Programme InformationProgramme Information

Target Audience– This CME activity is designed for gastroenterologists,

hepatologists, and other clinicians who treat patients with HCV infection.

Activity Goal– The goal of this activity is to provide state-of-the-art,

clinically relevant information that will provide clinicians with new insights into HCV, molecular approaches to anti-HCV therapy, pipeline protease and polymerase inhibitors, and enable them to identify the potential role that these agents may play in the future.

Learning ObjectivesLearning Objectives

Integrate knowledge of molecular interactions with HCV at the cellular level and mechanism of action of protease and polymerase inhibitors to determine the potential role of these therapies in HCV patients.

Relate viral kinetics to patient outcomes in evaluating HCV patient response to therapy.

Learning Objectives Learning Objectives (cont’d)(cont’d)

Differentiate potential efficacy and safety Differentiate potential efficacy and safety considerations of protease and polymerase considerations of protease and polymerase inhibitors, based on preliminary data, as inhibitors, based on preliminary data, as therapeutic options in the future treatment of therapeutic options in the future treatment of patients with HCV infection. patients with HCV infection.

Assess potential therapeutic strategies involving Assess potential therapeutic strategies involving protease and polymerase inhibitors to improve protease and polymerase inhibitors to improve patient response based on preliminary data.patient response based on preliminary data.

CME InformationCME Information

Statement of AccreditationStatement of Accreditation– Projects In Knowledge is accredited by the Projects In Knowledge is accredited by the

Accreditation Council for Continuing Medical Accreditation Council for Continuing Medical Education to provide continuing medical Education to provide continuing medical education for physicians.education for physicians.

CME Information CME Information (cont’d)(cont’d)

Credit Designation Credit Designation – Projects In Knowledge designates this educational Projects In Knowledge designates this educational

activity for a maximum of 1.5 activity for a maximum of 1.5 AMA PRA Category 1 AMA PRA Category 1 CreditsCreditsTMTM. Physicians should only claim credit . Physicians should only claim credit commensurate with the extent of their participation commensurate with the extent of their participation in the activity.in the activity.

– This activity is planned and implemented as an This activity is planned and implemented as an independent CME activity in accordance with the independent CME activity in accordance with the ACCME Essential Areas and Policies.ACCME Essential Areas and Policies.

Disclosure InformationDisclosure Information

The Disclosure Policy of Projects In Knowledge requires that The Disclosure Policy of Projects In Knowledge requires that presenters comply with the Updated Standards for presenters comply with the Updated Standards for Commercial Support. All faculty are required to disclose any Commercial Support. All faculty are required to disclose any personal interest or relationship they or their spouse/partner personal interest or relationship they or their spouse/partner have with the supporters of this activity or any commercial have with the supporters of this activity or any commercial interest that is discussed in their presentation. Any interest that is discussed in their presentation. Any discussions of unlabeled/unapproved uses of drugs or discussions of unlabeled/unapproved uses of drugs or devices will also be disclosed in the course materials.devices will also be disclosed in the course materials.

For complete prescribing information on the products For complete prescribing information on the products discussed during this CME activity, please see your current discussed during this CME activity, please see your current Physicians’ Desk Reference (PDR).Physicians’ Desk Reference (PDR).

Disclosure Information Disclosure Information (cont’d)(cont’d)

Alfredo Alberti, MD,Alfredo Alberti, MD, has received grant/research support has received grant/research support from Roche Pharmaceuticals and Schering-Plough from Roche Pharmaceuticals and Schering-Plough Corporation; is a consultant for Gilead Sciences, Inc, Idenix Corporation; is a consultant for Gilead Sciences, Inc, Idenix Pharmaceuticals Inc, Novartis Pharmaceuticals Corporation, Pharmaceuticals Inc, Novartis Pharmaceuticals Corporation, Roche Pharmaceuticals, Schering-Plough Corporation, and Roche Pharmaceuticals, Schering-Plough Corporation, and Vertex Pharmaceuticals Incorporated; and is on the speakers Vertex Pharmaceuticals Incorporated; and is on the speakers bureau of Roche Pharmaceuticals and Schering-Plough bureau of Roche Pharmaceuticals and Schering-Plough Corporation. Dr. Alberti has disclosed that he will reference Corporation. Dr. Alberti has disclosed that he will reference unlabeled/unapproved uses of BILN 2061, SCH 503034, and unlabeled/unapproved uses of BILN 2061, SCH 503034, and VX-950.VX-950.

Disclosure Information Disclosure Information (cont’d)(cont’d)

Yves Benhamou, MD,Yves Benhamou, MD, has received grant/research support from Abbott has received grant/research support from Abbott Laboratories, Gilead Sciences, Inc, Roche Pharmaceuticals, and Schering-Laboratories, Gilead Sciences, Inc, Roche Pharmaceuticals, and Schering-Plough Corporation; is a consultant for Abbott Laboratories, Boehringer Plough Corporation; is a consultant for Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Inc, Human Genome Sciences, Idenix Ingelheim Pharmaceuticals, Inc, Human Genome Sciences, Idenix Pharmaceuticals Inc, Novartis Pharmaceuticals Corporation, Roche Pharmaceuticals Inc, Novartis Pharmaceuticals Corporation, Roche Pharmaceuticals, Schering-Plough Corporation, Valeant Pharmaceuticals Pharmaceuticals, Schering-Plough Corporation, Valeant Pharmaceuticals International, and Vertex Pharmaceuticals Incorporated; and is on the International, and Vertex Pharmaceuticals Incorporated; and is on the speakers bureau of Abbott Laboratories, Boehringer Ingelheim speakers bureau of Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Inc, GlaxoSmithKline, Human Genome Sciences, Idenix Pharmaceuticals, Inc, GlaxoSmithKline, Human Genome Sciences, Idenix Pharmaceuticals Inc, Novartis Pharmaceuticals Corporation, Roche Pharmaceuticals Inc, Novartis Pharmaceuticals Corporation, Roche Pharmaceuticals, Schering-Plough Corporation, and Valeant Pharmaceuticals, Schering-Plough Corporation, and Valeant Pharmaceuticals International. Dr. Benhamou has disclosed that he will Pharmaceuticals International. Dr. Benhamou has disclosed that he will reference unlabeled/unapproved uses of NM-283, R1626, reference unlabeled/unapproved uses of NM-283, R1626, SCH 503034, and VX-950.SCH 503034, and VX-950.

Disclosure Information Disclosure Information (cont’d)(cont’d) John G. McHutchison, MD, FRACP,John G. McHutchison, MD, FRACP, has received grant/research support from has received grant/research support from

Coley Pharmaceutical Group, First Circle Medical, Inc, GlaxoSmithKline, Human Coley Pharmaceutical Group, First Circle Medical, Inc, GlaxoSmithKline, Human Genome Sciences, Idenix Pharmaceuticals Inc, InterMune Inc, Roche Genome Sciences, Idenix Pharmaceuticals Inc, InterMune Inc, Roche Pharmaceuticals, Schering-Plough Corporation, SciClone Pharmaceuticals, Valeant Pharmaceuticals, Schering-Plough Corporation, SciClone Pharmaceuticals, Valeant Pharmaceuticals International, and Vertex Pharmaceuticals Incorporated; and is a Pharmaceuticals International, and Vertex Pharmaceuticals Incorporated; and is a consultant for or on the speakers bureau of Anadys Pharmaceuticals, Inc, Aus Bio consultant for or on the speakers bureau of Anadys Pharmaceuticals, Inc, Aus Bio PTL, Coley Pharmaceutical Group, First Circle Medical, Inc, GlaxoSmithKline, PTL, Coley Pharmaceutical Group, First Circle Medical, Inc, GlaxoSmithKline, Human Genome Sciences, Idenix Pharmaceuticals Inc, National Genetics Institute, Human Genome Sciences, Idenix Pharmaceuticals Inc, National Genetics Institute, Novartis Pharmaceuticals Corporation, Nucleonics, Inc, Otsuka America Novartis Pharmaceuticals Corporation, Nucleonics, Inc, Otsuka America Pharmaceutical, Inc, Peregrine Pharmaceuticals, Inc, Roche Pharmaceuticals, Pharmaceutical, Inc, Peregrine Pharmaceuticals, Inc, Roche Pharmaceuticals, Schering-Plough Corporation, SciClone Pharmaceuticals, United Therapeutics, Schering-Plough Corporation, SciClone Pharmaceuticals, United Therapeutics, Valeant Pharmaceuticals International, Vertex Pharmaceuticals Incorporated, and Valeant Pharmaceuticals International, Vertex Pharmaceuticals Incorporated, and XTL. Dr. McHutchison has disclosed that he will reference unlabeled/unapproved XTL. Dr. McHutchison has disclosed that he will reference unlabeled/unapproved uses of NMuses of NM‑‑283, SCH 503034, and VX-950. 283, SCH 503034, and VX-950.

Disclosure Information Disclosure Information (cont’d)(cont’d)

Stefan Zeuzem, MD,Stefan Zeuzem, MD, has received grant/research has received grant/research support from, is a consultant for, and is on the support from, is a consultant for, and is on the speakers bureau of Gilead Sciences, Inc, Idenix speakers bureau of Gilead Sciences, Inc, Idenix Pharmaceuticals Inc, InterMune Inc, Roche Pharmaceuticals Inc, InterMune Inc, Roche Pharmaceuticals, Schering-Plough Corporation, Pharmaceuticals, Schering-Plough Corporation, Novartis Pharmaceuticals Corporation, Valeant Novartis Pharmaceuticals Corporation, Valeant Pharmaceuticals International, and Vertex Pharmaceuticals International, and Vertex Pharmaceuticals Incorporated. Dr. Zeuzem has Pharmaceuticals Incorporated. Dr. Zeuzem has disclosed that he will reference unlabeled/unapproved disclosed that he will reference unlabeled/unapproved uses of NM-283, SCH 503034, and VX-950.uses of NM-283, SCH 503034, and VX-950.

Disclosure Information Disclosure Information (cont’d)(cont’d)

Peer Reviewer has disclosed no significant relationships.

Projects In Knowledge’s staff members have no significant relationships to disclose.

Conflicts of interest are thoroughly vetted by the Executive Committee of Projects In Knowledge. All conflicts are resolved prior to the beginning of the activity by the Trust In Knowledge peer review process.

Disclosure Information Disclosure Information (cont’d)(cont’d)

The opinions expressed in this activity are those of the faculty and do not necessarily reflect those of Projects In Knowledge.

This CME activity is provided by Projects In Knowledge solely as an educational service. Specific patient care decisions are the responsibility of the clinician caring for the patient.

This independent CME activity is supported by an educational grant from Vertex Pharmaceuticals Incorporated.

Contract for Mutual Contract for Mutual Responsibility in CMEResponsibility in CME

Projects In Knowledge has developed the contract to Projects In Knowledge has developed the contract to demonstrate our commitment to providing the highest demonstrate our commitment to providing the highest quality professional education to clinicians, and to help quality professional education to clinicians, and to help clinicians set educational goals to challenge and clinicians set educational goals to challenge and enhance their learning experience. enhance their learning experience.

For more information on the contract, please go to For more information on the contract, please go to www.projectsinknowledge.com/Contract.htmlwww.projectsinknowledge.com/Contract.html

Peer-reviewed content validation Scientific integrity and objectivity Evidence-based for effective clinical practice Commitment to excellence

IntroductionIntroduction

Alfredo Alberti, MDAlfredo Alberti, MD Associate ProfessorAssociate Professor

Department of Clinical and Experimental MedicineDepartment of Clinical and Experimental MedicineUniversity of PadovaUniversity of Padova

Padova, ItalyPadova, Italy

Current Level ofCurrent Level ofTherapeutic Success Therapeutic Success

Acute HCVAcute HCV CurableCurable11

Chronic HCVChronic HCV

Genotype 1Genotype 1 ~50% SVR~50% SVR2,32,3

Genotype 2/3Genotype 2/3 ~65–80% SVR~65–80% SVR2,3,42,3,4

Genotype 4Genotype 4 >60% SVR>60% SVR55

Genotype 5/6Genotype 5/6 ??????

1. Jaeckel E, et al. N Engl J Med. 2001;345:1452. 2. Manns MP, et al. Lancet. 2001;358:958. 3. McHutchison JP, et al. Gastroenterology. 2002;123:1066. 4. Shiffman M, et al. 41st EASL. April 26-30, 2006. Abstract 734. 5. Kamal SM, et al. Gut. 2005;54:858.

Anti-HCV Treatment ParadigmAnti-HCV Treatment Paradigmis Changingis Changing

New interferonsNew interferons Oral interferon inducersOral interferon inducers Ribavirin alternatives Ribavirin alternatives Immune therapiesImmune therapies VIRAL ENZYME INHIBITORSVIRAL ENZYME INHIBITORS

Viral Enzyme InhibitorsViral Enzyme InhibitorsEmerging TherapiesEmerging Therapies

Viral Enzyme TargetsViral Enzyme Targets

ProteaseProtease

HelicaseHelicase

PolymerasePolymerase

STAT-CSpecifically Targeted Anti-Viral Therapy for

HCV

Protease and Polymerase Inhibitors Protease and Polymerase Inhibitors in Developmentin Development

DrugDrug Inhibitor TypeInhibitor Type StatusStatus

BILN 2061BILN 2061 ProteaseProtease FailedFailed

HCV-796HCV-796 PolymerasePolymerase Phase 1Phase 1

ITMN-191ITMN-191 ProteaseProtease Preclinical*Preclinical*

NM-283NM-283 PolymerasePolymerase Phase 2Phase 2

R1626R1626 PolymerasePolymerase Phase 1Phase 1

SCH 503034SCH 503034 ProteaseProtease Phase 2Phase 2

VX-950VX-950 ProteaseProtease Phase 2Phase 2

*Many others also in preclinical development*Many others also in preclinical development

STAT-C AgentsSTAT-C Agents

Mathematical modeling will allow us to compare the ability Mathematical modeling will allow us to compare the ability of STAT-C agents to disrupt steady-state HCV replication of STAT-C agents to disrupt steady-state HCV replication kineticskinetics– Define treatment durationDefine treatment duration– Identify and predict emergence of resistanceIdentify and predict emergence of resistance– Individualize strategiesIndividualize strategies

STAT-C agents are progressing in clinical developmentSTAT-C agents are progressing in clinical development– NM-283, SCH 503034, VX-950 in phase 2 testingNM-283, SCH 503034, VX-950 in phase 2 testing– R1626 in phase I testingR1626 in phase I testing

Future role of STAT-C agents may be to meet currently Future role of STAT-C agents may be to meet currently unmet clinical needs and improve overall standard of careunmet clinical needs and improve overall standard of care

Modeling, Kinetics, and Resistance Modeling, Kinetics, and Resistance Profiles of New Protease and Profiles of New Protease and

Polymerase InhibitorsPolymerase Inhibitors

Stefan Zeuzem, MDStefan Zeuzem, MDProfessor of Internal MedicineProfessor of Internal Medicine

Department of Internal Medicine, Gastroenterology,Department of Internal Medicine, Gastroenterology,Hepatology, and EndocrinologyHepatology, and Endocrinology

University HospitalUniversity HospitalHomburg/Saar, GermanyHomburg/Saar, Germany

HCV DynamicsHCV Dynamics

Virus Infectious CycleVirus Infectious Cycle

DegradationDegradation- Antigen-specific- Antigen-specific- Unspecific- Unspecific

Y

Y

YY

Y

Y Y

Y

dT/dtdT/dt = = ss––dTdT–(1––(1–))VTVTdI/dtdI/dt = (1– = (1–))VTVT––IIdV/dtdV/dt = (1– = (1–))pIpI––cVcV

: de novo infection ratec: Clearance rate (virions/day): Decay rate of infected cellsd: Decay rate of infectable cellsI: Infected cellsp: Production rate (virions/cell/day)s: Production rate of infectable cellsT: Infectable cellsV: Viral load(1 – ): Reduction of de novo infection (1– ): Reduction of virus production

Cell DeathCell Death

p

c

Herrmann E, et al. Eur J Gastroenterol Hepatol. 2006;18:339. Graphic courtesy of Dr. S. Zeuzem.

Kinetic Analyses in Chronic HCV, HBVKinetic Analyses in Chronic HCV, HBV,, and HIV Infectionand HIV Infection

Hermann E, et al. Antivir Ther. 2000;5:85. Reprinted with permission from International Medical Press.

HCVHCV HBVHBV HIVHIV

VirusVirus

Half-life Half-life 2–5 h2–5 h 19–38 h 19–38 h 4–8 h 4–8 h

Daily turnoverDaily turnover 97%–99%97%–99% 35%–58% 35%–58% 87%–98% 87%–98%

Daily productionDaily production 4 x 104 x 101010–1 x 10–1 x 101313 5 x 105 x 101010–1 x 10–1 x 101313 4 x 104 x 1088–3 x 10–3 x 101010

Infected cellsInfected cells

Half-life Half-life 2–>70 d 2–>70 d 10–30 d 10–30 d 1–3 d 1–3 d

Daily turnoverDaily turnover <1%–33%<1%–33% 2%–7%2%–7% 23%–50%23%–50%

ModelingModeling((Peg)Interferon alfaPeg)Interferon alfa

0 7 14 21 28 35 42

10 2

10 4

10 6

10 8

Time (Days)Time (Days)

HC

V R

NA

(IU

/mL)

HC

V R

NA

(IU

/mL)

1. Herrmann E, et al. Antivir Ther. 2000;5:85. 2. Perelson AS, et al. Hepatology. 2005;42:749. Graph courtesy of Dr. S. Zeuzem.

Phase 1 HCV RNA DeclinePhase 1 HCV RNA Decline

— Initial 24–48 hoursInitial 24–48 hours1,21,2

— Extent of decline represents efficacy of Extent of decline represents efficacy of therapy therapy ((εε))1,21,2

— Exponential rate corresponds with viral Exponential rate corresponds with viral decay (decay (c)c)1,21,2

0 7 14 21 28 35 42

10 2

10 4

10 6

10 8

Time (Days)Time (Days)

HC

V R

NA

(IU

/mL)

HC

V R

NA

(IU

/mL)

Phase 2 HCV RNA DeclinePhase 2 HCV RNA Decline

— After 24–48 hoursAfter 24–48 hours1,21,2

— Exponential rate corresponds to the Exponential rate corresponds to the loss rate of infected cells (loss rate of infected cells ())1,21,2

— Highly correlated with SVR in Highly correlated with SVR in interferon-based therapiesinterferon-based therapies

1. Herrmann E, et al. Antivir Ther. 2000;5:85. 2. Perelson AS, et al. Hepatology. 2005;42:749. Graph courtesy of Dr. S. Zeuzem.

Genomic Response to Interferon alfaGenomic Response to Interferon alfaImplications of Rapid Downregulation for Implications of Rapid Downregulation for

Hepatitis C KineticsHepatitis C Kinetics Transcriptional response to interferon alfa in uninfected chimpanzeesTranscriptional response to interferon alfa in uninfected chimpanzees 1778 genes were altered in expression 1778 genes were altered in expression ≥2 fold≥2 fold Response partially tissue-specific, 538 and 950 being unique to liver Response partially tissue-specific, 538 and 950 being unique to liver

or PBMC, respectivelyor PBMC, respectively Most induced genes achieved maximal response within 4 h, began to Most induced genes achieved maximal response within 4 h, began to

decline by 8 h, and were at baseline levels by 24 h, a time when high decline by 8 h, and were at baseline levels by 24 h, a time when high levels of PEG IFN were still presentlevels of PEG IFN were still present

Rapid downregulation may be involved in the transition between Rapid downregulation may be involved in the transition between phase 1 and 2 viral kineticsphase 1 and 2 viral kinetics

PBMC = peripheral blood mononuclear cellLanford RE, et al. Hepatology. 2006;43:961.

ModelingModeling((Peg)Interferon alfa + RibavirinPeg)Interferon alfa + Ribavirin

Effect of Ribavirin on HCV Kinetics in Patients Effect of Ribavirin on HCV Kinetics in Patients Treated with Peginterferon alfa-2aTreated with Peginterferon alfa-2a

107

105

103

107

105

103

0 7 14 21 28 35 42 49 56

DaysDays

Cop

ies/

mL

Cop

ies/

mL

Cop

ies/

mL

Cop

ies/

mL

Peginterferon alfaMonotherapy

Peginterferon alfa + Ribavirin

Zeuzem, S. Unpublished data. 0 7 14 21 28 35 42 49 56

DaysDays

Viral Kinetic Parameters in Patients Viral Kinetic Parameters in Patients Treated with Peginterferon alfa ± RBVTreated with Peginterferon alfa ± RBV

PEG IFN/RBVPEG IFN/RBV PEG IFNPEG IFN IFN/RBVIFN/RBV

Triphasic decayTriphasic decay 8/108/10 9/179/17 4/74/7

Efficiency factor (Efficiency factor (εε)) 0.67 ± 0.30.67 ± 0.3 0.63 ± 0.30.63 ± 0.3 0.36 ± 0.30.36 ± 0.3

Degradation rate (c)Degradation rate (c) 4.7 ± 2.64.7 ± 2.6 3.7 ± 2.33.7 ± 2.3 4.9 ± 3.64.9 ± 3.6

Death rate (Death rate ()) 0.05 ± 0.10.05 ± 0.1 0.02 ± 0.040.02 ± 0.04 0.08 ± 0.10.08 ± 0.1

New death rate (MNew death rate (M)) 0.51 ± 0.60.51 ± 0.6 0.22 ± 0.30.22 ± 0.3 0.24 ± 0.30.24 ± 0.3

Start of 3Start of 3rdrd phase phase 16 ± 1016 ± 10 18 ± 918 ± 9 15 ± 815 ± 8

VV11 at 3 at 3rdrd phase phase 4.9 ± 0.64.9 ± 0.6 5.2 ± 0.85.2 ± 0.8 5.2 ± 0.55.2 ± 0.5

Herrmann E, et al. Hepatology. 2003;37:1351. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.

ModelingModelingProtease InhibitorsProtease Inhibitors

BILN 2061BILN 206110,000,000

1,000,000

100,000

10,00010,000

10000 2 4 6 8

DaysDays

HC

V R

NA

(IU

/mL)

HC

V R

NA

(IU

/mL)

NonrespondersNonresponders

BILN 2061BILN 2061

PlaceboPlacebo

Treatment-naiveTreatment-naive

PlaceboPlacebo

Reprinted from Hinrichsen H, et al. Gastroenterology. 2004;127:1347-1355, with permission from Elsevier.

HCV Protease Inhibitor BILN 2061HCV Protease Inhibitor BILN 2061Virologic Efficacy in HCV-1 Phase 1 StudyVirologic Efficacy in HCV-1 Phase 1 Study

Viral Kinetics in Patients Treated with Viral Kinetics in Patients Treated with PEG IFN or Protease InhibitorPEG IFN or Protease Inhibitor

Kinetics in Patients Treated with PEG IFN + RBV1

1. Zeuzem S, et al. Unpublished data. 2. Herrmann E, et al. Antivir Ther. 2006;11:371. Reprinted with permission from International Medical Press.

Kinetics in Patients Treated with BILN 20612

0 1 2 3 4 5 0 1 2 3 4 5DaysDaysDaysDays

106

104

102HCV

RNA

(IU/m

L)HC

V RN

A (IU

/mL)

106

104

102

0 1 2 3 4 50 1 2 3 4 5DaysDays DaysDays

106

104

102

HCV

RNA

(IU/m

L)HC

V RN

A (IU

/mL) 106

104

102

C=8.0, =0.37, Є=0.997C=5,4, =0.01, Є=0.999

C=2.7, =0.51, Є=0.702C=7.0, =0.84, Є=0.925

Phase 1 and 2 SummaryPhase 1 and 2 Summary

Phase 1 HCV RNA decline represents direct inhibition of Phase 1 HCV RNA decline represents direct inhibition of viral replication by interferon alfaviral replication by interferon alfa– Mathematical modeling Mathematical modeling – In vitro studies (replicon)In vitro studies (replicon)– Direct antiviral substancesDirect antiviral substances

Phase 2 HCV RNA decline represents elimination of Phase 2 HCV RNA decline represents elimination of infected cells infected cells – Mathematical modeling Mathematical modeling – Direct antiviral substancesDirect antiviral substances

New HCV InhibitorsNew HCV InhibitorsDrug Targets and ResistanceDrug Targets and Resistance

NS3 protease NS3 protease

NS3 helicaseNS3 helicase

NS3 bifunctionalNS3 bifunctional protease/helicaseprotease/helicase

NS5B RNA-dependentNS5B RNA-dependent RNA polymerase RNA polymerase

Specific Inhibitors of HCVSpecific Inhibitors of HCV

-5

-4.5

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0 10 20 30 40 50 60 70 80 90

Study Day

Mea

n Se

rum

HC

V R

NA

: Cha

nge

from

Bas

elin

e (lo

g 10 IU

/mL)

NM-283 +/- PEG IFN Phase 2a StudyNM-283 +/- PEG IFN Phase 2a Study Week 12 Viral ResponseWeek 12 Viral Response

- 0.87 log10 IU/mL

- 3.01 log10 IU/mL

NM-283 (n = 12)

NM-283 + PEG IFN -2b 1.0 g/kg (n = 16)

Week 12= day 85

Patients with Data Past Week 1 (n = 28)

NM-283 + PEG IFN at week 12:12 patients > 1.7 log10 reduction; 4 PCR negative

Reprinted from Afdhal N, et al. J Hepatol. 2005;42:A93, with permission from Elsevier.

-7

-6

-5

-4

-3

-2

-1

0

1

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Study Time (Days)Study Time (Days)

*

*

VX-950 750 mg q8hVX-950 750 mg q8h Individual Change from Baseline HCV RNAIndividual Change from Baseline HCV RNA

Lowest VX-950 exposure in dose group-7.0

-6.0

-5.0

-4.0

-3.0

-2.0

-1.0

0.0

HC

V R

NA

Cha

nge

from

HC

V R

NA

Cha

nge

from

Bas

elin

e (L

ogB

asel

ine

(Log

1010 IU

/mL)

IU/m

L)

Median, placebo group

Reesink HW, Zeuzem S, et al. DDW May 14–19, 2005. Abstract 527. Reprinted with permission from Dr. S. Zeuzem

Protease Inhibitor ResistanceProtease Inhibitor Resistance

VX-950PI Resistance: Alanin 156

BILN 2061PI Resistance: Asparagin 168

• Reversible, covalent warhead motifReversible, covalent warhead motif• Ki, at steady state: 3 nMKi, at steady state: 3 nM

• Reversible bindingReversible binding• CompetitiveCompetitive• NoncovalentNoncovalent• Ki: 7.5 nMKi: 7.5 nM

Lin C, et al. J Biol Chem. 2004;279:17508. Reprinted with permission.

BILN 2061VX-950

Sensitivity of Variant Proteases to VX-950Sensitivity of Variant Proteases to VX-950

Wild-Wild-typetype

Double ChangeDouble Change

V36M/L/A

T54S R155K/M/S/T

A156S

V36A/M+R155K/T

V36M/A156T

1a1a

1b1b

T54A

A156T/V

Single Amino Acid ChangeSingle Amino Acid Change

Wild-Type Sensitivity

Upper Limit of Upper Limit of AssayAssay

1010

100100

Enzy

me

ICEn

zym

e IC

5050 (n

M)

(nM

)

10001000

10,00010,000

100,000100,000

Upper Limit of Assay

Rep

licon

Cel

l IC

Rep

licon

Cel

l IC

5050 (µ

M)

(µM

)

0.10.1

11

1010

100100

Kieffer T, et al. 41st EASL. April 26-30, 2006. Abstract 12. Reprinted with permission from Dr. T. Kieffer and Dr. S. Zeuzem.

Combination TherapyCombination TherapyPeginterferon alfaPeginterferon alfa

+ Protease Inhibitor+ Protease Inhibitor+/- Ribavirin+/- Ribavirin

SCH 503034 + PEG IFNSCH 503034 + PEG IFNMedian HCV RNA Change in HCV-1 NonrespondersMedian HCV RNA Change in HCV-1 Nonresponders

PEG IFN alfa-2bPEG IFN alfa-2balone (n = 22)alone (n = 22)

PEG IFN alfa-2bPEG IFN alfa-2b+ SCH 503034+ SCH 503034200 mg TID200 mg TID(n = 12)(n = 12)

PEG IFN alfa-2bPEG IFN alfa-2b+ SCH 503034+ SCH 503034400 mg TID400 mg TID(n = 12)(n = 12)

-3

-2.5

-2

-1.5

-1

-0.5

0

Mea

n H

CV

RN

A C

hang

e (L

ogM

ean

HC

V R

NA

Cha

nge

(Log

1010))

Treatment DayTreatment Day0 5 10 15

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

Mean, -1.1Mean, -1.1

Mean, -2.4Mean, -2.4

Mean, -2.9Mean, -2.9

SCH 503034 alone (not pictured)SCH 503034 alone (not pictured)

200 mg TID monotherapy: range 0.4–1.77200 mg TID monotherapy: range 0.4–1.77

400 mg TID monotherapy: range 0.5–2.5400 mg TID monotherapy: range 0.5–2.5

0

1

2

3

4

5

6

7

8

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Study Time (Days)Study Time (Days)

HC

V R

NA

(Log

HC

V R

NA

(Log

1010 IU

/mL)

IU/m

L)VX-950 750 mg q8h + PEG IFN, Phase 1bVX-950 750 mg q8h + PEG IFN, Phase 1b

Individual HCV RNA CurvesIndividual HCV RNA Curves

Limit of QuantitationLimit of Quantitation

Limit of DetectionLimit of Detection

Reesink HW, et al. 41st EASL. April 26-30, 2006. Abstract 737. Reprinted with permission from Dr. Reesink.

B

Lawitz EJ, et al. DDW 2006. May 20–25, 2006. Abstract 686.

VX-950 + PEG IFN alfa-2a/RBVVX-950 + PEG IFN alfa-2a/RBVHCV RNA inHCV RNA in HCV-1 Treatment-Naïve Patients, Phase 2bHCV-1 Treatment-Naïve Patients, Phase 2b

N = 12N = 12

Limit of Quantitation

Limit of Detection

Study Time (in Days)

median

0

1

2

3

4

5

6

7

8

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

HC

V R

NA

(L

og 1

0 IU

/mL

)

0 4 8 12 16 20 24

10 -x

10 0

10 6

Time (Weeks)

HC

V R

NA

(IU

/mL)

Prediction of Treatment Duration Prediction of Treatment Duration to Achieve SVRto Achieve SVR

Limit of HCV RNA Detection

Fictitious Threshold to Achieve SVR

Zeuzem, S. Unpublished data.

Open QuestionsOpen Questions

Duration of combination therapy to achieve SVR?Duration of combination therapy to achieve SVR? Emergence of resistant strains during combination therapy Emergence of resistant strains during combination therapy

(protease inhibitor, PEG IFN, ribavirin)?(protease inhibitor, PEG IFN, ribavirin)? Viral fitness of mutant strains in vivo and sensitivity to Viral fitness of mutant strains in vivo and sensitivity to

PEG IFN PEG IFN ± RBV?± RBV? Slope of phase 2/3 constant below the level of HCV RNA Slope of phase 2/3 constant below the level of HCV RNA

quantification?quantification? Extrahepatic replication sites (different accessibility of Extrahepatic replication sites (different accessibility of

different antiviral drugs)?different antiviral drugs)? Restoration of (innate) immunity and response to IFN during Restoration of (innate) immunity and response to IFN during

anti-HCV protease inhibitors?anti-HCV protease inhibitors?

ConclusionsConclusions

Current mathematical models are at best an Current mathematical models are at best an approximation of the biological situation and require approximation of the biological situation and require further refinementfurther refinement

Mathematical modeling cannot substitute for appropriate Mathematical modeling cannot substitute for appropriate clinical studies, but can help to ask the right questionsclinical studies, but can help to ask the right questions

Viral kinetics allow for direct assessment and Viral kinetics allow for direct assessment and comparison of the efficacy of antiviralscomparison of the efficacy of antivirals– May help to define duration of therapyMay help to define duration of therapy– May help to individualize antiviral strategiesMay help to individualize antiviral strategies

Update on Current Update on Current Clinical Trial ResultsClinical Trial Results

Yves Benhamou, MDYves Benhamou, MDPraticien Hospitalier

Service d’Hepato-Gastro-EnterologieGroupe Hospitalier Pitié-Salpêtrière

Paris, France

Tailoring therapywith existing drugs

Improving existing drugs

Viramidine Albumin-interferon alfa

STAT-C-R1626-NM-283-SCH 503034-VX-950

TLR

Fibrogenesisinhibitors

20062006 2007? 2009 2007? 2009 2010 2010 2011 2011

Courtesy of Dr. Y. Benhamou.

Anti-HCV Therapeutic ApproachesAnti-HCV Therapeutic Approaches

R1626R1626

R1626 Phase 1b Study in HCV-1R1626 Phase 1b Study in HCV-1Treatment-Naïve PatientsTreatment-Naïve PatientsChange in HCV RNA from BaselineChange in HCV RNA from Baseline

Roberts S, et al. 41st EASL. April 26-30, 2006. Abstract 731. Reprinted with permission from Dr. Roberts.

Mean viral load decrease at day 14, 1500 mg: 1.2 logMean viral load decrease at day 14, 1500 mg: 1.2 log1010 (0.5 to 2.5) (0.5 to 2.5)

Mea

n H

CV

RN

A (l

og10

)

Dec

reas

e fr

om B

asel

ine

Follow-upTreatment1.0

0.5

0.0

-0.5

-1.0

-1.5

-2.0

Placebo (n = 5)

500 mg (n = 9)

1500 mg (n = 9)

Study Day0 5 10 15 20 25 30

R1626 Phase 1b Study in HCV-1 R1626 Phase 1b Study in HCV-1 Treatment-NaTreatment-Naïïve Patientsve Patients

Change in Haemoglobin from BaselineChange in Haemoglobin from Baseline

*relative to placeboRoberts S, et al. 41st EASL. April 26-30, 2006. Abstract 731. Reprinted with permission from Dr. Roberts.

Mild decrease in Haemoglobin at day 14, 1500 mg: 0.8g/dL*Mild decrease in Haemoglobin at day 14, 1500 mg: 0.8g/dL*

-08 g/dL

Follow-upTreatment

Study Day

Mea

n ha

emog

lobi

n C

hang

efr

om B

asel

ine

(g/d

L)

}

0 5 10 15 20 25 30

Placebo (n = 5)

500 mg (n = 9)

1500 mg (n = 9)

1.0

0.5

0.0

-0.5

-1.0

-1.5

-2.0

Valopicitabine (NM-283)Valopicitabine (NM-283)

400→800 mgNM-283 QD

PEG IFN-α + 800 mg NM-283 Follow-up

200 mgNM-283 QD

PEG IFN-α + 200 mg NM-283 Follow-up

800 mgNM-283 QD

PEG IFN-α + 800 mg NM-283 Follow-up

PEG IFN-α + 800 mg NM-283 Follow-up

PEG IFN-α + 800 mg NM-283 Follow-upNo treatment PEG IFN-α only

Baseline Week 1 Week 4 Week 48 Week 72

AA

EE

BB

CC

DD

Dieterich DT, et al. 41st EASL. April 26-30, 2006. Abstract 736. Reprinted with permission from Dr. Dieterich.

NM-283 Phase 2b Study in NM-283 Phase 2b Study in HCV-1 Treatment-Naïve PatientsHCV-1 Treatment-Naïve Patients

Initial Study Design

NM-283 in HCV-1 Treatment-Naïve Patients NM-283 in HCV-1 Treatment-Naïve Patients Convergence of HCV RNA Reductions by Week 12Convergence of HCV RNA Reductions by Week 12

-3.93 log10

-3.99 log10

-4.27 log10

-4.32 log10 -4.46 log10

PEG IFN-αinitiated in arms A–D

No PEG IFN-α alonearm after week 4

Mea

n lo

g 10 R

educ

tion

in H

CV

RN

A

from

Bas

elin

e (IU

/mL)

A PEG IFN 180 µg QW @ d8 + NM-283 400→800 mg QD @ d29 (n = 30)B NM-283 200 mg QD @ d1 + PEG IFN 180 µg QW @ d8 (n = 31)C NM-283 400→800 mg QD ramp @ D1 + PEG IFN 180 µg QW @ d8 (n = 31)D NM-283 800 mg QD @ d1 + PEG IFN 180 µg QW @ d8 (n = 30)E NM-283 800 mg QD @ d1 + PEG IFN 180 µg QW @ d1 (n = 31)

Week 12 (partial data)

NM 283 started for Group A

B: 87%E: 81%A: 87%C: 94% D: 90%

EVR* (%)

-5

-4

-3

-2

-1

0

1

0 2 4 6 8 10 12Weeks

*EVR = Early virologic response*EVR = Early virologic responseDieterich DT, et al. 41st EASL. April 26-30, 2006. Abstract 736. Reprinted with permission from Dr. Dieterich.

NM-283 in HCV-1 Treatment-Naïve Patients NM-283 in HCV-1 Treatment-Naïve Patients HCV RNA at Weeks 12 and 16HCV RNA at Weeks 12 and 16

Week 12 Week 16

HC

V R

NA

PC

R N

egat

ive,

HC

V R

NA

PC

R N

egat

ive,

Pat

ient

s (%

)Pa

tient

s (%

)

Solid Bars<600 IU/mL(Amplicor detection limit)

Shaded Bars <20 IU/mL(Taqman detection limit)

70 7165 67

77 7673

8377

80

Dieterich DT, et al. 41st EASL. April 26-30, 2006. Abstract 736. Reprinted with permission from Dr. Dieterich.

60

45 48

67

5261 62 60

72

50

0

10

20

30

40

50

60

70

80

90

A B C D E A B C D E

A PEG IFN 180 µg QW @ d8 + NM-283 400→800 mg QD @ d29 B NM-283 200 mg QD @ d1 + PEG IFN 180 µg QW @ d8C NM-283 400→800 mg QD ramp @ D1 + PEG IFN 180 µg QW @ d8D NM-283 800 mg QD @ d1 + PEG IFN 180 µg QW @ d8E NM-283 800 mg QD @ d1 + PEG IFN 180 µg QW @ d1

400→800 mgNM-283 QD

PEG IFN-α + 800 mg NM-283 Follow-up

400 mgNM-283 QD

PEG IFN-α + 400 mg NM-283 Follow-up

800 mgNM-283 QD

PEG IFN-α + 800 mg NM-283 Follow-up

PEG IFN-α + 1000–1200 mg ribavirin Follow-up

Follow-up

Baseline Week 1 Week 48 Week 72

A

E

B

C

D

Notreatment

800 mg NM-283 monotherapy

NM-283 Phase 2b Study in NM-283 Phase 2b Study in HCV-1 Nonresponders HCV-1 Nonresponders

Initial Study DesignInitial Study Design

Afdhal N, et al. 41st EASL. April 26-30, 2006. Abstract 39. Reprinted with permission from Dr. Afdhal.

NM-283 in HCV-1 Nonresponders NM-283 in HCV-1 Nonresponders Mean Reduction HCV RNA to Week 24Mean Reduction HCV RNA to Week 24

A NM-283 800 mg QD (n = 21) B NM-283 400 mg QD + PEG IFN 180 µg QW (n = 41) C NM-283 400→800 mg QD ramp (1st week)→ 800 mg QD + PEG IFN 180 µg QW (n = 41)D NM-283 800 mg QD + PEG IFN 180 µg QW (n = 41)E Ribavirin + PEG IFN 180 µg QW @ d8 (n = 34)

n = ITT PopulationAfdhal N, et al. 41st EASL. April 26-30, 2006. Abstract 39. Reprinted with permission from Dr. Afdhal.

E 2.27 log

B 2.45 log

C 2.99 log

D 3.29 log

Seru

m H

CV

RN

A

Seru

m H

CV

RN

A

(Mea

n Lo

g(M

ean

Log 10

10

Cha

nge

from

Bas

elin

e)C

hang

e fr

om B

asel

ine) Wk 12–24 (n = 7)

Study WeekStudy Week

A 0.46 log

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0 6 12 18 24 30

NM-283 DevelopmentNM-283 DevelopmentNext StepsNext Steps

200–400 mg NM-283 doses chosen for further study in 200–400 mg NM-283 doses chosen for further study in treatment-naïve patientstreatment-naïve patients

Ribavirin/NM-283 interaction study expected to start Ribavirin/NM-283 interaction study expected to start in 2006in 2006

Potential investigation of double and triple regimens in Potential investigation of double and triple regimens in phase 3 clinical trialsphase 3 clinical trials– NM-283 + PEG IFN + ribavirinNM-283 + PEG IFN + ribavirin

GI adverse effects common with initial dosingGI adverse effects common with initial dosing– Studies of high dosing in animal model under way to Studies of high dosing in animal model under way to

evaluate mechanism and prevention of GI toxicityevaluate mechanism and prevention of GI toxicity

SCH 503034SCH 503034

SCH 503034 Monotherapy Phase 1b StudySCH 503034 Monotherapy Phase 1b StudyDose-Related Antiviral Response in Dose-Related Antiviral Response in

HCV-1 NonrespondersHCV-1 Nonresponders

Zeuzem S, et al. Hepatology. 2005;42:233A. Reprinted with permission from Dr. Zeuzem.

Max HCV RNA LogMax HCV RNA Log10 10 Reductions Reductions (n)(n)

TreatmentTreatment nn ≤≤11 >1–2>1–2 >2–3>2–3

PlaceboPlacebo 1616 1010 66 00

100 mg BID100 mg BID 1212 88 33 11

200 mg BID200 mg BID 1212 66 44 22

400 mg BID400 mg BID 1111 22 77 22

400 mg TID400 mg TID 1010 00 44 66

SCH 503034 + PEG IFN alfa-2bSCH 503034 + PEG IFN alfa-2b in HCV-1 Nonrespondersin HCV-1 Nonresponders

Phase 1b Study DesignPhase 1b Study Design

Genotype 1, refractory to

PEG IFN ± RBV

B. PEG IFN alfa-2b 1.5 g/kg/QW

as monotherapyfor 14 days

A + B Combination therapy

for 14 days

A. SCH 503034200 or 400 mg TIDas monotherapy

for 7 days

Zeuzem S, et al. Hepatology. 2005;42:276A.

3-way crossover design3-way crossover design Random sequenceRandom sequence Open labelOpen label 3-wk washout between 3-wk washout between

treatmentstreatments

SCH 503034 SCH 503034 +/- +/- PEG IFNPEG IFN Antiviral Activity in HCV-1 PEG IFN Antiviral Activity in HCV-1 PEG IFN

NonrespondersNonresponders

-3

-2.5

-2

-1.5

-1

-0.5

0

Mea

n H

CV

RN

A C

hang

e (L

ogM

ean

HC

V R

NA

Cha

nge

(Log

1010))

Treatment DayTreatment Day

Mean, -1.1Mean, -1.1

Mean, -2.4Mean, -2.4

Mean, -2.9Mean, -2.9

0 5 10 15

PEG IFN alfa-2b (n = 22)PEG IFN alfa-2b (n = 22)

PEG IFN alfa-2b + SCH 503034 200 mg TID (n = 12)PEG IFN alfa-2b + SCH 503034 200 mg TID (n = 12)

PEG IFN alfa-2b + SCH 503034 400 mg TID (n = 12)PEG IFN alfa-2b + SCH 503034 400 mg TID (n = 12)

HCV RNA ChangeHCV RNA Change

MeanMean RangeRange

PEG IFN alonePEG IFN alone

-1.1-1.1

SCH 503034 alone (not pictured)SCH 503034 alone (not pictured)

200 mg TID200 mg TID -0.4 to-0.4 to -1.77 -1.77

400 mg TID400 mg TID -0.5 to -0.5 to -2.5-2.5

SCH 503034 + PEG IFNSCH 503034 + PEG IFN

200 mg TID200 mg TID -2.4-2.4 -1 to -1 to -4.5-4.5

400 mg TID400 mg TID -2.9-2.9 -2.3 to -2.3 to -4.1-4.1

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

Zeuzem S, et al. Hepatology. 2005;42:276A.

SCH 503034 + PEG IFN SCH 503034 + PEG IFN Undetectable HCV RNA in HCV-1 NonrespondersUndetectable HCV RNA in HCV-1 Nonresponders

Endpoint HCV RNA undetectable (<29 IU/mL) at day 14Endpoint HCV RNA undetectable (<29 IU/mL) at day 14– SCH 503034 (400 mg TID) + PEG IFN alfa-2bSCH 503034 (400 mg TID) + PEG IFN alfa-2b

4/10 patients in the 400 mg 4/10 patients in the 400 mg – PEG IFN alfa-2bPEG IFN alfa-2b

0/22 patients0/22 patients AE profile for combination treatment was AE profile for combination treatment was

similar to PEG IFNsimilar to PEG IFN

SCH 503034 + PEG IFN ± RBV SCH 503034 + PEG IFN ± RBV Phase 2 Study DesignPhase 2 Study Design

Dose-finding study in PEG IFN/RBV nonrespondersDose-finding study in PEG IFN/RBV nonresponders Study design: randomized, double-blind, Study design: randomized, double-blind,

placebo-controlled, parallel assignment, safety/efficacy placebo-controlled, parallel assignment, safety/efficacy studystudy– 300 patients300 patients– 24 or 48 weeks 24 or 48 weeks – SCH 503034 + PEG IFN alfa-2b +/- RBVSCH 503034 + PEG IFN alfa-2b +/- RBV

Eligibility Eligibility – Age: 18–65 yearsAge: 18–65 years– Genders: bothGenders: both

Enrollment completedEnrollment completedhttp://www.clinicaltrials.gov/ct/show/NCT00160251?order=1.

VX-950VX-950

*COBAS Taqman HCV RNA assay, Roche Molecular Diagnostics

VX-950 MonotherapyVX-950 MonotherapyUndetectable HCV RNA at Day 14Undetectable HCV RNA at Day 14

001250 mg q12h (n = 10)

24750 mg q8h (n = 8)

01450 mg q8h (n = 10)

HCV RNA* <10 IU/mL

HCV RNA* <30 IU/mL

Reesink HW, et al. Hepatology. 2005;42:234A. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.

-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

Cha

nge

from

Bas

elin

e (L

og10

IU/m

L)

VX-950 + VX-950 + PEG-IFN alfa-2aPEG-IFN alfa-2a

VX-950VX-950

PEG IFN alfa-2a + PEG IFN alfa-2a + placeboplacebo

Baseline Baseline

VX-950 750 mg q8h + PEG IFN, Phase 1bVX-950 750 mg q8h + PEG IFN, Phase 1b Median Change from Baseline HCV RNAMedian Change from Baseline HCV RNA

B

Reesink HW, et al. 41st EASL. April 26-30, 2006. Abstract 737. Reprinted with permission from Dr. Reesink.

0

1

2

3

4

5

6

7

8

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Study Time (Days)Study Time (Days)

HC

V R

NA

(Log

HC

V R

NA

(Log

1010 IU

/mL)

IU/m

L)VX-950 750 mg q8h + PEG IFN, Phase 1bVX-950 750 mg q8h + PEG IFN, Phase 1b

Individual HCV RNA CurvesIndividual HCV RNA Curves

Limit of QuantitationLimit of Quantitation

Limit of DetectionLimit of Detection

B

Reesink HW, et al. 41st EASL. April 26-30, 2006. Abstract 737. Reprinted with permission from Dr. Reesink.

*COBAS Taqman HCV RNA assay, Roche Molecular Diagnostics

9/129/1212/1212/12Week 3Week 3

3/123/1211/1211/12Week 2Week 2

2/122/126/126/12Week 1Week 1

HCV RNA* <10 IU/mL

HCV RNA * <30 IU/mL

12/1212/1212/1212/12Week 4Week 4

Lawitz EJ, et al. DDW 2006. May 20–25, 2006. Abstract 686.

VX-950 + PEG IFN alfa-2a/RBVVX-950 + PEG IFN alfa-2a/RBVHCV RNA inHCV RNA in HCV-1 Treatment-Naïve Patients, HCV-1 Treatment-Naïve Patients,

Phase 2bPhase 2bN = 12N = 12

VX-950 + PEG IFN ± RBVVX-950 + PEG IFN ± RBVPhase 2b StudiesPhase 2b Studies

HCV-1 Treatment-Naïve (N = 580)HCV-1 Treatment-Naïve (N = 580)

Patients in the 12 & 24 W arms and HCV RNA < 10 UI/mL @ W4 – W10 & W20HCV RNA < 10 UI/mL @ W4 – W10 & W20

– Stop @ W12 or W24Stop @ W12 or W24 HCV RNA > 10 UI/mL @ W4 – W10 & W20HCV RNA > 10 UI/mL @ W4 – W10 & W20

– PEG/RBV until W48PEG/RBV until W48

Vertex Pharmaceuticals Incorporated. Press release; May 23, 2006. Available at: http://www.vpharm.com/Pressreleases2006/pr052306.html.

VX-950 + PEG IFN ± RBVVX-950 + PEG IFN ± RBVPhase 2b StudiesPhase 2b Studies

HCV-1 Treatment-Naïve (N = 580)HCV-1 Treatment-Naïve (N = 580)

Vertex Pharmaceuticals Incorporated. Press release; May 23, 2006. Available at: http://www.vpharm.com/Pressreleases2006/pr052306.html.

12-week regimens of VX-950 in combination with peglyated interferon (peg-IFN) and ribavirin (RBV) 2080 100

12-week regimens of VX-950 in combination with only peg-IFN) 080 80

12-week regimens of VX-950 in combination with peg-IFN and RBV, followed by 12 weeks of therapy with peg-IFN and RBV 8080 160

12-week regimens of VX-950 in combination with peg-IFN and RBV, followed by 36 weeks of therapy with peg-IFN and RBV 800 80

Standard of Care HCV Treatment 8080 160

Total 260320 580

Phase II Studies for VX-950Patients in Patients in

Treatment Regimen PROVE 1 PROVE 2 Total

VX-950 VX-950 SummarySummary

VX-950 750 mg q8h, 14 daysVX-950 750 mg q8h, 14 days Monotherapy Monotherapy

– >4-log reduction in median HCV RNA>4-log reduction in median HCV RNA11

– Rebound or plateau in 4/8 patientsRebound or plateau in 4/8 patients22

Combination with PEG IFN alfa-2aCombination with PEG IFN alfa-2a33

– 5.5-log reduction in median HCV RNA5.5-log reduction in median HCV RNA– No rebound observedNo rebound observed

Combination with PEG IFN alfa-2a and RBVCombination with PEG IFN alfa-2a and RBV44

– All patients <10 IU/mL by day 14All patients <10 IU/mL by day 141. Reesink HW, et al. Hepatology. 2005;42:234A. 2. Reesink HW, et al. 41st EASL. April 26-30, 2006. Abstract 737. 3. Reesink HW, et al. 41st EASL. April 26-30, 2006. Abstract 737. 4. Lawitz EJ, et al. DDW 2006. May 20–25, 2006. Abstract 686.

ConclusionConclusion STAT-CSTAT-C

– Promising in the treatment of chronic HCV Promising in the treatment of chronic HCV genotype 1genotype 1

– Next step: phases 2b/3Next step: phases 2b/3 Dose selection and duration of therapyDose selection and duration of therapy Registration 2009–2010?Registration 2009–2010?

Interferon will remain the backbone of anti-HCV therapy Interferon will remain the backbone of anti-HCV therapy for many yearsfor many years

Role of RBV in future strategies?Role of RBV in future strategies? Treatment of nongenotype 1: PEG IFN + RBVTreatment of nongenotype 1: PEG IFN + RBV

Clinical Implications of Clinical Implications of Treatment Paradigm ShiftsTreatment Paradigm Shifts

in HCVin HCV

John G. McHutchison, MD, FRACPJohn G. McHutchison, MD, FRACP

Professor of MedicineProfessor of MedicineDuke Clinical Research Institute and Duke Clinical Research Institute and

Division of GI/HepatologyDivision of GI/HepatologyDuke University Medical CenterDuke University Medical Center

Durham, North CarolinaDurham, North Carolina

Viral Enzyme InhibitorsViral Enzyme InhibitorsEmerging TherapiesEmerging Therapies

Viral Enzyme InhibitorsViral Enzyme Inhibitors

Protease

Helicase

Polymerase

STAT-CSpecifically Targeted Anti-Viral Therapy for

HCV

New STAT-C Drugs New STAT-C Drugs Goals of Future Therapy: 2006–2010Goals of Future Therapy: 2006–2010

Multiple drugs and mechanism of actionMultiple drugs and mechanism of action Effective across a range of genotypesEffective across a range of genotypes Enhanced response Enhanced response Decreased durationDecreased duration Improved tolerabilityImproved tolerability Diminished resistanceDiminished resistance Applicable to difficult-to-treat populationsApplicable to difficult-to-treat populations How will they eventually be used?How will they eventually be used?

BILN 2061BILN 206110,00,000

1,000,000

100,000

10,00010,000

1,0000 2 4 6 8

DaysDays

HC

V R

NA

(IU

/mL)

HC

V R

NA

(IU

/mL)

Non respondersNon responders

BILN 2061 RxBILN 2061 Rx

PlaceboPlacebo

Tx-NaTx-Naïïveve

PlaceboPlacebo

1. Reprinted from Hinrichsen H, et al. Gastroenterology. 2004;127:1347, with permission from Elsevier.2. Reiser M, et al. Hepatology. 2005;41:832.

100-fold less activity in genotypes 2/3

100-fold less activity in genotypes 2/322

Program halted due to cardiotoxicity

Program halted due to cardiotoxicity

100-fold less activity in genotypes 2/3

100-fold less activity in genotypes 2/322

Program halted due to cardiotoxicity

Program halted due to cardiotoxicity

Phase 11

Can STAT-C Drugs Be Designed That Can STAT-C Drugs Be Designed That Are Equally EffectiveAre Equally EffectiveAcross Genotypes?Across Genotypes?

Reprinted from Ferenci P, et al. J Hepatol. 2005;43:4251, with permission from Elsevier.

Patie

nts

with

SVR

(%)

HCV RNA StatusWeek 4 Negative ≥2 log <2 log ≥2 log <2 log Week 12 Negative Negative Negative ≥2 log ≥2 log Week 24 Negative Negative Negative Negative Negative

Rates of Early Viral Clearance Predict Rates of Early Viral Clearance Predict SVR with PEG IFN/RBVSVR with PEG IFN/RBV

PEG IFN PEG IFN -2a 180 µg QW-2a 180 µg QW + RBV 1000+ RBV 1000––1200 mg/d1200 mg/d

91

72

60

4843

0

20

40

60

80

100

STAT-C Triple TherapySTAT-C Triple TherapyPEG IFN alfa-2a + RBV + VX-950PEG IFN alfa-2a + RBV + VX-950

RVR rates exceed those with PEG IFN/RBVRVR rates exceed those with PEG IFN/RBV

0

2

4

6

8

10

12

1 2 3 4

PCR +PCR -*

*PCR neg is <10 IU/mL

No.

Pat

ient

sN

o. P

atie

nts

Lawitz EJ, et al. DDW 2006. May 20–25, 2006. Abstract 686. Graphic courtesy of Dr. J. McHutchison.

Week 4 RVR = 100%

Week 4 RVR PEG IFN/RBV 10%

WeekWeek RVR = Rapid virologic response

2nd phase2nd phase

77 1414 T(n)T(n)

CutoffCutoff

LagLag

1st phase1st phase

1100 11 22 33

22

33

44

55

66

77

DDaysays

Vira

l Vi

ral LL

oad

(log

IU/m

L)oa

d (lo

g IU

/mL)

Applying HCV Kinetics to Applying HCV Kinetics to FFuture Therapies uture Therapies Can We Can We Shorten Therapy?Shorten Therapy?

Neumann AU, et al. Science. 1998;282:103. Graphic courtesy of Dr. J. McHutchison.

Blocking Virion Production

Net Loss Infected Cells

High Viral Burden 1011–1012

Half-Life Measured in Hours

HCV RNA neg End of TreatmentStart

The “Accordion” Effect in anti-HCV TherapyThe Earlier HCV RNA Clears, the Shorter the Treatment Required

How much will this effect pertain to STAT-C therapies?How much will this effect pertain to STAT-C therapies?Courtesy of Dr. I. Jacobson.

HCV Evades the Immune Response—Can We Replace/Dispense Interferon?

Adapted from Rehermann, B, et al. Nat Rev Immunol. 2005;5:215. Reprinted with permission.

XX

X

XX

X

XX

XXX X

X

X

Mechanisms of Action of Mechanisms of Action of Interferon on HCVInterferon on HCV

Antiviral but not via replication complexAntiviral but not via replication complex

Induction of IFN-stimulated genes (ISGs) Induction of IFN-stimulated genes (ISGs)

– Produces a non–virus-specific antiviral stateProduces a non–virus-specific antiviral state

Inhibits translation of viral proteinsInhibits translation of viral proteins

May decrease RNA stabilityMay decrease RNA stability

Feld JJ, et al. Nature. 2005;436:967.

Mechanisms of Action of Mechanisms of Action of HCV on InterferonHCV on Interferon

HCV protease blocks IFN-regulatory factor 3 (IRF-3)HCV protease blocks IFN-regulatory factor 3 (IRF-3) HCV protease blocks retinoic-acid-inducible gene 1 (RIG-1)HCV protease blocks retinoic-acid-inducible gene 1 (RIG-1) Certain proteins interfere with IFN signalingCertain proteins interfere with IFN signaling

Feld JJ, et al. Nature. 2005;436:967.

Future of RibavirinFuture of RibavirinCan it Be Discarded or Replaced?Can it Be Discarded or Replaced?

Ribavirin effectsRibavirin effects– Increases end-of-treatment responseIncreases end-of-treatment response– Decreases relapseDecreases relapse– Small effect on early viral kineticsSmall effect on early viral kinetics

Next stepsNext steps– Prove its redundancy Prove its redundancy – Prove relapse is not dependent on ribavirinProve relapse is not dependent on ribavirin– Consider nucleoside analog issuesConsider nucleoside analog issues– Perform studies Perform studies

Then, and only then, dispense with ribavirinThen, and only then, dispense with ribavirin

Prevention of Viral ResistancePrevention of Viral Resistance

Maximally reduce virus replicationMaximally reduce virus replication– Use of highly potent antiviralUse of highly potent antiviral

Raise the “pharmacologic barrier” to viral escapeRaise the “pharmacologic barrier” to viral escape– High trough levelsHigh trough levels– Tissue distribution that permits no sanctuariesTissue distribution that permits no sanctuaries– Optimal patient adherenceOptimal patient adherence

Raise the “genetic barrier” to viral escapeRaise the “genetic barrier” to viral escape– Combination therapiesCombination therapies

Forseeable, unavoidable, preventableForseeable, unavoidable, preventable Must be tested for thoroughly and systematicallyMust be tested for thoroughly and systematically

Probability of Detecting a Minority CloneNo. of clones analysed 75% 85% 90% 95%

13% 17% 21% 26%

11% 15% 17% 22%

7% 9% 11% 14%

5% 6% 7% 10%

3% 5% 6% 7%

3% 4% 5% 6%

2% 3% 4% 5%

2% 3% 3% 4%

2% 2% 3% 4%

2% 2% 3% 3%

1% 2% 2% 3%

10

12

20

30

40

50

60

70

80

90

100

Detecting Resistance is a Function Detecting Resistance is a Function of How Carefully you Lookof How Carefully you Look

Courtesy of Dr. J. McHutchison.

STAT-C Agents in CombinationSTAT-C Agents in Combinationwith PEG IFN +/- RBVwith PEG IFN +/- RBV

Greater antiviral effect compared with monotherapyGreater antiviral effect compared with monotherapy

Reduced development of resistanceReduced development of resistance

Reduced duration of therapyReduced duration of therapy

NS3/4A Interference with the NS3/4A Interference with the Innate Immune Response to HCV Innate Immune Response to HCV

A Viral On/Off Switch for Interferon – Is the Protease a Better Target for this Reason?A Viral On/Off Switch for Interferon – Is the Protease a Better Target for this Reason?

X

Adapted with permission from Williams BRG, et al. Science. 2003;300:1100. Copyright 2003, AAAS. Readers may view, browse, and/or download material for temporary copying purposes only, provided these uses are for noncommercial personal purposes. Except as provided by law, this material may not be further reproduced, distributed, transmitted, modified, adapted, performed, displayed, published, or sold in whole or in part, without prior written permission from the publisher.

HCV Protease Inhibitors Have HCV Protease Inhibitors Have Significant Viral Load ReductionsSignificant Viral Load Reductions

-6

-5

-4

-3

-2

-1

0

1

1 2 3 4 5 6 7 8 9 10 11 12 13 14Study Time (Days)

HC

V R

NA

Cha

nge

from

Bas

elin

e (L

og10

IU/m

L)

VX-950 + VX-950 + PEG-IFN alfa-2aPEG-IFN alfa-2a

VX-950VX-950

PEG IFN alfa-2a + PEG IFN alfa-2a + placeboplacebo

Baseline Baseline

B

Reesink HW, et al. 41st EASL. April 26–30, 2006. Abstract 737. Reprinted with permission from Dr. Reesink .

Flap

Thumb

Palm

Fingers

• Unique shapeUnique shape• 3 closely related domains3 closely related domains• Large binding cleftLarge binding cleft• Highly conserved across genotypesHighly conserved across genotypes• No mammalian RdRpNo mammalian RdRp

Butcher SJ, et al. Nature. 2001;410:235. Reprinted with permission.

HCV RNA-dependent RNA PolymeraseHCV RNA-dependent RNA Polymerase

HCV Polymerase Inhibitors To Date All HCV Polymerase Inhibitors To Date All Have Similar Viral Load ReductionsHave Similar Viral Load Reductions

NM-283NM-28311 R1626R162622 HCV-796HCV-79633

-1 log -1 log

14 days, monotherapy14 days, monotherapy

>2.5–5.5 logs >2.5–5.5 logs Protease inhibitorsProtease inhibitors

1. Godofsky E, et al. DDW 2004. May 15–20, 2004. Abstract 407. 2. Roberts S, et al. 41st EASL. April 26–30, 2006. Abstract 731.3. Chandra P, et al. DDW 2006. May 20–25, 2006. Abstract 1.

Polymerase InhibitorsPolymerase Inhibitors

Development of HCV DirectDevelopment of HCV DirectEnzyme InhibitorsEnzyme InhibitorsDual Time FramesDual Time Frames

Short-term development for unmet medical needsShort-term development for unmet medical needs– Decompensated cirrhosisDecompensated cirrhosis– Nonresponders to previous treatmentsNonresponders to previous treatments– Prevention of recurrent HCV after liver transplantPrevention of recurrent HCV after liver transplant– Acute hepatitis CAcute hepatitis C– End-stage renal diseaseEnd-stage renal disease– Hard-to-treat patients: HIV/HCV, recurrent HCVHard-to-treat patients: HIV/HCV, recurrent HCV– Hemoglobinopathies, cytopenia, thalassemiaHemoglobinopathies, cytopenia, thalassemia

Long-term development for improving standard of careLong-term development for improving standard of care– Combined with PEG IFN +/- RBVCombined with PEG IFN +/- RBV

New STAT-C Antiviral Agents New STAT-C Antiviral Agents as Monotherapy?as Monotherapy?

Patients with advanced liver cirrhosisPatients with advanced liver cirrhosis Patients with contraindications to or intolerantPatients with contraindications to or intolerant

of IFN or RBVof IFN or RBV Patients with difficulty adhering to PEG IFN/RBV Patients with difficulty adhering to PEG IFN/RBV

therapytherapy High likelihood of drug resistanceHigh likelihood of drug resistance Transplant patientsTransplant patients

– Possible prevention of reinfectionPossible prevention of reinfectionof the donor liver?of the donor liver?

Predictors of Adherence toPredictors of Adherence toHCV TherapyHCV Therapy1,21,2

How will this apply to STAT-C?How will this apply to STAT-C? IncreaseIncrease

Patient belief Patient belief in treatmentin treatment

Provider Provider experienceexperience

Social supportsSocial supports

Adherence to visitsAdherence to visits

DecreaseDecrease

Active IVDU Active IVDU or EtOHor EtOH

Active Active psychiatric psychiatric diseasedisease

Side effectsSide effects

No EffectNo Effect

RaceRace

GenderGender

Inactive IVDUInactive IVDU

Disease stageDisease stage

1. Gebo KA, et al. 8th CROI; February 5–8, 2001. Abstract 477. 2. Ostrow D, et al. 8th CROI: February 5–8, 2001. Abstract 484.

STAT-C STAT-C Likely Picture—Near FutureLikely Picture—Near Future

Viral EnzymeInhibitors

ImmuneModulation

RBV orRelated Drugs± ±

Interferon as a Platform for Future Combinations

Potent Viral Enzyme Inhibitors

Other Viral EnzymeInhibitors

- Same Class?- Different Class?

± ImmuneModulator

±

STAT-CSTAT-CLikely Picture—FutureLikely Picture—Future

Will an immunologic component always be needed to eradicate infection?Will an immunologic component always be needed to eradicate infection? Will there be synergy between drugs of various potencies & different classes?Will there be synergy between drugs of various potencies & different classes? Can we develop new rules for very rapid viral response that predict SVR?Can we develop new rules for very rapid viral response that predict SVR? How much can therapy be truncated?How much can therapy be truncated? Will q8h or q6h dosing of STAT-C drugs be feasible?Will q8h or q6h dosing of STAT-C drugs be feasible? Will monotherapy ever be sufficiently effective for clinical use?Will monotherapy ever be sufficiently effective for clinical use? What are the most effective strategies to prevent resistance?What are the most effective strategies to prevent resistance?

ConclusionConclusion

Exciting advances in anti-HCV treatmentExciting advances in anti-HCV treatment Much work to be doneMuch work to be done Clinical algorithms will need to be establishedClinical algorithms will need to be established Goals for future therapies Goals for future therapies

– Greater efficacy and applicabilityGreater efficacy and applicability

– Improved tolerabilityImproved tolerability

– Translate into community settings and practice Translate into community settings and practice guidelinesguidelines

Questions & AnswersQuestions & Answers

ConclusionConclusion

Alfredo Alberti, MDAlfredo Alberti, MD

Modeling, Kinetics, and Resistance Modeling, Kinetics, and Resistance Profiles of New Protease and Profiles of New Protease and

Polymerase InhibitorsPolymerase Inhibitors

Steady-state HCV kinetics involves equilibrium between Steady-state HCV kinetics involves equilibrium between infected cells, uninfected cells, and circulating virions infected cells, uninfected cells, and circulating virions

Mathematical modeling of HCV therapies helps in identifying Mathematical modeling of HCV therapies helps in identifying relevant questions but cannot give definitive answersrelevant questions but cannot give definitive answers

STAT-C agents exhibit different HCV RNA kinetics compared STAT-C agents exhibit different HCV RNA kinetics compared with each other and compared with interferon alfawith each other and compared with interferon alfa– Emergence of resistance cannot be modeledEmergence of resistance cannot be modeled

Update on Current ClinicalUpdate on Current ClinicalTrial ResultsTrial Results

Interferon will remain the backbone of anti-HCV treatment Interferon will remain the backbone of anti-HCV treatment for many years but STAT-C drugs show significant for many years but STAT-C drugs show significant potential for future treatment of HCVpotential for future treatment of HCV

Three direct viral enzyme inhibitors—NM-283, Three direct viral enzyme inhibitors—NM-283, SCH 503034, and VX-950—are now in phase 2 testingSCH 503034, and VX-950—are now in phase 2 testing– Have demonstrated potent antiviral effects in Have demonstrated potent antiviral effects in

genotype 1 infection, particularly when administered in genotype 1 infection, particularly when administered in combination with peginterferoncombination with peginterferon

Other targeted drugs, such as R1626, are still in phase 1 Other targeted drugs, such as R1626, are still in phase 1 testing but show promising preliminary antiviral effectstesting but show promising preliminary antiviral effects

Clinical Implications of Treatment Clinical Implications of Treatment Paradigm Shifts in HCVParadigm Shifts in HCV

Many clinical needs remain unmet by current therapyMany clinical needs remain unmet by current therapy– Enhanced response in genotype 1 and other hard-to-treat Enhanced response in genotype 1 and other hard-to-treat

infection, decreased duration of therapy, and improved tolerability infection, decreased duration of therapy, and improved tolerability As alternatives to or in combination with peginterferon with or without As alternatives to or in combination with peginterferon with or without

ribavirin, STAT-C agents may have dual roleribavirin, STAT-C agents may have dual role– Meet these unmet clinical needs Meet these unmet clinical needs – Improve overall standard of care Improve overall standard of care

Resistance to STAT-C agents is foreseeable and unavoidable, but also Resistance to STAT-C agents is foreseeable and unavoidable, but also preventablepreventable

Questions answered and future role of STAT-C agents defined through Questions answered and future role of STAT-C agents defined through ongoing clinical developmentongoing clinical development