatosis 1–3 Alpha-1 antitrypsin deficiency 3 Glycogen storage disease 4 Porphyria cutanea tarda 3 Tyrosinemia 3 Autoimmune hepatitis 2

1. Dorfman JD, et al.

World J Gastroenterol.

3. Montalto G, et al.

Ann N Y Acad Sci.

2007;13:781. 2. El-Serag H, et al. 2002;963:13. 4. Franco LM, et al.

Arch Intern Med.

J Inherit Metab Dis.

2000;160:3227.

2005;28:153.

Risk Factors for HCC Among US Veterans

120 100 80 60 40 20 0

N = 823 cases with HCC N = 3459 controls 9 HBV 17 HCV 79 19 15 ALD HCV + ALD HCV + HBV

ALD = alcoholic liver disease El-Serag HB, et al.

Am J Gastroenterol.

2001;96:2462. Graphic courtesy of Dr. H.B. El-Serag.

Only HCV-related HCC Increased Among Veterans Between 1993 and 1998

  

VA hospitals HCV-related HCC accounted for 50% of increase Overall, only one third of cases were HCV-related

20 15 10 5 0 1993 –95

ALD Years Idiopathic

ALD = alcoholic liver disease El-Serag HB, et al.

Arch Intern Med.

2000;160:3227. Graphic courtesy of Dr. H.B. El-Serag.

*

1996 –98

HBV HCV

Proportion of US-Born Patients with HCC Related to Viral Hepatitis

60 50 40 30 20 10 0 1993 –95 (n = 143) 1996 –98 (n = 216)

P = .01

P = .06

P = .5

HCV HBV

Viral Markers

None Reprinted from Hassan MM, et al.

J Clin Gastroenterol.

2002;35:266, with permission.

Viral Hepatitis in HCC in the United States 1,2 47% 33%

HCV Both HBV Neither (N = 691)

15% 5%



HBV most frequent in Asians



HCV most frequent in whites and blacks

1. Reprinted from El-Serag HB, et al.

Gastroenterology.

2004;127:S27, with permission from Elsevier.

2. Di Bisceglie AM, et al.

Am J Gastroenterol.

2003;98:2060.

Rate of Chronic HCV Infection in the United States Highest Among Young African-American Adults

2 1 0 7 6 5 4 3

African-American Hispanic Caucasian

6 –11 12–19 20–29 30–39 40–49 50–59 60–69 ≥70

Age Group (y)

CDC.

MMWR.

1998;47:1-39.

HCV to HCC Pyramid

HCC

1% (1% –3%/y)

Cirrhosis

15% (10% –30%/y)

Chronic Hepatitis

90% (60% –95%/y) 25 years

HCV Infection

100%

Graphic courtesy of Dr. H.B. El-Serag.

Efficacy of IFN +/- Ribavirin in Preventing HCV-HCC

  

Meta-analysis of 20 controlled trials (3 randomized controlled)

–

4659 patients with HCV-cirrhosis Decreased incidence of HCC in treated patients

–

19/20 studies, significant difference in 13 studies Pooled estimate of treatment effect

– –

Risk difference: -12.2% (CI -8.4% to -16.1%, P < .00001) Pooled risk difference for sustained biochemical responders: -19.1% (CI -13.1% to -25.2%, P < .00001)

Craxi A, et al.

Clin Liver Dis.

2005;9:329.

HCC After IFN Therapy for HCV

30 25 20 15 10 5 0 0 1 Imai Y, et al.

Ann Intern Med.

1998;129:94.

Reprinted with permission.

2

No Response

3 4

Follow-up (y)

5

Relapse Sustained Response

6 7

Efficacy of Peginterferon + Ribavirin in Achieving SVR Category Overall Genotype 1 Genotype 2/3 Genotype 4 African American Cirrhosis SVR (%) 54 –56 1,2 42 –46 1,2 76 –82 1,2 77 2 28 3 43 –44 1,2

1. Manns M, et al.

Lancet.

2001;358:958. 2. Fried M, et al.

N Engl J Med.

3. Conjeevaram H, et al.

Gastroenterology.

2006;131:470.

2002;347:975.

Prevention and Treatment of HCC

Community Effectiveness = Efficacy x Access x Correct Diagnosis x Recommendation x Acceptance x Adherence

Clinical Trials Clinical Practice

Reprinted from El-Serag HB.

Gastroenterology

. 2007;132:8, with permission from Elsevier.

Efficacy and Effectiveness

A Demonstration of the Multiplicative Effect of Factors

Rx A Efficacy Access Correct Diagnosis 50% 80% 85% Recommend Acceptance Adherence Effectiveness 85% 85% 70% 17% Rx B Rx A modify 70% 50% 80% 90% 85% 90% 85% 90% 85% 90% 70% 80% 24% 26%

Reprinted from El-Serag HB.

Gastroenterology

. 2007;132:8, with permission from Elsevier.

Estimated Chronic HCV Patient Status in the US Veteran Population n = 52 Seropositive and prior testing (86%) Seropositive with no prior testing (14%) Aware of diagnosis (54%)

Dominitz JA, et al.

Hepatology.

2005;41:88.

Unaware of diagnosis (46%)

Eligibility and Acceptability of Anti-HCV Treatment

   

4084 HCV+ patients in VA multi-center study 12/99–12/00 Eligibility: 32% by standard criteria, 41% by treating physician

–

Predictors of noneligibility



Ongoing substance abuse OR 17.68

–   

Advanced liver disease Acceptability: 76% of eligible patients Reasons for nonacceptance

 

Co-morbid medical disease Psychiatric disease Defer Rx until better therapies Concerns regarding side effects Treatment completion rates

–

~50% (~8% of all patients) OR 9.62

OR 9.45

OR 8.43

50% 22%

Bini E, et al.

Am J Gastroenterol.

2005;100:1772.

Prevention and Treatment of HCC

Community Effectiveness = Efficacy x Access x Correct Diagnosis x Recommendation x Acceptance x Adherence

Clinical Trials Clinical Practice

Reprinted from El-Serag HB.

Gastroenterology

. 2007;132:8, with permission from Elsevier.

HCC in the United States

The Handwriting on the Wall



A 2-fold increase in incidence during the past 2 decades



The greatest increase seen in

–

The latter half of the 1990s

–

White men between ages 45 and 65



HCV is likely responsible for a large part of the increase



Current therapy is unlikely to reduce HCC incidence appreciably

Reality Check:

Assessing the Present to Anticipate the Future

Nezam H. Afdhal, MD

Chief of Hepatology Director, Liver Center Beth Israel Deaconess Medical Center Boston, Massachusetts

Milestones in Anti-HCV Therapy

100 80 60 40 20 0

1986 6 IFN 6 mo 16 34 1998 42 2001 39 2002 54 –56 IFN 12 mo IFN/RBV 6 mo IFN/RBV 12 mo PEG IFN 12 mo PEG IFN/ RBV 12 mo

Strader DB, et al.

Hepatology.

2004;39:1147. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.

IFN

Interferon-



Signal Transduction STAT 1/2 PKR 2 ′ 5 ′ OAS IFN-stimulated genes Viral replication

STAT = Signal transducer and activator of transcription; PKR = RNA-dependent protein kinase; 2 ′5′ OAS = 2 ′5′-oligoadenylate synthetase.

Katze MG, et al.

Nature.

2002;2:675. Graphic courtesy of Dr. N. H. Afdhal.

Constellation of Factors Affecting Anti-HCV Therapy Patient mind-set Extrahepatic features

• • • • • • •

Genotype Viral load Race Age Fibrosis Body weight HIV coinfection Duration of infection ALT Family support Cost Occupation Personal plans (marriage, pregnancy) Inflammation on biopsy Lifestyle issues Contraindications

Graphic courtesy of Dr. I. Jacobson.

Tailoring the Duration of Anti-HCV Therapy to the Individual Patient



New emphasis on rapidity of viral clearance as a key determinant of duration of therapy



Baseline viral load important in some patient groups

Early Virologic Response (EVR)

The Negative Predictor*

EVR achieved † (HCV RNA negative or ≥ 2-log decrease at wk 12; n = 380/511) HCV RNA negative n = 308 (81%) SVR n = 258 (84%)

*Negative predictive value = 100%; positive predictive value = 72%.

† PEG IFN  2b 1.5 µg/kg QW + RBV 800 mg/d Davis GL, et al.

Hepatology.

2003;38:645.

HCV RNA positive n = 72 (19%) HCV neg at wk 24 n = 43 HCV pos at wk 24 n = 24 SVR n = 14 (33%) SVR n = 1 (4%)

100

Rapid Virologic Response (RVR)

The Positive Predictor*

91 PEG IFN



-2a 180 mg + RBV 1000 –1200 mg

80

72 60

60

48 43

40 20 0

HCV RNA Status Week 4 Negative ≥2 log



Week 12 Negative Negative Week 24 Negative Negative <2 log



≥2 log



Negative ≥2 log



<2 log ≥2 log

 

Negative Negative Negative

*Negative predictive value = 74%; positive predictive value = 75%.

Ferenci P, et al.

J Hepatol

. 2005;43:425, with permission from Elsevier.

Critical Concept

RVR, SVR, and Relapse

Fast response Less relapse Slow response More relapse

What are the implications of this for duration of therapy?

New studies provide some answers…

Tailoring the Duration of Therapy

Genotypes 2 and 3

Genotypes 2, 3 Standard duration: 24 weeks Rapid response RNA (-) at week 4 12 –16 weeks

HVL = high viral load.

Graphic courtesy of Dr. N. H. Afdhal.

RNA (+) week 4, genotype 3, high viral load ≥24 weeks

Tailoring the Duration of Therapy

HCV Genotype 1

Genotype 1 Low viral load (<600,000 IU/mL) Standard duration: 12 months Rapid response: RNA (-) at week 4 24 weeks?

Graphic courtesy of Dr. N. H. Afdhal.

Slow response: RNA (+) at week 12 RNA (-) at week 24 72 weeks?

Should Late Responders with Genotype 1 Be Treated Longer?

8 late responders PCR positive at wk 12 PCR negative at wk 24 72 wk treatment PEG IFN 1.0 µg/kg QW/RBV 800 mg/d 7 sustained responders

Buti M, et al.

Hepatology.

2003;37:1226.

100

48 vs 72 Weeks of PEG IFN/RBV

~90% Genotype 1

Patients with detectable HCV RNA at week 4 P = .014

80

ETR SVR 61

60

52

40

32 48% Relapse 45 13% Relapse

20

n=165 n=162

0

48 Weeks 72 Weeks PEG IFN



-2a 180



g/wk + RBV 800 mg/d

ETR = end of treatment response.

Sanchez-Tapias JM, et al.

Hepatology.

2004;40:218A. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.

Prolonging Therapy May Decrease Relapse in Late Responders 81%



N = 456, genotype 1



PEG IFN



-2a + RBV 800 mg/d 48 vs 72 wk



No effect on overall rate of SVR 44% Week 12 (+) 48 wk Week 12 (+) 72 wk Duration of Therapy

(+) = HCV RNA positive.

Berg T, et al.

Hepatology.

2004;40:238A. Abstract 169.

Rapidity of Response

Conclusions



Rapidity of viral clearance is a major predictor of relapse and sustained response



Implication that rapid responders have more rapid clearance of intracellular HCV



Rapidity of viral response can drive duration of therapy in several major patient groups



Rapidity of response should be critically evaluated as new therapies are developed

PEG IFN/RBV in Genotype 1 African American and Caucasian American Patients

Virahep-C Study

100 80

PEG IFN



-2a 180 µg QW + RBV 1000–1200 mg/d

60

52% P < .0001

40

28%

20

N=205

0

Caucasian American (n = 205)

Conjeevaram H, et al.

Gastroenterology.

2006;131:470.

N=196 African American (n = 196)

Racial Differences in Relapse and Breakthrough

Virahep-C Study

Breakthrough Posttreatment relapse SAEs, dose modifications, and discontinuations African American

13% 32%

Caucasian American

6% 25% Similar

P

-Value

.05

.30

Conjeevaram H, et al.

Gastroenterology.

2006;131:470.

SVR Rates Across Individual Fibrosis Stages

WIN-R Trial

4913 Patients Treated with PEG IFN (



-2b 1.5



g/kg/d) + WBD (800 –1400 mg/d) or FD (800 mg/d) RBV

60 50

P < .0005

vs F4 44% 46% P < .0001

vs F4 44% 44%

40

34%

30 20 10

n = 654 n = 1460 n = 1324 n = 975 n = 500

0

F0 F1 F2 Metavir Score F3 F4

WBD = weight-based dose; FD = fixed dose.

Afdhal N, et al. DDW 2006. May 20-25, 2006. Abstract 655. Graphic courtesy of Dr. N. H. Afdhal.

Propensity Score

WIN-R Trial

Fixed dosing Weight-based dosing 0.6

0.4

African-American male age 50, F3 HCV-1 0.2

0 -2 -1.5

-1 -0.5

Propensity Score 0

Jacobson WIN-R data abstract. Courtesy of Dr. I. Jacobson.

0.5

Caucasian female, age 22, F1 HCV-2 1

Clinical Trials of PEG IFN + RBV in HIV/HCV Coinfection

   

APRICOT 1

–

(n = 895) 3 arms: IFN



-2a/RBV vs PEG



-2a vs PEG



-2a/RBV for 48 wk

–

RBV 800/d A5071 2

–

(n = 133) 2 arms: IFN



-2a/RBV vs PEG



-2a/RBV for 48 wk

–

Escalating dose RBV RIBAVIC 3 (n = 412)

–

2 arms: IFN



-2b/RBV vs PEG



-2b/RBV for 48 wk

– –

RBV 800 g/d > 30% F3 or F4, high rate of discontinuation Barcelona 4

–

(n = 95) 2 arms: IFN



-2a/RBV vs PEG IFN



-2a/RBV for 24 or 48 wk

–

RBV 800–1200 g/d

– –

Nongenotype 1 treated for 24 wk 30% F3 or F4

1. Torriani FJ, et al.

New Engl J Med.

3. Carrat F, et al.

JAMA.

2004;351:438. 2. Chung RT, et al. 2004;292:2839. 4. Laguno M, et al.

AIDS.

New Engl J Med.

2004;18:F27.

2004;351:451.

Response Rates with PEG IFN/RBV in HIV/HCV Coinfection

80 70 60 50 40 30 20 10 0

29 APRICOT 1 A5071 2 RIBAVIC 3 Barcelona 4 14 17 Genotype 1 or 4 38 62 73 44 53 Nongenotype 1

1. Torriani FJ, et al.

New Engl J Med.

3. Carrat F, et al.

JAMA.

2004;351:438. 2. Chung RT, et al. 2004;292:2839. 4. Laguno M, et al.

AIDS.

New Engl J Med.

2004;351:451. 2004;18:F27. Graphic courtesy of Dr. N. H. Afdhal.

Reasons for Lack of Response Virus Genotype 1 High viral load HIV coinfection Patient Cirrhosis African-American Obesity Steatosis Treatment Underdosing Nonadherence Interfering agent (alcohol) Insufficient duration

Current Options for Nonresponders to PEG IFN and RBV Modify current treatment Suppress with “maintenance” treatment Test safety and efficacy of new antivirals Try to inhibit liver fibrosis

Previous therapy Consensus Interferon/RBV in Genotype 1 Nonresponders

DIRECT Study Design

PEG IFN alfa-2a or 2b + RBV 12 Weeks* < 2 log 10 drop in HCV RNA 24 Weeks HCV RNA positive Randomization 510 patients, ~41 sites 9 µg QD IFN alfacon-I + RBV (N = 170) *Patients with < 2 log 10 drop in HCV RNA between week 12 and 24 No treatment control arm (N = 170) May be eligible for roll-over study

Bacon BR, et al. 57th AASLD. October 27-31, 2006. Abstract LB18. Courtesy of Dr. B. Bacon.

DIRECT Study

Interim Results

50 40 30

32% 26% 25% 22%

20 10 0

14% 20% 16% 19% 9 µ g CIFN 15 µ g CIFN 9 µ g CIFN 15 µ g CIFN n = 171 n = 172 n = 171 n = 172 24 weeks 48 weeks bDNA TMA

CIFN = consensus IFN or IFN alfacon-1.

Bacon BR, et al. 57th AASLD. October 27-31, 2006. Abstract LB18. Courtesy of Dr. B. Bacon.

Colchicine vs PEG IFN in Nonresponders

COPILOT Study Design

PEG IFN



2b 0.5 µg/kg/wk IFN/RBV or PEG IFN/RBV Nonresponders LB, US, endoscopy Clinical evaluation q 12 wk Colchicine 0.6 mg BID US q 24 wk Endoscopy, LB Endoscopy, LB Baseline 12 wk 24 wk 2 y

600 patients; 557 currently enrolled Ishak fibrosis stage >3.

LB = liver biopsy; US = ultrasound.

Afdhal N, et al.

Hepatology.

2004;40:239A. Graphic courtesy of N. H. Afdhal.

COPILOT Interim Results

All Patients

100 90 80 70

P = .007; 95% Cl 1.18

–3.08

PEG IFN

60 0 360 720

Days

1080 Afdhal N, et al.

Hepatology.

2004;40:239A. Graphic courtesy of N. H. Afdhal.



-2b Colchicine

1440

COPILOT Interim Results

Stratification by Portal Hypertension

PEG IFN



-2b

1.0

0.8

0.5

Colchicine

0.3

0.0

0 250 500 750

Days

1000

Log rank; P < .01

1250 1500 Afdhal N, et al.

Hepatology.

2004;40:239A. Graphic courtesy of Dr. N. H. Afdhal.

Conclusions: Current Status of Interferon-Based Treatment



Genotype 1, HVL, African-American race, HIV and cirrhosis remain significant challenges



Manipulations of dose and duration are unlikely to increase SVR significantly and have not been successful in prior nonresponders



Novel therapies will require antiviral activity through a mechanism exclusive of IFN gene activation

Finding Our Way in the Maze: Changing Direction Toward More Effective Treatment

Mark S. Sulkowski, MD

Associate Professor of Medicine Medical Director, Viral Hepatitis Center Johns Hopkins University School of Medicine Division of Infectious Disease Baltimore, Maryland

Emerging Therapies STAT-C Polymerase Protease Genome Sequence-Based RNA interference Ribozymes Other Other IFNs

•

cIFN, gamma, IFN-alb

• •

RBV refinements Viramidine

• • • • •

Immune approaches CpG oligos Isatoribine Therapeutic vaccines HCIg Monoclonal antibodies Helicase Antisense oligo nucleotides Antifibrotic therapy

cIFN = interferon alfacon-1; CpG = cytosine-guanosine oligonucleotides; HClg = hepatitis C immunoglobulin; IFN-alb = albumin interferon. Graphic courtesy of Dr. I. Jacobson.

Hepatitis C Drug Development On Market RBV IFN & PEG IFN Phase III Thymosin Albumin IFN-alfa Viramidine Phase II Telaprevir Antisense Ribozymes Antifibrotics Gamma IFN HCV-796 IL 10 & IL 12 others E2 Vaccine Boceprevir CPG 10101 IC41 Vaccine Phase I Valopicitabine Histamine HCl R1626 BILB 1941 Omega IFN Imino sugars ANA 245 Preclinical Research Many others including immune stimulants gene therapy

Graphic courtesy of Dr. J. McHutchison.

4 3 5 7 6

Interferon Has a Potent Antiviral Effect Mean HCV RNA Response to IFN



-2b 3, 5, and 10 MU QD in Genotype 1 Mean Log Reductions –1.06

2 0

3 MU TIW 3 MU 5 MU 10 MU

7 14

Time (days)

21 28

–2.51

* –3.10

–3.49

*

P

< .05 v 3 MU TIW Courtesy of Dr. M. Sulkowski.

Albumin Interferon alfa-2b

Phase II Trial

alb-IFN 1200 μg Q2W + RBV 1000–1200 mg alb-IFN 900 μg Q2W + RBV 1000–1200 mg alb-IFN 1200 μg Q4W + RBV 1000–1200 mg PEG IFN alfa-2a 180 μg QW + RBV 1000–1200 mg

• • • •

Design: randomized, open-label, active control Population: IFN-naive, genotype 1 Conducted at 82 sites in Canada, Europe, Israel, Australia 4 cohorts stratified by

−

HCV RNA (<800,000 IU/mL, ≥800,000 IU/mL)

−

BMI (<25 kg/m 2 , ≥25 kg/m 2 )

BMI = body mass index; alb-IFN = albumin interferon.

Zeuzem S, et al. 41st EASL. April 26 –30, 2006. Poster and a bstract 733.

100 75

Albumin Interferon alfa-2b Plus RBV

SVR12* Results

alb IFN 1200 µg Q2W (n = 110) alb IFN 900 µg Q2W (n = 118) alb IFN 1200 µg Q4W (n = 116) PEG IFN 180 µg QW (n = 114)

55.5

59.3

52.6

54.4

50 25 0

Treatment Groups

*SVR12 = HCV RNA < 10 IU/mL at week 12 posttreatment Zeuzem S, et al. 42nd EASL. April 11-15, 2007. Poster and a bstract 779.

Viral Enzyme Inhibitors Polymerase Viral Enzyme Inhibitors

Emerging Therapies

Protease STAT-C (Specifically Targeted Antiviral Therapy for HCV) Helicase

NS3/4a Cleaves Nonstructural Proteins from the Polypeptide Chain 1,2

Viral Replication Initiated

P7 NS2 NS3/4a Protease NS4B E2 NS5A E1 C

Graphic courtesy of Dr. M. Sulkowski.

1. Lindenbach BD, et al.

Nature

. 2005;436:933. 2. Lindenbach BD, et al.

Science.

2005;309:623.

NS5B

HCV Protease Interferes with IFN Signaling RIG 1 and TLR3 signaling ablation by the HCV NS3/4A protease blocks IRF-3 activation and attenuates the host response to infection HCV protease

IRF = interferon regulatory factor 3; PRD = positive regulatory domain; RIG 1 = retinoic acid-inducible gene-1; TLR3 = toll-like receptor 3. Adapted from Gale M, et al.

Nature

. 2005;436:939. Reprinted with permission.

Protease Inhibitor Telaprevir (VX-950) Monotherapy

Proof of Principle

7

VX-950 750 mg Q8H (n = 8) VX-950 450 mg Q8H (n = 10) VX-950 1250 mg Q12H (n = 10) Placebo (n = 6)

6 5 4 3

2 patients HCV RNA <10 IU/mL

2 1 0 1 2 3 4 5 6 7 8

Study Time (days)

9 10 11 12 13 14 Reprinted from Reesink HW, et al.

Gastroenterology.

2005;128:A-697, with permission from Elsevier.

Inhibition of Wild-Type HCV May “Select” Naturally Occurring Drug-Resistant Variants Wild Type Potent Drug Mutants Mutant

Graphic courtesy of Dr. M. Sulkowski.

Sensitivity of Variant Proteases to Telaprevir

100,000 A156T/V

Upper Limit of Assay

10,000 A156S 1000 T54A 1b V36A/M+ R155K/T 100 V36M/L/A R155K/M/S/T

Wild-Type Sensitivity

10 1a

Wild-Type Single Residue Change

IC 50 = half maximal inhibitory concentration.

Sarrazin C, et al.

Gastroenterology.

2007;132(5):1767. Courtesy of T. Kieffer, MD.

Double Change

7 6 5 4 3 2 1

Frequency of Variants Over Time

Breakthrough Group (n = 12)

Telaprevir Dosing Period Postdosing Long-Term Follow-Up

Baseline EOD 14 d Follow-up 7 –10 d postdosing Long-term follow-up 3 –7 mo postdosing WT

36/155 T54 155 WT 36 36/155 WT T54 155 36 155 36 WT IC 50 fold change WT V36 M/A/L R155 K/T/S/M T54A 36/155 A156V/T

1 4 7 12 46 466 781

EOD = end of dosing.

Sarrazin C, et al.

Gastroenterology.

2007;132(5):1767. Courtesy of T. Kieffer, MD.

36/156

PROVE 1: Telaprevir + PEG IFN/RBV

Phase II Study Design

Start Tx Wk 12* Wk 24 Wk 36 Wk 48 Wk 72 A (n = 80) PEG/RBV Follow-up B (n = 80) TVR/PEG/RBV PEG/RBV Follow-up C (n = 80) TVR/PEG/RBV PEG/RBV Follow-up D (n = 20 ) Follow-up

All study patients HCV-1, treatment-naive *Interim analysis TVR = telaprevir 750 mg TID; PEG = peginterferon alfa 2a 180 µg QW; RBV = ribavirin 1000–1200 mg/d.

Clinicaltrials.gov. Available at: http://www.clinicaltrials.gov/ct/show/NCT00372385?order=1.

PROVE 1

Week 4 HCV RNA Results

100 90 80 70 60 50 40 30 20 10 0 79% ˆP < .001

11% <10 IU/mL P < .001

88% 16% <30 IU/mL

ITT analysis: patients who discontinued before week 4 were counted as non-RVR McHutchison JG, et al. Presented at: 42nd EASL. April 11-15, 2007. Abstract 786.

TVR groups: arms B, C, D (n = 175) Control group: arm A (n = 75)

PROVE 1

Group D (“12-week arm”)

17 received at least 1 dose of study drug 1 withdrew consent (wk 1) 16 had undetectable HCV RNA during treatment 3 discontinued for adverse events 13 completed 12 wk of TVR/PEG IFN/RBV 4 did not have RVR at wk 4 (all <30 IU/mL) 9 met RVR criteria and stopped all treatment at wk 12 3 relapsed 6 undetectable 20 wk after completion of treatment

McHutchison JG, et al. Presented at: 42nd EASL. April 11-15, 2007. Abstract 786.

PROVE 1

Interim Analysis, 12-Week Data

N = 80 Patients with AEs

• • •

Diarrhea Anemia (Grade 1+2) Rash (Severe) Discontinued due to AEs Undetectable HCV RNA* PEG IFN/RBV (Arm A) 75% 21% 38% 0% 3% 52% PEG IFN/RBV + TVR (Arms B, C, and D) 80% 34% 57% 6% 11% 88% †

*Taqman assay limit of detection 10 IU/mL †

P

= .0001

McHutchison JG, et al. 42nd EASL. April 11-15, 2007. Abstract 786.

Boceprevir (SCH 503034) + PEG IFN



-2b vs PEG IFN



-2b Monotherapy

Antiviral Activity in Genotype 1 Nonresponders

0 -0.5

-1 -1.5

-2 -2.5

-3 0 4/10 became HCV RNA negative 5 Treatment Day 10 15 PEG IFN



-2b QW alone (n = 22) PEG IFN



-2b QW + boceprevir 200 mg TID (n = 12) PEG IFN



-2b QW + boceprevir 400 mg TID (n = 12) PEG IFN



-2b Alone + boceprevir 200 mg + boceprevir 400 mg Mean Maximum ΔHCV (log 10 ) -1.1

-2.4

-2.9

Zeuzem S, et al.

Hepatology

. 2005;42:276A. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.; Sarrazin C, et al.

Gastroenterology

. 2007;132(4):1270.

Boceprevir Monotherapy

15-Day Dose-Ranging Study

3 2

Viral load reduction correlates with boceprevir exposure in HCV-1 PEG IFN α nonresponders

-1 -2 1 0 N = 61 patients  Placebo (n = 16)  Boceprevir (n = 45) – Doses: 100 mg BID; 200 mg BID; 400 mg BID; 400 mg TID -3 10 100

Boceprevir Trough Concentration (ng/mL)

1000

Mean max viral load reduction in the 400 mg TID group was 2.06 log 10 from baseline (1.1

–2.7 log 10 , n = 10)

Zeuzem S, et al.

Hepatology

. 2005;42:233A. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.

Pharmacologic Boosting of HCV Protease Inhibitors

Boceprevir + Low-Dose Ritonavir in Rats

10

Boceprevir alone Boceprevir + ritonavir

1

AUC



20-fold

0.1

C 8h >100-fold

 0.01

0 2 4

Hours After Dose

6 AUC = area under the curve.

Kempf D, et al. 41st EASL. April 26-30, 2006. Abstract 4 . Reprinted with permission.

8

NS5b Is Part of HCV Replicase— Critical to RNA Replication Replicated RNA NS5B HCV Replicase RNA Template

Lindenbach BD, et al.

Nature

. 2005;436:933.

Graphic courtesy of Dr. M. Sulkowski.

HCV RNA-Dependent RNA Polymerase Allosteric GTP-binding sites Thumb Fingers Flap NNI Thumb inhibitors Catalytic site Nucleoside analogs NNI Palm

Adapted from Butcher SJ, et al.

Nature

. 2001;410:235. Reprinted with permission.

HCV-796 500 mg PO BID + PEG IFN alfa-2b

Individual Change in HCV RNA

1 PEG PEG

HCV-796 dosing

0 1 2 3 4 5 1 2 5 8 11 14 17

Study Day

Villano S, et al. 42nd EASL. April 11-15, 2007. Abstract 50.

Graphic courtesy of Dr. S. Villano.

20 23 26 29 Genotype 1a Genotype 1b Genotype non-1

HCV-796 Resistance

 

In vitro, selection of resistant replicons maps to a number of variants within the binding pocket, including C316Y In subjects treated for 14 days with HCV-796 monotherapy, on-therapy increases in HCV RNA levels were associated with emergence of C316Y C316/ HCV-796 interaction surface

Villano S, et al. 42nd EASL. April 11-15, 2007. Abstract 50. Graphic courtesy of Dr. S. Villano.

Y316 conformation overlaps HCV-796

R1626 HCV Polymerase Inhibitor

Mean Log 10 HCV RNA Reduction from Baseline at Day 14

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

-1.2

-2.6

-3.7

- 0.3 500 mg BID 1 (n = 9) 1500 mg BID 1,2 (n = 9) 3000 mg BID 2 (n = 8) 4500 mg BID 2 (n = 9)

1. Roberts S, et al.

J Hepatol.

2006;44:S269. 2. Roberts S, et al.

Hepatology.

2006;44:692A.

Valopicitabine + PEG IFN

Phase IIb Trial in Treatment-Naive Genotype 1 Patients

PEG IFN 180 µg QW NM283 W4: NM283 400–800 mg/d A B NM283 200 mg/d C NM283 400–800 mg/d D NM283 800 mg/d NM283 800 mg/d E Due to GI side effects with NM283 800 mg/d, dose reduced to either 200 mg/d or 400 mg/d after 12–20 weeks of treatment 48 Weeks Rx Duration

Lawitz E, et al. 42nd EASL. April 11-15, 2007. Abstract 14.

Valopicitabine + PEG IFN

Phase IIb Trial in Treatment-Naive Genotype 1 Patients



End of treatment response for group B (200 mg) and pooled groups (800 mg) Week 48 HCV RNA <20 IU/mL NM283 200 mg/d + PEG IFN (n=34) 53% NM283 800 mg/d + PEG IFN (n=139) 38%

Lawitz E, et al. 42nd EASL. April 11-15, 2007. Abstract 14.

Valopicitabine + PEG IFN (No RBV)

Phase IIb Trial in Nonresponders

EOT* SVR* 45 40 15 10 5 0 35 30 25 20 15 NM283 800 mg 0 NM283 400 mg + PEG 24 32 0 NM283 800 mg + PEG 0 No SVR in NM283 Groups

* TaqMan™ negative Afdhal N, et al. 42nd EASL. April 11-15, 2007. Abstract 6.

24 RBV + PEG 1

What About Ribavirin?

   

Ribavirin = the major advance in anti-HCV treatment

–

Doubles SVR rate 1,2

–

Decreases relapse rate 1,2 Mechanism remains elusive

–

“Mutagen” acting to increase error rate of the RNA-dependent RNA polymerase 3 Anemia is problematic but manageable Don’t count RBV out!

1. McHutchison JG, et al.

N Engl J Med.

3. Lanford RE, et al.

J Virol.

1998;339:1485. 2. Poynard T, et al. 2001;75:8074.

Lancet.

1998;352:1426.

VISER1: Viramidine vs RBV in Combination with PEG IFN



-2b

Phase III Study Results

100 100

Anemia (<10 g/dL) SVR (ITT) 78%

75 75

Viramidine (FD) + PEG IFN



-2b RBV (WBD) + PEG IFN



-2b 62% 52%

50

42%

50

38% 29%

25 25

P < .001

24% 5%

0 0

Overall Geno 1,4,5,6 Geno 2,3 Viramidine

FD = fixed dose; WBD = weight-based dose; ITT = intent to treat.

Benhamou Y, et al. 41st EASL. April 26-30, 2006. Abstract 751. Reprinted with permission.

RBV

New Treatment Paradigm

Addition of STAT-C Agents

IFN + RBV +

  

IFN is an effective antiviral

– –

Decreases emergence of STAT-C resistance Immunologic effect: role in eradication?

RBV—for now STAT-C

– –

Potent HCV suppression Increased rapid viral response rate STAT-C

New Treatment Paradigm

Beyond IFN and RBV

Protease inhibitors + Polymerase inhibitor +/ Additional STAT-C?

 

Multiple STAT-C agents

–

Potent suppression of replication

–

Different targets: protease, polymerase non-nucleoside and nucleoside

–

Different resistance mutations Adherence will be critical to STAT-C agents

Conclusion Eugene R. Schiff, MD

The Handwriting on the Wall

The Increasing Challenge of HCV Disease Burden

Trends in US Cancer Mortality Rates All Other Cancers (Average) Corpus & Uterus, NOS Testis Lung & Bronchus (Female) Esophagus Thyroid Liver

-2 -1.5

-1 -0.5

0 0.5

1

Annual Percent Change (1994 –2003)

1.5

2 National Cancer Institute. Seer Summary Figures and Tables. Available at: http://seer.cancer.gov/csr/1975_2003/results_merged/topic_graph_trends.pdf. Accessed on March 27, 2007.

Reality Check

Assessing the Present to Anticipate the Future

Nonresponders to PEG IFN and RBV

Modify current treatment Suppress with “maintenance” treatment Test safety and efficacy of new antivirals Try to inhibit liver fibrosis

Finding Our Way in the Maze

Changing Direction Toward More Effective Treatment

IFN Addition of STAT-C Agents + RBV + STAT-C Protease inhibitors Beyond IFN and RBV + Polymerase inhibitor +/ Additional STAT-C?

Take-Home Messages

   

Current therapy is unlikely to significantly reduce HCC incidence Increased understanding of the hepatitis C virus increases the capacity to develop and assess new antivirals STAT-C agents require us to think more like virologists than hepatologists or gastroenterologists Change is inevitable

– –

Anticipate it Be prepared