Poordad F. NEJM 2014;368:45-532D Phase IIa

Design

Treatment regimens– Paritaprevir/rironavir (PTV/r) : PTV 250 or 150 mg qd/ritonavir 100 mg qd (2 tablets)– Dasabuvir (DSV) : 400 mg bid– RBV : 1000 or 1200 mg/day (bid dosing) according to body weight (< or ≥ 75 kg)

Endpoints– Primary : eRVR (undetectable HCV RNA from W4-W12), with 95% CI– Secondary : SVR12 (HCV RNA < 25 IU/mL), with 95% CI

PTV250/r + DSV + RBV

Not randomisedOpen label

18-65 yearsChronic HCV genotype 1

Detectable HCV RNANo cirrhosis

No HBV or HIV co-infection

2D Phase IIa Study: paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1

N = 14

N = 19

W12

PTV150/r + DSV + RBV SVR12

SVR12

PTV150/r + DSV + RBV SVR12

N = 17

Treatment naïve

Treatment naïve

Null or partial responseto PEG-IFN + RBV

2D Phase IIa Study: paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1

Treatment-naïve Treatment-experienced

PTV250/r + DSV + RBVN = 19

PTV150/r + DSV + RBVN = 14

PTV150/r + DSV + RBVN = 17

Mean age, years 54 51 52Female 47% 0 35%Race : white/black 79% / 21% 86% / 14% 76% / 24%Body mass index, mean 27.3 24.6 27.6Genotype 1a / 1b 89% / 11% 79% / 21% 94% / 6%IL28B CC genotype 53% 36% 0HCV RNA log10 IU/mL, mean 6.25 6.44 6.91Response to previous therapy

PartialNull

- - 107

Discontinued treatment, N 1ALT elevation

1Inability to comply

0

Baseline characteristics and patient disposition

2D Phase IIa Poordad F. NEJM 2014;368:45-53

HCV RNA < 25 IU/mL, % (95% CI)PTV250/r + DSV + RBV PTV150/r + DSV + RBV PTV150/r + DSV + RBV exp

25

50

100

75

89(67-99)

% 100

eRVR EOT SVR12

95(74-100)

79(49-95)

6559(33-82)

N 19 19 19 14 17 1714 14 17

93

47(23-72)

93(66-100)

eRVR EOT SVR12 eRVR EOT SVR12

SVR12 in IL28B non-CC naïve patients : 18/18 vs 13/15 in CC

2D Phase IIa Study: paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1

2D Phase IIa Poordad F. NEJM 2014;368:45-53

2D Phase IIa Study: paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1

Virologic breakthrough– None in naïve patients– Six (35%) in previous non-responders

Relapse– None in naïve patients– 3 in pre-treated patients

Resistance testing (population sequencing) of the 9 failures– 8/9 had ≥ 1 mutant resistant variants in NS3 and NS5B

• NS3 : position 168 (N = 8) + 155 (N = 1)• NS5B : position 316 (N = 2), 414 (N = 3), 554 (N = 2), 556 (N = 4), 559 (N = 1)

– 1 patient had a baseline NS3 168 mutation

2D Phase IIa Poordad F. NEJM 2014;368:45-53

2D Phase IIa Study: paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1

Adverse events, n (%)Treatment-naïve Experienced

PTV250/r + DSV + RBV

N = 19

PTV150/r + DSV + RBV

N = 14

PTV150/r + DSV + RBV

N = 17Adverse event in > 10% in any group

Fatigue 47% 43% 35%Nausea 21% 21% 24%Headache 26% 14% 18%Dizziness 5% 29% 24%Insomnia 26% 21% 0Pruritus 21% 0 12%Rash 21% 7% 6%Vomiting 5% 21% 0

Laboratory abnormalitiesTotal bilirubin ≥ 2 x ULN 3 3 0Creatinine ≥ 1.5 mg/dL 2 0 0ALT ≥ 5 x ULN 1 0 0

2D Phase IIa Poordad F. NEJM 2014;368:45-53

2D Phase IIa Study: paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1 Summary

– This preliminary study suggests that the all-oral combination of paritaprevir/r, dasabuvir, and ribavirin for 12 weeks is associated with a sustained virologic response in a high proportion of previously untreated patients with HCV genotype 1 infection

– This regimen is less effective in patients who have HCV genotype 1 infection with a null or partial response to previous therapy

– In most cases, virologic failure was associated with the emergence of variants with substitutions in both NS3 and NS5B, at positions known to confer resistance in vitro to PTV and DSV, respectively

– Discontinuation for adverse event occurred in 1 patient (asymptomatic ALT elevation)

2D Phase IIa Poordad F. NEJM 2014;368:45-53