Study on Grazoprevir and Elbasvir in Genotype 1 with Child-Pugh B Cirrhosis

The C-SALT study evaluated the efficacy of grazoprevir and elbasvir in patients with genotype 1 chronic HCV infection and Child-Pugh B cirrhosis. The primary endpoint was achieving sustained virologic response at 12 weeks. The study included treatment-naive and pre-treated patients with IFN-based regimens. Results showed high SVR12 rates, especially in non-cirrhotic patients. Pharmacokinetic analysis demonstrated differences in drug exposure between Child-Pugh B cirrhotic patients receiving different doses. Subgroup analyses and baseline characteristics provided valuable insights into the patient population.

• Grazoprevir
• Elbasvir
• Genotype 1
• Cirrhosis
• Hepatitis C

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1. C-SALT Study: grazoprevir + elbasvir in genotype 1 with Child-Pugh B cirrhosis Design Open-label W12 18 years Chronic HCV infection Genotype 1 Na ve or pre-treated with IFN-based regimen Child-Pugh B cirrhosis No HBV or HIV co-infection Child-Pugh B GZR 50 mg + EBR 50 mg N = 30 SVR12 Non-cirrhotic No-cirrhosis (PK intensive study) GZR 100 mg + EBR 50 mg N = 10 Objective Primary endpoint : SVR12(HCV RNA < 15 IU/ml), by ITT analysis C-SALT Jacobson IM. EASL 2015, Abs. O008

2. C-SALT Study: grazoprevir + elbasvir in genotype 1 with Child-Pugh B cirrhosis Baseline characteristics Child Pugh-B N = 30 58.3 Non-cirrhotic (PK arm) N = 10 60.4 Mean age, years Female 43.3% 50% White Genotype 96.7% 90% 1a 1b 90% 10% 60% 40% Prior treatment status Naive Null response Partial response Relapse 60% 20% 10% 10% 63.3% 20% 0% 16.7% Child-Pugh score 7 8 9 MELD score, (mean 0 0 0 1.0 70% 23.3% 6.7% SD) 9.9 2.5 6.4 C-SALT Jacobson IM. EASL 2015, Abs. O008

3. C-SALT Study: grazoprevir + elbasvir in genotype 1 with Child-Pugh B cirrhosis SVR12(HCV RNA < 15 IU/ml) , % (95% CI) 100 % (69.2-100) 100 90 100 93 (73.5-97.9) 89 87 75 50 25 30 10 15 15 27 3 0 Child-Pugh B Non-cirrhotic > 1 M Genotype 1a Genotype 1b 1 M Baseline HCV RNA (IU/ml) Virologic failure Breakthrough Rebound Relapse 2 (6.7%) 0 0 2 0 0 0 0 Child-Pugh B sub-groups C-SALT Jacobson IM. EASL 2015, Abs. O008

4. C-SALT Study: grazoprevir + elbasvir in genotype 1 with Child-Pugh B cirrhosis Child-Pugh score change from baseline to follow-up W12 2 1 N = 18 * 0 N = 7 N = 4 -1 * -2 -3 1 died at follow-up W4 *Relapse patients (N = 2) C-SALT Jacobson IM. EASL 2015, Abs. O008

5. C-SALT Study: grazoprevir + elbasvir in genotype 1 with Child-Pugh B cirrhosis Pharmacokinetics Plasma samples collected over 24 hours at treatment W4 PK group (non-cirrhotic, N = 9) with GZR 100 mg Child-Pugh B (N = 9) with GZR 50 mg GMR (90% CI) Child-Pugh B / Non-cirrhotic Grazoprevir C2hr C24hr AUC0-24 Elbasvir C2hr C24hr AUC0-24 1.06 (0.53, 2.11) 1.71 (0.87, 3.33) 1.25 (0.70, 2.24) 0.93 (0.64, 1.33) 1.04 (0.67, 1.60) 0.90 (0.63, 1.60) GZR exposure was slightly higher (not significant) in patients with Child-Pugh B cirrhosis receiving 50 mg dose compared to non-cirrhotic patients receiving 100 mg dose EBR (50 mg) PK was similar in both patient populations C-SALT Jacobson IM. EASL 2015, Abs. O008

6. C-SALT Study: grazoprevir + elbasvir in genotype 1 with Child-Pugh B cirrhosis Adverse events, N (%) Child-Pugh B N = 30 Non cirrhotic (PK) N = 10 Discontinuation due to an AE, N (%) 0 0 Serious adverse event, N (%) 4 (13.3%)* 0 Adverse events, N (%) Fatigue Arthralgia Nausea Pyrexia Headache 30% 16.7% 10% 10% 10% 30% 20% 20% 0 50% Grade 3-4 ALT/AST elevation, N (%) 0 0 Grade 3-4 bilirubin elevation, N (%) 4 (13.3) 0 Death**, N (%) 1 (3.3) 0 * All unrelated to study treatment : hepatocellular carcinoma, N = 1; ascites and encephalopathy, N = 1 ; bacterial peritonitis, cerebral infarction and hepatic failure (**death at follow-up W4) N = 1 ; hematemesis, N = 1 C-SALT Jacobson IM. EASL 2015, Abs. O008

7. C-SALT Study: grazoprevir + elbasvir in genotype 1 with Child-Pugh B cirrhosis Summary High rates of virologic response were observed in Child-Pugh B patients receiving a combination of once-daily GZR 50 mg + EBR 50 mg The regimen was well tolerated with no evidence of hepatotoxicity Plasma GZR exposure was slightly higher in Child-Pugh B patients receiving 50 mg compared to non-cirrhotic patients receiving 100 mg EBR exposure was similar in both Child-Pugh B and non-cirrhotic groups This regimen was highly effective and well-tolerated in a traditionally hard-to-treat patient group with no currently approved treatment options C-SALT Jacobson IM. EASL 2015, Abs. O008