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Hepatol 2016 641928 MALACHITE TVR PEGIFN RBV Randomisation Openlabel 1865 years HCV genotype 1 HCV RNA gt 10000 IUml Naïve MALACHITEI Failure to prior PEGIFN RBV MALACHITEII ID: 548659

ifn rbv ptv peg rbv ifn peg ptv dsv malachite obv genotype treatment rbvn tvr response hcv study hepatol

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Slide1

Dore G. J

Hepatol 2016; 64:19-28

MALACHITE

TVR + PEG-IFN + RBV

Randomisation

Open-label

18-65 years

HCV genotype 1

HCV RNA > 10,000 IU/ml

Naïve (MALACHITE-I)Failure to prior PEG-IFN + RBV(MALACHITE-II)No cirrhosis No HBV or HIV co-infection

MALACHITE study: OBV/PTV/r + DSV + RBV versus telaprevir + PEG-IFN + RBV in genotype 1

Design

N = 69

W12

W48

* Randomisation

was

stratified

on IL28B (CC or non-CC)

PEG-IFN + RBV

OPV/PTV/r + DSV + RBV

PEG-IFN + RBV

TVR + PEG-IFN + RBV

PEG-IFN + RBV

OPV/PTV/r + DSV + RBV

PEG-IFN + RBV

OPV/PTV/r + DSV

TVR + PEG-IFN + RBV

PEG-IFN + RBV

OPV/PTV/r + DSV + RBV

PEG-IFN + RBV

GT1a

aïve

GT1b

aïve

Experienced

** Randomisation was stratified on genotype (1a or 1b) and previous response to PEG-IFN + RBV (null response, partial response, relapse)

W24

N = 34

N = 84

N = 83

N = 101

N = 47

N = 41Slide2

Treatment regimens

Co-formulated ombitasvir (OBV)/paritaprevir

(PTV)/rironavir

(r): 25/150/100 mg qd = 2 tablets

Dasabuvir (DSB) : 250 mg bidTVR: 750 mg

tid, 8h apartPEG-IFN

a-2a : 180 m

g SC once weeklyRBV: 1000 or 1200 mg/day (bid dosing) according to body weight (< or ≥ 75 kg)In TVR groups, additional 12 or 36 weeks of PEG-IFN + RBV depended on virologic response at treatment W4-12Primary efficacy endpointMALACHITE-I: Non inferiority of OBV/PTV/r + DSB + RBV compared to TVR + PEG-IFN + RBV in genotype 1a and of

OBV/PTV/r + DSB compared to TVR + PEG-IFN + RBV in genotype 1b: SVR12 (HCV RNA < 25 IU/ml) by intention to treat (lower margin of the 2-sided 95% CI for the difference with TVR = - 10.5%)

MALACHITE-II: % of patients achieving SVR12 between treatment arms using a logistic regression model with treatment arm, baseline log10 HCV RNA level, HCV subgenotype (1a, non-1a), and previous PEG-IFN + RBV treatment response (relapse,

partial response, null response)MALACHITE study: OBV/PTV/r + DSV

+ RBV

versus telaprevir + PEG-IFN + RBV in genotype 1

Dore G. J

Hepatol 2016; 64:19-28

MALACHITESlide3

Genotype 1a

Genotype 1b

OBV/PTV/r

+ DSV + RBV

N = 69

TVR + PEG-IFN + RBV

N = 34 *

OBV/PTV/r

+ DSV + RBV

N = 84

OBV/PTV/r + DSV

N = 83

TVR + PEG-IFN + RBV

N = 41 *

Mean

age, years

Female

30%

50%

55%

52%

59%

White

90%

88%

95%

99%

93%

IL28B CC genotype

28%

32%

17%

HCV RNA log

IU/ml, mean

6.29

6.37

6.36

6.33

6.23

Metavir

fibrosis score

F0-F1 / F2 / ≥ F3

72% / 18% / 10%

71% / 21% / 9%

83% / 8% / 8%

72% / 13% / 14%

76% / 10% / 15%

Discontinued treatment, N

Virologic failureAdverse eventWithdrawal Other21101612120095411

Baseline characteristics and patient disposition (MALACHITE-I, treatment-naïve)

MALACHITE study: OBV/PTV/r + DSV + RBV versus telaprevir + PEG-IFN + RBV in genotype 1

* Among the 75 patients in the TVR groups, 59 received 24 weeks of PEG-IFN + RBV, 16 received 48 weeks

Dore G. J Hepatol 2016; 64:19-28

MALACHITESlide4

OBV/PTV/r + DSV + RBV

N = 101

TVR + PEG-IFN + RBV

N = 47

Mean

age, years

Female

46%

40%

White

100%

Genotype 1a / 1b

19% / 81%

15% / 85%

IL28B CC genotype

13%

HCV RNA log

IU/ml, mean

6.37

6.39

Metavir

fibrosis score F0-F1 / F2 / ≥ F3

78% / 17% / 5%

68% / 23% / 9%

Response to prior PEG-IFN + RBV : Relapse / Partial response / Null response

27% / 25% / 49%

26% / 26% / 49%

Duration of PEG-IFN + RBV : 24W / 48W, N

10 (prior relapse) /

37 (null-partial response)

Discontinued treatment, N

Virologic

failure

Adverse event

Withdrawal

Baseline characteristics and patient

disposition

(MALACHITE-II, Treatment-experienced)

MALACHITE study: OBV/PTV/r + DSV

RBV

versus

telaprevir

+ PEG-IFN + RBV in genotype 1

Dore G. J

Hepatol 2016; 64:19-28MALACHITESlide5

SVR

12 (HCV RNA < 25 IU/ml), % (95% CI)

On treatment

failure

Relapse

1**

Failure to achieve SVR

for other reasons ***

5Genotype 1a: non-inferiority

of OBV/PTV/r + DSV + RBVto TVR + PEG-IFN + RBVGenotype 1b: non-inferiority and superiority of OBV/PTV/r + DSV and of OBV/PTV/r + DSV + RBV to TVR + PEG-IFN + RBV** Reinfection (Genotype 2a) *** Missing data or premature discontinuation* These 3 patients wereadherent. At the time of failure, detection of resistance variants at in NS3, NS5A, and/or NS5B that were not present at baselineMALACHITE study: OBV/PTV/r + DSV + RBV

versus telaprevir + PEG-IFN + RBV in genotype 1Dore G. J Hepatol 2016; 64:19-28

MALACHITE%

N69413484

(93-100)

(97-100)

(68-96)

(94-100)

(53-79)

100

Genotype 1b

All patients

OBV/PTV/r + DSV + RBV

OBV/PTV/r + DSVTVR + PEG-IFN + RBVGenotype 1aMALACHITE-I (treatment-naïve)MALACHITE-II(treatment-experienced)78(66-91)101Slide6

MALACHITE-I

MALACHITE-II

OBV/PTV/r

+ DSV + RBV

N = 153

OBV/PTV/r

+ DSV

N = 83

TVR + PEG-IFN + RBV

N = 75

OBV/PTV/r

+ DSV + RBV

N = 101

TVR + PEG-IFN + RBV

N = 47

Serious adverse event, N

AE leading to discontinuation

1 *

AE occurring in ≥ 5% in non IFN-groups

Headache

27%

19%

31%

29%

45%

Nausea

21%

40%

10%

43%

Pruritus

12%

35%

13%

40%

Fatigue

14%

31%

12%

26%

Anemia

45%

3%34%Rash8%023%3%26%Asthenia7%2%

20%

34%

Cough

12%

26%

Insomnia

21%

Adverse events

MALACHITE study: OBV/PTV/r + DSV

RBV

versus

telaprevir

+ PEG-IFN + RBV in genotype 1

* Hot flush and fatigue

Dore G. J

Hepatol

2016; 64:19-28

MALACHITESlide7

MALACHITE-I

MALACHITE-II

OBV/PTV/r + DSV + RBV

N = 153

OBV/PTV/r + DSV

N = 83

TVR + PEG-IFN + RBV

N = 75

OBV/PTV/r + DSV + RBV

N = 101

TVR + PEG-IFN + RBV

N = 47

Hemoglobin

, g/dl

8 to < 10

43%

26%

< 8

ALT > 5 x ULN

AST > 5 x ULN

Total bilirubin > 3 x ULN

Laboratory abnormalities, %

Patient-reported outcomes

SF-36v2 self-administered questionnaire: overall, the difference between the 2 regimens

in the changes from baseline in Mental Component Summary and Physical Component Summary throughout the treatment and post-treatment periods in both treatment-naïve and treatment-experienced patients favored the OBV/PTV/r + DSV

RBV regimen

MALACHITE study: OBV/PTV/r + DSV

RBV

versus

telaprevir

+ PEG-IFN + RBV in genotype 1

Dore G. J Hepatol 2016; 64:19-28MALACHITESlide8

Summary

This is the first head-to-head study of an all-oral, DAA (

OBV/PTV/r + DSV

+ RBV) and a PEG-IFN

-containing (TVR + PEG-IFN + RBV) regimen that quantitatively compares efficacy and safety benefits in treatment-naïve and treatment-experienced HCV

genotype 1-infected patientsSVR12 rate was numerically

higher with OBV/PTV/r + DSV

+ RBV (97-99%) than with TVR + PEG-IFN + RBV (66-82%) regardless of subgenotype or prior treatment statusBetter tolerability of OBV/PTV/r + DSV + RBV Higher improvement in mental and physical health in patients receiving OBV/PTV/r + DSV + RBV

LimitationsExclusion of cirrhosisAbsence of black patientsLow number of experienced patients with genotype 1a

MALACHITE study: OBV/PTV/r + DSV + RBV versus telaprevir + PEG-IFN + RBV in genotype 1Dore G. J Hepatol 2016; 64:19-28

MALACHITE