EASL 2014 Abstract Review Dr KK Li Content Chronic Hepatitis C - PowerPoint PPT Presentation

EASL 2014 Abstract Review Dr KK Li

Content • Chronic Hepatitis C – Interferon-free regimen – Difficult-to-treat – Portal hypertension and decompensation • Chronic Hepatitis B – Combination therapy

IFN-free regimens for G1 NS5B NS5B NS3/4A nonnucleoside nucleos(t)ide Ribavirin Abstract Phase Rx status Cirrhosis Protease NS5A Inhibitor polymerase polymerase included Inhibitor inhibitor inhibitor O60 3 Naïve No ABT 450/r Ombitasvir Dasabuvir Y SAPPHIRE-1 O1 3 Exp No ABT 450/r Ombitasvir Dasabuvir Y SAPPHIRE-2 O163 Naïve 3 100% ABT 450/r Ombitasvir Dasabuvir Y TURQUOISE-2 Exp O164 3 Naïve 16% Ledipasvir Sofosbuvir Y/N ION-1 O109 3 Exp 20% Ledipasvir Sofosbuvir Y/N ION-2 O56 3 Naïve No Ledipasvir Sofosbuvir Y/N ION-3 O165 Naïve COSMOS 2a F3-4 Simeprevir Sofosbuvir Y/N Exp (Cohort 2) O7 COSMOS 2a Exp F0-2 Simeprevir Sofosbuvir Y/N (Cohort 1) O166 Naïve 3 16-47% Asunaprevir Daclatasvir HALLMARK DUAL Exp O10 2b Naïve No MK 5172 MK 8742 Y/N C-WORTHY O61 Naïve 2b MK 5172 MK 8742 Y/N C-WORTHY Exp

IFN-free regimens for G1 NS5B NS5B NS3/4A nonnucleoside nucleos(t)ide Ribavirin Abstract Phase Rx status Cirrhosis Protease NS5A Inhibitor polymerase polymerase included Inhibitor inhibitor inhibitor O60 3 Naïve No ABT 450/r Ombitasvir Dasabuvir Y SAPPHIRE-1 O1 3 Exp No ABT 450/r Ombitasvir Dasabuvir Y SAPPHIRE-2 O163 Naïve 3 100% ABT 450/r Ombitasvir Dasabuvir Y TURQUOISE-2 Exp O164 3 Naïve 16% Ledipasvir Sofosbuvir Y/N ION-1 O109 3 Exp 20% Ledipasvir Sofosbuvir Y/N ION-2 O56 3 Naïve No Ledipasvir Sofosbuvir Y/N ION-3 O165 Naïve COSMOS 2a F3-4 Simeprevir Sofosbuvir Y/N Exp (Cohort 2) O7 COSMOS 2a Exp F0-2 Simeprevir Sofosbuvir Y/N (Cohort 1) O166 Naïve 3 16-47% Asunaprevir Daclatasvir HALLMARK DUAL Exp O10 2b Naïve No MK 5172 MK 8742 Y/N C-WORTHY O61 Naïve 2b MK 5172 MK 8742 Y/N C-WORTHY Exp

ABT-450/RTV/Ombitasvir + Dasabuvir + RBV (AOD+R) in non-cirrhotic G1 SAPPHIRE I (#O60) SAPPHIRE II (#O1) • Double-blinded, placebo • Double-blinded, placebo controlled controlled • Naïve, non-cirrhotic • PR-exp, non-cirrhotic • N = 631 • N = 394 Wk 12 Wk 12 AOD + RBV (n = 473) AOD + RBV (n = 297) Placebo (n = 158)* Placebo (n = 97)

SAPPHIRE I • High response rates Virologic failure • Virologic failure occurred in 7 patients with across subgenotypes GT1a and 1 patient with GT1b • Relapses occurred at posttreatment Wk 2 (n = 98.0 95.3 96.2 3), Wk 8 (n = 3), and Wk 12 (n = 1) 100 • Emergent resistance-associated variants uncommon: 8/473 pts (1.7%) 75 SVR12 (%) • GT1a: D168V (6/7) in NS3; M28T (2/7) and Q30R (3/7) in NS5A; and S556G (3/7) in NS5B 50 • GT1b: Y56H + D168V in NS3; L31M + Y93H in NS5A; and S556G in NS5B 25 455/473 307/322 148/151 0 All GT1a GT1b Patients

SAPPHIRE II • High response rates across Virologic failure subgenotypes regardless of • No virologic breakthroughs previous response to PR • 7/297 (2.4%) relapses (5 pts with GT1a, 2 pts with GT1b) – Occurred at posttreatment Wk 2 (n = 100 100 100 97.2 95.2 95.4 100 95.3 94.9 94.0 2), Wk 4 (n = 3), and Wk 8 (n = 2) 80 – Resistance-associated variants were Previous Response SVR12 (%) Relapse detected in 5 of 7 patients 60 Partial response Null response 40 20 0 All Patients GT1a GT1b

SAPPHIRE I and II: Adverse Events

IFN-free regimens for G1 NS5B NS5B NS3/4A nonnucleoside nucleos(t)ide Ribavirin Abstract Phase Rx status Cirrhosis Protease NS5A Inhibitor polymerase polymerase included Inhibitor inhibitor inhibitor O60 3 Naïve No ABT 450/r Ombitasvir Dasabuvir Y SAPPHIRE-1 O1 3 Exp No ABT 450/r Ombitasvir Dasabuvir Y SAPPHIRE-2 O163 Naïve 3 100% ABT 450/r Ombitasvir Dasabuvir Y TURQUOISE-2 Exp O164 3 Naïve 16% Ledipasvir Sofosbuvir Y/N ION-1 O109 3 Exp 20% Ledipasvir Sofosbuvir Y/N ION-2 O56 3 Naïve No Ledipasvir Sofosbuvir Y/N ION-3 O165 Naïve COSMOS 2a F3-4 Simeprevir Sofosbuvir Y/N Exp (Cohort 2) O7 COSMOS 2a Exp F0-2 Simeprevir Sofosbuvir Y/N (Cohort 1) O166 Naïve 3 16-47% Asunaprevir Daclatasvir HALLMARK DUAL Exp O10 2b Naïve No MK 5172 MK 8742 Y/N C-WORTHY O61 Naïve 2b MK 5172 MK 8742 Y/N C-WORTHY Exp

ABT-450/RTV/Ombitasvir + Dasabuvir + RBV (AOD+R) in Cirrhotic G1 TURQUOISE II (#O163) • Open-label phase III trial • Compensated cirrhosis (Child-Pugh A), DAA naïve • 58% of patients were PR-experienced, and 36% were previous null responders Wk 24 Wk 12 ABT-450/RTV/Ombitasvir + Dasabuvir + RBV (n = 208) DAA-naive cirrhotic pts with HCV GT1 (N = 380) ABT-450/RTV/Ombitasvir + Dasabuvir + RBV (n = 172)

TURQUOISE II • Virologic failure in 17/380 pts (4.5%) • Relapse more frequent with 12-wk vs 24-wk treatment (12 vs 1 pt) • 7/12 relapsers by posttreatment Wk 12 were GT1a null responders GT1a GT1b 12 wks 93.3 100 100 100 92.9 100 100 100 100 85.7 100 100 100 24 wks 92.2 92.9 100 100 80.0 80 80 60 60 SVR12 (%) 40 40 20 20 22/ 18/ 25/ 20/ 6/7 3/3 14/ 10/ 59/6 52/5 14/1 13/ 11/1 10/ 40/5 39/4 22 18 25 20 14 10 4 6 5 13 1 10 0 2 0 0 Naive Relapse Partial Null Naive Relapse Partial Null Response Response Response Response

TURQUOISE II: Adverse Events  ALT elevation asymptomatic, transient, improved/resolved with continued dosing  Bilirubin elevation transient, predominantly indirect, did not result in discontinuation  Hemoglobin decrease managed with RBV dose reduction in 34 of 380 pts (8.9%)

IFN-free regimens for G1 NS5B NS5B NS3/4A nonnucleoside nucleos(t)ide Ribavirin Abstract Phase Rx status Cirrhosis Protease NS5A Inhibitor polymerase polymerase included Inhibitor inhibitor inhibitor O60 3 Naïve No ABT 450/r Ombitasvir Dasabuvir Y SAPPHIRE-1 O1 3 Exp No ABT 450/r Ombitasvir Dasabuvir Y SAPPHIRE-2 O163 Naïve 3 100% ABT 450/r Ombitasvir Dasabuvir Y TURQUOISE-2 Exp O164 3 Naïve 16% Ledipasvir Sofosbuvir Y/N ION-1 O109 3 Exp 20% Ledipasvir Sofosbuvir Y/N ION-2 O56 3 Naïve No Ledipasvir Sofosbuvir Y/N ION-3 O165 Naïve COSMOS 2a F3-4 Simeprevir Sofosbuvir Y/N Exp (Cohort 2) O7 COSMOS 2a Exp F0-2 Simeprevir Sofosbuvir Y/N (Cohort 1) O166 Naïve 3 16-47% Asunaprevir Daclatasvir HALLMARK DUAL Exp O10 2b Naïve No MK 5172 MK 8742 Y/N C-WORTHY O61 Naïve 2b MK 5172 MK 8742 Y/N C-WORTHY Exp

Sofosbuvir+Ledipasvir FDC +/- RBV Wk 12 Wk 24 • ION 1 (#O164) SOF/LDV (n = 214) SOF/LDV + RBV (n = 217) – Open-label Treatment- naive pts with – 15-17% cirrhosis SOF/LDV (n = 217) HCV GT1 – (N = 865) G1a 67%, G1b 33% SOF/LDV + RBV (n = 217) • ION 3 (#O56) Wk 8 Wk 12 – Open-label SOF/LDV (n = 215) – no cirrhosis Treatment-naive, SOF/LDV + RBV (n = 216) – G1a 80%, G1b 20% noncirrhotic pts with SOF/LDV (n = 216) HCV GT1 • ION 2 (#O109) (N = 647) – Open-label Wk 12 Wk 24 – 20% cirrhosis – 41-46% previous nonresponders SOF/LDV (n = 109) – 46-61% failed a PI SOF/LDV + RBV (n = 111) Treatment- – G1a 67%, G1b 33% experienced pts SOF/LDV (n = 109) with HCV GT1 (N = 440) SOF/LDV + RBV (n = 111)

ION 1 & ION 3 ION 1 ION 3 • • SVR12 rates did not differ by GT1a vs GT1b in SVR12 rates did not differ by GT1a vs GT1b in any treatment arm any treatment arm • • Virologic failure: 1 breakthrough in 24-wk Virologic failure: 23 relapses (11 in 8-wk SOF/LDV; 2 relapses (1 in 12-wk SOF/LDV, 1 in SOF/LDV, 9 in 8-wk SOF/LDV/RBV, 3 in 12-wk 24-wk SOF/LDV) SOF/LDV) • 16% of patients had NS5A resistance-associated variants at baseline; 96% of these achieved P = .52 SVR12 P = .30 P = .70 99 94 97 100 98 94 99 100 100 100 95 94 93 80 80 SVR12 (%) 60 60 SVR12 (%) 40 40 20 20 179/ 178/ 33/ 181/ 31/ 179/ 32/ 36/ 180 184 184 33 181 202/215 201/216 206/216 34 33 36 0 0 SOF/LDV SOF/LDV + RBV SOF/LDV SOF/LDV + RBV SOF/LDV SOF/LDV + RBV SOF/LDV 12 Wks 24 Wks 8 Wks 12 Wks No cirrhosis Cirrhosis

ION 2 • • Virologic failure: 1 breakthrough in 24-wk SVR12 rates were significantly lower in cirrhotic SOF/LDV/RBV due to nonadherence; 11 relapses vs noncirrhotic patients in the pooled 12-wk (7 in 12-wk SOF/LDV, 4 in 12-wk SOF/LDV/RBV) arms • 14% of patients had NS5A resistance-associated variants at baseline; 89% of these achieved SVR12 Failure on Failure on PI pegIFN/RBV Cirrhosis No cirrhosis 100 98 98 100 100 96 97 93 94 100 99 100 99 100 95 86 100 82 80 80 60 SVR12 (%) 60 SVR12 (%) 40 40 20 20 8 1 1 2 2 62 62 49 51 89 86 88 40/ 45/ 58/ 58/ 3/ 9/ 8/ 2/ 2/ / / / / / / / 43 47 58 59 8 2 2 2 2 66 64 50 51 89 87 89 7 2 2 2 2 0 0 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Wks 24 Wks 12 Wks 24 Wks

ION1 & ION2: Adverse events ION 1 ION 3