Future HCV Drugs Download Able

The Beckoning Future:How Hepatitis C Drugs in Development May Affect Practice Today and Tomorrow

This program is supported by educational grants from

clinicaloptions.com/hepatitisHow Hepatitis C Drugs in Development May Affect Practice Today and Tomorrow

About These Slides

Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent

These slides may not be published or posted online without permission from Clinical Care Options (email [email protected])

DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.


Program Faculty

Program Director:

Stefan Zeuzem, MD Professor of Medicine Chief, Department of Medicine I JW Goethe University Hospital Frankfurt, Germany

Faculty:

Nezam H. Afdhal, MD, FRCPI Associate Professor of MedicineHarvard Medical SchoolChief of HepatologyBeth Israel Deaconess Medical CenterBoston, Massachusetts

Eric Lawitz, MD, CPIMedical DirectorAlamo Medical ResearchHepatologistCamden Medical CenterSan Antonio, Texas

Andrew J. Muir, MD, MHS Associate Professor of Medicine Division of Gastroenterology Director, Gastroenterology/Hepatology Research Duke Clinical Research Institute Duke University School of Medicine Durham, North Carolina


Faculty Disclosures

Nezam H. Afdhal, MD, FRCPI, has disclosed that he has received consulting fees from Biogen, Biolex, Boehringer Ingelheim, Echosens, Fibrogen, Gilead Sciences, GlaxoSmithKline, Human Genome Sciences, Idera Pharmaceuticals, Ligand, Merck/Schering-Plough, Novartis, Spring Bank, and Vertex; and has contracted research with Echosens, Gilead Sciences, GlaxoSmithKline, Merck/Schering-Plough, Novartis, Quest, and Vertex.

Eric Lawitz, MD, CPI, has disclosed that he has received research or grant support from Abbott, Achillion, Anadys, Biolex, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck, Novartis, Pharmasset, Pfizer, Roche, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec/Janssen Therapeutics, Vertex, ViroChem Pharma, and ZymoGenetics; is on the speaker’s bureaus for Gilead Sciences, Merck, and Vertex; and is on the advisory board for Abbott, Achillion, Anadys, Biolex, GlobeImmune, Inhibitex, Merck, Pharmasset, and Tibotec/Janssen Therapeutics.


Faculty Disclosures

Andrew J. Muir, MD, MHS, has disclosed that he has received grant or research support from Abbott, Anadys, Gilead Sciences, GlaxoSmithKline, Idera Pharmaceutical, Inc, Medtronic, Merck, Pfizer, Pharmasset, Roche, Scynexis, Santaris, Three Rivers Pharma, Vertex, and Zymogenetics; and has received consulting fees from Bristol-Myers Squibb, Merck, Pharmasset, Salix, Santaris, Vertex, and Zymogenetics.

Stefan Zeuzem, MD, has disclosed that he has received consulting fees from Abbott, Anadys, Achillion, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, iTherX, Janssen Therapeutics, Merck, Novartis, Pfizer, Pharmasset, Roche, Santaris, and Vertex; and has received fees for non-CME services from Bristol-Myers Squibb, Gilead Sciences, Novartis, Merck, and Roche.

Nezam H. Afdhal, MD, FRCPIAssociate Professor of MedicineHarvard Medical SchoolChief of HepatologyBeth Israel Deaconess Medical CenterBoston, Massachusetts

Today’s Direct-Acting Antivirals: Benefits and Limitations


To Treat or Not to Treat: A Constellation of Considerations

Duration ofinfection

Personal plans(marriage, pregnancy)

Age

ALT

HIV coinfectionExtrahepatic

features(fatigue, EMC, PCT)

Patient mindset

Genotype:virus,

patient (IL28B)

Contraindications& comorbidities;

insulin resistance

Histologic stage20%+ lifetime risk

of cirrhosis

Family and other support

Occupation

How Have Boceprevir and Telaprevir Improved HCV Care?


Boceprevir or Telaprevir + PegIFN/RBV:The New Standard of Care for Genotype 1 Potent inhibitors of HCV NS3/4A protease

Both approved by FDA and EMA in mid 2011

– Indicated in combination with pegIFN/RBV for treatment of genotype 1 HCV–infected patients

– Previously untreated or previous treatment failures

Telaprevir [package insert]. May 2011. Boceprevir [package insert]. May 2011. EMA. Telaprevir [package insert] 2011. EMA. Boceprevir [package insert] 2011.


750 mg (two 375-mg tablets) q8hr with food (not low fat; standard fat meal is 21 g, eg, 1/2-cup nuts or 2-oz cheddar cheese)

Treatment-naive patients with compensated cirrhosis and eRVR may benefit from additional 36 wks of pegIFN + RBV (ie, to Wk 48)

No eRVR; PR

Telaprevir in Genotype 1 Patients

TVR + PReRVR; stop at Wk 24

PR

Telaprevir [package insert]. May 2011. EMA. Telaprevir [package insert] 2011.

Time Point Criterion Stopping Rule

Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy

Wk 24 Detectable HCV RNA Discontinue PR

Any Discontinuation of PR for any reason Discontinue TVR

Treatment Naive and Previous Relapsers

Previous Partial or Null Responders

TVR + PR

480 24124

PR


Boceprevir in Genotype 1 Patients

800 mg (four 200-mg capsules) q8hr with meal or light snack

All cirrhotic patients should receive lead-in followed by PR + BOC for 44 wks If considered for treatment, null responders should receive lead-in then PR + BOC for 44 wks EMA label recommends fixed-duration therapy for all trt-expd patients: LI + 32 wks triple + 12 wks PR

BOC + PR

PRPR

BOC + PR

Boceprevir [package insert]. May 2011. EMA. Boceprevir [package insert] 2011.

Treatment Naive

Previous Relapsers or Partial Responders

BOC + PR

Wks480 28124

PRPR

8 36

BOC + PR

24

Time Point Criterion Stopping Rule

Wk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapy

Wk 24 Detectable HCV RNA Discontinue all therapy

Any Discontinuation of PR for any reason Discontinue BOC

Early response; stop at Wk 28

Early response; stop at Wk 36


SVR Rates With BOC or TVR in Genotype 1 Treatment-Naive Patients

0

20

40

60

80

100S

VR

(%

)

PegIFN/RBV BOC or TVR + PegIFN/RBV

38-44

63-75

Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.


152/213

118/149

100

0

50

1b 1a

Genotype

79

71

< 800K ≥ 800K

HCV RNA (IU/mL)

7874

F0-2 F3-F4

Fibrosis

62

78

SV

R (

%)

75

25

High SVR Rates Across Baseline Patient and Virus Factors

ADVANCE: TVR + PegIFN/RBV in Treatment-Naive Genotype 1

207/281

64/82

45/73

226/ 290

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

Data from T12PR arm only

n/N =n/N =


SVR Rates With BOC or TVR in GT1 Treatment-Experienced Patients

0

20

40

60

80

100

SV

R (

%)

Relapsers Partial Responders

69-83PegIFN + RBV

Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.Vierling JM, et al. AASLD 2011. Abstract 931.

NullResponders

BOC or TVR + PegIFN + RBV

24-29

40-59

7-15

29-38

5

What New Challenges Have Boceprevir and Telaprevir

Presented?


Challenges to Categorizing Previous Therapy Response Challenges in clinic setting

– Lack of detailed records

– Lack of standardized definitions of response

– Lack of patient evaluation at key time points on previous therapy

– Potential lapses in patient memory

Differentiation of previous partial response vs null response

– Many clinics unable to characterize exact log10 decline in HCV RNA levels at key time points


Adherence

Triple therapy presents challenges with already busy schedules[143]

– TID dosing

– Food requirements

Data show pegIFN/RBV adherence decreases over time[5]

– Addition of PIs may exacerbate this trend

1. Telaprevir [package insert]. May 2011. 2. Boceprevir [package insert]. May 2011. 3. EMA. Boceprevir [package insert] 2011.4. EMA. Telaprevir [package insert] 2011. 5. Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.

6:00 AM

7:00 AM

8:00 AM

9:00 AM

10:00 AM

11:00 AM

12:00 PM

1:00 PM

2:00 PMTVR/BOC

(with food)TVR/BOC

(with food)TVR/BOC (with

food)

3:00 PM

4:00 PM

5:00 PM

6:00 PM Dinner RBV RBV RBV

7:00 PM

8:00 PM

9:00 PM

10:00 PM

Dinner

Dentist Appt

Travel to and Meet With

Clients

Patient Appointments

Study Group

Chemistry Lab

Biology

English Composition

Lunch

TVR/BOC (with food) + RBV

Monday

Work

Monday

TVR/BOC (with food) + RBV

Lunch

TVR/BOC (with food)

Daily Team Conference Call

Typical Student Busy Sales Professional Mother With Small Children and Full-time Nurse

Monday

TVR/BOC (with food) + RBVWake, feed, and dress children

for schoolSchool and daycare drop-off,

commute to work

Patient Appointments

Lunch

TVR/BOC (with food)

Travel to and Meet With Client

Calls to Clients

Running Club

Researching Trade Articles

Dinner

TVR/BOC (with food)

Dinner cleanup, make lunches for next day

Pick up kids, commute home

Get children ready for and in to bed


Drug-Drug Interactions Represent a Clinical Challenge*

1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011.

Drug Class Contraindicated With BOC[1] Contraindicated With TVR[2]

Alpha 1-adrenoreceptor antagonist

Alfuzosin Alfuzosin

Anticonvulsants Carbamazepine, phenobarbital, phenytoin

N/A

Antimycobacterials Rifampin Rifampin

Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine

Dihydroergotamine, ergonovine, ergotamine, methylergonovine

GI motility agents Cisapride Cisapride

Herbal products Hypericum perforatum (St John’s wort) Hypericum perforatum

HMG CoA reductase inhibitors Lovastatin, simvastatin Atorvastatin, lovastatin, simvastatin

Oral contraceptives Drospirenone N/A

Neuroleptic Pimozide Pimozide

PDE5 inhibitor Sildenafil or tadalafil when used for tx of pulmonary arterial hypertension

Sildenafil or tadalafil when used for tx of pulmonary arterial hypertension

Sedatives/hypnotics Triazolam; orally administered midazolam Orally administered midazolam, triazolam*Studies of drug-drug interactions incomplete.


Helpful Drug-Drug Interaction Resource


Treatment-Emergent Substitutions During PI-Based Therapy Pooled analyses of subjects who had on-treatment failure or relapse during

clinical trials with boceprevir or telaprevir

– Patterns of treatment-emergent substitutions varied by subtype 1a vs 1b

– Resistance most common among previous null responders and patients with subtype 1a

HCV Genotype 1 Subtype

Treatment-Emergent Substitutions

Telaprevir[1] Boceprevir[2]

1aV36MR155K

Combination of V36M and R155K

V36MT54S

R155K

1bV36A

T54A/SA156S/T

T54A/SV55A

A156SI/V170A

1. Telaprevir [package insert]. May 2011. 2. Boceprevir [package insert]. May 2011.


Loss of Detectable Resistance in Patients Stopping BOC or TVR + PegIFN/RBV

1. Vierling JM, et al. EASL 2010. Abstract 2016. 2. Sullivan J, et al. EASL 2011. Abstract 8.

Cu

mu

lati

ve R

ate

of

Wil

d-T

ype

Var

ian

t (%

)

Mos After End of Therapy

100

80

60

40

20

00 6 12 18 24

Boceprevir*[1] Telaprevir[2]

1622

32

60

94

46

66

8798

100

0

20

40

60

80

100

0 3 6 12 16

Genotype 1a HCVGenotype 1b HCV

Mos After Treatment Failure

Pts

Wit

h W

ild

-Typ

e V

iru

s (%

)

*Data from phase II studies.

V36MT548R155KAny mutation


Boceprevir-Related Adverse Events in Clinical Trials Most notable adverse events occurring more frequently

with boceprevir-based therapy vs pegIFN/RBV alone

– Anemia, neutropenia, and dysgeusia

Adverse Event, % Boceprevir + PegIFN/RBV

PegIFN/RBV

Treatment-naive patientsAnemiaNeutropeniaDysgeusia

(n = 1225)502535

(n = 467)301916

Treatment-experienced patientsAnemiaDysgeusia

(n = 323)4544

(n = 80)2011

Boceprevir [package insert]. May 2011.


Telaprevir-Related Adverse Events in Clinical Trials Most notable adverse events occurring more frequently

with telaprevir-based therapy vs pegIFN/RBV alone

– Rash, anemia, and anorectal symptoms

Adverse Event, % Telaprevir + PegIFN/RBV

(n = 1797)

PegIFN/RBV(n = 493)

Rash 56 34

Anemia 36 17

Anorectal symptoms 29 7

Telaprevir [package insert]. May 2011.

Which Patient Groups Have Greatest Need for

Further Improved Therapies?


Telaprevir and Boceprevir SVR by Patient Type

1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 5. Zeuzem S, et al. EASL 2011. Abstract 5. 6. Vierling JM, et al. AASLD 2011. Abstract 931.

0

20

40

60

80

100

SV

R (

%)

Relapser Naive White/

Nonblack

Null Responder

Naive Black

Partial Responder

Cirrhotic Null

Responder

68-75[3,4]

53-62[3-4]

*Pooled TVR arms of REALIZE trial.

75-83[1,2]

52-59[1,2]

29-38[1,6]

14[5]*


Additional Patient Populations With Need

Contraindication or poor tolerance to pegIFN or RBV

Safety and efficacy of boceprevir and telaprevir not yet established in certain special populations

– Organ transplant recipients

– Patients with end-stage liver disease

– Patients with HIV and/or HBV coinfection

– Pediatric patients

PIs not recommended in patients with decompensated cirrhosis or moderate to severe hepatic impairment

Though pegIFN/RBV effective for genotypes 2/3, better options desired, ideally IFN free

Boceprevir [package insert]. May 2011. Telaprevir [package insert]. May 2011.

Andrew J. Muir, MD, MHSAssociate Professor of MedicineDivision of GastroenterologyDirector, Gastroenterology/Hepatology ResearchDuke Clinical Research InstituteDuke University School of MedicineDurham, North Carolina

Tomorrow’s HCV Therapy: What’s on the Horizon?


Looking Beyond 2011 in HCV Therapy

2011: Boceprevir/Telaprevir

SVR for many

RGT, 24-28 wks

IFN-freeShorter durationEfficacy in difficult

to treat QD dosing

↓ Resistance ↑ Tolerability

↑ Genotypic coverage


What Are the Key Elements of an Ideal HCV Regimen?

Highly Effective

High efficacy in traditionally challenging populations

(ie, nulls, cirrhosis)

Safe and Tolerable

Few or easily manageable adverse effects

All Oral

PegIFN/RBV replaced with alternate backbone with low

chance of resistance

Pan-Genotypic

Regimen can be used across all genotypes

Simple Regimen

Short duration, simple, straightforward stopping rules

Easy Dosing

Once daily, low pill burden

What’s on the Horizon?Targets


HCV Life Cycle

Illustration courtesy of Alison Jazwinski, MD.


Each Drug Class Has Unique Features

NS3/4A Protease Inhibitors

NS5B Polymerase Inhibitors NS5A Inhibitors

Cyclophilin A InhibitorsNucleos(t)ide

AnalogueNon-

nucleos(t)ide

High efficacy

Low genetic barrier to resistance

Macrocyclic or linear

Phase III: BI 201335, TMC435

Mimic natural substrates of the polymerase

Incorporated into RNA chain causing chain termination

Broad genotypic coverage

High genetic barrier to resistance

Phase III: PSI-7977

Bind to several different allosteric enzyme sites; results in conformational change

Resistance more frequent than nucs

Several agents in phase II

NS5A has role in assembly of replication complex

Mechanism of inhibition under study

Phase III: Daclatasvir (BMS-790052)

Supports HCV-specific RNA replication, protein expression

Interacts with NS2, NS5A, NS5B

May regulate polypeptide processing, viral assembly

Phase III: Alisporivir


Evolution of HCV Therapy

2001 2011

PegIFN/RBVProtease inhibitorNucleos(t)ide polymerase inhibitorNonnucleoside polymerase inhibitorNS5A inhibitorHost targeting agent


Evolution of HCV Therapy

2001 2011 Beyond

PegIFN/RBVProtease inhibitorNucleos(t)ide polymerase inhibitorNonnucleoside polymerase inhibitorNS5A inhibitorHost targeting agent


Some Agents Under Investigation Have Broad Genotypic Coverage Majority of protease inhibitors have targeted genotypic

coverage

– MK-5172, TMC435 have broad coverage[1,2]

Nonnucleoside polymerase inhibitors active against GT1

Most nucleos(t)ide analogue polymerase inhibitors are pan-genotypic

Most NS5A inhibitors have targeted genotypic coverage

Cyclophilin inhibitors are pan-genotypic

1. Brainard DM, et al. AASLD 2010. Abstract 807. 2. Fried M, et al. AASLD 2010. Abstract LB-5 .

Can New Agents Maintain Efficacy While Simplifying Therapy?


New Agents Generally Maintain or Improve Upon Efficacy in GT1 Treatment-NaivePhase II Studies, Drug + PegIFN/RBV

0

20

40

60

80

100

SV

R (

%)

71-83 68-85 65-85 75-86 61-84

BI 201

335

[3]

Danop

revi

r[4]

Narla

prev

ir[5

]

TMC43

5[6

]Van

ipre

vir[

7]BOC or TVR [1,2]

63-75

38-50

Filib

uvir

[8]

56

Tego

buvi

r[9]

42-83

Dacla

tasv

ir[1

0]

53-76

Alispo

rivir

[11]

1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 3. Sulkowski M, et al. EASL 2011. Abstract 60. 4. Terrault N, et al. AASLD 2011. Abstract 79. 5. Vierling JM, et al. AASLD 2011. Abstract LB-17. 6. Fried M, et al. AASLD 2011. Abstract LB-5. 7. Manns MP, et al. AASLD 2010. Abstract 82. 8. Jacobson I, et al. EASL 2010. Abstract 2088. 9. Lawitz E, et al. EASL 2011. Abstract 445. 10. Pol S. ICAAC 2011. Abstract HI-376. 11. Flisiak R, et al. EASL 2011. Abstract 4.

Not head-to-head comparisons

Can Future Regimens Improve Responses in

Difficult-to-Treat Patients?


Efficacy in Null Responders

Agent Trial, Phase Pts Meeting Efficacy Measure, %

Telaprevir and Boceprevir[1,2]

BOC or TVR + PR REALIZE/PROVIDE, III SVR: 29-38

Investigational Protease inhibitors

BI 201335 + PR[3] SILEN-C2, IIb SVR: 21-35

TMC435 + PR* ASPIRE, IIb SVR: 41-59

Vaniprevir + PR[4] IIb SVR: 40-80

1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Vierling JM, et al. AASLD 2011. Abstract 931. 3. Sulkowski M, et al. EASL 2011. Abstract 66. 4. Lawitz E, et al. AASLD 2011. Abstract LB-13.

*These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.


Daclatasvir (BMS-790052) QD (NS5A inhibitor) + asunaprevir (BMS-650032) BID (NS3 protease inhibitor) ± pegIFN/RBV for 24 wks

Combination Therapy for Null Responders

1. Lok A, et al. EASL 2011. Abstract 1356.2. Chayama K, et al. AASLD 2011. Abstract LB-4.

100

80

60

40

20

0

36

Daclatasvir + Asunaprevir

Daclatasvir + Asunaprevir + PR

SV

R24

(%

)

90 90*

N/A

US Study[1] Japan Study[2]

*all genotype 1b patients.


Additional announced IFN-free study designs in treatment-experienced patients

Combination Therapy for Null Responders

Drug 1 Drug 2 Overall Regimen

TMC435 QD PSI-7977 QD ± RBV12 or 24 wks

ABT-450/RTV QD

ABT-333 BID + RBV

Danoprevir/ RTV BID

Mericitabine BID

+ RBV24 wks

Protease inhibitorNucleos(t)ide analogue polymerase inhibitorNonnucleoside polymerase inhibitor

Can We Shorten Therapy?


24 28

Future Regimens Have Potential to Shorten Duration, Simplify TherapyBoceprevir/telaprevir

24/28 wks min, 48 wks max

Duration varies: dependent on treatment experience, treatment response, fibrosis level

Additional assessments for futility

New options under investigation

0 36 48 0 24 48

Boceprevir

Telaprevir

Protease Inhibitor BID in IL28B CC

Novel Therapies Currently in Trials

124124

Can We Make Regimens Simpler?Can We Improve Adherence?


Current Standard-of-Care Therapy Is Complex

Triple therapy has greatly increased treatment complexity, involves multiple daily pills plus injection drug

– BOC TID: 12 pills/day

– TVR TID: 6 pills/day

– RBV BID: 4-6 pills/day

– PegIFN: QW injection

Increased risks with nonadherence to triple therapy include potential for resistance

Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.

Treatment Wk

Adherence to pegIFN/RBV therapy decreases over time

(N = 5706)

100

80

60

40

20

0PegIFN Ribavirin

1000-1213-2425-3637-48

95 9589

97

86 8476

Mea

n A

dh

eren

ce (

%)


Several Drugs in Development Are Dosed Once or Twice Daily

*With RTV boosting.

QD

ABT-072

ABT-267

ABT 450*

ACH-1625

BI 201335

Daclatasvir

GS 5885

GS9451

IDX 184

INX-189

MK-5172

Narlaprevir*

PSI-7977

PSI-938

TMC435

BID

ABT-333

Asunaprevir

BI 201335

BI 207127

BMS 791325

Danoprevir*

Filibuvir

GS9256

Mericitabine

Setrobuvir

Tegobuvir

Vaniprevir

VX-222

TID

BI 207127

Danoprevir


Fewer AEs With Some Investigational Agents (Preliminary Data)Agent AEs More Frequent in

Experimental Arm vs PegIFN/RBVDiscontinuations

due to AEs, % (Wk)

Boceprevir/Telaprevir[1,2] Anemia, dysgeusia, neutropenia, rash, anorectal symptoms

13-14 (48)

ABT-072[3] (N = 27) Headache 0 (12)

ABT-333[3] (N = 18) None 0 (12)

ABT-450/r[4] (N = 30) None 0 (12)

Alisporivir[5] (N = 215) Transient hyperbilirubinemia 5 (48)

Asunaprevir[7] (N = 36) Fatigue 11 (12)

BI 201335[6] (N = 355) GI events, jaundice, and rash 8 (48)

Daclatasvir[8] (N = 36) None 8 (12)

Danoprevir[9] (N = 194) ALT elevation, neutropenia, nausea, diarrhea 4 (12)

Mericitabine[10] (N = 81) None 6 (36)

PSI-7977[11] (N = 95) None 3 (12)

Setrobuvir[12] (N = 63) Rash 2 (12)

TMC435[13] (N = 309) Mild bilirubin increases 7 (24)

Vaniprevir[14] (N = 169) GI events 6 (48)Studies displayed include those with data through at least 12 wks and with discontinuation rates lower than BOC/TVR.

1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011. 3. Gaultier, et al. APASL 2011. 4. Lawitz E, et al. EASL 2011. Abstract 1220. 5. Flisiak R, et al. EASL 2011. Abstract 4. 6. Bronowicki JP, et al. EASL 2011. Abstract 1195. 7. Sulkowski M, et al. EASL 2011. Abstract 60. 8. Pol S, et al. EASL 2010. Abstract 1189. 9. Terrault N, et al. AASLD 2010. Abstract 32. 10. Pockros P, et al. EASL 2011. Abstract 1359. 11. Nelson D, et al. EASL 2011. Abstract 1372. 12. Lawitz E, et al. AASLD 2010. Abstract 31. 13. Fried M, et al. AASLD 2010. Abstract LB-5. 14. Lawitz E, et al. AASLD 2011. Abstract LB-13.

Do We Need Interferon-α?


Evaluation of Combination Regimens in GT1 Treatment-Naive Patients Strategy: protease inhibitor

(telaprevir) + nonnucleoside polymerase inhibitor (VX-222)[1]

– ± pegIFN/RBV for 12 wks, then RGT

Strategy: protease inhibitor (ABT-450/r) + nonnucleoside polymerase inhibitor (ABT-333 or ABT-072)*

– + RBV for 12 wks

– All 44 patients achieved cEVR

– Of 10 patients tested thus far, 9 achieved SVR24

100

80

60

40

20

0

Pat

ien

ts (

%)

*These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.

9382 87 83

VX-222 400 mg BID + TVR + PRVX-222 100 mg BID + TVR + PR

SVR24; 12 total wks of therapy

SVR12; 24 total wks of therapy

1. Nelson DR, et al. AASLD 2011. Abstract LB-14.


Ongoing Research Evaluates Potential for All-Oral TherapySeveral all-oral regimens under investigation

Drug 1 Drug 2 Drug 3 RBV

BI 201335 BI 207127 N/A ±

PSI-7977 PSI-938 N/A ±

ABT-450/ RTV

ABT-333or ABT-072

N/A +

PSI-7977 Daclatasvir N/A ±

GS-9256 Tegobuvir N/A ±

GS-9451 GS-5885 ± Tegobuvir ±

Asunaprevir DaclatasvirBMS-

791325N/A

Protease inhibitorNucleos(t)ide analogue polymerase inhibitorNonnucleoside polymerase inhibitor

NS5A inhibitor

All-oral regimens of single drug + RBV also under investigation.

IFN-free regimens shown to be highly effective in GT2/3[1]

Nucleotide analogue PSI-7977 + RBV for 12 wks

– PegIFN included for 0, 4, 8, or 12 wks

100

80

60

40

20

0

SV

R (

%)

100 100 100 100

PSI-7977 + 0 wks PegIFN

(IFN-free)

PSI-7977 + 4 wksPegIFN



1. Gane EJ, et al. AASLD 2011. Abstract 34.


Future Directions: Patient/Virus Factors Determine Course?

Course 1:Combination

DAAs

Favorable response profile

Course 2:PegIFN/RBV + combination

DAAs

Fails?

Unfavorable response profile

Course 1:PegIFN/RBV + combination

DAAs


Conclusion: The Beckoning FutureCurrent Phase III Trials

TVR BID + PR

TVR BID + PR PR

Telaprevir in GT1 IL28B CC patients

PSI-7977 + R

PSI-7977 across genotypes

TMC435 + PR

TMC435 + PR PR

PR

TMC435 in GT1 patients

BI 201335 + PR

BI 201335 + PRPR

PR

BI 201335 in GT1 patients

BI 201335 + PRPR

Daclatasvir + PRPR

Daclatasvir in GT1/4 patients

Daclatasvir + PR

QUAD

Telaprevir + VX-222 + PR in GT1


Treat

Weighing the Options: Treat or Defer?

Consider treatment for all patients

Most treatment-naives and relapsers

Treatment urgent for medical well-being

Motivated patients

Adherence issues

Tolerability challenges with IFN and/or RBV

Very poor prognostic factors (ie, null and advanced disease)

Patient not motivated, poor timing with life events

Treatment not urgent

Complicated drug interaction issues may be considered

Defer

Go Online for More HCV Programming!

Conference Coverage of major liver disease meetings

Capsule Summaries and Expert Commentaries on key papers in the literature

CME-certified Treatment Updates on key elements of HCV management

clinicaloptions.com/hepatitis

http://www.clinicaloptions.com/hepatitis

Documents

Future HCV Drugs Download Able