Efficacy of Glecaprevir and Pibrentasvir in Cirrhosis

Study on the efficacy of glecaprevir and pibrentasvir in genotypes 1 and 3 cirrhosis patients, with promising SVR12 rates. Baseline characteristics, relapse data, and resistance analysis provided. The treatment showed high efficacy even in patients with baseline substitutions.

• Cirrhosis Treatment
• Glecaprevir
• Pibrentasvir
• SVR12
• Genotype 1

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1. SURVEYOR-I & II study Part 2 in cirrhosis: glecaprevir + pibrentasvir in genotypes 1 or 3 Design Not randomised Open-label W12 W16 N = 27 GLE 200 mg qd + PIB 120 mg qd 18-70 years HCV genotype 1 or 3 Na ve or failure to PEG-IFN + RBV No prior DAA HCV RNA > 10 000 IU/ml Compensated cirrhosis * with Child-Pugh score 6 Creatinine clearnce > 50 ml/min No HBV or HIV coinfection Genotype 1 SVR12 N = 28 GLE 300 mg qd + PIB 120 mg qd SVR12 *** Genotype 3 GLE 300 mg qd + PIB 120 mg qd + RBV 800 mg qd N = 27 SVR12 Randomised** Open-label * Metavir > 3 or Ishak > 4 or Fibroscan 14.6 kPa or FibroTest 0.75 + APRI > 2 ** Randomisation stratified by treatment history (naive or PEG-IFN + RBV experienced) *** Treatment extended to 16 weeks in 4 PEG-IFN + RBV experienced patients Objective SVR12(HCV RNA < 25 IU/ml), by ITT SURVEYOR-I-II Part 2 cirrhosis Gane E. Gastroenterology 2016;151:651-9

2. SURVEYOR-I & II study Part 2 in cirrhosis: glecaprevir + pibrentasvir in genotypes 1 or 3 Baseline characteristics Genotype 3 GLE 300 + PIB 200 + RBV 800 N = 27 Genotype 1 GLE 200 + PIB 120 N = 27 Genotype 3 GLE 300 + PIB 200 N = 28 Mean age, years 58.9 55.2 55.7 Female, % 26 46 33 Race, white, % 89 93 89 Mean BMI, kg/m2 27.7 27.8 27.0 Mean HCV RNA, log10IU/ml 6.6 6.4 6.2 Genotype 1a / 1b / undetermined, % 74 / 26 / 0 - - Genotype 3a / 3b / undetermined, % - 86 / 4 / 11 100 / 0 / 0 IL28B CC, % 15 43 37 Treatment-na ve, % 78 86 89 NS3 substitutions at baseline, % 41 24 NS5A substitutions at baseline, % 19 22 SURVEYOR-I-II Part 2 cirrhosis Gane E. Gastroenterology 2016;151:651-9

3. SURVEYOR-I & II study Part 2 in cirrhosis: glecaprevir + pibrentasvir in genotypes 1 or 3 SVR12(HCV RNA < 25 IU/ml), % (95% CI) 100 96 96 % (88-100) (82-99) (82-99) 100 Genotype 1, 12 weeks Genotype 3, 12 weeks Genotype 3, 12 weeks 75 50 25 27 28 27 N= 0 GLE 200 + PIB 120 GLE 300 + PIB 120 GLE 300 + PIB 120 + RBV SURVEYOR-I-II Part 2 cirrhosis Gane E. Gastroenterology 2016;151:651-9

4. SURVEYOR-I & II study Part 2 in cirrhosis: glecaprevir + pibrentasvir in genotypes 1 or 3 Relapses NS3 RASs NS5A RASs Time of relapse Genotype Naive Gender Baseline Failure Baseline Failure Post- treatment W4 L31M + Y93N (195-fold EC50 to PIB) 1a Yes Female I170V I170V L31M Post- treatment W2 M28G (replicon not viable in vitro) 3 No Male A166S None None Resistance analysis (population sequencing with 15% threshold) SVR12was achieved in 100% of patients without baseline substitutions and efficacy remained high in the presence of baseline substitutions All 11 genotype 3-infected patients with baseline NS5A substitutions, including 4 patients with additional NS3 substitutions, achieved SVR12 SURVEYOR-I-II Part 2 cirrhosis Gane E. Gastroenterology 2016;151:651-9

5. SURVEYOR-I & II study Part 2 in cirrhosis: glecaprevir + pibrentasvir in genotypes 1 or 3 Adverse events and laboratory abnormalities, % Genotype 3 GLE 300 + PIB 120 + RBV 800 N = 27 Genotype 1 GLE 200 + PIB 120 N = 27 Genotype 3 GLE 300 + PIB 120 N = 28 Any adverse event 52 86 85 Serious adverse event 4 (N = 1) 7 (N = 2) 7 (N = 2) Adverse event leading to study discontinuation 0 0 0 Common adverse events Headache` Fatigue Nausea Diarrhea Upper respiratory tract infection Dizziness Insomnia Irritability 11 11 0 4 7 0 0 0 18 11 11 21 14 7 0 0 33 30 26 4 7 15 19 15 Laboratory abnormalities ALT > 3 x ULN Total bilirubin > 3 x ULN Hemoglobin 8-10 g/dl 0 0 0 0 4 0 0 0 4 SURVEYOR-I-II Part 2 cirrhosis Gane E. Gastroenterology 2016;151:651-9

6. SURVEYOR-I & II study Part 2 in cirrhosis: glecaprevir + pibrentasvir in genotypes 1 or 3 Summary In this phase 2 study, the once-daily combination of Glecaprevir and Pibrentasvir for 12 weeks is sufficient to achieve high rates of SVR12in patients with genotype 1 or genotype 3 infection and compensated cirrhosis Adverse events were mostly mild in severity Potential for a pangenotypic therapy without RBV co-administration SURVEYOR-I-II Part 2 cirrhosis Gane E. Gastroenterology 2016;151:651-9