Paul Y. Kwo, MD Professor of Medicine Medical Director of Transplantation Division of Medicine/Gastroenterology/ Hepatology Indiana University School of

Paul Y. Kwo, MD Professor of Medicine

Medical Director of TransplantationDivision of

Medicine/Gastroenterology/ Hepatology

Indiana University School of Medicine

Indianapolis, Indiana

HCV Treatment With New Therapiesin Patients With Cirrhosis

This activity is supported by educational grants from Gilead Sciences and Janssen.

Estimated 1 Million HCV-Infected Persons in the US Will Have Cirrhosis by 2020

Projection based on multicohort natural history model

Davis GL, et al. Gastroenterology. 2010;138:513-521.

6,000,000

5,000,000

4,000,000

3,000,000

2,000,000

1,000,000

0

To

tal N

um

ber

of

HC

V-

Infe

cted

Per

son

s

195

0

196

0

197

0

198

0

200

0

199

0

201

0

203

0

202

0

Peak incidence Peak cirrhosis

40 yrs

Yr

Acute hepatitisCirrhosisEver infectedChronic HCV

GBD 2010: HCV-Related Cirrhosis, Liver Cancer, and Death in the United States

Estimated 19,500 liver cancer and 49,500 cirrhosis deaths in US in 2010 Total liver-related deaths increased from 45,000 to 70,000 over 20 yrs

Cowie BC, et al. AASLD 2013. Abstract 23.

Causes of CLD Death, US 2010

Dea

ths

(%)

50

40

30

20

10

0

41

16

29

14

8

40 39

13

Liver Cancer Cirrhosis

Causes of CLD Death, US

Yr

Dea

ths

(n)

HBVHCV

Liver cancer–HBVCirrhosis–HBV

AlcoholOther

Liver cancer–HCVCirrhosis–HCVLiver cancer–alcoholCirrhosis–alcohol

1990 1995 2000 2005 2010

25,000

20,000

15,000

10,000

5000

0

Birth Cohort Screening and DAA Tx Could Greatly Reduce HCV-Related Transplants

Markov model[1] based on birth cohort developed to predict transplant rate[2]

Assumptions in model: All stages of fibrosis treated at same rate; 90% response rate to new Tx; all pts with decompensated cirrhosis or HCC within Milan criteria considered potential transplant candidates

Liv

er

Tra

nsp

lan

ts (

n)

20,000

2013 2018 2023 2028 2033 2038 2043

40,000

60,000

80,000

100,000

120,000

140,000

160,000

180,000

0

Yr in Model

150,617162,559 162,747

24,258 21,994

49,013

91,310

126,296

18,19325,573 27,175 26,207

No treatment

25% treated

50% treated

75% treated

All treated

1. Davis GL, et al. Gastroenterology. 2010;138:513. 2. Desai AP, et al. AASLD 2013. Abstract 1427.

Fibrosis Assessment: Important to Diagnose CirrhosisAASLD/IDSA guidance

An assessment of the degree of hepatic fibrosis, using noninvasive testing or liver biopsy, is recommended (rating: Class I, Level A)

Fibrosis assessment used to determine treatment urgency if limited resources prevent treatment of all cases of HCV infection and need for additional screening

Cirrhotic patients require regular screening for HCC, varices, other complications

Achieving SVR in cirrhotic HCV pts highly beneficial

AASLD/IDSA HCV Management Guidance. October 2014.

Options for Liver Fibrosis Assessment

Liver Biopsy

Serum Biomarke

rs

Liver biopsy: gold standard

Axial CT/MRI, US can demonstrate cirrhotic morphology, portal hypertension

Serum markers of fibrosis

Elastography: approved in United States

Strategies for Noninvasive Fibrosis Assessment

AASLD/IDSA guidance[1]

Most efficient strategy combines direct serum biomarkers and transient liver elastography[2]

Consider biopsy for any patient with discordant results between 2 testing methods if the information will affect clinical decisions

Persons with clinical evidence of cirrhosis do not require further disease staging

1. AASLD/IDSA HCV Management Guidance. October 2014. 2. Boursier J, et al. Hepatology. 2012;55:58-67.

AASLD/IDSA: Patients With F3/F4 Fibrosis Have Highest Priority for HCV TreatmentTreatment recommended for all patients with

chronic HCV infection (rating: Class I, Level A)When constrained resources prevent treatment

of all HCV infection cases, highest priority should be given to patients with advanced fibrosis (Metavir F3) or compensated cirrhosis (Metavir F4), liver transplant recipients, and patients with severe extrahepatic hepatitis C

Based on available resources, treatment should be prioritized as necessary so that patients at high risk for liver-related complications and severe extrahepatic hepatitis C complications are given high priority


NS3/4A Protease Inhibitors (PI)

High potency

Limited genotypic coverage

Low barrier to resistance

NS5A Inhibitors

High potency

Multigenotypic coverage


NS5B Nucleos(t)ide Inhibitors (NI)

Intermediate potency

Pangenotypic coverage

High barrier to resistance

NS5B Nonnucleoside Inhibitors (NNI)

Intermediate potency

Limited genotypic coverage


Direct-Acting Antiviral Agents: Key Characteristics

C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B

Evolving Options for HCV Therapy

New in 2013: beginning of all-oral therapySofosbuvir Simeprevir

New in 2014 and early 2015: all-oral therapy options for allSofosbuvir/ledipasvirParitaprevir/ritonavir/ombitasvir + dasabuvir Daclatasvir

Additional development of new therapies ongoing

Management of Genotype 1 HCV With Cirrhosis

Current AASLD/IDSA Guidance: GT1, Previous Nonresponders to pegIFN/RBV

Note that guidelines do not yet reflect FDA approval of sofosbuvir/ledipasvir or other agents that may be approved in coming months


IFN Eligible IFN Ineligible

Preferred Sofosbuvir 400 mg/day + simeprevir 150 mg/day ± weight-based RBV 1000-1200 mg/day for 12 wks*

Alternative

Sofosbuvir 400 mg/day for 12 wks + weight-based RBV 1000-1200 mg/day + wkly pegIFN for 12-24 wks

Simeprevir 150 mg/day for 12 wks + weight-based RBV 1000-1200 mg/day + wkly pegIFN for 48 wks*

Sofosbuvir 400 mg/day + weight-based RBV 1000-1200 mg/day for 24 wks

*Pts with cirrhosis must have well compensated liver disease to receive simeprevir.

Current AASLD/IDSA Guidance: GT1, Tx-Naive and Previous Relapsers

Note that guidelines do not yet reflect FDA approval of sofosbuvir/ ledipasvir or other agents that may be approved in coming months

Recommendations for Tx-naive/previous relapse pts with compensated cirrhosis, including those with HCC, same as for pts without cirrhosis


IFN Eligible IFN Ineligible

Preferred Sofosbuvir 400 mg/day + weight-based RBV 1000-1200 mg/day + wkly pegIFN for 12 wks

Sofosbuvir 400 mg/day + simeprevir 150 mg/day ± weight-based RBV 1000-1200 mg/day for 12 wks

Sofosbuvir 400 mg/day + weight-based RBV 1000-1200 mg/day for 24 wks*

Alternative

Simeprevir 150 mg/day for 12 wks + weight-based RBV 1000-1200 mg/day plus wkly pegIFN for 24 wks (GT1b or 1a without Q80K only)

*Likely less effective than sofosbuvir + simeprevir, particularly among pts with cirrhosis.

SofosbuvirOral, once-daily nucleotide NS5B polymerase inhibitor

Potent antiviral activity; pangenotypic

High barrier to resistance

Pharmacology profileNo significant drug interactions, including tacrolimus or

cyclosporine

Approved for combination treatment of HCV in following settingsGT1-4 HCVHCC meeting Milan criteria; awaiting transplantationHIV coinfection

Sofosbuvir [package insert].

NEUTRINO: SVR12 With Sofosbuvir + pegIFN/RBV in Tx-Naive GT1/4/5/6

Open-label, single-arm, phase III study (N = 327): sofosbuvir 400 mg QD + pegIFN/RBV for 12 wks – 17% cirrhosis

Patel K, et al. AASLD 2013. Abstract 1093.

SVR12 by Biopsy Fibrosis Stage SVR12 by FibroTest Stage

SV

R12

(%

)

n/N =

100

80

60

40

20

0

91

78

10089

16/16 124/137 34/38

100

80

60

40

20

0

85

97

79

96

76/78 101/105 46/5432/41 68/86

F0 F1-F2 F3 F4

Cirrhosis Predictive of Relapse With Sofosbuvir + pegIFN/RBV in GT1

Pooled multivariate regression analysis from NEUTRINO and ATOMIC* studies[1]

*ATOMIC: Open-label multicenter phase II study of sofosbuvir + pegIFN/RBV in noncirrhotic treatment-naive patients; SVR rates 87% to 89% in GT1 HCV[2]

1. Foster GR, et al. EASL 2014. Abstract O66. 2. Kowdley KV, et al. Lancet. 2013;381:2100-2107.

SimeprevirOral, once-daily NS3 PI for GT1 HCVImproved adverse effect profile vs previous PIs: no

anemiaFewer drug–drug interactions vs previous PIs: no

meaningful drug–drug interactions with tacrolimus No data yet in CTP class B/C pts, but higher

simeprevir exposure in CTP class B/C individuals without HCV infection makes dosing problematic

Approved for combination treatment of GT1 HCVScreening for Q80K in GT1a pts recommended

Simeprevir [package insert].

COSMOS: Simeprevir + Sofosbuvir ± RBV in GT1 HCV Patients

Randomized phase IIa study

Simeprevir 150 mg QD; sofosbuvir 400 mg QD; weight-based RBV 1000-1200 mg/day.

Patients With GT1 HCV Cohort 1:

Previous null responders, F0-F2

(N = 80)

Cohort 2:

Naives and previous null responders, F3-F4

(N = 87)

Simeprevir + Sofosbuvir + RBV (n = 54)

Simeprevir + Sofosbuvir (n = 31)

Wk 12 Wk 24

Simeprevir + Sofosbuvir (n = 28)

Simeprevir + Sofosbuvir + RBV (n = 54)

Lawitz E, et al. Lancet. 2014;[Epub ahead of print].

COSMOS: SVR12 in Tx-Naive and Previous Null Responders With F3-F4 Fibrosis

Treatment-naive patients and previous null responders

Lawitz E, et al. Lancet. 2014;[Epub ahead of print].

Overall

28/30 16/16n/N =

100

80

60

40

20

0

93

25/27 82/87

100

24 Wks

SMV + SOF + RBV

SMV + SOF

12 Wks

SMV + SOF + RBV

SMV + SOF

13/14

SMV + SOF + RBV

93 93 94

SV

R12

(%

)

HCV-TARGET: Adverse Events With Sofosbuvir + Simeprevir ± RBV in GT1

Longitudinal observational analysis of patients receiving DAA-based HCV therapy in North America and Europe 60% of patients with GT1 HCV initiated sofosbuvir + simeprevir ± RBV

Most frequent adverse events: mild fatigue, headache, nausea Discontinuations for virologic failure or adverse event: n = 3 Serious adverse events: 10 in 8 patients Deaths: n = 1 (hepatic decompensation)

Sulkowski MS, et al. AASLD 2014. Abstract 955. Note that these data were available in abstract form only at the time of drafting this slideset and are subject to change at the AASLD 2014 presentation.

Sofosbuvir + RBV in Pts With Cirrhosis and Portal HTN ± Decompensation

Interim results of an open-label phase II trial

Observation (n = 25)

Sofosbuvir + Ribavirin (n = 25)

Wk 72

Afdhal N, et al. EASL 2014. Abstract O68.

Sofosbuvir 400 mg once daily; RBV 1000-1200 mg/day divided twice daily.*Among 25 patients allocated sofosbuvir + RBV, 10 had GT1a HCV, 9 had GT1b, 2 had GT2, 2 had GT3, and 2 had GT4.

HCV-infected patients with portal HTN ±

decompensated liver disease*

(N = 50)

Wk 24Current analysis

Sofosbuvir + Ribavirin (n = 25)

Wk 48

Sofosbuvir + RBV in Pts With Cirrhosis and Portal HTN: On-Tx Virologic Response

HC

V R

NA

< L

LO

Q (

%)

100

80

60

40

20

0Wk 2 Wk 4 Wk 8 Wk 12

56

10094*

Wk 24

CTP A44

75

100 100 10094 93

CTP B

5/9 9/9n/N = 8/8 7/77/16 12/16 15/16 8/8 15/16 14/15

*1 patient with nonresponse at Wk 8.


Sofosbuvir + RBV in Pts With Cirrhosis/ Portal HTN: Disease Marker Changes

Platelets (103/µL) Albumin (g/dL)SOF + RBV (n = 25) Observation 24 wks (n = 25)

CTP A CTP B

P = .003

P = NS

P = .001 P = .001

Clinical Events, n

Ascites Hepatic Encephalopathy

SOF + RBV(n = 25)

Observation(n = 25)

SOF + RBV(n = 25)

Observation(n = 25)

Baseline 6 9 5 2

Wk 12 5 8 3 3

Wk 24 0 7 0 4


201510

50

-5-10-15

17

-9

1

-1

CTP A CTP B

0.60.50.40.30.20.1

0-0.1-0.2

0.50.4

0

-0.1

130

-75-72

ALT (U/L)

CTP A CTP B

20

0

-20

-40

-60

-80

Sofosbuvir/LedipasvirOral, once-daily fixed-dose combination of nucleotide

NS5B polymerase inhibitor and NS5A inhibitorSofosbuvir: potent antiviral activity; pangenotypicLedipasvir: potent antiviral activity against GT1a, 1b,

4a, 5a, 6aCombination has high barrier to resistancePharmacology profile

Clinically significant drug interactions include with P-gp inducers

No clinically significant drug interactions with tacrolimus or cyclosporine

Approved for treatment of GT1 HCV

Sofosbuvir/ledipasvir [package insert].

Sofosbuvir/Ledipasvir 400/90 mg: Prescribing Information for GT1 HCV

*8-wk duration can be considered in treatment-naive patients without cirrhosis who have pretreatment HCV RNA < 6 million IU/mL. †Treatment-experienced patients who have experienced treatment failure with either pegIFN/RBV or an HCV PI plus pegIFN/RBV.

Sofosbuvir/ledipasvir [package insert].

ION-1: SOF/LDV FDC ± RBV for 12 or 24 Wks in Treatment-Naive GT1 Patients Open-label phase III trial[1,2]

15% to 17% of participants had cirrhosis No upper age or BMI limit; platelet count ≥ 50,000/mm3, no

neutrophil min

SOF/LDV + RBV (n = 217)

SOF/LDV (n = 214)

Wk 24

Afdhal N, et al. N Engl J Med. 2014;370:1889-1898.

Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day.

Treatment-naive pts with GT1 HCV

(N = 865)


SOF/LDV (n = 217)

Wk 12Stratified by HCV subtype (1a vs 1b) and

cirrhosis

ION-1: SVR12 According to Cirrhosis Status

SVR12 rates did not differ by GT1a vs GT1b in any treatment arm

No cirrhosis

Cirrhosis

179/179

32/33

178/178

33/33

181/182

31/32

179/179

36/36

12 Wks 24 Wks

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

SV

R12

(%

)


100

80

60

40

20

0

100 97 100 100 10010096.999.5

n/N =

ION-2: SOF/LDV FDC ± RBV for 12 or 24 Wks in Tx-Experienced GT1 Pts

Open-label phase III trial 20% of participants had cirrhosis, 41% to 46% were previous

nonresponders, and 46% to 61% had experienced PI failure No upper age or BMI limit; platelet count ≥ 50,000/mm3, no neutrophil min


SOF/LDV (n = 109)

Wk 24


Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day.

Tx-experienced pts with GT1 HCV

(N = 440)


SOF/LDV (n = 109)

Wk 12

Stratified by HCV subtype (1a vs 1b), cirrhosis, and previous

Tx response

ION-2: SVR12 According to Cirrhosis Status

Absence of cirrhosis was significantly associated with SVR12 in multivariate exact logistic regression model (OR: 5.1; P = .012)


83/87

19/22

89/89

18/22

86/87

22/22

88/89

22/22

12 Wks 24 Wks

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

SV

R12

(%

)

100

80

60

40

20

0

95 86 10082

1009910099

n/N =

No cirrhosis

Cirrhosis

Pooled Efficacy/Safety Analysis of Sofosbuvir/Ledipasvir in Cirrhosis Pooled analysis of GT1 HCV–infected pts with cirrhosis

from phase II and III trials of sofosbuvir/ledipasvir ± RBV for 12-24 wks

Safety similar to that observed in pts without cirrhosis AEs more frequent in pts treated with RBV; no other AE or

SAE trends observed SVR12 rate in 284 pts with available data: 95%

Bourlière M, et al. AASLD 2014. Abstract 82. Note that these data were available in abstract form only at the time of drafting this slideset and are subject to change at the AASLD 2014 presentation.

Opportunities and Challenges With Current Therapies in GT1 CirrhosisHigher SVR rates in GT1 HCV with compensated

cirrhosis with just 12 wks of therapy with sofosbuvir + pegIFN/RBV than with first-generation protease inhibitorsNo adjustment of sofosbuvir required Adverse effects of pegIFN/RBV still problematic in

cirrhotics

All oral therapy now available for patients with GT1 HCV with 2 different regimensSofosbuvir/ledipasvir Sofosbuvir + simprevir ± RBV

Based on limited data in F3/F4 disease (39 patients)

Viral suppression associated with clinical improvement

Current AASLD/IDSA Guidance: Genotype 2/3


Genotype 2 Genotype 3

Recommended Sofosbuvir 400 mg/day + weight-based RBV 1000-1200 mg/day for 12 wks*

Sofosbuvir 400 mg/day + weight-based RBV 1000-1200 mg/day for 24 wks

Alternative (if IFN eligible)

Previous nonresponders only: Sofosbuvir 400 mg/day + weight-based RBV 1000-1200 mg/day + wkly pegIFN for 12 wks

Sofosbuvir 400 mg/day + weight-based RBV 1000-1200 mg/day + wkly pegIFN for 12 wks

*Previous nonresponders to pegIFN/RBV with cirrhosis may benefit from extending treatment to 16 wks.

FISSION: Sofosbuvir + RBV vs pegIFN/ RBV in Tx-Naive GT2/3 HCV Patients

Randomized, controlled, open-label phase III noninferiority trial– 20% to 21% had cirrhosis; 71% to 72% had GT3 HCV

Treatment-naive patients with

GT2/3 HCV(N = 499)

Sofosbuvir 400 mg/day + RBV 1000-1200 mg/day

(n = 256)

PegIFN alfa-2a 180 µg/wk + RBV 800 mg/day(n = 243)

Wk 24Wk 12

Stratified by HCV GT (2 vs 3), HCV RNA (< vs ≥ 106 IU/mL),

cirrhosis (yes vs no)

Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

FISSION: SVR12 According toGenotype and Fibrosis Level

Gane E, et al. EASL 2013. Abstract 5.


SV

R12

(%

)

No cirrhosis No cirrhosisCirrhosis Cirrhosis

58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37n/N =

100

80

60

40

20

0

98

8291

62 6171

34 30

Sofosbuvir + RBV PegIFN + RBV

FUSION: Sofosbuvir + RBV for 12 or 16 Wks in Tx-Experienced GT 2/3 HCV Pts

Randomized, double-blind, placebo-controlled phase III trial– 62% to 64% had GT3 HCV, 33% to 35% had cirrhosis, 74% to 76%

were previous relapsers

Tx-experienced pts with GT2/3 HCV

(N = 201)


(n = 103)


(n = 98)

Wk 16Wk 12

Placebo

Stratified by HCV GT (2 vs 3),

cirrhosis (yes vs no)

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

FUSION: SVR12 According to Genotype and Fibrosis Level

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

Sofosbuvir + RBV 12 wks Sofosbuvir + RBV 16 wks

100

6/10 5/26

SV

R12

(%

)

25/26 7/923/

2314/38

14/23

25/40

No cirrhosis No cirrhosisCirrhosis Cirrhosis


19

6163

37

n/N =

100

80

60

40

20

0

96

60

78

100

80

60

40

20

0

SV

R12

(%

)

VALENCE: Sofosbuvir + RBV for 12 or 24 Wks in Naive and Exp’d GT2/3 HCV Pts

Phase III study in Europe 21% had cirrhosis, 58% previously treated with IFN-based therapy

Original protocol amended to lengthen treatment for all GT3 pts when emerging data suggested benefit of additional treatment for this group*

HCV-infected

Tx-naive or exp’d pts(N = 323)

Sofosbuvir 400 mg/day + RBV 1000 mg or 1200

mg/day(n = 73)

Sofosbuvir 400 mg/day + RBV 1000 mg or 1200 mg/day

(n = 250)

Wk 24Wk 12

GT2

GT3

*Small number of GT3 pts (n = 11) who had already completed 12 wks at time of protocol amendment were included in safety analysis with GT2 but analyzed separately for efficacy. Pts randomized to placebo in original protocol offered alternative treatment protocol.

Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001.

VALENCE: SVR12

No increase in AEs seen with longer duration treatmentAEs consistent with RBV

GT2 12-Wk Treatment(n = 73)

GT3 24-Wk Treatment(n = 250)

100

80

60

40

20

0

SV

R12

(%

)

SV

R12

(%

)

100

80

60

40

20

0Naive,

NoncirrhoticNaive,

Cirrhotic

97 10094

78

Exp’d Noncirrhotic

Exp’d, Cirrhotic

29/30 2/2 30/32 7/9

95 92 87

62

Naive, Noncirrhotic

Naive, Cirrhotic

Exp’d Noncirrhotic

Exp’d, Cirrhotic

87/92 12/13 85/98 29/47n/N = n/N =

Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001.

LONESTAR-2: Sofosbuvir + P/R for 12 Wks in Treatment-Exp’d GT2/3 HCV Pts

Single-arm trial of pts with treatment failure on P/R Approximately 50% with compensated cirrhosis

Lawitz E, et al. AASLD 2013. Abstract LB-4.

Pts with GT2 or GT3 HCV

and previous treatment

failure with P/R

(N = 47)

Sofosbuvir 400 mg/day +PegIFN 180 µg once wkly

+RBV 1000 mg or 1200

mg/day

Wk 12

No cirrhosis

93

10/ 12

SV

R12

(%

)

9/ 9

13/ 14

GT2 GT3

n/N =

100

80

60

40

20

0

100

83 83

10/ 12

Cirrhosis

Anticipated Changes in HCV Therapy

All-oral regimens will be the standard of care by end of 2014 for all genotypes

Excellent efficacy in pts with compensated cirrhosis

More data required in pts with decompensated cirrhosis

On-Treatment Monitoring: GT1 With Cirrhosis Safety data from phase II/III studies suggest no difference in

monitoring required for patients with CTP class A cirrhosis Assessments for drug-related adverse events should be

conducted more frequently if clinically indicated (eg, CBC count for patients receiving RBV)


Treatment Wk 4 8 12/EOT 16* 20* 24* SVR 12

CBC X X X X X X

Creatinine X X X X X X

Calculated GFR X X X X X X

Hepatic fxn panel

X X X X X X

TSH (with IFN) X X

HCV RNA X X X X*If using a 24-wk treatment option.




Treatment Wk 4 8 12/EOT 16* SVR 12

CBC X X X X

Creatinine X X X X

Calculated GFR X X X X

Hepatic fxn panel X X X X

TSH (with IFN) X

HCV RNA X X X

*Previous nonresponders to pegIFN/RBV with cirrhosis may benefit from extending treatment to 16 wks.






Treatment Wk 4 8 12 16 20 24/EOT

SVR 12

CBC X X X X X X

Creatinine X X X X X X

Calculated GFR X X X X X X

Hepatic fxn panel

X X X X X X

TSH (with IFN) X X

HCV RNA X X X X

Triple DAA Therapy With Paritaprevir/ Ritonavir/Ombitasvir + Dasabuvir + RBV

Paritaprevir is a potent NS3/4A protease inhibitor Ritonavir boosting of paritaprevir increases

the peak, trough, and overall drug exposures of paritaprevir to enable once-daily dosing

Ombitasvir is a potent NS5A inhibitorDasabuvir is a nonnucleoside NS5B

polymerase inhibitor

TURQUOISE II: Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV in Cirrhotic GT1 Pts Open-label phase III trial Inclusion criteria: GT1, compensated cirrhosis (CTP class A), DAA naive,

radiographic ascites and varices permitted, serum albumin ≥ 2.8 g/dL, total bilirubin < 3 mg/dL, serum AFP ≤ 100 ng/mL, INR ≤ 2.3, platelets ≥ 60,000 cells/mL

Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV(n = 172)

Paritaprevir/RTV/Ombitasvir + Dasabuvir +

RBV(n = 208)

Wk 24

Poordad F, et al . N Engl J Med. 2014;370:1973-1982.

Paritaprevir/RTV/ombitasvir 150/100/25 mg once daily; dasabuvir 250 mg twice daily; RBV 1000-1200 mg/day.

DAA-naive cirrhotic pts with GT1 HCV

(N = 380)

Wk 12

TURQUOISE-II: ITT SVR12

Superiority threshold: 54%[1]

Noninferiority threshold: 43%[1]

High SVR12 rates regardless of sex, age, BMI, or baseline HCV RNA in subgroup analyses[2]

Pts with platelet counts < 100,000/mm3: 89% to 97%

Pts with serum albumin < 3.5 g/dL: 84% to 89%

1. Poordad F, et al. N Engl J Med. 2014;370:1973-1982. 2. Fried MW, et al. AASLD 2014. Abstract 81. Note that these data were available in abstract form only at the time of drafting this slideset and are subject to change at the AASLD 2014 presentation.

SV

R12

(%

)

n/N =

100

80

60

40

20

0

96

165/172

92

191/208

12 wks 24 wks

P = .09

Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV

TURQUOISE II: SVR12 According to GT1 HCV Subtype and Treatment Experience

Virologic failure in 17/380 pts (4.5%); relapse more frequent with 12-wk vs 24-wk treatment (12 vs 1 pt), 7/12 relapsers by posttreatment Wk 12 were GT1a null responders

12 wks24 wks 100 100

Naive Relapse

100 100 85.7100 100 100

PR NullResponse

GT1b

Poordad F, et al. N Engl J Med. 2014;370:1973-1982.

SV

R12

(%

)

Naive Relapse PR NullResponse

GT1a

59/64

14/15

52/56

13/13

11/11

40/50

10/10

39/42

100

80

60

40

20

0

92.292.9 93.3100 100 100

80.0

92.9100

80

60

40

20

0

22/22

25/25

18/18

20/20

6/7 14/14

3/3 10/10n/N =

TURQUOISE-II: Laboratory Abnormalities

ALT elevation– Asymptomatic, transient, and improved or resolved with ongoing study drug dosing

Bilirubin elevation– Transient, predominantly indirect, no discontinuations due to hyperbilirubinemia

Hemoglobin decrease– Managed with reduction of ribavirin dose in 34 pts (8.9%)

Event 12-Wk Arm(n = 208)

24-Wk Arm(n = 172)

ALT > 5 x ULN, % 2.9 0

Total bilirubin > 3 x ULN, % 13.5 5.2

Hemoglobin, % < 10 g/dL 7.2 11.0 < 8.0 g/dL 1.4 0.6

Poordad F, et al. EASL 2014. Abstract O163. Poordad F, et al. N Engl J Med. 2014;370:1973-1982.

GT1 HCV SVR Summary: Treatment-Naive Patients With Cirrhosis

SV

R (

%)

100

80

60

40

20

0

67

SOF +SMV

12 Wks

1. Lawitz E, et al. Lancet. 2014;[Epub ahead of print]. 2. Afdhal N, et al. N Engl J Med. 2014;370:1889-1898. 3. Poordad F, et al. N Engl J Med. 2014;370:1973-1982.

COSMOS[1]

100 100 100ION-1[2] TURQUOISE-II[3]

SOF +SMV +

RBV12 Wks

SOF +SMV

24 Wks

SOF +SMV +

RBV24 Wks

SOF/ LDV

12 Wks

SOF/ LDV

24 Wks

SOF/ LDV + RBV

12 Wks

SOF/ LDV + RBV

24 Wks

3DAA + RBV

12 Wks

3DAA + RBV

24 Wks

32/33 33/33 31/32 36/36

97100 100

97

n/N =

95

70/74

94

81/862/3 6/6 6/6 3/3

GT1 HCV SVR Summary: Treatment-Experienced Patients With Cirrhosis

SV

R (

%)

80

SOF +SMV

12 Wks

100 100

90

SOF +SMV +

RBV12 Wks

SOF +SMV

24 Wks

SOF +SMV +

RBV24 Wks

100 97

95/ 98

90

110/ 122

4/4 4/5 4/49/ 10

19/22

18/22

22/22

22/22

8682

100

3DAA + RBV

12 Wks

3DAA + RBV

24 Wks

SOF/ LDV

12 Wks

SOF/ LDV

24 Wks

SOF/ LDV + RBV

12 Wks

SOF/ LDV + RBV

24 Wks

COSMOS[1] ION-2[2] TURQUOISE-II[3]

100

80

60

40

20

0

n/N =

1. Lawitz E, et al. Lancet. 2014;[Epub ahead of print]. 2. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493. 3. Poordad F, et al. N Engl J Med. 2014;370:1973-1982.

ELECTRON 2: SOF/LDV FDC ± RBV in Diverse Hard-to-Treat PatientsPartially randomized, open-label phase II

trial

Gane EJ, et al. EASL 2014. Abstract O6.

SOF/LDV FDC (n = 20)

Wk 12

Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day

GT1 and CTP class B cirrhosis(N = 20)

SVR12: 65% (13/20); 7 relapses

Sofosbuvir/Ledipasvir + RBV in Patients With Decompensated Cirrhosis Study population: GT 1 or 4 HCV infection, Tx naive or

experienced, CTP B (n = 55) or C (n = 53) decompensated cirrhosis

Treatment: 12 or 24 wks of sofosbuvir/ledipasvir plus RBV (escalating doses beginning at 600 mg/day)

Tx-emergent SAEs occurred in 28 patients (26%) 4 SAEs in 4 pts deemed related to study treatment: anemia,

decreased hemoglobin, hepatic encephalopathy, peritoneal hemorrhage

Most common AEs: fatigue, nausea, headache

SVR4 rates among patients with available dataCTP B: 89% with 12 wks, 92% with 24 wksCTP C: 91% with 12 wks, 33% with 24 wks (based on 3 pts)

Flamm SL, et al. AASLD 2014. Abstract 239. Note that these data were available in abstract form only at the time of drafting this slideset and are subject to change at the AASLD 2014 presentation.

AI444-040: Sofosbuvir + Daclatasvir ± RBV for GT3 HCV Pts

Randomized, open-label phase IIa study14% of patients with GT2/3 HCV had cirrhosis (specific

number for GT3 not reported)

Tx-naive pts with GT3 HCV

(N = 18)

Daclatasvir 60 mg QD + Sofosbuvir 400 mg QD*

(n = 13)

Wk 24

Daclatasvir 60 mg QD + Sofosbuvir 400 mg QD +

RBV 1000 mg or 1200 mg/day(n = 5)

Sulkowski MS, et al. N Engl J Med. 2014;370:211-221.

*7 patients received 4-week lead-in with sofosbuvir 400 mg QD alone before addition of daclatasvir.

AI444-040: SVR12 in GT3 by Treatment Arm

A potential option for cirrhotic GT3 pts, more data required in cirrhotic nonresponders

SV

R12

(%

)

n/N =

100

80

60

40

20

0

100

5/5

85

11/13

All GT3 Pts (Including Pts With Cirrhosis)

Daclatasvir + sofosbuvir + RBVDaclatasvir + sofosbuvir

Sulkowski MS, et al. N Engl J Med. 2014;370:211-221.

Management of HCV With Cirrhosis: Summary

All oral therapies for patients with GT1 HCV infection approved in 2014> 90% SVR rate, 12- to 24-wk duration Cirrhosis: some treatment-experienced patients

require 24 wks of treatment

Interferon not requiredRBV-free therapies now availableMore data needed in decompensated liver disease

GT2: High SVR rates regardless of cirrhosisGT3: High SVR rates in treatment-naive patients

Additional strategies needed for cirrhotic nonresponders

Documents

Paul Y. Kwo, MD Professor of Medicine Medical Director of Transplantation Division of Medicine/Gastroenterology/ Hepatology Indiana University School of