OBV/PTV/r + DSV + RBV Placebo Randomisation** 3 : 1 Double blind 18-70 years Chronic HCV genotype 1...

OBV/PTV/r+ DSV + RBV

Placebo

Randomisation**3 : 1

Double blind18-70 yearsChronic HCV genotype 1HCV RNA ≥ 10,000 IU/mlFailure to pre-treatment

with PEG-IFN + RBVNo Cirrhosis*

No prior failure with PINo HBV or HIV co-

infection

* Liver biopsy with Metavir ≤ 3 or Ishak ≤ 4, or Fibrotest® ≤ 0.72 + APRI ≤ 2, or Fibroscan kPa < 9.6

N = 97

N = 297

W12 W24

** Randomisation stratified on prior PEG-IFN + RBV therapy response (null, partial, relapse) and on genotype subtype (1a or 1b)

OBV/PTV/r + DSV + RBV SVR12

SVR12

Open label

SAPPHIRE-II Zeuzem S. NEJM 2014;370:1604-14

SAPPHIRE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1 with failure to PEG-IFN + RBV

Treatment regimens– Co-formulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) :

25/150/100 mg qd = 2 tablets– Dasabuvir (DSV) : 250 mg bid– RBV : 1000 or 1200 mg/day (bid dosing) according to body weight (< or ≥ 75 kg)

Design

OBV/PTV/r+ DSV + RBV

Placebo

Randomisation**3 : 1

Double blind18-70 yearsChronic HCV genotype 1HCV RNA ≥ 10,000 IU/mlFailure to pre-treatment

with PEG-IFN + RBVNo Cirrhosis*

No prior failure with PINo HBV or HIV co-

infection

* Liver biopsy with Metavir ≤ 3 or Ishak ≤ 4, or Fibrotest® ≤ 0.72 + APRI ≤ 2, or Fibroscan kPa < 9.6

W12 W24

** Randomisation stratified on prior PEG-IFN + RBV therapy response (null, partial, relapse) and on genotype subtype (1a or 1b)

OBV/PTV/r + DSV + RBV SVR12

SVR12

Open label



Objective– Non-inferiority and superiority of SVR12 assessed vs estimated rate of SVR12 with a

telaprevir-based regimen in prior failure to PEG-IFN + RBV : 65%; 95% CI : 60 to 70).A noninferiority margin of 10.5 % of the 95% CI for the SVR12 of the new regimen established 60% as the noninferiority threshold; the superiority threshold was 70%.

– Analyses by mITT, power > 90%

Design

N = 97

N = 297

OBV/PTV/r + DSV (3D) + RBV

N = 297

PlaceboN = 97

Mean age, years 51.7 54.9

Female 44% 38%

Race : white/black 90.6% / 7.4% 88.7% / 10.3%

Body mass index, mean 26.3 26.3

HCV subgenotype : 1a / 1b 58.2% / 41.4% 58.8% / 41.2%

Fibrosis score F2 or F3 32% 33%

IL28B CC genotype 11.4 % 7.2 %

HCV RNA log10 IU/ml, mean 6.55 6.52

Prior treatment with PEG-IFN + RBV, N (%)

Null response 146 (49%) 47 (49%)

Partial response 65 (22%) 21 (22%)

Relapse 86 (29%) 29 (30%)

Discontinued treatment, N 5 1

For adverse event / for virologic failure 3 / 0 0 / 0



Baseline characteristics and patient disposition

25

50

100

75

96.3* 96.0

1a 1b

96.7 95.3 95.2100

RelapsePartial

response Null response

Prior treatment

94.095.497.2 94.9

1b1a 1b1aOverallOverall

* 95% CI: 94.2 to 98.4 : noninferior and superior to the historical SVR12 with TVR + PEG-IFN + RBV



SVR12 (HCV RNA < 25 IU/ml)

%

297 173 123 86 65 14650 36 87 59N

OBV/PTV/r + DSV + RBV

Overall

HCV subgenotype

0


Outcomes for patients without SVR12 on OBV/PTV/r + DSV + RBV


Virologic failure Treatment discontinuation

N 7 4

On-treatment virologic failure 0

Relapse 7 (2.4%)

Type of prior response to PEG-IFNRelapsePartial responseNull response

106

301

SVR12 similar accross subgroups defined by race, age, fibrosis score, and IL28B genotype

Resistance testing (population sequencing) of the 7 relapses– 4/5 genotype 1a + 1/2 genotype 1b had ≥ 1 mutant resistant variants

• Genotype 1a : D168V (N =2) in NS3 ; M28V (N = 3) and Q30R (N = 2) in NS5A ; S556G (N = 2) in NS5B

• Genotype 1b : Y56H + D168V (NS3), Y93H (NS5A) and C316N + S556G (NS5B)


OBV/PTV/r + DSV (3D) + RBVN = 297

PlaceboN = 97

Any adverse event 271 (91.2) 80 (82.5)

AE leading to treatment discontinuation 3 (1.0) 0

Serious AE 6 (2.0) 1 (1.0)

AE occurring in > 10% in either group

Headache 36.4% 35.1%

Fatigue 33.3% 22.7% ; p = 0.06

Nausea 20.2% 17.5%

Asthenia 15.8% 11.3%

Insomnia 14.1% 7.2%

Pruritus 13.8% 5.2% ; p = 0.03

Diarrhea 13.1% 12.4%

Dyspnea 12.5% 10.3%

Cough 10.8% 5.2%

Myalgia 7.7% 10.3%


Adverse events, N (%)


OBV/PTV/r + DSV (3D) + RBV Placebo

ALT 1.7% 3.1%

AST 1.0% 1.0%

Alkaline phosphatase 0 0

Total bilirubin 2.4% 0

Hemoglobin 0.3% 0

Creatinine 0.7% 0

Dose of RBV was modified in 6.4% because of adverse events


Grade 3-4 laboratory abnormalities, N (%)

Other adverse events more frequent in the active-regimen group– Anemia, p = 0.01– Decrease in hemoglobin level, p = 0.04– Vomiting, p = 0.006


Summary– Rates of response to a 12-week interferon-free combination regimen of

ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin, were more than 95% among previously treated patients with HCV genotype 1 infection, including patients with a prior null response.

– SVR12 was non inferior and superior to the historical control rate with telaprevir plus PEG-IFN + RBV in a similar patient population

– SVR12 was similar in patients with HCV genotype 1a or 1b infection, and in various subgroups (age, sex, fibrosis, IL28B)

– Tolerability was good, with• 1% of patients discontinuing for AE• Pruritus, anemia and vomiting more frequent in active group• Low incidence of grade 3-4 bilirubin elevation

– In conclusion, an all-oral combination regimen of OBV/PTV/r + DSV + RBV resulted in SVR12 > 95%, regardless of HCV genotype (1a or 1b) and with low rates of treatment discontinuation, in previously treated patients with HCV genotype 1 infection and no cirrhosis,, including those with a prior null response


OBV/PTV/r + DSV + RBV Placebo Randomisation** 3 : 1 Double blind 18-70 years Chronic HCV genotype 1...

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