unity-1 dcv/asv/bcb no randomisation open-label unity-1 study: daclatasvir/asunaprevir/beclabuvir in...

UNITY-1

DCV/ASV/BCB

Norandomisation

Open-label

UNITY-1 Study: daclatasvir/asunaprevir/beclabuvir in genotype 1 without cirrhosis

Design W12

≥ 18 yearsChronic HCV infection

Genotype 1HCV RNA > 10,000 IU/ml

Naïve or pre-treated with IFN-based regimen

No cirrhosis*No HBV or HIV co-infection

N = 415 SVR12

* Liver biopsy with Metavir < F4, or Fibrotest® ≤ 0.48 + APRI < 1, or Fibroscan kPa ≤ 9.6

Co-formulated DCV/ASV/BCB 30/100/75 mg qd : 1 pill bid

Objective– Primary endpoint : SVR12 (HCV RNA < 25 IU/ml) in treatment-naïve patients, non-

inferiority margin of 15% = lower bound of 2-sided 95% CI > 79%, rate of historical control (SVR achieved in this population with SOF + PEG-IFN + RBV)

– Secondary endpoint : SVR12 (HCV RNA < 25 IU/ml) in treatment-experienced patients, with lower bound of 2-sided 95% CI > 49%, rate of historical control (composite SVR in this population with SMV + PEG-IFN + RBV), 95% power

Poordad F. JAMA 2015;313:1728-35

Treatment-naïve

N = 312

Treatment-experienced

N = 103Median age, years 53.5 57

Female 44% 38%

Race : white / black 87% / 11% 88% / 7%

Genotype : 1a / 1b 73% / 27% 73% / 27%

IL28B CC genotype 29% 16%

HCV RNA > 800,000 IU/ml 78% 90%

Prior IFN-based treatment, N (%) - 90.3%

Relapse 37.9%

Null response 24.3%

Partial response 11.7%

Interferon intolerant 6.8%

Indeterminate 9.7%

Discontinuation, N 7 4

Lack of virologic response / adverse event / pregnancy 6 / 0 / 1 1 / 3 / 0

Baseline characteristics and patient disposition

UNITY-1


Poordad F. JAMA 2015;313:1728-35

SVR12 (HCV RNA < 25 IU/ml) , % (95% CI)

25

50

100

75

89.3*(83.4-95.3)

% 92*(89-95)

1a

N

1bNon-response 3 2

Virologic breakthrough 6 2

Relapse 15 6

SVR12 comparable across subgroups :

– Gender– Age– HCV RNA level – IL28B genotype

90 85.397.6 100

* Superior to historical control

All patients

UNITY-1


Poordad F. JAMA 2015;313:1728-35

Naïve Experienced

0 103 229312 75 83 28

Resistance analysis– Genotype 1a : 32 virologic failures

• NS5A resistance-associated variants in 28/29 (most frequent : Q30)• NS3 RAVs in 25/26 (most frequent : R155)• NS5B RAVs in 12/28 (most frequent : P495)

– Genotype 1b : 2 virologic failures

– Baseline NS5A polymorphims (28, 30, 31, 93) associated with resistance to DCV

• Genotype 1a : 34/102 (11%) : SVR12 in 25/34 (74%)• Genotype 1b : 17/106 (16%) : SVR12 in 17/17 (100%)

– Baseline NS3 and NS5B variants did not affect SVR12

UNITY-1


Poordad F. JAMA 2015;313:1728-35

Adverse events and laboratory abnormalities, N

UNITY-1

N = 415

Discontinuation for adverse event 3 (0.7%)

Serious adverse event 7 (1.7%)

Adverse event in > 10% of patients

Headache 25.8%

Fatigue 16.6%

Diarrhea 14.0%

Nausea 13.5%

Grade 3-4 laboratory abnormalities

Hemoglobin < 9 g/dl 0

Lymphocytes < 0.5 x 109/l 1 (0.2%)

Neutrophils < 0.75 x 109/l 2 (0.5%)

ALT > 5 x ULN 19 (4.6%)

AST > 5 x ULN 9 (2.2%)

Lipase > 3 x ULN 16 (3.9%)


Poordad F. JAMA 2015;313:1728-35

Summary– In this open-label, uncontrolled study, 12 weeks of treatment with a fixed-

dose combination of daclatasvir, asunaprevir and beclabuvir in HCV genotype 1-infected patients without cirrhosis was associated with high SVR12

• 92% in treatment-naive patients • 89% in patients previously treated for HCV infection• SVR12 rates were higher with genotype 1b than with genotype 1a in both the

treatment-naive (98% vs 90%, respectively) and -experienced (100% vs 85%, respectively) cohorts

– There were low rates of serious AEs and treatment discontinuations – All genotype 1b-infected patients with baseline NS5A polymorphisms

achieved SVR12 while only 74% with genotype 1a had SVR12

– Resistance-associated variants at amino acids positions NS5A-Q30, NS3-R155K and NS5B-P495 were observed most frequently at viral breakthrough; NS5B variants were generally not observed in patients experiencing relapse

UNITY-1


Poordad F. JAMA 2015;313:1728-35

unity-1 dcv/asv/bcb no randomisation open-label unity-1 study: daclatasvir/asunaprevir/beclabuvir in...

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