new & emerging interferon ‐ free, direct ‐ acting antiviral regimens for the treatment of...

New & Emerging Interferon‐Free, Direct‐Acting Antiviral Regimens for the Treatment of Hepatitis C: An Expert Review of Recent Clinical Data

New & Emerging Interferon‐Free, Direct‐Acting Antiviral Regimens for the Treatment of Hepatitis C: An Expert Review of Recent Clinical Data

Sponsored for CME credit byRush University Medical Center

Supported by independent educational grants from AbbVie,

Boehringer Ingelheim and Janssen Therapeutics

2

Content Development FacultyContent Development Faculty

Paul Kwo, MDProfessor of Medicine

Medical Director, Liver TransplantationIndiana UniversityIndianapolis, IN

IntroductionIntroduction

4

Chronic HCV in the US:Underdiagnosed and UntreatedChronic HCV in the US:Underdiagnosed and Untreated

Estimated treatment rate is based on Q2 and Q4 2011 chart audits.Hepatitis C Monitor. Ipsos Healthcare.

0

500

1000

1500

2000

2500

3000

3500

4000

4500

Nu

mb

er (

in ‘

000s

)

Prevalence Diagnosed Treated

4.1 M

1.6 M

89,000

38%Diagnosed

5.5%Treated

Unaware of Infection

5

Chronic HCV Undetected by Risk-Based Screening in Primary CareChronic HCV Undetected by Risk-Based Screening in Primary Care

Cross-sectional study (2005-2010) of adult ( ≥18 years) patients in 4 large primary health care systems

Among 209,076 patients who attended at least 1 medical appointment:– 8.4% (17,464) had been tested for HCV, and 1115 cases were detected

Risk factors for HCV positivity among identified cases

Applying these risk factors to the entire cohort predicted that 6005 patients had HCV infection

Undetected cases (4890) accounted for 81% of HCV infections

Yartel AK, et al. Hepatology. 2013;58(suppl 1):219A. Abstract 24.

Predictors of HCV positivity Adjusted odds ratio*

Born 1945-1965Male genderBlackHispanicElevated ALTIntravenous drug use

4.41.41.91.54.86.3

6

HCV Screening RecommendationsHCV Screening Recommendations

Testing recommended at least once for persons born between 1945 and 1965

Others: Screen for risk factors and perform one-time testing if risk factors present

Annual HCV testing recommended for persons who inject drugs and for HIV-seropositive men who have unprotected sex with men

Periodic testing should be offered to other persons with ongoing risk factors for exposure to HCV

AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version March 21, 2014

7

Risk Factors That Should Prompt One-Time or Periodic TestingRisk Factors That Should Prompt One-Time or Periodic Testing

Risk behaviors– Injection drug use (current or ever, including only once)– Intranasal illicit drug use

Risk exposures– Long-term hemodialysis (ever)– Getting a tattoo in an unregulated setting– Healthcare, emergency medical, and public safety workers after needle sticks, sharps, or

mucosal exposures to HCV-infected blood– Children born to HCV-infected women– Prior recipients of transfusions or organ transplants, including persons who:

• Were notified that they received blood from a donor who later tested positive for HCV infection• Received a transfusion of blood or blood components, or underwent an organ transplant before July 1992• Received clotting factor concentrates produced before 1987• Were ever incarcerated

Other medical conditions associated with risk– HIV infection– Unexplained chronic liver disease and chronic hepatitis including elevated alanine

aminotransferase levels


8

Preferred Treatment Recommendations: Initial Therapy or Relapsed after Prior PRAASLD-IDSA

Preferred Treatment Recommendations: Initial Therapy or Relapsed after Prior PRAASLD-IDSA

Genotype 1IFN eligible

IFN ineligible†

Sofosbuvir + PR 12 weeks

Sofosbuvir + simeprevir* ± RBV 12 weeks

Genotype 2 Sofosbuvir + RBV 12 weeks



IFN ineligible

Sofosbuvir + PR 12 weeks

Sofosbuvir + RBV 24 weeks

Genotype 5 or 6 Sofosbuvir + PR 12 weeks


PR: Pegylated interferon + Ribavirin.

† Currently recommended only for patients who require immediate treatment.

*For genotype 1a, baseline resistance testing for the Q80K polymorphism should be performed and alternative treatments considered if this mutation is present.

Do not treat decompensated cirrhosis with PegIFN or simeprevir

9

Alternative Treatment Recommendations: Initial Therapy or Relapsed after Prior PRAASLD-IDSA

Alternative Treatment Recommendations: Initial Therapy or Relapsed after Prior PRAASLD-IDSA


IFN ineligible†

Simeprevir* 12 weeks + PR 24 weeks

Sofosbuvir + RBV 24 weeks

Genotype 2 None

Genotype 3 Sofosbuvir + PR 12 weeks


IFN ineligible

Simeprevir 12 weeks + PR 24-48 weeks

None

Genotype 5 or 6 PR 48 weeks



†Currently recommended only for patients who require immediate treatment.

*Acceptable alternative for genotype 1b patients, or genotype 1a patients in whom the Q80K polymorphism is not detected before treatment.


10

Not Recommended as Therapy for Treatment-Naïve PatientsAASLD-IDSA

Not Recommended as Therapy for Treatment-Naïve PatientsAASLD-IDSA

Genotype 1PR ± telaprevir or boceprevir for 24 or 48 weeksMonotherapy with PegIFN, RBV, or a DAA

Genotype 2PR for 24 weeksMonotherapy with PegIFN, RBV, or a DAATelaprevir-, boceprevir-, or simeprevir-based regimens

Genotype 3PR for 24 or 48 weeksMonotherapy with PegIFN, RBV, or a DAATelaprevir-, boceprevir-, or simeprevir-based regimens

Genotype 4PR for 24 or 48 weeksMonotherapy with PegIFN, RBV, or a DAATelaprevir-, boceprevir-, or simeprevir-based regimens

Genotype 5 or 6Monotherapy with PegIFN, RBV, or a DAATelaprevir- or boceprevir-based regimens




11

Preferred Treatment Recommendations: Partial or Null Response to Prior PR†

AASLD-IDSA

Preferred Treatment Recommendations: Partial or Null Response to Prior PR†

AASLD-IDSA

Genotype 1Prior PR Sofosbuvir + simeprevir ± RBV 12 weeks

Prior PR-based triple therapy

Sofosbuvir 12 weeks + PR 12-24 weeks




Genotype 5 or 6 Sofosbuvir + PR 12 weeks



†Consideration should be given to postponing treatment, pending release of new drugs for patients with limited hepatic fibrosis (F 0-2)


12

Alternative Treatment Recommendations: Partial or Null Response to Prior PR†

AASLD-IDSA

Alternative Treatment Recommendations: Partial or Null Response to Prior PR†

AASLD-IDSA

Genotype 1Prior PR

Sofosbuvir 12 weeks + PR 12-24 weeksSofosbuvir + RBV 24 weeksSimeprevir 12 weeks + PR 48 weeks*

Prior PR-based triple therapy

Sofosbuvir + RBV 24 weeks (IFN ineligible)Sofosbuvir + PR 24 weeks (IFN eligible)

Genotype 2 None



IFN ineligible

Simeprevir 12 weeks + PR 24-48 weeks

None

Genotype 5 or 6 PR 48 weeks



†Consideration should be given to postponing treatment, pending release of new drugs for patients with limited hepatic fibrosis (F 0-2).

*For genotype 1a, baseline resistance testing for Q80K should be performed and alternative treatments considered if this mutation is present.


13

Not Recommended as Therapy for Patients with Partial or Null Response to Prior PR† AASLD-IDSA

Not Recommended as Therapy for Patients with Partial or Null Response to Prior PR† AASLD-IDSA

Genotype 1PR ± telaprevir or boceprevir Monotherapy with PegIFN, RBV, or a DAA

Genotype 2PR ± telaprevir or boceprevir Monotherapy with PegIFN, RBV, or a DAA

Genotype 3PR ± any current protease inhibitorMonotherapy with PegIFN, RBV, or a DAA

Genotype 4PR ± any current HCV protease inhibitorMonotherapy with PegIFN, RBV, or a DAA

Genotype 5 or 6PR ± any current HCV protease inhibitorMonotherapy with PegIFN, RBV, or a DAA




IFN-Free Regimens for Chronic HCV InfectionIFN-Free Regimens for Chronic HCV Infection

15

Rationale for IFN-Free Direct-Acting Antiviral Therapy for HCVRationale for IFN-Free Direct-Acting Antiviral Therapy for HCV

Drawbacks of IFN-based Therapy– Challenging tolerability – High percentage of patients are ineligible for IFN– Long duration of therapy– Low SVR rates compared to modern all-oral regimens

• PR: ~40-50% in treatment-naïve patients

• Triple therapy PR + boceprevir or telaprevir: ~70%

– Many patient-specific and virus-specific factors affecting eligibility or treatment response (Race, IL28B, cirrhosis, prior treatment, etc)

– Development of resistance– Requires injection

16

Overview of DAAsOverview of DAAs

NS3/4A NS5A NS5B

Function Serine Protease Component of HCV Replication Complex

RNA-dependent RNA polymerase

Drugs CovalentBoceprevirTelaprevir Non-covalentFaldaprevirSimeprevirABT-450AsunaprevirMK-5172

LedipasvirDaclatasvirOmbitasvirMK-8742PPI-668

Nucleoside analogsSofosbuvir Non-nucleosideBMS-791325DasabuvirDeleobuvir

C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B

Core Envelope Glycoproteins Protease SerineProtease

Helicase SerineProteaseCofactor

RNA-dependent RNA polymerase

Component of HCV Replicase

17

Guide to Trials of Sofosbuvir ± SimeprevirGuide to Trials of Sofosbuvir ± Simeprevir

1 IFN ineligibleSofosbuvir +

simeprevir ± RBV 12 weeks

GenotypePatient

characteristicRecommended(AASLD-IDSA)

Supporting Trial Evidence

COSMOS(phase II)

2/3Sofosbuvir + RBV

12 weeks/24 weeks

FISSIONPOSITRON (IFN ineligible)

VALENCE

Failed prior PRSofosbuvir + RBV

12 weeks/24 weeks

FUSION

18

COSMOS: Simeprevir + Sofosbuvir ± RBV: Genotype1COSMOS: Simeprevir + Sofosbuvir ± RBV: Genotype1

Sulkowski M, et al. EASL International Liver Congress, 2014. Abstract O7.

Jacobson IM, et al. Hepatology. 2013;58(suppl 1):73A. Abstract LB-3.

SV

R12

, %

Pat

ien

ts

No Cirrhosis (F0-F2)Prior PR Null-Responders

93%

24 Weeks12 Weeks

Simeprevir + sofosbuvir

No RBV With RBV

96% 93%

79%

SV

R12

, %

Pat

ien

ts

F3-F4Treatment-naive and Prior PR Null

Responders

Overall

Simeprevir + sofosbuvir

n=27 n=14 n=24 n=15 n=87 14 30 16

12 weeks 24 Weeks±R

BV

+R

BV

+R

BV

-RB

V

-RB

V

27

2 relapses

1 relapse

2 non-virological

failures

19

FISSION Trial: Sofosbuvir + RBV: GT2 &3 FISSION Trial: Sofosbuvir + RBV: GT2 &3

Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5.Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

0

20

40

60

80

100

SV

R12

, %

Pat

ien

ts

Genotype 2

98%

91%

82%

62%

No Cirrhosis Cirrhosis0

20

40

60

80

100

SV

R12

, %

Pat

ien

ts

Genotype 3

61%

71%

34%30%

No Cirrhosis Cirrhosis

Sofosbuvir + RBV

PR

n=59 n=54 n=11 n=13 n=145 n=139 n=38 n=37

Sofosbuvir + RBV

PR

20

POSITRON: Sofosbuvir + RBV for 12 WeeksPOSITRON: Sofosbuvir + RBV for 12 Weeks

Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61.Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

0

20

40

60

80

100

SV

R12

(%

)

Genotype 2

92% 94%

No Cirrhosis(n=92)

Cirrhosis(n=17)

0

20

40

60

80

100

Pat

ien

ts (

%)

Genotype 3

68%

21%

No Cirrhosis(n=84)

Cirrhosis(n=14)

SVR12 rate was 0% in the placebo arm.

21

VALENCE Trial: Sofosbuvir + RBVVALENCE Trial: Sofosbuvir + RBV

Zeuzem S, et al. Hepatology. 2013;58(suppl 1):733A-734A. Abstract 1085.

0

20

40

60

80

100

SV

R12

(%

)

93100

8591

97

Overall

94 9287

Genotype 2 (12 weeks)

Genotype 3 (24 weeks)

Noncirrhotic

60

88

Treatment-Naive

Cirrhotic Noncirrhotic Cirrhotic

Treatment-Experienced

No resistance detected in patients with relapse.

n=73 n=250 n=30 n=92 n=2 n=13 n=33 n=100 n=8 n=45

Treatment-naïve or experiencedApproximately 20% with cirrhosis

22

FUSION Trial: SVR12 Rates by Genotype and CirrhosisFUSION Trial: SVR12 Rates by Genotype and Cirrhosis

Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6.

Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

0

20

40

60

80

100

Pat

ien

ts (

%)

Genotype 2

96%

60%

100%

78%

No Cirrhosis Cirrhosis0

20

40

60

80

100

Pat

ien

ts (

%)

Genotype 3

37%

63%

19%

61%

No Cirrhosis Cirrhosis

Sofosbuvir + RBV

12 weeks 16 weeks

Sofosbuvir + RBV

12 weeks 16 weeks

n=26 n=23 n=10 n=9 n=38 n=40 n=26 n=23

Failed prior IFN-based therapyTargeted 30% with cirrhosis

23


Kris Kowdley, MDDirector, Liver Center of Excellence

Digestive Disease InstituteVirginia Mason Medical CenterClinical Professor of Medicine

University of WashingtonSeattle, WA

Investigational, IFN-Free, DAA Combination Regimens Investigational, IFN-Free, DAA Combination Regimens

Part A: Treatment-Naïve Patients Phase III Trials

25

SAPPHIRE-I: ABT-450/r + Ombitasvir + Dasabuvir + RBV (3D + RBV)SAPPHIRE-I: ABT-450/r + Ombitasvir + Dasabuvir + RBV (3D + RBV)

Feld JJ, et al. EASL International Liver Congress, 2014. Abstract O60.

Feld JJ, et al. NEJM 2014 DOI: 10.1056/NEJMoa1315722

3D + RBV

Placebo 3D + RBV

0 12 24 60 72

Double-blind Treatment Period

Open-label Treatment Period

Primary analysis:SVR12

3D: Co-formulated ABT-450/ritonavir/ombitasvir, 150 mg/ 100 mg/ 25 mg + dasabuvir, 250 mgRBV: 1000-1200 mg daily, weight-based

NS3/4A

NS5A

NS5B Non-Nuc

Genotype 1Treatment-naïveNo cirrhosis

Phase 3

Weeks

26




NS3/4A

NS5A

NS5B Non-Nuc96.2 95.3 98.1

0

20

40

60

80

100

All Patients(N=473)

GT1a(n=322)

GT1b(n=151)

SV

R12

, % P

atien

ts

SVR12 non-inferior and superior to a historical control of telaprevir + PR (78%)

Phase 3

27




NS3/4A

NS5A

NS5B Non-Nuc

95.2 96.4 97 97 98.193.5

97.5 96.291.5

94.3 95.7 96.492.5

0

20

40

60

80

100

Male

SVR1

2, %

Pati

ents

Female Black Non-Black

<30 ≥30 F0-F1 F2 F3 <800K ≥3800K Yes No

Gender Race BMI (kg/m2)

FibrosisStage

RBVModification

Baseline HCV RNA

(IU/ml)

Phase 3

28

PEARL-III: ABT-450/r + Ombitasvir + Dasabuvir (3D) ± RBV PEARL-III: ABT-450/r + Ombitasvir + Dasabuvir (3D) ± RBV

Ferenci P, et al. EASL International Liver Congress, 2014. Abstract P1299.

NS3/4A

NS5A

NS5B Non-Nuc99.5 99

0

20

40

60

80

100

3D +RBV(n=210)

3D(n=209)

SV

R12

, %

Pat

ien

ts

Genotype 1bTreatment-naïveNo cirrhosis3D + RBV versus 3D alone

Phase 3


29

ION-1: Ledipasvir + Sofosbuvir12 Weeks Versus 24 Weeks and ± RBV


Mangia A, et al. EASL International Liver Congress, 2014. Abstract O164.

Afdhal N, et al. NEJM 2014 DOI: 10.1056/NEJMoa1402454

NS3/4A

NS5A

NS5B NucLDP/SOF

LDP/SOF + RBV

0 12 24 36

Genotype 1Treatment-naïveTargeted 20% with cirrhosis (actual 15-17%)Platelet count ≥50,000, no neutrophil minimum

Phase 3

LDP/SOF

LDP/SOF + RBV

SVR12

SVR12

SVR12

SVR12

LDP/SOF: Ledipasvir/Sofosbuvir fixed-dose combination tablet (90 mg/400 mg daily)

Weeks

30





NS3/4A

NS5A

NS5B Nuc99 97 98 99

0

20

40

60

80

100

LDV/SOF(n=214)

SV

R12

, %

Pat

ien

ts

LDV/SOF + RBV(n=217)

LDV/SOF(n=217)


12 Weeks 24 Weeks Treatment duration

Phase 3

31





NS3/4A

NS5A

NS5B Nuc99 97 98 9994

10094

100

0

20

40

60

80

100C

irrho

sis

Cirr

hosi

s

Cirr

hosi

s

Cirr

hosi

s

LDV/SOF

SV

R12

, %

Pat

ien

ts

LDV/SOF + RBV LDV/SOF LDV/SOF + RBV


Phase 3

n=180 n=34 n=184 n=33 n=180 n=33 n=181 n=36

32

ION-3: Sofosbuvir + Ledipasvir 8 Weeks Vs 12 Weeks

ION-3: Sofosbuvir + Ledipasvir 8 Weeks Vs 12 Weeks

Kowdley KV, et al. EASL International Liver Congress, 2014. Abstract O56.

Kowdley KV, eta l. NEJM 2014;370:1879-1888

NS3/4A

NS5A

NS5B NucLDP/SOF

LDP/SOF + RBV

Genotype 1Treatment-naïveNon-cirrhotic

Phase 3

LDP/SOF

SVR12

SVR12

SVR12


0 12 248 20 Weeks

33

ION-3: Sofosbuvir + Ledipasvir8 Weeks Vs 12 Weeks

ION-3: Sofosbuvir + Ledipasvir8 Weeks Vs 12 Weeks

Kowdley KV, et al. EASL International Liver Congress, 2014. Abstract O56.

Kowdley KV, eta l. NEJM 2014;370:1879-1888

NS3/4A

NS5A

NS5B Nuc94 93 95

0

20

40

60

80

100

LDV/SOF(n=215)

SV

R12

, %

Pat

ien

ts


LDV/SOF(n=216)


Non-inferiority analysis

P=0.70 P=0.30

P=0.52

34

HALLMARK DUAL: Daclatasvir + Asunaprevir: GT1bHALLMARK DUAL: Daclatasvir + Asunaprevir: GT1b

Manns M, et al. EASL International Liver Congress, 2014. Abstract O166.

NS3/4A

NS5A

NS5B

DCV + ASV

DCV + ASV Enter another studyDCV + ASV 24 weeks

0 12 24 36

Genotype 1bTreatment-naïve, prior null or partial response to PR, IFN intolerant or ineligible

Phase 3

Weeks

STOP

12-week arm discontinued and participants invited to enroll in separate 24-week trial

DCV: Daclatasvir, 60 mg dailyASV: Asunaprevir, 100 mg twice daily

DCV + ASV

DCV + ASV

Treatment-naive

Nonresponder

Ineligible/ Intolerant

35



NS3/4A

NS5A

NS5B90

82 82

0

20

40

60

80

100

Treatment-naive(n=203)

16% cirrhosis

SV

R12

, %

Pat

ien

ts

Nonresponders(n=205)

31% cirrhosis

Ineligible/Intolerant(n=235)

47% cirrhosis

Phase 3


Part A: Treatment-Naïve Patients Phase II Trials

37

Study 014: Daclatasvir + Asunaprevir + BMS-791325Study 014: Daclatasvir + Asunaprevir + BMS-791325

Everson GT, et al. Hepatology. 2013;58(suppl 1):73A. Abstract LB-1.

DCV + ASV + BMS-791325 (75 mg twice daily)

DCV + ASV + BMS-791325 (150 mg twice daily)

Genotype 1Treatment-naïveCirrhosis allowed (9% enrolled)

Phase 2

SVR12

SVR12

0 12 24 Weeks

NS3/4A

NS5A

NS5B Non-nuc

DCV: Daclatasvir, 30 mg twice dailyASV: Asunaprevir, 200 mg twice daily

38

Study 014: Daclatasvir + Asunaprevir + BMS-791325Study 014: Daclatasvir + Asunaprevir + BMS-791325

Everson GT, et al. Hepatology. 2013;58(suppl 1):73A. Abstract LB-1.

92 91

10096

91

100

9192 9194 96

89

71

94

0

20

40

60

80

100

Overall 1a

Genotype

CC Non-cirrhotic

Cirrhotic

IL28B

Phase 2

NS3/4A

NS5A

NS5B Non-nuc

SV

R12

, % P

atie

nts

N=77 84 65 68 12 16 24 28 53 56 8 7 69 77

1b Non-CC

Daclatasvir (30 mg twice daily) + Asunaprevir (200 mg twice daily)

+ BMS 791325 75 mg twice daily

150 mg twice daily

39

C-WORTHY: MK-5172 + MK-8742 ± RBVC-WORTHY: MK-5172 + MK-8742 ± RBV

Hezode C, et al. EASL International Liver Congress, 2014. Abstract O10.

NS3/4A

NS5A

NS5B

Phase 2

MK-5172 (100 mg)MK-8742 (20 mg)+ RBV

Genotype 1Treatment-naïveNon-cirrhotic

SVR24

0 12 24 36 Weeks

MK-5172 (100 mg)MK-8742 (50 mg)+ RBV

MK-5172 (100 mg)MK-8742 (50 mg)

MK-5172 (100 mg)MK-8742 (50 mg)+RBV

MK-5172 (100 mg)MK-8742 (50 mg) +RBV

MK-5172 (100 mg)MK-8742 (50 mg)

Ongoing

GT1a/b

GT1a/b

GT1b

GT1a

GT1a/b

GT1a

Par

t A

Par

t B

(8 weeks)

40

C-WORTHY: MK-5172 + MK-8742 ± RBVC-WORTHY: MK-5172 + MK-8742 ± RBV

Hezode C, et al. EASL International Liver Congress, 2014. Abstract O10.

NS3/4A

NS5A

NS5B

Phase 283

9498

0

20

40

60

80

100

SV

R 4

-24,

% P

atie

nts

8 Weeks+RBV(GT1a)

12 Weeks+RBV

(GT1a 61%GT1b 39%)

12 Weeks no RBV

(GT1a 68%GT1b 32%)

Interim results (SVR4-24)

n=30 n=35 n=44

41

Faldaprevir + Deleobuvir + PPI-668 ± RBVFaldaprevir + Deleobuvir + PPI-668 ± RBV

Lalezari J, et al. EASL International Liver Congress, 2014. Abstract O65.

NS3/4A

NS5A

NS5B Non-nuc

DBV (600 mg twice dailyFDV (120 mg daily)PPI-668 (200 mg daily)+RBV

DBV (400 mg twice dailyFDV (120 mg daily)PPI-668 (200 mg daily)+RBV

Genotype 1aTreatment-naïveIL28BB restricted to no more than 1/3 of patientsNon-cirrhotic

Phase 2

SVR12

0 12 24 Weeks

DBV (600 mg twice dailyFDV (120 mg daily)PPI-668 (200 mg daily)(no RBV)

DBV: DeleobuvirFDV: Faldaprevir

42

Faldaprevir + Deleobuvir + PPI-668 ± RBVFaldaprevir + Deleobuvir + PPI-668 ± RBV

Lalezari J, et al. EASL International Liver Congress, 2014. Abstract O65.

NS3/4A

NS5A

NS5B Non-nuc

SV

R 1

2, %

Pat

ien

ts

n=12 n=12

DBV 600 mg twice daily

+RBV

Phase 2

n=12 (Confounding factors)


+RBV


no RBV


Part B: Treatment-Experienced Patients

44

SAPPHIRE-II: ABT-450/r + Ombitasvir + Dasabuvir + RBV (3D + RBV)SAPPHIRE-II: ABT-450/r + Ombitasvir + Dasabuvir + RBV (3D + RBV)

Zeuzem S, et al. EASL International Liver Congress, 2014. Abstract O1.

Zeuzem S, et al. NEJM 2014 DOI: 10.1056/NEJMoa1401561

NS3/4A

NS5A

NS5B Non-Nuc

3D + RBV

Placebo 3D + RBV

0 12 24 60 72

Double-blind Treatment Period

Open-label Treatment Period

Primary analysis:SVR12


Genotype 1Prior PR (Relapse, Partial response, or Null response)No cirrhosis

Phase 3

Weeks

45

SAPPHIRE-II: ABT-450/r + Ombitasvir + Dasabuvir + RBV (3D + RBV)SAPPHIRE-II: ABT-450/r + Ombitasvir + Dasabuvir + RBV (3D + RBV)

Zeuzem S, et al. EASL International Liver Congress, 2014. Abstract O1.

Zeuzem S, et al. NEJM 2014 DOI: 10.1056/NEJMoa1401561

NS3/4A

NS5A

NS5B Non-Nuc95.3100

95.2

0

20

40

60

80

100

Prior Relapse(N=86)

Prior Partial Response

(n=65)

Prior Null Response

(n=146)

SV

R12

, % P

atie

nts

Phase 3

46

ION-2: Sofosbuvir + LedipasvirION-2: Sofosbuvir + Ledipasvir

Afdahl N, et al. EASL International Liver Congress, 2014. Abstract O109.


NS3/4A

NS5A

NS5B NucLDP/SOF

LDP/SOF + RBV

0 12 24 36

Genotype 1Failed prior PR or Triple therapy20% of patients had cirrhosisPlatelet count ≥50,000, no neutrophil minimum

Phase 3

LDP/SOF

LDP/SOF + RBV

SVR12

SVR12

SVR12

SVR12


Weeks

47

ION-2: Sofosbuvir + LedipasvirION-2: Sofosbuvir + Ledipasvir

Afdahl N, et al. EASL International Liver Congress, 2014. Abstract O109.


NS3/4A

NS5A

NS5B Nuc94 96 99 99

0

20

40

60

80

100

LDV/SOF(n=109)

SV

R12

, %

Pat

ien

ts


LDV/SOF(n=109)



Phase 3

48

HALLMARK-DUAL: Daclatasvir + Asunaprevir: GT1bHALLMARK-DUAL: Daclatasvir + Asunaprevir: GT1b


NS3/4A

NS5A

NS5B

DCV + ASV

DCV + ASV Enter another studyDCV + ASV 24 weeks

0 12 24 36

Genotype 1bTreatment-naïve, prior null or partial response to PR, IFN intolerant or ineligible

Phase 3

Weeks

STOP

12-week arm discontinued and participants invited to enroll in separate 24-week trial

DCV: Daclatasvir, 60 mg dailyASV: Asunaprevir, 100 mg twice daily

DCV + ASV

DCV + ASV

Treatment-naive

Nonresponder

Ineligible/ Intolerant

49

HALLMARK-DUAL: Daclatasvir + Asunaprevir: GT1bHALLMARK-DUAL: Daclatasvir + Asunaprevir: GT1b


NS3/4A

NS5A

NS5B

82 8081

91

73

0

20

40

60

80

100

Prior Non-responders

SV

R12

, %

Pat

ien

ts

Ineligible/Intolerant

Phase 3

Null Partial

N=119 N=84

Depression Anemia/neutropenia

Advanced fibrosis/cirrhosis with thrombocytopenia

N=71 N=87 N=77

50


Mark Sulkowski, MDProfessor of Medicine

Medical Director, Viral Hepatitis CenterJohns Hopkins University

School of MedicineBaltimore, MD


Part C: Cirrhosis

52

TURQUOISE-II: ABT-450/r + Ombitasvir + Dasabuvir + RBV (3D + RBV)TURQUOISE-II: ABT-450/r + Ombitasvir + Dasabuvir + RBV (3D + RBV)

Poordad F, et al. EASL International Liver Congress, 2014. Abstract O163.

Poordad F, et al. NEJM 2014 DOI: 10.1056/NEJMoa1402869

NS3/4A

NS5A

NS5B Non-Nuc

3D + RBV

3D + RBV

0 12 24


Genotype 1Treatment-naïve or prior PR; no prior therapy with DAAsAll patients had compensated cirrhosis (Child-Pugh A) at screening

Phase 3

SVR12

SVR12

53




NS3/4A

NS5A

NS5B Non-Nuc

88.6

98.594.2

100

0

20

40

60

80

100

12 Weeks

GT1a

SV

R12

, % P

atie

nts

Phase 3

24 Weeks 12 Weeks

GT1b

24 Weeks

N=140 N=121 N=68 N=51

54




NS3/4A

NS5A

NS5B Non-Nuc

92.2 93.3

100

80

92.9

100 100

92.9

0

20

40

60

80

100

Naive

GT1a

SV

R12

, % P

atie

nts

Phase 3

Prior Relapse

N=64 56 15 13 11 10 50 42

Prior Partial Response

Prior Null Response

12 Weeks

24 Weeks

Treatment Duration

55




NS3/4A

NS5A

NS5B Non-Nuc

88.992.6

84

92.997 95.7

88.9

96.8

0

20

40

60

80

100

<100

SV

R12

, % P

atie

nts

Phase 3

≥100

N=45 33 163 139 25 18 183 154

<35 ≥35

12 Weeks

24 Weeks

Treatment Duration

Baseline Platelet Count(x109/L)

Baseline Serum Albumin(g/L)

56





NS3/4A

NS5A

NS5B NucLDP/SOF

LDP/SOF + RBV

0 12 24 36

Genotype 1Treatment-naïveTargeted 20% with cirrhosis (actual 15-17%)Platelet count ≥50,000, no neutrophil minimum

Phase 3

LDP/SOF

LDP/SOF + RBV

SVR12

SVR12

SVR12

SVR12


Weeks

57

ION-1: Ledipasvir + SofosbuvirTreatment-Naïve, Cirrhotic Patients

ION-1: Ledipasvir + SofosbuvirTreatment-Naïve, Cirrhotic Patients



NS3/4A

NS5A

NS5B Nuc99 97 98 9994

10094

100

0

20

40

60

80

100Ci

rrho

sis

Cirr

hosis

Cirr

hosis

Cirr

hosis

LDV/SOF

SV

R12

, %

Pat

ien

ts



Phase 3

n=180 n=34 n=184 n=33 n=180 n=33 n=181 n=36

58

ION-2: Sofosbuvir + Ledipasvir Treatment-Experienced, Cirrhotic Patients

ION-2: Sofosbuvir + Ledipasvir Treatment-Experienced, Cirrhotic Patients

Afdahl N, et al. NEJM 2014. DOI10/1056/NEJMoa1316366.


NS3/4A

NS5A

NS5B Nuc95.4

100 98.9 98.9

86.481.8

100 100

0

20

40

60

80

100Ci

rrho

sis

Cirr

hosis

Cirr

hosis

Cirr

hosis

LDV/SOF

SV

R12

, %

Pat

ien

ts



Phase 3

n=87 n=22 n=89 n=22 n=87 n=22 n=89 n=22

59


Kao J-H, et al. EASL International Liver Congress, 2014. Abstract P1300.

NS3/4A

NS5A

NS5B

84

9187

8185

91

8084

0

20

40

60

80

100

SV

R12

, %

Pat

ien

ts

Phase 3

Cirrhotic

Non-Cirrhotic

Treatment Duration

Overall Treatment-Naive

N=206 437 32 171 63 142 111 124

Non-Responder Ineligible/Intolerant

60

C-WORTHY: MK-5172 + MK-8742 ± RBVCirrhosis

C-WORTHY: MK-5172 + MK-8742 ± RBVCirrhosis

Lawitz E, et al. EASL International Liver Congress, 2014. Abstract O61.

NS3/4A

NS5A

NS5B

Phase 2

MK-5172 MK-8742 + RBV

Genotype 1Treatment-Naïve with CirrhosisPrior Null-Responders ± Cirrhosis

0 12 24 36 Weeks

MK-5172 MK-8742 No RBV

MK-5172 (100 mg)MK-8742 (50 mg)+RBV

MK-5172 100 mg dailyMK-8742 50 mg daily

18

MK-5172 (100 mg)MK-8742 (50 mg)No RBVNo RBV

61

C-WORTHY: MK-5172/ MK-8742 ± RBVCirrhosis

C-WORTHY: MK-5172/ MK-8742 ± RBVCirrhosis

Lawitz E, et al. EASL International Liver Congress, 2014. Abstract O61.

NS3/4A

NS5A

NS5B

94

100

94

100

0

20

40

60

80

100

HC

V R

NA

<25

IU/m

l, %

Pat

ien

ts

Null-Response

Treatment-Naive

N=85 N=32 N=33 N=14

Null-Response

Treatment-Naive

GT1a, Cirrhosis GT1b, Cirrhosis

Phase 2

Pooled 12- and 18-week arms

±RBV

4-8 week follow-up


Part D: HIV Co-infection

63

HIV-ERADICATE: Sofosbuvir + Ledipasvir HIV-ERADICATE: Sofosbuvir + Ledipasvir

Osinusi A, et al. EASL International Liver Congress, 2014. Abstract O14.

NS3/4A

NS5A

NS5B NucARV UntreatedCD4 count stable and HIV RNA <500 copies ORCD4 count >500 cells/mm3

0 12

HIV/HCV Co-infectedHCV Genotype 1Treatment-NaiveF0-3

SVR12

SOF: Sofosbuvir 400 mg dailyLDV: Ledipasvir 90 mg daily

SOF + LDV

ARV TreatedCD4 count >100 cells/mm3HIV RNA <40 copiesCurrent ARVs ≥8 weeks

Currently SVR4

ARVs: tenofovir, emtricitabine, efavirenz, rilpivirine, and raltegravir

64


Regimen N(%)

Tenofovir/Emtricitabine plus

Efaviranz (EFV) 15 (41)

Raltegravir (RAL) 10 (27)

Rilpivirine (RPV) 8 (21)

RPV/RAL 3 (8)

EFV/RAL 1 (3)


NS3/4A

NS5A

NS5B NucARV regimens in the ARV-treated group (n=37)

65



NS3/4A

NS5A

NS5B Nuc100 100 100 100 100100 100 100

0

20

40

60

80

100

HC

V R

NA

< L

LQ

, % p

atie

nts

Week 8 End of Treatment

13 37

SVR4 SVR12SVR8

ARV TreatedARV Untreated

13 30 12 22 10 10

Interim Results

66


ARV Untreated (n=13)

No clinically significant changes in HIV RNA during HCV treatment

ARV Treated (n=37)

One patient with transient HIV viral breakthrough– Missed ARV for 4 days

– Re-suppressed on the same regimen


HIV RNA tests on treatment days 0, 1, 3, 5, 7 and weeks 2, 4, 8,and 12

67

C-WORTHY: MK-5172/ MK-8742 ± RBVC-WORTHY: MK-5172/ MK-8742 ± RBV


NS3/4A

NS5A

NS5BMK-5172 MK-8742 + RBV

0 12 24

HIV/HCV Co-infectedHCV Genotype 1Non-cirrhotic

Phase 2

SVR12

SVR12MK-5172 MK-8742 No RBV

Stable on raltegravir + two NRTIs for 8 weeks prior to enrollmentART dose modification not permitted during 8 weeks preceding enrollment unless dose modification due to tolerability failureCD4 >300 cells/mm3

Undetectable HIV RNA for 24 weeks

68

C-WORTHY: MK-5172/ MK-8742 ± RBVC-WORTHY: MK-5172/ MK-8742 ± RBV


NS3/4A

NS5A

NS5B

HC

V R

NA

< L

LQ

, %

pat

ien

ts

Week 4 Week 8 Week 12 SVR4

No RBV+ RBV

Interim Results

100 100 10097

100

90 90 90

0

20

40

60

80

100Phase 2

MK-5172 + MK-8742

29 30 29 30 29 30 29 29

69

Summary (1 of 4): Genotype 2/3 Chronic HCVSummary (1 of 4): Genotype 2/3 Chronic HCV

Sofosbuvir + RBV is approved and recommended for treatment of genotype 2/3 patients with chronic HCV and who are treatment-naïve or relapsed after prior PR– Genotype 2 chronic HCV (12 weeks of therapy)– Genotype 3 chronic HCV (24 weeks of therapy)

70

Summary (2 of 4): Genotype 1 Chronic HCVSummary (2 of 4): Genotype 1 Chronic HCV

Two regimens have demonstrated very high SVR12 rates (>90%) in phase III trials of treatment-naïve patients, and patients who failed prior therapy (relapsed, null response, partial response)– 3D +RBV (ABT-450 + ombitasvir + dasabuvir +RBV)– Ledipasvir + Sofosbuvir

Both regimens were studied in trials using 12-week duration of therapy– The ION-3 trial suggests that 8 weeks of therapy may be

sufficient for ledipasvir + sofosbuvir therapy (±RBV) in treatment-naïve patients without cirrhosis

71


Other regimens showing high SVR12 rates in phase II trials include– Daclatasvir + asunaprevir + BMS-791325– MK-5172 + MK8742 ± RBV– Faldaprevir + Deleobuvir + PPI-668 ± RBV

Cirrhotic Patients– The phase III TURQUOISE-II trial enrolled only patients with

compensated cirrhosis and showed high SVR12 rates for 12 or 24 weeks of therapy with 3D + RBV (treatment-naïve and prior PR failures)

– The cirrhotic subgroups of other trials also showed high SVR12 rates for• Ledipasvir + sofosbuvir ± RBV (treatment-naïve patients)• Daclatasvir + asunaprevir (Gt1b patients)

72


HIV Co-infected Patients– Phase II trials have found high SVR12 rates for treatment of HCV

genotype 1 patients, with acceptable HIV-related safety for:• Sofosbuvir + ledipasvir

• MK-5172 + MK-8742 ± RBV

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