Jean-Michel Pawlotsky, Shiv K. Sarin, Graham R. Foster, Cheng-Yuan Peng, Jens Rasenack, Robert Flisiak, Teerha Piratvisuth, Heiner Wedemeyer, Wan-Long Chuang, Wei Zhang and Nikolai V. Naoumov Abstract 233 ALV loading* at W4 W24 W6 ALV 1 n=83 W36 W48 SVR12 SVR24 ALV 1 mg QD No ALV 6 mg QD + PegIFN/RBV ALV 6+RBV n=84 ALV 6 mg QD + RBV No ALV 6 mg QD + PegIFN/RBV ALV 8+RBV n=94 ALV 8 mg QD + RBV Post-treatment follow up No ALV 6 mg QD + PegIFN/RBV ALV 6+PegIFN n=39 ALV 6 mg QD + PegIFN No ALV 6 mg QD + PegIFN/RBV PegIFN+RBV n=4 PegIFN + RBV Patients stratified according to viral load and HCV genotype 2 or 3 *Loading dose: ALV 6 mg BID for 1 week; by LOQ (<25 IU/mL) after 4 weeks of treatment; QD=once daily; RBV=ribavirin 8 mg/day; PegIFN=pegylated interferon α2a 18 μg/week; LOQ=limit of quantification
9% 8% 8% 85% 81% 8% 7% 6% 58% 5% 4% 3% 25% 2% 1% 11% 8% 6% 1% % ALV 1 alone/add Peg/RBV (n=83) ALV6+RBV alone/add Peg-IFN (n=84) ALV8+RBV alone/add Peg-IFN (n=94) ALV+Peg-IFN alone/add Peg/RBV (n=39) Peg-IFN+RBV (n=4) SVR24 Relapse Treatment week 1 2 3 4 5 6 Mean change from baseline in HCV RNA (log 1 IU/mL) -.5-1.5-2.5-3.5-4.5 LOQ=limit of quantification (<25 IU/mL) -1-2 -3-4 ALV1 ALV6 + RBV ALV8 + RBV
Odds ratio 9% CI P value Log (ALV C min at Week 4, ng/ml) 1.8 [1.3, 2.4].2 Baseline HCV RNA (log 1 IU/mL) 2.9 [2.1, 4.2] <.1 RBV mg/kg dose 1.1 [1.4, 1.16].3 Age (year) 1.3 [1.1, 1.6].4 Alisporivir exposure (Cmin) strongly predicted high Low baseline viral load strongly predicted high High RBV mg/kg dose is associated with high Proportion of patients with HCV RNA <LOQ 6% 5% 4% 3% 32% 29% 37% 49% 46% 42% 2% 1% % ALV1 (n=82) ALV6+RBV (n=84) ALV 8+RBV (n=94) Week 4 Week 6 LOQ=limit of quantification (<25 IU/mL)
Proportion of patients (%) 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % 71% 24% 9% 87% 3% 3% ALV1 (n=17) Per protocol ALV 6+RBV (n=29) SVR24 VB Relapse Per protocol = patients with who completed scheduled 24-week treatment and SVR24 assessment; Patients missing the SVR24 assessment were counted as treatment failure; SVR24 according to limit of quantification (<25 IU/mL); VB = viral breakthrough 9% ALV 8+RBV (n=32) ITT SVR24 68% 9% 78% Proportion of patients (%) 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % Per protocol 9% 92% 94% 8% 8% ALV 1 add-on IFN (n=51) ALV 6+RBV add-on IFN (n=47) SVR24 VB Relapse 4% ALV 8+RBV add-on IFN (n=48) ITT SVR24 9% 86% 89% Per protocol = patients with who completed scheduled 24-week treatment and SVR24 assessment; Patients missing the SVR24 assessment were counted as treatment failure; SVR24 according to limit of quantification (<25 IU/mL); VB = viral breakthrough
A ALV 1, IFN-free (n=22) ALV with add-on Peg/RBV (n=55) Mean AEs/per patient 2. 5.4 B ALV 6+RBV IFN-free (n=3) ALV + RBV add-on Peg (n=51) 3.1 5.2 C ALV 8+RBV IFN-free (n=37) ALV + RBV add-on Peg (n=37) 3.4 8.6 5 1 15 2 25 3 35 Adverse Events (n) IFN-containing arms, n (%) (N=234) IFN-free arms, n (%) (N=91) Clinical AEs Psychiatric disorders 89 (38.) 22 (24.2) Fatigue 85 (36.3) 12 (13.2) Headache 73 (31.2) 12 (13.2) Pyrexia 6 (25.6) 4 (4.4) Nausea 5 (21.4) 17 (18.7) Decreased appetite 5 (21.4) 9 (9.9) Pruritus 46 (19.7) 6 (6.6) Myalgia 4 (17.1) 6 (6.6) Rash 36 (15.4) 2 (2.2) Diarrhoea 35 (15.) 4 (4.4) Arthralgia 35 (15.) 3 (3.3) Asthenia 29 (12.4) 1 (11.) Influenza-like illness 29 (12.4) 3 (3.3) All reported SAEs were in the IFN-containing arms
Neutropenia Laboratory - Hematology (n=247) (n=89) ALV + IFN (n=158) 6 Week Thrombocytopenia (n=247) 24 48 (n=89) ALV + IFN (n=158) Anemia 6 Week 24 48 (n=247) (n=89) ALV + IFN (n=158) 6 Week 24 48 Total bilirubin level Bilirubin level (µmol/l) 11 1 9 8 7 6 5 4 3 2 1-1 ALV 1 mg (N=82) ALV 6 mg + pegifn (N=39) ALV 6 mg + RBV (N=84) ALV 8 mg + RBV (N=94) pegifn + RBV (N=37) BL WI W2 W3 W4 W6 W8 W12 W16 W2 EOT 5xULN 3xULN Treatment Week ULN=upper limit of normal; BL=baseline; W=week; EOT=end of treatment
PegIFN+RBV ALV +/- RBV, IFN-free Fasting triglycerides (mg/dl) 12 11 1 9 8 7 6 5 4 3 2 1 5 mg/dl 35 mg/dl 15 mg/dl BL WI W2 W3 W4 W6 W8 W12 W16 W2 EOT W28 W36 Time Fasting triglycerides (mg/dl) ALV/RBV with add-on Peg-IFN 12 11 1 9 8 7 6 5 4 3 2 1 BL WI W2 W3 W4 W6 W8 W12 W16 W2 EOT W28 W36 Time 5 mg/dl 35 mg/dl 15 mg/dl Fasting triglycerides (mg/dl) 12 11 1 9 8 7 6 5 4 3 2 1 BL WI W2 W3 W4 W6 W8 W12 W16 W2 EOT W28 W36 Time 5 mg/dl 35 mg/dl 15 mg/dl Alisporivir + Ribavirin treatment achieves high rates of SVR in patients with early HCV clearance, with low viral breakthrough or post-treatment relapse Alisporivir exposure and Ribavirin dose are the most important determinants for The results provide insights into Alisporivir attributes as interferon-free treatment option: Antiviral activity of cyclophilin inhibition with Alisporivir is associated with down-regulation of Interferon-Stimulated Genes Low rates of viral breakthrough, mostly associated with low Alisporivir exposure, further highlight the high barrier to resistance The safety profile of Alisporivir, IFN-free was markedly better compared to IFN-containing regimens