a new era of hcv treatment begins: direct-acting … new era of hcv treatment begins: direct-acting...

Table of ConTenTs CMe/Ce Information.........................................................................................................................................................2

Introduction.........................................................................................................................................................................3

faculty biographies..........................................................................................................................................................4

agenda

7:00.PM. . Introduction: a sea Change in Practice — Implementing new Models of Care with daa Therapy. . Ira.M..Jacobson,.MD

7:10.PM. . .Translating HCV Virology for the Hepatologist..............................................................................6Jeffrey.S..Glenn,.MD,.PhD

7:35.PM. . daa Therapies: What do the data show?...................................................................................... 12. . David.R..Nelson,.MD

8:00.PM.. . Practical Considerations for Integrating new Therapies......................................................... 19 Nezam.H..Afdhal,.MD

8:25.PM. . Panel discussion/Q&A Faculty.Panel

8:40.PM. . Concluding Remarks Ira.M..Jacobson,.MD

a new era of HCV Treatment begins: direct-acting antiviral (daa) TherapyA.Live.CME/CE.Satellite.Symposium

Supported through a medical education grant from Vertex Pharmaceuticals Incorporated.

®

2004-SyllabusBW-AH10-21v3.indd 1 10/21/10 3:28 PM

a new era of HCV Treatment begins: direct-acting antiviral (daa) Therapy

2

Target audienceThis activity is designed for hepatologists, gastroenterologists, infectious disease specialists, and primary care clinicians (including family practice, internists, and general practitioners), as well as nurses, nurse practitioners, pharmacists, and physician assistants, who manage and treat patients with HCV or those at risk of acquiring the infection.

activity goalThe goal of this activity is to provide clinicians with state-of-the-science knowledge on managing hepatitis C infection, including key virologic principles and practical considerations for integrating emerging DAA therapies into clinical practice.

learning objectives• Integrate knowledge of HCV virology, targets for intervention, and

mechanisms of action of current and emerging anti-HCV therapies to assess their potential role in the management of chronic HCV infection.

• Evaluate predictors and factors associated with nonresponse, partial response, and relapse in order to improve outcomes in patients receiving anti-HCV treatment.

• Analyze preliminary efficacy and safety data and duration of treatment of emerging anti-HCV therapies in order to formulate therapeutic regimens in treatment-naive and treatment-experienced patients with chronic HCV.

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Ira M. Jacobson, Md, has received grant/research support from Anadys Pharmaceuticals, Inc, Boehringer Ingelheim, Genentech, Inc, Gilead Sciences, Inc, GlobeImmune, Inc, Human Genome Sciences, Merck & Co, Inc, Novartis Pharmaceuticals Corporation, Pharmasset Pharmaceuticals Inc, Roche Pharmaceuticals, Schering-Plough Corporation, Tibotec Pharmaceuticals, and Vertex Pharmaceuticals Incorporated; is a consultant for Abbott Labo-ratories, Anadys Pharmaceuticals, Inc, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Inc, Gilead Sciences, Inc, GlobeImmune, Inc, Human Genome Sciences, Merck & Co, Inc, Novartis Pharmaceuticals Corporation, Pfizer Inc, Pharmasset Pharmaceuticals Inc, Roche Pharmaceuticals, Sanofi-Aventis, Schering-Plough Corporation, Tibotec Pharmaceuticals, Vertex Pharmaceuticals Incorporated and ZymoGenetics Inc; and is on the speakers bureaus of Bristol-Myers Squibb, Genentech, Inc, Gilead Sciences, Inc, Merck & Co, Inc, Novartis Pharmaceuticals Corporation, Roche Pharmaceuticals, and Schering-Plough Corporation. Dr. Jacobson’s presentation will include off-label discussion of anti-HCV drugs.

nezam H. afdhal, Md, has received research support from Echosens, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Novartis Pharmaceuticals Corporation, Quest Diagnostics, Schering-Plough Corporation, Valeant Phar-maceuticals International, and Vertex Pharmaceuticals, Inc; is a consultant for Biogen Idec, Biolex, Boehringer Ingelheim, Echosens, FibroGen, Gilead Sciences, Inc, GlaxoSmithKline, Human Genome Sciences, Inc, Idera Pharma-ceuticals, Ligand Pharmaceuticals Inc, Novartis Pharmaceuticals Corporation Ono Pharmaceutical, Schering-Plough Corporation, Scynexis, Inc, and Vertex Pharmaceuticals, Inc.; and is on the speakers bureau of Bristol Myers-Squibb, Gilead Sciences, Inc, Idenix/Novartis, and Schering-Plough Corporation. Dr. Afdhal’s presentation will include off-label discussion of anti-HCV drugs.

Jeffrey s. glenn, Md, Phd, has received grant/research support from Genentech, Inc and Romark Laboratories; is a consultant for Eiger BioPhar-maceuticals, Genentech, Inc, Merck & Co, Inc, Roche Pharmaceuticals, and Romark Laboratories; and has ownership interest in Eiger BioPharmaceuti-cals and Romark Laboratories. Dr. Glenn’s presentation will include off-label discussion of anti-HCV drugs.

david R. nelson, Md, has received grant/research support from Bayer Phar-maceuticals, Bristol-Myers Squibb, Genentech, Inc, Merck & Co, Inc, Novartis Pharmaceuticals Corporation, Pharmasset Pharmaceuticals Inc, and Vertex Pharmaceuticals Incorporated; and is a consultant for Bayer Pharmaceuti-cals, Genentech, Inc, and Gilead Sciences, Inc. Dr. Nelson’s presentation will include off-label discussion of anti-HCV drugs.

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2004-SyllabusCoverAH10-11v7.indd 2 10/11/10 7:49 PM

Practical Considerations for Integrating new TherapiesDavid.R..Nelson,.MD

3

Introduction: a sea Change in Practice—Implementing new Models of Care with daa TherapyIra.M..Jacobson,.MD

Initially approved 20 years ago for the treatment of chronic hepatitis C, interferon, alone at first and then with ribavirin, was an empirically derived, nonspecific treatment with broad biologic properties, but lacking target specificity, sufficiently high cure rates, or an attractive safety profile. We are now moving into an era of antiviral agents specifically targeted to the hepatitis C virus (HCV) genome, with the first two direct-acting antiviral (DAA) agents—boceprevir and telaprevir, both protease inhibi-tors—likely to be approved in 2011.

Higher cure rates, when these agents are added to current standard of care peginterferon/ribavirin therapy, are on the horizon. Sustained viro-logic response rates of up to 75% appear attainable for genotype-1 treatment-naive patients and 30% to 85% for treatment-experience patients. To ensure that these agents are used optimally, clinicians must be familiar with the efficacy, safety, and response-guided therapy algorithms associated with the agents, as well as the issue of resistance. A deeper level of understanding of virologic principles, particularly as related to resistance, will be important in order to minimize the incidence and long-term impact of viral resistance to antiviral drugs in our patients.

With other DAA agents in clinical development, including polymerase inhibitors, NS5A inhibitors, additional protease inhibitors, and agents with novel mechanisms of action, including those acting on host factors such as cyclophilin inhibitors, a question of profound import about the future of anti-HCV therapy is whether the huge leap forward represented by the addition of DAA agents to standard-of-care therapy will prove to be a “way station” on the path toward full recapitulation of the combina-tion therapy paradigm that revolutionized HIV therapy years ago. Progress in addressing this question, with the intrinsic requirement that viral eradication, not just long-term suppression, after a finite course of therapy be demonstrated, is being made with a rapidity that would not have been expected until very recently.



4

Chair

Ira M. Jacobson, Md

Vincent Astor Professor of Medicine Chief, Division of Gastroenterology and Hepatology Medical Director of the Center for the Study of Hepatitis C Weill Cornell Medical College New York, New York

Ira M. Jacobson, MD, is chief of the Division of Gastroenterology and Hepatology and Vincent Astor Professor of Medicine at Weill Cornell Medical College in New York City, and attending physician at New York-Presbyterian Hospital. He is also medical director of the Center for the Study of Hepatitis C at Weill Cornell and Rockefeller University. After receiving his BS summa cum laude from Yale University in New Ha-ven, Connecticut, and his MD from the Columbia University College of Physicians and Surgeons in New York City, Dr. Jacobson completed an internship and residency in internal medicine at the University of California, San Francisco. He completed a fellowship in gastroenterol-ogy at Massachusetts General Hospital and Harvard Medical School. He is board certified in internal medicine and gastroenterology.

In addition to maintaining an active practice with a focus on patients with liver disease, Dr. Jacobson has been an investigator in many trials on antiviral therapy for hepatitis B and C, including most of the pivotal trials on interferon-based therapy since the 1980s, and was the principal investigator of the WIN-R trial, the largest trial performed to date on HCV therapy. At Weill Cornell Medical College, he directs a highly diversified clinical trials program dedicated to novel therapies for hepatitis B and C.

Dr. Jacobson has authored more than 200 papers, chapters, and abstracts, and his papers have appeared in New England Journalof Medicine, Annals of Internal Medicine, Hepatology, Journal of Hepatology, American Journal of Gastroenterology, Journal of Viral Hepatitis, and Clinical Gastroenterology and Hepatology, among other journals. He has edited two books, ERCP: Diagnostic and Therapeutic Applications and ERCP and Its Applications. In addition, he edited a volume on hepatitis B for Clinics in Liver Disease, which appearedin 2007. He is a recently named associate editor of Journal of Hepatology, and is on the editorial boards of Alimentary Pharmacology and Therapeutics, and Digestive Diseases and Sciences, in addition to being a reviewer for numerous journals. Dr. Jacobson is a Fellow of the American College of Physicians, the American Gastroenterological Association, and the American College of Gastroenterology, and a member of the American Association for the Study of Liver Diseases, the American Society for Gastrointestinal Endoscopy, and the European Association for the Study of the Liver. He is a past president of the New York Society for Gastrointestinal Endoscopy and the New York Gastroenterological Association. In addition, he has served on both the Gastroenterology Board and the Transplant Hepatology Board of the American Board of Internal Medicine.

Faculty

nezam H. afdhal, Md

Associate Professor of Medicine Harvard Medical School Chief of Hepatology Beth Israel Deaconess Medical Center Boston, Massachusetts

Nezam H. Afdhal, MD, is chief of hepatology anddirector of the Liver Center at Beth Israel Deaconess Medical Center in Boston, Massachusetts. He is also an associate professor of medicine at Harvard Medical School.

Dr. Afdhal received his MD in 1981 from the Royal College of Surgeons in Ireland and did fellowship training at Univer-sity College Dublin and at Boston University School of Medicine.

Dr. Afdhal’s clinical expertise focuses on the management of the complications of liver disease, including cirrhosis and portal hypertension. He is the director of a clinical trials group focusing on novel treatments of hepatitis B and C. Additional research interests include basic and translational research in gallstone disease, liver cancer, and liver fibrosis.

Dr. Afdhal is on the advisory board of the American Liver Foundation and the Massachusetts State Advisory Board for HCV. He has served on the editorial board and as a reviewer for multiple journals. He has published more than 100 papers in journals, such as Gastroenterol-ogy, Hepatology, Gut, and Journal of Hepatology, as well as 30 book chapters and two books. He has spoken nationally and internation-ally on chronic liver disease and received many awards, including the American Liver Foundation Award for Excellence and the Mitchell Lectureship of the Royal College of Physicians. He is a member of the American Gastroenterological Association, the American Association for the Study of Liver Diseases, and the European Association for the Study of the Liver.


Practical Considerations for Integrating new TherapiesDavid.R..Nelson,.MD

5

Faculty

Jeffrey s. glenn, Md, Phd

Associate Professor of Medicine Division of Gastroenterology and Hepatology Director, Center for Hepatitis and Liver Tissue Engineering Stanford University School of Medicine Stanford, California

Jeffrey S. Glenn, MD, PhD, is associate professor of medicine and director of the Center for Hepatitis and Liver Tissue Engineering at Stanford University School of Medicine in Stanford, California. Dr. Glenn received his bachelor’s degree, summa cum laude, from University of California, Berkeley, and his medical degree and PhD in biochemistry and biophysics from University of California, San Francisco. He completed training and board certification in internal medicine and gastroenterology at Stanford University’s School of Medicine, where he joined the faculty in 1999.

Dr. Glenn’s clinical focus is general gastroenterology and hepatology. His research interests lie in molecular virology, with a strong emphasis on translating this knowledge into novel antiviral therapies. Other interests include exploitation of hepatic stem cells, engineered human liver tissues, and new biodefense antiviral strategies.

Dr. Glenn has been the recipient of the Burroughs Wellcome Fund’s Clinical Scientist Award in Translational Research and an elected member of the American Society for Clinical Investigation. His publications have appeared in journals such as Annals ofChemistry, Antiviral Research, Gastroenterology, Hepatology, Journal of Infectious Disease, Liver Transplantation, and ScienceTranslational Medicine.

Faculty

david R. nelson, Md

Professor of Medicine Associate Dean, Clinical Research and Training Director, Clinical and Translational Science Institute University of Florida Gainesville, Florida

David R. Nelson, MD, is professor of medicine and associate dean for clinical research at the University of Florida, where he also serves as the director of the Clinical and Translational Science Institute. He received his medical degree from the State University of New York, Upstate Medical University in Syracuse, completed a residency in internal medicine at the University of Massachusetts, and obtained fellowship training in gastroenterology and hepatology at the University of Florida.

Dr. Nelson’s area of clinical expertise is hepatology with an emphasis on the management of viral hepatitis and liver cancer. He also has strong basic research interests, focusing primarily on the immunopathogenesis and treatment of chronic hepatitis C and hepatocellular carcinoma. He currently oversees more than 15 active clinical trials and has a 15-year track record of funding from the National Institutes of Health. Dr. Nelson serves as principal investigator on both basic science and translational research grants, along with mentoring/training grants in gastroenterology and hepatobiliary diseases.

Dr. Nelson’s record of academic achievement includes more than $10 million in research funding and more than 200 publications in journals such as Clinical Gastroenterology and Hepatology, Clinics in Liver Disease, Gastroenterology, Hepatology, Journal of Hepatology, and Liver Transplantation. He currently serves as associate editor forHepatology.

faculty biographies



The decade of the 1990s saw a tremendous increase in hepatitis C virus (HCV) treatment success, while the first decade of the 21st century has seen only modest additional growth since the availability of peginterferon in 2001. The sustained virologic response (SVR) for individuals with genotype-1 infection remains plateaued at 40% to 50% despite intense interest and research. Importantly, the study of HCV molecular virology has revealed an array of potential new targets for virus-specific therapy. This knowledge is being translated into new candidate drugs for treating hepatitis C. These drugs include HCV NS3 protease and NS5B polymerase inhibitors, some of which are approaching approval, as well as other molecules that interfere with HCV replication, such as inhibitors of other HCV non-structural proteins, that are also in development. The promise of these direct-acting antivirals (DAAs), previously referred to as specifically targeted antiviral therapies for HCV (STAT-C), has produced a sense of anticipation about the possibility of higher genotype-1 cure rates when administered in combination with peginterferon and ribavirin.

With the potential benefit, come potential risks. Key concepts of viral resistance must be understood by clinicians using DAAs to treat HCV infection: pre-existence of viral variants, selection of high level drug resistance on inadequate therapy, and vary-ing genetic barriers to resistance among drug classes. Although resistance can lead to treatment failure, steps can be taken to mitigate this risk. At present, DAAs should always be given in combination with standard-of-care peginterferon/ribavirin therapy because resistant variants develop rapidly with DAA monotherapy. Pretreatment clinical, virologic, and genetic (ie,

IL28B genotype) factors, as well as initial on-treatment HCV RNA declines, can be used to help predict response to pegin-terferon/ribavirin. Emerging data demonstrate that all groups of patients, including null responders to peginterferon and ribavirin, will benefit from the addition of DAAs, but the risks of virologic failure and resistance will be higher for patients with intrinsically poor interferon responsiveness. Individualized decision-making prior to treatment, along with careful atten-tion to on-treatment viral response and guidelines for stopping therapy, will be required of clinicians. The long-term implica-tions of resistance to DAAs, including the potential for reduced response to future regimens containing the drug or other same-class drugs to which resistance has emerged, will require further study. For all groups of patients, adherence to prescribed therapy and appropriate dosing levels also help mitigate the risk of resistance and optimize efficacy.

Effective pharmacologic control of HCV with antiviral drugs will ultimately require a cocktail of multiple drugs with inde-pendent mechanisms of action, to both increase response rates and combat the emergence of resistance. In the near-term, new drugs will be added to current standard-of-care regimens. As the number of available agents increases, however, there will be an opportunity for completely oral regimens.

The dawn of the DAA therapy era is an exciting time. The first DAA to be approved will require great caution and understand-ing of potential pitfalls to its misuse, but will also enable SVR rates significantly beyond those that have been achieved with current standard-of-care therapies.

6

suggested Readings

Gelman MA, Glenn JS. Mixing the right hepatitis C inhibitor cocktail. Trends Mol Med. 2010; In press.

Kieffer TL, Kwong AD, Picchio GR. Viral resistance to specifically targeted antiviral therapies for hepatitis C (STAT-Cs). J Antimicrob Chemother.2010;65:202-212.

Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature. 2005;436:933-938.

Pawlotsky JM, Chevaliez S, McHutchison JG. The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology. 2007;132:1979-1998.

Pereira AA, Jacobson IM. New and experimental therapies for HCV. Nat Rev Gastroenterol Hepatol. 2009;6:403-411.

Susser S, Welsch C, Wang Y, et al. Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology. 2009;50:1709-1718.

Translating HCV Virology for the HepatologistJeffrey.S..Glenn,.Md,.Phd



7

Slides.produced.as.of.October.18,.2010.(may.not.reflect.final.presentation)

Slide 1 Slide 2

Slide 5 Slide 6

Slide 3 Slide 4

Generations of Anti-HCV Therapies

First Generation Peginterferon Ribavirin

Effective pharmacologic control of HCV will require a cocktail of agents against multiple, independent, virus-specific targets (eg, HIV, TB).

Core E1 E2 P7

NS2 NS3 NS4A

NS4B NS5A NS5B

Second Generation

5! 3! (U/UC)

Core E1 E2 P7

NS2 NS3 NS4A

NS4B NS5A NS5B

Third Generation

5! 3! (U/UC)

HCV Genome

Drug Targets

Resistance

Future Therapy

Core E1 E2 P7

NS2 NS3 NS4A

NS4B NS5A NS5B

ARFP

UTR

IRES

5! 3! (U/UC)

UTR

Protease Helicase

Polymerase

Nonstructural

HCV Nonstructural Proteins

Glenn JS. Clin Liver Dis. 2005;9:353-369. Glenn JS. Clin Liver Dis. 2005;9:353-369. Graphic of virion courtesy of Dr. Jeffrey S. Glenn.

Core E1 E2 P7

NS2 NS3 NS4A

NS4B NS5A NS5B

ARFP

UTR

IRES

5! 3! (U/UC)

UTR Envelope

Structural

HCV Structural Proteins

Abbreviations: ARFP, alternate reading frame protein; IRES, internal ribosome entry site; UTR, untranslated region. Glenn JS. Clin Liver Dis. 2005;9:353-369.

Core E1 E2 P7

NS2 NS3 NS4A

NS4B NS5A NS5B

ARFP

UTR

IRES

5! 3! (U/UC)

UTR

Protease Helicase

Polymerase

Structural Nonstructural

Hepatitis C Virus Genome

Envelope

HCV Genome

Drug Targets

Resistance

Future Therapy

7



8


Slide 7 Slide 8

Slide 11 Slide 12

Slide 9 Slide 10

MOA of Selected Third-Generation Therapies

!! Direct-acting antivirals (DAA) –! Inhibitors of genome replication

–! Entry/assembly inhibitors

!! Agents targeting host functions

!! Others

NS5B Polymerase Inhibitors

!! NS5B crystal structure solved1 –! “Right hand”

–! RNA channel

!! Two classes of inhibitors2 –! Active site

(nucleoside analogs)

–! Allosteric (non-nucleoside)

1. Lesburg CA, et al. Nat Struct Biol. 1999;6:937-943. 2. Glenn JS. Clin Liver Dis. 2005;9:353-369. Graphic with permission from O'Farrell D, et al. Available at: http://www.astbury.leeds.ac.uk/Report/2000/Jager.2.htm. Accessed on: October 13, 2010.

Ribbon Diagram of NS5B Protein

Core E1 E2 P7

NS2 NS3 NS4A

NS4B NS5A NS5B

ARFP

UTR

IRES

5! 3! (U/UC)

UTR

NS5B

!! Catalytic subunit of viral RNA-dependent RNA polymerase

!! Another obvious early target for drug development –! Specificity

–! Precedence

Glenn JS. Clin Liver Dis. 2005;9:353-369.

NS3 Protease Inhibitors

!! NS3 crystal structure (+/- NS4A) solved

!! Rational drug design optimization –! Challenges: shallow

substrate cleft

!! Two classes of inhibitors –! Noncovalent, product

based

–! Covalent binding to catalytic site serine (“serine trap” or “warhead” inhibitors) Ribbon Diagram of NS3 Protein

Glenn JS. Clin Liver Dis. 2005;9:353-369. Graphic with permission from da Silveira NJ, et al. BMC Struct Biol. 2005;5:1-8.

Core E1 E2 P7

NS2 NS4A

NS4B NS5A NS5B

ARFP

UTR

IRES

5! 3! (U/UC)

UTR

NS3

Serine Protease

RNA Helicase

!! 630 amino acid protein

!! Obvious early target for drug development –! Specificity

–! Precedence

!! Serine protease –! NS4A cofactor

"! Promotes membrane association

–! Polyprotein processing

!! RNA helicase –! RNA duplex unwinding

NS3

Glenn JS. Clin Liver Dis. 2005;9:353-369.

Core E1 E2 P7

NS2 NS3 NS4A NS4B NS5A NS5B

Targets for Anti-HCV Drugs in Clinical Trials

5!– –3!

Linear Telaprevir Boceprevir

Macrocyclic Danoprevir (RG7227) TMC 435350 BI-201335 BMS-650032

BMS-790052

Active site (nucleosides)

RG7128 IDX184 PSI-7977

Non-nucleosides ABT-333 ABT-072 GS 9190 ANA598 VCH-759 VCH-916 VX-222 Filibuvir BI-207127

Protease inhibitors

Polymerase inhibitors

Cyclophilin Debio 025 SCY-635

Not all-inclusive.

Clemizole



9


Slide 13 Slide 14

Slide 17 Slide 18

Slide 15 Slide 16

Resistance Develops Rapidly During Monotherapy with a Protease Inhibitor

0

2

4

6

8

0

2

4

6

8

Lo

g10

HC

V R

NA

(IU

/mL

)

Lo

g10

HC

V R

NA

(IU

/mL

)

HCV RNA (>100 IU/mL) Wild-type T54A V36A/M

R155K/T 36/155 A156V/T 36/156

Days Days

Patient 1002 Patient 1018

Telaprevir Dosing Telaprevir Dosing

LOD LOD

With permission from Kieffer TL, et al. Hepatology. 2007;46:631–639.

1 14 1 14

Rep

licat

ion

Fit

nes

s

No Drug Protease Inhibitor No Drug

Wild Type Resistant Compensatory Mutations

Resistance and Replication Fitness

Graphic courtesy of Dr. Jeffrey S. Glenn.

Return of Wild Type

Core E1 E2 P7

NS2 NS3 NS4A

NS4B NS5A NS5B

ARFP

UTR

IRES

5! 3! (U/UC)

UTR

Error-Prone NS5B Polymerase Generates Genomic Variants

!! Lack of proofreading function # high frequency of mutations

!! Basis for quasispecies, evolution of resistance

!! Pre-existing resistant variants # selected under drug pressure

Gelman MA, et al. Trends Mol Med. 2010; In press. Lower graphic courtesy of Dr. Jeffrey S. Glenn.

HCV Genome

Drug Targets

Resistance

Future Therapy

Drugs Targeting Host Cell Functions

!! Cyclophilin inhibitors

!! Toll-like receptor agonists

!! Immunomodulatory strategies

!! Host lipid synthesis inhibitors

!! Nitazoxanide

!! MicroRNA-122 inhibitors

Core E1 E2 P7

NS2 NS3 NS4A

NS4B NS5A NS5B

ARFP

UTR

IRES

5! 3! (U/UC)

UTR

NS5A

!! Amphipathic helix1 –! Required for membrane

association1

–! RNA replication can be targeted pharmacologically1

!! Subject to phosphorylation (? modulates replication), binds RNA2

!! Multiple essential interactions with host cell proteins1

!! Several anti-NS5A compounds identified by random screening –! Inhibitors with picomolar (!) EC50

2

–! Resistant mutations map to N-terminus of NS5A2

NS5A Position Relative to ER Membrane

Abbreviations: EC50, half maximal effective concentration; ER, endoreticulum. 1. Elazar M, et al. J Virol. 2003;77:6055-6061. 2. Gao M, et al. Nature. 2010;465:96-100. Graphic with permission from Appel N, et al. J Biol Chem. 2006;281:9833-9836.



10


Slide 19 Slide 20

Slide 23 Slide 24

Slide 21 Slide 22

PI #1 Nuc #1 PI #2 Common resistance mutations

R155T R155K V170A

C136Y S365T

R155K A156S

Cross-resistance (bad combination) No cross-resistance

(possible combination)

Cross-Resistance and Choice of DAA Future DAA Combination Therapy

Abbreviations: DAA, direct-acting antivirals; Nuc, nucleoside; PI, protease inhibitor. Graphic courtesy of Dr. Jeffrey S. Glenn.

Core E1 E2 P7

NS2 NS3 NS4A

NS4B NS5A NS5B

ARFP

UTR

IRES

5! 3! (U/UC)

UTR

NS3/4A protease NS5B polymerase

Drugs Differ in Genetic Barriers to Resistance High Barrier

!! Primary mutation = high cost to fitness

!! May require 2nd (3rd) mutation(s) to increase fitness

!! Example: primary site evolved to mediate specific critical interaction (eg, with another viral element)

Low Barrier

!! Primary mutation = low cost to fitness

!! Can emerge quickly

!! Example: primary site tolerates multiple amino acid substitutions (eg, including 1 that prevents drug binding)

High

Low

1st gen. PI

NN

N

Abbreviations: N, nucleoside inhibitor; NN, non-nucleoside inhibitor; PI, protease inhibitor.

Replication Fitness

Wild Type

Graphic courtesy of Dr. Jeffrey S. Glenn.

Low vs High Genetic Barriers to Clinical Resistance

Low barrier resistance drug

High barrier resistance drug

First Resistance Mutation

Compensatory Mutations

Longer pathway to clinical resistance

Characterization of Boceprevir Resistance

!! Overall frequency of resistance mutations and the level of resistance increased with greater HCV RNA decline

!! Frequency of variants declined 2 weeks after discontinuation of therapy

!! All single mutations had impaired replicative fitness

Susser S, et al. Hepatology. 2009;50:1709-1718.

V36M/A T54A/S R155K/T A156S V170A

!! Resistance mutations occurring alone or in combination

Telaprevir ± PEG IFN Median Change HCV RNA From Baseline

With permission from Kieffer TL, et al. Hepatology. 2007;46:631–639.

-6

-5

-4

-3

-2

-1

0

1

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Study Time (days)

HC

V R

NA

Ch

ang

e fr

om

Bas

elin

e

(Lo

g10

IU/m

L)

Telaprevir + PEG IFN alfa-2a n = 8

Telaprevir n = 8

PEG IFN alfa-2a + placebo n = 4

Baseline

Sequence analysis

•! More resistant variants emerged with TVR monotherapy •! Patients went on to receive 24 wk PEG IFN + RBV •! Resistant variants were suppressed by PEG IFN + RBV

WT WT 36

155

36 155

36/155

T54

WT

36 155

T54 36/155

WT

1 2 3 4 5 6 7

1 2 3 4 5 6 7

1 2 3 4 5 6 7

EOD 14 Days

Baseline Follow-up

7/10 days post-dosing

Long-term follow-up

3–7 months post-dosing

Telaprevir Dosing Period Post-Dosing Long-Term Follow-Up

Protease Inhibitor Resistant Variants Telaprevir Monotherapy, Breakthrough Group (n = 12)

Med

ian

Log

HC

V R

NA

Abbreviations: EOD, end of dosing; IC50, half maximal inhibitory concentration; WT, wild type. With permission from Kieffer T, et al. Paper presented at: 41st EASL; April 26-30, 2006. Abstract 12.

WT V36 M/A/L

R155 K/T/S/M T54A 36/155 A156V/T 36/156 IC50 fold

change 1 4 7 12 46 466 781



11

Slide 25 Slide 26

Slide 29 Slide 30

Slide 27 Slide 28

Summary !! Dawn of DAA era is an exciting time !! First DAA to be approved will enable increased SVR rates

BUT requires great caution and understanding of pitfalls !! Resistant variants pre-exist and can be rapidly selected

under DAA treatment !! DAA + PEG IFN/RBV in a null responder to

PEG IFN/RBV = suboptimal viral suppression with DAA –! Can select high-level resistance

–! Might reduce eligibility for future cocktails containing that DAA

–! Potential for tailoring of regimen based on predictors of response to IFN

!! Additional DAAs (many in pipeline) will increase anti-HCV cocktail efficacy & decrease danger of resistance development

Optimal Use of Direct-Acting Antivirals

DAA Proper selection, monitoring, other clinical/host/virus

predictors

+ +

Other DAAs

HCV

(eg, IL28B status, adherence, etc)

Potential and Dangers of First Direct-Acting Antiviral

Approaching possible approval of some NS3 protease inhibitors is exciting, but also a two-edged sword

!! 1st new DAA can be very cost-effective in correct setting

!! In absence of other DAAs, danger of functional monotherapy in some nonresponders to standard of care (defeats purpose of “warehousing”)

!! Poor compliance (usual vs due to side effects) "resistance

Antagonistic Additive Synergistic

Least Desirable Most Common Most Desirable

(eg, NS3 protease + NS5B polymerase

inhibitors)

(eg, NS3 protease + NS4B RNA binding

inhibitor)

Possible Drug-Drug Interactions Between HCV Direct-Acting Antivirals

Einav S, et al. J Infect Dis. 2010;202:65-74. Graphics courtesy of Dr. Jeffrey S. Glenn (using MacSynergy software).

Considerations for New Therapies

!! Safety

!! Viral suppression

!! Resistance

!! Drug-drug interactions –! Usual drug combinations

–! Antiviral combinations


HCV Genome

Drug Targets

Resistance

Future Therapy



12

daa Therapies: What do the data show?David.R..Nelson,.MD

suggested Readings

Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360:1839-1850.

Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010;376:705-716.

Lemon SM, McKeating JA, Pietschmann T, et al. Development of novel therapies for hepatitis C. Antiviral Res. 2010;86:79-92.

McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360:1827-1838.

With the introduction of direct-acting antiviral (DAA) agents, we are on the verge of a new era that will transform the anti-agents HCV treatment landscape. The class of drugs furthest along in development is the inhibitors of the HCV serine protease NS3-NS4A. The most mature protease inhibitors are telaprevir and boceprevir, which have now completed phase III trials and will likely be approved mid-2011.

Two key telaprevir phase III trials include ADVANCE and ILLUMINATE. The ADVANCE trial enrolled treatment-naive genotype-1 HCV-infected patients to evaluate 24 weeks of tel-aprevir-based therapy. Telaprevir was given for 8 or 12 weeks in combination with peginterferon alfa-2a and ribavirin, followed by peginterferon/ribavirin alone until week 24. Patients who did not achieve an extended rapid virologic response (eRVR; HCV RNA negative at week 4 and week 12) were treated with peginterferon/ribavirin until week 48. A significantly greater proportion of patients achieved sustained virologic response (SVR) with 12-week and 8-week telaprevir-based combination regimens (75% and 69%, respectively) compared with the standard-of-care control arm (44%). In the ILLUMINATE trial, telaprevir was given for 12 weeks in combination with peginterferon/ribavirin, followed by peginterferon/ribavirin alone until treatment week 24 or 48. Overall, 72% of all subjects achieved SVR, while 92% and 88% of those with eRVR in randomized 24- and 48-week treatment groups, respectively, achieved SVR. Thus, data from these two phase III trials support the use of 24-week telaprevir-based therapy (ie, telaprevir in combination with peginterferon/ribavirin) within a response-guided regimen for patients with eRVR. The most common adverse events reported were fatigue, pruritus, nausea, anemia, rash, and headache. The majority of these adverse events were mild or moderate. Adverse events leading to discontinuation of all study drugs during the 12-week telaprevir dosing period occurred in 6.9% of people in the ADVANCE trial.

The phase III SPRINT-2 trial evaluated boceprevir in treatment-naive patients (two separate cohorts; black and nonblack). Patients were randomized to one of three treatment arms: 1) placebo plus peginterferon alfa-2b and weight-based ribavirin for 44 weeks, or; 2) boceprevir plus peginterferon/ribavirin for 44 weeks, or; 3) boceprevir plus peginterferon/ribavirin for 24 or 44 weeks if HCV RNA undetectable or detectable, respectively, at weeks 8 and 24. In all treatment arms, a lead-in strategy for 4 weeks with peginterferon/ribavirin was utilized. Among the nonblack patients (cohort 1) in the boceprevir 48-week treatment group (includes 4 weeks peginterferon/ribavirin), 68% achieved SVR, compared with 67% in the response-guided therapy group and 40% in the control group. Among black patients (cohort 2), SVR was achieved by 53%, 42%, and 23% of patients in the boceprevir 48-week, response-guided therapy, and control groups, respectively.

New DAAs also appear to offer realistic SVR rates to treatment-experienced patients. Phase III treatment-experienced trials with telaprevir-based therapy (REALIZE) and boceprevir-based therapy (RESPOND-2) have produced SVRs of 75% to 86% in previous relapsers, 52% to 57% in prior partial responders, and 31% in previous null responders.

In summary, potent viral suppression and shortened duration of therapy have been shown in clinical trials with the addition of DAAs to standard-of-care peginterferon/ribavirin therapy. SVR rates approaching 75% can now be anticipated for genotype-1 treatment-naive patients and 30% to 85% for treatment-experienced patients, which should lead to increased treatment opportunities for many HCV-infected individuals. Lastly, interferon-free regimens are gaining increased momen-tum with encouraging data on combining various classes of DAAs. New issues of viral resistance and increased adverse events, however, will increase the importance of close medical management. The new era of DAAs is upon us and offers new hope for HCV-infected patients.


daa Therapies: What do the data show?David.R..Nelson,.Md

13


Slide 1 Slide 2

Slide 5 Slide 6

Slide 3 Slide 4

PROVE-21 PROVE-32

SV

R (

%)

0

20

40

60

80

100

PR 48 wk (no lead-in)

(n = 16)

PB + low-dose RBV (48 wk)

(n = 59)

SPRINT-13

36% 50% 36% 24% 53% 60%

Ribavirin Is Critical for Protease Inhibitor Combination Therapy

1. Hezode C, et al. N Engl J Med. 2009;360:1839-1850. 2. McHutchison JG, et al. N Engl J Med. 2010;362:1292-1303. 3. Kwo PY, et al. Lancet. 2010;376:705-716.

Dosages not consistent between above studies. Abbreviations: B, boceprevir; P, peginterferon !-2a and -2b; R, ribavirin; T, telaprevir.

T 12 wk + PR 12 wk (n = 82)

T 12 wk + P 12 wk (n = 78)

T 24 wk + PR 48 wk (n = 113)

T 24 wk + P 24 wk (n = 111)

Interferon Limits Breakthrough (Resistance) to Protease Inhibitors

Abbreviations: PEG IFN, peginterferon; TVR, telaprevir. With permission from Kieffer TL, et al. Hepatology. 2007;46:631-639.

1

-6

-5

-4

-3

-2

-1

0

1 2 3 4 5 6 7 8 9 10 11 12 13 14 Days

HC

V R

NA

Ch

ang

e fr

om

B

asel

ine,

Lo

g10

IU/m

L

TVR + PEG IFN (n = 8)

TVR (n = 8)

15

Resistance mutations emerged within 4–7 days of telaprevir monotherapy and

subsequently suppressed by PEG IFN

Baseline

Lessons Learned from Phase II Trials Resistance Will Impact Future Therapy

!! Pre-existing resistant variants to protease inhibitors are common and preclude monotherapy use –! Peginterferon and ribavirin are still required

!! Barrier to resistance can be subtype dependent

!! Strategies to limit resistance

–! Optimize pharmacokinetics "! Peginterferon (lead-in, choice and dose of interferon)

"! Ribavirin (lead-in, use of growth factors)

"! DAA (dose, schedule, ritonavir boosting)

"! Adherence

–! Combination DAA approaches

Overview

DAA in Tx-Naive

DAA in Tx-Experienced

Next Generation

Lessons from Phase II

Potential Antiviral Targets and Approaches

IFN Host target

Immuno-modulators

Therapeutic vaccine

Antiviral targets

Polymerase Receptor entry

NS5A/B

Protease

Replication assembly

Entry inhibitors

Graphic courtesy of Dr. David R. Nelson.

Overview

DAA in Tx-Naive


Next Generation




14


T + P + R P + R eRVR: Follow-up

No eRVR: P + R Follow-up

T + P + R

P + R eRVR: Follow-up


P + R Follow-up

Abbreviations: eRVR, extended rapid virologic response (undetectable HCV RNA at weeks 4 and 12); R, ribavirin 1000–1200 mg/d; P, peginterferon !-2a 180 !g/wk; T, telaprevir 750 mg q8h. Jacobson IM, et al. Hepatology. 2010;52:Abstract 211.

ADVANCE—Telaprevir in Treatment-Naive Genotype-1 Patients

Response-Guided Therapy

T8/P24 (n = 364)

PR48 (n = 361)

T12/PR24 (n = 363)

24 0 48 72 12 Weeks 8

24 0 48 72 12 Weeks 8

Overview

DAA in Tx-Naive


Next Generation


0

20

40

60

80

100

29

59

Impact of Lead-In—No Clinical Benefit in Phase III Telaprevir Trial

83

SV

R (

%)

Abbreviations: PEG IFN, peginterferon; RBV, ribavirin; TVR, telaprevir. NATAP. Press release. Sept. 7, 2010. Available at: http://www.natap.org/2010/HCV/090710_01.htm. Graphic courtesy of Dr. David R. Nelson.

Null Responder Partial Responder Relapsers

Simultaneous Start (PEG IFN/RBV/TVR) Lead-in/Delayed Start

33

54

88

38

0

20

40

60

80

100

SV

R (

%)

PR4/ PRB44

PRB48 PR4/ PRB24

PRB28 PR48

Tx 28 Weeks Tx 48 Weeks

*P = .005; †P = .013; ‡P <.0001, compared with PR48 Control. Kwo PY, et al. Lancet. 2010;376:705-716.

56 * 54 †

75 ‡ 67 ‡

n =

104 103 107 103 103

n = n = n = n =

SPRINT-1—Impact of 4-Week PEG IFN/RBV Lead-In

Potential Rationale for Lead-in Phase !! Cost-effective model

–! Identify interferon-sensitive patients who may not need DAA

!! Optimization of DAA

–! Decrease viral resistance development at time of protease inhibitor introduction and enhance response-guided therapy strategy

4 weeks

PEG IFN + RBV

PEG IFN/RBV

PEG IFN/RBV + protease inhibitor

RVR

no RVR

PEG IFN + RBV PEG IFN/RBV + protease inhibitor

4 weeks

Abbreviations: DAA, direct-acting antiviral; PEG IFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response; RGT, response guided therapy. Graphic courtesy of Dr. David R. Nelson.

Pat

ien

ts w

ith

Co

nfi

rmed

V

iro

log

ic B

reak

thro

ug

h (

%)

0

10

20

30

40

50

T24/ P24

T24/ PR48

Genotype 1a

Genotype 1b

2 1

T12/ PR24

10

2

10

3

23

6

With permission from McHutchison JG, et al. Hepatology. 2009;50:334A-335A.

PR48

PROVE-3—Virologic Breakthrough Impact of RBV and Viral Subtype

Slide 7 Slide 8

Slide 11 Slide 12

Slide 9 Slide 10



15

Slide 13 Slide 14

Slide 17 Slide 18

Slide 15 Slide 16

T + P + R P + R

eRVR: Follow-up

eRVR: P + R Follow-up


Abbreviations: eRVR, extended rapid virologic response (undetectable HCV RNA at weeks 4 and 12); P, peginterferon !-2a 180 !g/wk; R, ribavirin 1000–1200 mg/d; T, telaprevir 750 mg q8h. Sherman KE, et al. Hepatology. 2010;52:Abstract LB-2.

ILLUMINATE—24 Weeks vs 48 Weeks Response-Guided Therapy vs Fixed Duration

n = 540

24 0 48 72 12 Weeks

24 0 48 72 12 Weeks

Patients who achieved eRVR were randomized at week 20 to either stop all treatment at week 24 or to continue on P + R through week 48.

Sherman KE, et al. Hepatology. 2010;52:Abstract LB-2.

ILLUMINATE—SVR Overall and by Treatment Duration

92

72

88

0

20

40

60

80

100

24 Wk (n = 162)

Overall (N = 540)

SV

R (

%)

48 Wk (n = 160)

ILLUMINATE—Adverse Events and Discontinuations

Telaprevir

!! Overall, 17.4% of patients discontinued all study drugs for AEs

!! Most common AEs leading to discontinuation

–! Anemia: 0.6%

–! Fatigue: 1.1%

Sherman KE, et al. Hepatology. 2010;52:Abstract LB-2.

P + R

Placebo + P + R Follow-up

P + R

B + P + R Follow-up


P + R

B + P + R Follow-up

Abbreviations: B, boceprevir 800 mg TID; P, PEG IFN !-2b 1.5 !g/kg/wk; R, ribavirin 600–1400 mg/d; RGT, response-guided therapy; TW, treatment week. Poordad F, et al. Hepatology. 2010;52:Abstract LB-4.

SPRINT-2—Boceprevir in Treatment-Naive Genotype-1 Patients

Response-Guided Therapy vs Fixed Duration

RGT (1: n = 316

2: n = 52)

PR4/BPR44 (1: n = 311 2: n = 55)

PR48 (1: n = 311 2: n = 52)

24 0 48 72 12 Weeks 4 28

24 0 48 72 12 Weeks 4 28

TW8: Neg

TW8–24: Pos

Two cohorts: 1, nonblack; 2, black.


ADVANCE—Adverse Events and Discontinuations

Telaprevir Most common AEs (>25%) in the telaprevir arms: fatigue,

pruritis, nausea, headache, anemia, rash, influenza-like illness,

insomnia, pyrexia, and diarrhea

Overall 7 8 4

Rash 1.4 0.5 0.0

Anemia 0.8 3.3 0.6

Jacobson IM, et al. Hepatology. 2010;52:Abstract 211. Jacobson IM, et al. Hepatology. 2010;52:Abstract 211.

ADVANCE—SVR Rates

75 69

44

0

20

40

60

80

100

SVR

Per

cen

t

T12/PR24

T8/PR24

PR48

P <.0001

P <.0001



16

Slide 19 Slide 20

Slide 23 Slide 24

Slide 21 Slide 22


P + R


P + R

B + P + R Follow-up

Placebo + P + R

Follow-up

P + R

B + P + R Follow-up

Abbreviations: B, boceprevir 800 mg TID; P, PEG IFN !-2b 1.5 !g/kg/wk; R, ribavirin 600–1400 mg/d; RGT, response-guided therapy; TW, treatment week. Bacon BR, et al. Hepatology. 2010;52:Abstract 216.

RESPOND-2—Boceprevir in Genotype-1 Prior Nonresponders

RGT (n = 162)

PR4/BPR44 (n = 161)

PR48 (n = 80)

24 0 48 72 12 Weeks 4 36

24 0 48 72 12 Weeks 4 36

TW8: Neg

TW8–12: Neg

86

57

31

65

24

15

5

17

0

20

40

60

80

100

SV

R (

%)

T Combined

PR Control

Relapsers (n = 354)

Partial Responders

(n = 124)

Null Responders

(n = 184)

Overall, ITT

(n = 184)

REALIZE—SVR by Prior Response

Abbreviations: ITT, intent-to-treat; P, peginterferon !-2a 180 !g/wk; R, ribavirin 1000–1200 mg/d; T, telaprevir 750 mg q8h. NATAP. Press release. Sept. 7, 2010. Available at: http://www.natap.org/2010/HCV/090710_01.htm.

T + P + R P + R Follow-up

P + R

T + P + R P + R Follow-up

P + R Follow-up

Abbreviations: P, peginterferon !-2a 180 !g/wk; R, ribavirin 1000–1200 mg/d;T, telaprevir 750 mg q8h. Clinicaltrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00703118.

REALIZE—Telaprevir in Genotype-1 Prior Nonresponders

PR4/TPR/ PR24

PR48

TPR12/ PR48

0 24 48 72 12 Weeks 4

24 0 48 72 12 Weeks 4

N = 662

Overview

DAA in Tx-Naive


Second Generation


Poordad F, et al. Hepatology. 2010;52:Abstract LB-4.

SPRINT-2—Adverse Events and Discontinuations

Boceprevir

Anemia (%)

Overall 49 29

Dose reduction

21 13

D/C 2 1

D/C for AE, overall (%)

16 12 16

Poordad F, et al. Hepatology. 2010;52:Abstract LB-4.

SPRINT-2—SVR by Cohort and Treatment Arm

40

23

67

42

68

53

0

20

40

60

80

100

Cohort 1 Cohort 2

SV

R (

%) PR48

RGT

PR4/BPR44

Nonblack (N = 938)

Black (N = 159)



17

Slide 25 Slide 26

Slide 29 Slide 30

Slide 27 Slide 28

RESPOND-2—SVR by Prior Response

Abbreviations: B, boceprevir 800 mg TID; P, PEG IFN !-2b 1.5 !g/kg/wk; R, ribavirin 600–1400 mg/d; RGT, response-guided therapy. Bacon BR, et al. Hepatology. 2010;52:Abstract 216.

7

29

40

69

52

75

0

20

40

60

80

100

Partial Responder Relapser

SV

R (

%)

PR48

RGT

PR4/BPR44

n = 72/105

n = 2/29

n = 77/103

n = 15/51

n = 23/57

n = 30/58

RESPOND-2—Adverse Events and Discontinuations

Boceprevir

Discontinuation due to AEs

!! PR48: 3%

!! RGT: 8%

!! PR4/BPR44: 12%

Bacon BR, et al. Hepatology. 2010;52:Abstract 216.

Overview

DAA in Tx-Naive


Next Generation

Lessons from Phase II ANA5981 NN Pol 56 13

RG72272 PI 86 7

RG71283 N Pol 62 18

MK70094 PI 84 5

TMC 4355 PI 79 5

BI 2013356 PI 67 NA

PSI-79777 N Pol 94 21

Next Generation at AASLD 2010— DAA + PEG IFN + RBV

Improved Dosing and Potent Antivirals

Abbreviations: N Pol, nucleos(t)ide polymerase inhibitor; NA, not available; NN Pol, nonnucleos(t)ide polymerase inhibitor; PI, protease inhibitor. 1. Lawitz E, et al. Hepatology. 2010;52:Abstract 31. 2. Terrault N, et al. Hepatology. 2010;52:Abstract 32. 3. Jensen DM, et al. Hepatology. 2010;52:Abstract 81. 4. Manns MP, et al. Hepatology. 2010;52:Abstract 82. 5. Fried MW, et al. Hepatology. 2010;52:Abstract LB-5. 6. Berg T, et al. Hepatology. 2010;52:Abstract 804. 7. Lawitz E, et al. Hepatology. 2010;52:Abstract 806. Graphic courtesy of Dr. David R. Nelson.

IFN-Sparing DAA Combination Trials !! Proof of concept now demonstrated

–! PI + nucleoside polymerase

"! RG7227 (PI) + RG7128 (nucleoside polymerase)1

"! GS-9256 (PI) + GS-9190 (non-nucleoside polymerase) + RBV2

–! Potent antiviral activity and ability to limit breakthrough (resistance)

!! Many interferon-sparing trials planned –! BMS-650032 (PI) + BMS-790052 (NS5A)3

–! BI 201335 (PI) + BI 207127 (non-nucleoside polymerase)4

–! PSI-7977 + PSI-938 (nucleotide polymerases)5

–! Telaprevir + VX-222 (non-nucleoside polymerase)6

Abbreviation: IFN, interferon; PI, protease inhibitor.; RBV, ribavirin; 1. Gane EJ, et al. Hepatology. 2009;50:Abstract 193. 2. Zeuzem S, et al. Hepatology. 2010;52:Abstract LB-1. 3. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT01012895. Accessed on: October 18, 2010. 4. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT01132313. Accessed on: October 18, 2010. 5. Zennou V, et al. Presented at: 45th EASL; April 14-18, 2010. Abstract 921. 6. ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01080222. Accessed on: October 11, 2010.

RG7128 + RG7227—Antiviral Activity in G1 Interferon-Naive and Null Responders

Abbreviations: EOT, end-of-treatment; G, genotype; LLOD, lower limit of detection; TF, treatment failures. With permission from Gane EJ, et al. Presented at: 60th AASLD. October 30-November 3, 2009. Abstract 193.

RG7128 1000 mg BID + RG7227 900 mg BID




18

Slide 31 Slide 32

Slide 33

Day

Med

ian

HC

V R

NA

(IU

/ml)

Lo

g 1

0

0

1

3

2

4

7 14 21 28

6

5

7 GS-9256 + GS-9190 (n = 15)

GS-9256 + GS-9190 + RBV (n = 13)

GS-9256: protease inhibitor GS-9190: polymerase inhibitor

GS-9256 + GS-9190 + PEG/RBV (n = 3)

Breakthrough = resistance - NS3: (D168V/E/N) and/or R155K - NS5B (Y448H)

Interferon-Free Regimen Protease + Polymerase + Ribavirin

With permission from Zeuzem S, et al. Hepatology. 2010;52:Abstract LB-1.

Interferon-Sparing Trials The Next Step: Cure?

!! Combining a protease + polymerase inhibitor for 12 weeks –! 100 genotype-1 treatment-naive HCV-infected patients

Abbreviations: eRVR, HCV undetectable at week 2–8; TVR, telaprevir 1125 mg bid. Clinicaltrial.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01080222. Graphic courtesy of Dr. David R. Nelson.

TVR + VX-222 100 mg bid

TVR + VX-222 100 mg bid PEG IFN !-2a + RBV

Non-eRVR: PEG IFN + RBV

0 12 Weeks

TVR + VX-222 400 mg bid

TVR + VX-222 400mg bid PEG IFN !-2a + RBV

Non-eRVR: PEG IFN + RBV

36 24

if eRVR

if eRVR

n = 25

n = 25

n = 25

n = 25

Summary Expectations for New Therapies

!! Higher response rates: genotype 1 SVR

–! 75% naive

–! 30%–60% nonresponder, 85%–90% relapser

!! Response-guided therapy with extended RVR

!! Potential for combinations of novel agents

!! But...

–! Novel drugs may still require PEG IFN and RBV

–! Resistance will be a new barrier

–! Adding a third drug = greater adverse effects


18


19

Practical Considerations for Integrating new TherapiesNezam.H..Afdhal,.Md

Novel therapies for chronic hepatitis C genotype 1 are becom-ing a clinical reality with the expected availability of direct-act-ing antiviral (DAA) agents as soon as 2011. Integration of these therapies into clinical care requires an understanding of several key factors, including changes in patient evaluation, who to treat, how to monitor, and how to incorporate response-guided therapy into practice. Provider and patient education, with rig-orous management of side effects, will be critical for successful integration of therapies.

The reality of DAA has finally arrived and clinicians now need to prepare to use these agents in combination with peginter-feron and ribavirin for a variety of HCV-infected patients. With sustained virologic response (SVR) rates of 70% to 80% now reported with boceprevir and telaprevir, we can expect an increase in the number of treatment-naive patients willing to undergo treatment. Nearly all treatment-naive patients who do not have a contraindication to peginterferon or ribavirin are potential treatment candidates. Baseline evaluation of predic-tors will include genomic tests, such as host IL28B genotype, and liver biopsy will be reserved for selected patients and to exclude cirrhosis. For treatment-naive patients, the initial response to therapy will be both the major predictor of SVR and the determinant of therapy duration. Based on the phase III clinical trials, up to 60% of HCV genotype-1 patients may only require 24 weeks (telaprevir) or 28 weeks (boceprevir) of therapy.

Another significant group of patients that has been patiently awaiting new treatments are prior treatment-failure patients. Careful characterization of prior response will be required, and patients will be classified as relapsers, partial respond-ers (>1-log reduction in HCV RNA but never negative), and nonresponders (<1-log reduction in HCV RNA). With SVR rates in these groups of approximately 80%, 60%, and 35%, respectively, relapsers and partial responders are certainly treat-ment candidates. The relatively low rates of response in nonre-sponders and the risks of resistance will require individualiza-

tion of therapy for these patients and selection based on viral and host factors and disease severity. Although no guidelines exist for the use of DAA in either treatment-naive or treatment-failure patients, clinical algorithms for evaluation and response-guided therapy in clinical practice are suggested by the design and outcomes of phase III trials.

DAAs will also bring a new set of management issues for the clinician. Monitoring for breakthrough and resistance will be required during therapy and linear parameters of failure to suppress HCV RNA and or an increase of 1 log over nadir will be acceptable clinical indicators of resistance. The long-term sequelae of resistance are not fully known, but initial data suggest that reversion to wild type after cessation of DAAs is likely. Several studies are in place to look at long-term resistance after DAA treatment and their findings are eagerly awaited. Education on the importance of adherence will be critical and management of side effects will hopefully reduce the need for dose reduction, which increases the risk of viral breakthrough. DAAs are associated with increased anemia, which has been managed by both ribavirin dose reduction and use of erythro-poietin. Ribavirin dose reduction does not appear to adversely impact SVR with telaprevir, and the need for growth factors will be soon clarified by a study comparing ribavirin dose reduction with erythropoietin use. Skin rash, predominantly an eczematous reaction, is increased in patients with telaprevir, but rash requiring treatment discontinuation was seen in only 1% of patients in the phase III trials. Rash management plans will be available for clinical use. We should be encouraged that as experience with DAAs increased in the clinical trials, discon-tinuation rates dropped from 20% in phase II trials to only 9% in the phase III trials.

The clinical challenges are significant and to reap the rewards of both a shortened duration of therapy and an improved SVR for our patients, we will need to focus on further refining a practical and integrated team approach to anti-HCV treatment in the era of DAA.

suggested Readings

Akuta N, Suzuki F, Hirakawa M, et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology. 2010;52:421-429.

Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399-401.

Thompson AJ, Muir AJ, Sulkowski MS, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology. 2010;139:120-129.e18.



20

Slide 1 Slide 2

Slide 5 Slide 6

Slide 3 Slide 4


20

Challenges as Anti-HCV Therapy Evolves to Incorporate DAA Agents

Graphic courtesy of Dr. Nezam H. Afdhal.

The Goal of Combination Regimens

Different drugs may contribute variably to each of these goals.

Not all components have to be DAA.

+

+

Graphic courtesy of Dr. Ira M. Jacobson.

Who Are the Patients?

Who Should Be Treated?


Adverse Events

Low viral load Relapser

Treatment-naive

Partial responder High viral load

Mild disease

Who Are The Patients

To Be Evaluated

When a DAA Becomes

Available?

Nonresponder Cirrhosis

Improved SVR Naive/relapsers 70%–80%1,2,3

Partial responders 50%3 Nonresponders 35%4

Increased side effect profile Optimize side effect

management

Resistance preventable Optimize adherence

Reduced treatment duration

What DAA Trials Have Revealed

1. Poordad F, et al. Hepatology. 2010;52:Abstract LB-4. 2. Jacobson IM, et al. Hepatology. 2010;52:Abstract 211. 3. Bacon BR, et al. Hepatology. 2010;52:Abstract 216. 4. McHutchison JG, et al. N Engl J Med. 2010;362:1292-1303. Graphic courtesy of Dr. Nezam H. Afdhal.




Adverse Events



21

Slide 7 Slide 8

Slide 11 Slide 12

Slide 9 Slide 10


21

Ethnicity Genomics IL28B

Adherence Insulin

resistance Hepatic

steatosis

Age Gender


Predicting An Individual’s Response Is Currently Not Possible

Virus Regimen

Patient

60 M

b

Chromosome 19

A Polymorphism Upstream of the IL28B Gene Is Strongly Associated with SVR

Polymorphism rs12979860

IL28B gene

3 kb

19q13.13

Ge D, et al. Nature. 2009;461:399-401. Chromosome 19 graphic courtesy of Oak Ridge National Laboratory. Available at: http://www.ornl.gov/sci/techresources/meetings/ecr2/olsen.gif.

C Allele is Associated with SVR

0 20 40 60 80 100

C/C

T/C

T/T

SVR

Combined

European Americans

African Americans Hispanics

N = 1137

Ge D, et al. Nature. 2009;461:399-401.

n = 70 n = 14 n = 102

n = 91 n = 35 n = 433

n = 186

n = 559

n = 392

n = 30

n = 336

n = 26

RVR = 14% Non-RVR = 86%

CC 31%

CT 56%

TT 13%

Caucasians n = 1091

CC 77%

CT 19%

TT 4%

IL28B Genotype Predicts SVR in Patients Without RVR

SVR (%)

76% 100%

85%

CC CT TT

For all comparisons, P = NS.

SVR (%)

31% 24%

66%

CC TT CT

For CC vs CT and CC vs TT, P <.0001; for CT vs TT, P = NS.

Abbreviations: RVR, rapid virologic response; SVR, sustained virologic response. Thompson AJ, et al. Gastroenterology. 2010;139:120-129. Graphic courtesy of Dr. Alexander J. Thompson

28

87 92

69

14

5

38

56

33 31

5

28

51

27

37

14

55

69

46

23

0

20

40

60

80

100

RVR cEVR EOTR SVR Relapse

CC

CT

TT

Overall

Res

po

nse

Rat

e (%

)

n = 1091 n = 1089 n = 998 n = 1171 n = 687

IL28B Genotype Predicts On-Treatment Virologic Milestones in Caucasians

For all CC vs CT and CC vs TT comparisons: P <.0001. For all CT vs TT comparisons: P = NS. Abbreviations: cEVR, complete early virologic response; EOTR, end-of-treatment response; RVR, rapid virologic response; SVR, sustained virologic response. Thompson AJ, et al. Gastroenterology. 2010;139:120-129.



22


Clinical Treatment Programs

!! Recommended treatment paradigms will be based on phase III study designs and outcomes

!! Both DAAs (telaprevir and boceprevir): –! Use response-guided therapy to maximize

response for all patients

–! Are being studied in treatment-naive and previously treated patients




Adverse Events

Naive Relapser Partial

Responder (>1-log drop)

Nonresponder (<1-log drop)


Management for Genotype 1 Treatment Approaches for Different Patient Types

!! No guidelines

!! Clinicians should individualize according to specific patient needs

Role of Liver Biopsy in Era of DAA

!! SVR rates >70% reduce need for staging as seen for genotypes 2 and 3

!! DAA’s activity is independent of histology

!! Noninvasive tests have high sensitivity and specificity for cirrhosis

!! Key point: Just Diagnose Cirrhosis

Direct Antiviral Therapy Will IL28B Be Relevant?

Japanese genotype 1 HCV-infected adults (N = 72). Telaprevir + peginterferon/ribavirin for 12 (n = 20) or 24 (n = 52) weeks. Akuta N, et al. Hepatology. 2010;52:421-429.

83.8 83.8

29.6 34.5

0 0

0

20

40

60

80

100 rs8099917 rs12979860

SV

R%

TT TG GG CC CT TT 31/37 8/27 0/2 31/37 10/29 0/2

TT vs non-TT: P <.001 CC vs non-CC: P <.001

Slide 13 Slide 14

Slide 17 Slide 18

Slide 15 Slide 16

22



23


23

Slide 19 Slide 20

Slide 23 Slide 24

Slide 21 Slide 22

Plasma HCV RNA

Viral genotype

Baseline

RVR EVR

Others Weeks 2 & 4

Week 24 cEVR

On-Treatment Milestones


Treatment Duration (weeks)

1. Mangia A, et al. N Engl J Med. 2005;352:2609-2617. 2. Zeuzem S, et al. J Hepatol. 2006;44:97-103. 3. Berg T, et al. Gastroenterology. 2006;130:1086-1097. Graphic courtesy of Dr. Nezam H. Afdhal.

Current Status of Response-Guided Therapy—2010 Genotype 2/3, with RVR1

Genotype 1, with RVR and low viral load2

Genotype 1, with late virologic response (wk 12–24)3

Genotype 1, standard

72 24 12–16 Baseline 48

PEG IFN/RBV Response-Guided Therapy 2010 Summary

!! Allows some degree of personalized care

!! Rationale approach

!! Avoids exposure in many

!! Limits toxicity

!! Drives higher response rates for some

!! Sound and cost-effective strategy

!! Will be modified by IL28B and DAA

Response-Guided Therapy DAA Phase III Trials

!! SPRINT-2 (boceprevir)1 –! 28 wk of therapy if undetectable HCV

RNA at treatment wk 8-24 "! Lead-in with P/R followed by addition of

boceprevir for 24 wk

!! ADVANCE (telaprevir)2 –! 24 wk of therapy if undetectable HCV

RNA at treatment wk 4 and 12

1. Poordad F, et al. Hepatology. 2010;52:Abstract LB-4. 2. Jacobson IM, et al. Hepatology. 2010;52:Abstract 211.

SVR 40%–50%

Relapse 20%–30%

Discontinue 20%

NR 20%

Past Present (RGT with RVR)

NR 10%

SVR 60%–70%

Discontinue 25%

Relapse 5%–10%

SVR 80+%

Relapse 5%

Discontinue 10%

NR 5%

Future

Potential of Response-Guided Therapy with DAA


Response-Guided Therapy in the Era of DAAs

!! New baseline evaluation to include host genetics and selective use of liver biopsy

!! Increased personalization of care based on predictors and response

!! Limits toxicity

!! Higher SVR –! 70%–80% achievable for naive and relapsers

!! Sound and cost-effective strategy



24

Slide 25 Slide 26

Slide 29 Slide 30

Slide 27 Slide 28


24

Telaprevir Response-Guided Therapy Treatment-Naive Patients

Week 4 P + R + T

Week 12 P + R + T

Tx through wk 24 P + R only

HCV RNA Negative Positive

Negative Positive Negative Positive

Tx through wk 48 P + R only

Stop Failure

Abbreviations: P, peginterferon; R, ribavirin; T, telaprevir. Graphic courtesy of Dr. Nezam H. Afdhal.

Boceprevir Response-Guided Therapy Treatment-Naive Patients

Week 4 P + R

Week 8 P + R + B

HCV RNA

Tx through wk 48

P + R only Abbreviations: B, boceprevir; P, peginterferon; R, ribavirin. Graphic courtesy of Dr. Nezam H. Afdhal.

Negative Positive

Negative Positive Negative Positive Week 24 P + R + B

Stop SVR

Stop Breakthrough

Stop Failure

Negative (10% of patients)

90% SVR with P + R alone

Adherence and Resistance

!! Adherence has been good in clinical trials with education of importance of q8h or TID dosing of DAAs

!! Dose reduction and poor adherence expected to increase breakthrough of resistance virus in “real life”

!! Resistance monitoring is clinical and indicated by either failure to become HCV RNA negative or a 1-log increase in HCV RNA from nadir




Adverse Events

Adverse Event Management

!! Side effect management for PEG IFN and RBV still remains most important

!! Rash management will be important –! Rash is an eczematous reaction and responds to

local therapy

–! Severe rash is uncommon and Stevens-Johnson syndrome has not been reported

!! Anemia is exacerbated by DAAs and both RBV dose reduction and erythropoietin may be used effectively

Summary

!! 70%–80% SVR will drive increased treatment uptake in naive patients and prior relapsers

!! Careful baseline viral, host, and genetic staging of true non- and partial responders to individualize therapy

!! Response-guided therapy and viral kinetics will drive treatment duration

!! Strategies needed to optimize adherence, dose reduction, and side effect management


a new era of hcv treatment begins: direct-acting … new era of hcv treatment begins: direct-acting...

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