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

Abstract Phase Rx status Cirrhosis NS3/4A Protease Inhibitor NS5A Inhibitor NS5B nonnucleoside polymerase inhibitor NS5B nucleos(t)ide polymerase inhibitor Ribavirin included

O60 SAPPHIRE-1 3 Naïve No ABT 450/r Ombitasvir Dasabuvir Y O1 SAPPHIRE-2 3 Exp No ABT 450/r Ombitasvir Dasabuvir Y O163 TURQUOISE-2 3 Naïve Exp 100% ABT 450/r Ombitasvir Dasabuvir Y O164 ION-1 3 Naïve 16% Ledipasvir Sofosbuvir Y/N O109 ION-2 3 Exp 20% Ledipasvir Sofosbuvir Y/N O56 ION-3 3 Naïve No Ledipasvir Sofosbuvir Y/N O165 COSMOS (Cohort 2) 2a Naïve Exp F3-4 Simeprevir Sofosbuvir Y/N O7 COSMOS (Cohort 1) 2a Exp F0-2 Simeprevir Sofosbuvir Y/N O166 HALLMARK DUAL 3 Naïve Exp 16-47% Asunaprevir Daclatasvir O10 C-WORTHY

2b

Naïve No MK 5172 MK 8742 Y/N O61 C-WORTHY

2b

Naïve Exp MK 5172 MK 8742 Y/N

IFN-free regimens for G1

Abstract Phase Rx status Cirrhosis NS3/4A Protease Inhibitor NS5A Inhibitor NS5B nonnucleoside polymerase inhibitor NS5B nucleos(t)ide polymerase inhibitor Ribavirin included

O60 SAPPHIRE-1 3 Naïve No ABT 450/r Ombitasvir Dasabuvir Y O1 SAPPHIRE-2 3 Exp No ABT 450/r Ombitasvir Dasabuvir Y O163 TURQUOISE-2 3 Naïve Exp 100% ABT 450/r Ombitasvir Dasabuvir Y O164 ION-1 3 Naïve 16% Ledipasvir Sofosbuvir Y/N O109 ION-2 3 Exp 20% Ledipasvir Sofosbuvir Y/N O56 ION-3 3 Naïve No Ledipasvir Sofosbuvir Y/N O165 COSMOS (Cohort 2) 2a Naïve Exp F3-4 Simeprevir Sofosbuvir Y/N O7 COSMOS (Cohort 1) 2a Exp F0-2 Simeprevir Sofosbuvir Y/N O166 HALLMARK DUAL 3 Naïve Exp 16-47% Asunaprevir Daclatasvir O10 C-WORTHY

2b

Naïve No MK 5172 MK 8742 Y/N O61 C-WORTHY

2b

Naïve Exp MK 5172 MK 8742 Y/N

ABT-450/RTV/Ombitasvir + Dasabuvir + RBV (AOD+R) in non-cirrhotic G1

SAPPHIRE I (#O60)

• Double-blinded, placebo

controlled

• Naïve, non-cirrhotic
• N = 631

SAPPHIRE II (#O1)

• Double-blinded, placebo

controlled

• PR-exp, non-cirrhotic
• N = 394

Placebo (n = 158)* AOD + RBV (n = 473) Placebo (n = 97) AOD + RBV (n = 297) Wk 12 Wk 12

SAPPHIRE I

• High response rates

across subgenotypes

Virologic failure

• Virologic failure occurred in 7 patients with

GT1a and 1 patient with GT1b

• Relapses occurred at posttreatment Wk 2 (n =

3), Wk 8 (n = 3), and Wk 12 (n = 1)

• Emergent resistance-associated variants

uncommon: 8/473 pts (1.7%)

• GT1a: D168V (6/7) in NS3; M28T (2/7) and Q30R

(3/7) in NS5A; and S556G (3/7) in NS5B

• GT1b: Y56H + D168V in NS3; L31M + Y93H in

NS5A; and S556G in NS5B

SVR12 (%) GT1a GT1b 100 75 50 25 All Patients 96.2 95.3 98.0

455/473 307/322 148/151

SAPPHIRE II

• High response rates across

subgenotypes regardless of previous response to PR

Virologic failure

• No virologic breakthroughs
• 7/297 (2.4%) relapses (5 pts with

GT1a, 2 pts with GT1b)

– Occurred at posttreatment Wk 2 (n = 2), Wk 4 (n = 3), and Wk 8 (n = 2) – Resistance-associated variants were detected in 5 of 7 patients

SVR12 (%) 100 80 60 40 20 All Patients GT1a GT1b Previous Response Relapse Partial response Null response

95.3 100 95.2 94.0 100 100 95.4 97.2 94.9

SAPPHIRE I and II: Adverse Events

IFN-free regimens for G1

Abstract Phase Rx status Cirrhosis NS3/4A Protease Inhibitor NS5A Inhibitor NS5B nonnucleoside polymerase inhibitor NS5B nucleos(t)ide polymerase inhibitor Ribavirin included

O60 SAPPHIRE-1 3 Naïve No ABT 450/r Ombitasvir Dasabuvir Y O1 SAPPHIRE-2 3 Exp No ABT 450/r Ombitasvir Dasabuvir Y O163 TURQUOISE-2 3 Naïve Exp 100% ABT 450/r Ombitasvir Dasabuvir Y O164 ION-1 3 Naïve 16% Ledipasvir Sofosbuvir Y/N O109 ION-2 3 Exp 20% Ledipasvir Sofosbuvir Y/N O56 ION-3 3 Naïve No Ledipasvir Sofosbuvir Y/N O165 COSMOS (Cohort 2) 2a Naïve Exp F3-4 Simeprevir Sofosbuvir Y/N O7 COSMOS (Cohort 1) 2a Exp F0-2 Simeprevir Sofosbuvir Y/N O166 HALLMARK DUAL 3 Naïve Exp 16-47% Asunaprevir Daclatasvir O10 C-WORTHY

2b

Naïve No MK 5172 MK 8742 Y/N O61 C-WORTHY

2b

Naïve Exp MK 5172 MK 8742 Y/N

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 12 ABT-450/RTV/Ombitasvir + Dasabuvir + RBV (n = 172) ABT-450/RTV/Ombitasvir + Dasabuvir + RBV (n = 208) Wk 24 DAA-naive cirrhotic pts with HCV GT1

(N = 380)

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

10/ 10

12 wks 24 wks

100 100

Naive Relapse

100 100 85.7 100 100 100

Partial Response Null Response GT1b SVR12 (%) Naive Relapse Partial Response Null Response

GT1a

59/6 4 14/1 5 52/5 6 13/ 13 11/1 1 40/5 10/ 10 39/4 2

100 80 60 40 20

92.2 92.9 93.3 100 100 100 80.0 92.9

100 80 60 40 20

22/ 22 25/ 25 18/ 18 20/ 20 6/7 14/ 14 3/3

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

Abstract Phase Rx status Cirrhosis NS3/4A Protease Inhibitor NS5A Inhibitor NS5B nonnucleoside polymerase inhibitor NS5B nucleos(t)ide polymerase inhibitor Ribavirin included

O60 SAPPHIRE-1 3 Naïve No ABT 450/r Ombitasvir Dasabuvir Y O1 SAPPHIRE-2 3 Exp No ABT 450/r Ombitasvir Dasabuvir Y O163 TURQUOISE-2 3 Naïve Exp 100% ABT 450/r Ombitasvir Dasabuvir Y O164 ION-1 3 Naïve 16% Ledipasvir Sofosbuvir Y/N O109 ION-2 3 Exp 20% Ledipasvir Sofosbuvir Y/N O56 ION-3 3 Naïve No Ledipasvir Sofosbuvir Y/N O165 COSMOS (Cohort 2) 2a Naïve Exp F3-4 Simeprevir Sofosbuvir Y/N O7 COSMOS (Cohort 1) 2a Exp F0-2 Simeprevir Sofosbuvir Y/N O166 HALLMARK DUAL 3 Naïve Exp 16-47% Asunaprevir Daclatasvir O10 C-WORTHY

2b

Naïve No MK 5172 MK 8742 Y/N O61 C-WORTHY

2b

Naïve Exp MK 5172 MK 8742 Y/N

Sofosbuvir+Ledipasvir FDC +/- RBV

• ION 1(#O164)

– Open-label – 15-17% cirrhosis – G1a 67%, G1b 33%

• ION 3(#O56)

– Open-label – no cirrhosis – G1a 80%, G1b 20%

• ION 2(#O109)

– Open-label – 20% cirrhosis – 41-46% previous nonresponders – 46-61% failed a PI – G1a 67%, G1b 33%

SOF/LDV + RBV (n = 217) SOF/LDV (n = 214) Wk 24 Treatment- naive pts with HCV GT1 (N = 865) SOF/LDV + RBV (n = 217) SOF/LDV (n = 217) Wk 12 SOF/LDV + RBV (n = 216) SOF/LDV (n = 215) Wk 12 Treatment-naive, noncirrhotic pts with HCV GT1 (N = 647) SOF/LDV (n = 216) Wk 8 SOF/LDV + RBV (n = 111) SOF/LDV (n = 109) Wk 24 Treatment- experienced pts with HCV GT1 (N = 440) SOF/LDV + RBV (n = 111) SOF/LDV (n = 109) Wk 12

ION 1 & ION 3

ION 1

• SVR12 rates did not differ by GT1a vs GT1b in

any treatment arm

• Virologic failure: 1 breakthrough in 24-wk

SOF/LDV; 2 relapses (1 in 12-wk SOF/LDV, 1 in 24-wk SOF/LDV)

• 16% of patients had NS5A resistance-associated

variants at baseline; 96% of these achieved SVR12

ION 3

• SVR12 rates did not differ by GT1a vs GT1b in

any treatment arm

• Virologic failure: 23 relapses (11 in 8-wk

SOF/LDV, 9 in 8-wk SOF/LDV/RBV, 3 in 12-wk SOF/LDV)

179/ 180 32/ 34 178/ 184 33/ 33 181/ 184 31/ 33 179/ 181 36/ 36 12 Wks 24 Wks SOF/LDV + RBV SOF/LDV + RBV SOF/LDV SOF/LDV SVR12 (%)

100 80 60 40 20

99 94 97 100 100 99 94 98

No cirrhosis Cirrhosis

8 Wks 12 Wks SOF/LDV SOF/LDV SOF/LDV + RBV 201/216 202/215 206/216

P = .52

SVR12 (%) 100 80 60 40 20

94 93 95 P = .70 P = .30

ION 2

• Virologic failure: 1 breakthrough in 24-wk

SOF/LDV/RBV due to nonadherence; 11 relapses (7 in 12-wk SOF/LDV, 4 in 12-wk SOF/LDV/RBV)

• 14% of patients had NS5A resistance-associated

variants at baseline; 89% of these achieved SVR12

• SVR12 rates were significantly lower in cirrhotic

vs noncirrhotic patients in the pooled 12-wk arms

Failure on pegIFN/RBV Failure on PI 40/ 43 62 / 66 45/ 47 62 / 64 58/ 58 49 / 50 58/ 59 51 / 51 12 Wks 24 Wks LDV/SOF + RBV LDV/SOF + RBV LDV/SOF LDV/SOF SVR12 (%)

100 80 60 40 20

93 94 96 97 100 98 98 100

No cirrhosis Cirrhosis 8 3/ 8 7 1 9/ 2 2 89 / 89 1 8/ 2 2 86 / 87 2 2/ 2 2 88 / 89 2 2/ 2 2 12 Wks 24 Wks LDV/SOF + RBV LDV/SOF + RBV LDV/SOF LDV/SOF SVR12 (%)

100 80 60 40 20

95 86 100 82 100 99 100 99

ION1 & ION2: Adverse events

ION 1 ION 3

IFN-free regimens for G1

Abstract Phase Rx status Cirrhosis NS3/4A Protease Inhibitor NS5A Inhibitor NS5B nonnucleoside polymerase inhibitor NS5B nucleos(t)ide polymerase inhibitor Ribavirin included

O60 SAPPHIRE-1 3 Naïve No ABT 450/r Ombitasvir Dasabuvir Y O1 SAPPHIRE-2 3 Exp No ABT 450/r Ombitasvir Dasabuvir Y O163 TURQUOISE-2 3 Naïve Exp 100% ABT 450/r Ombitasvir Dasabuvir Y O164 ION-1 3 Naïve 16% Ledipasvir Sofosbuvir Y/N O109 ION-2 3 Exp 20% Ledipasvir Sofosbuvir Y/N O56 ION-3 3 Naïve No Ledipasvir Sofosbuvir Y/N O165 COSMOS (Cohort 2) 2a Naïve Exp F3-4 Simeprevir Sofosbuvir Y/N O7 COSMOS (Cohort 1) 2a Exp F0-2 Simeprevir Sofosbuvir Y/N O166 HALLMARK DUAL 3 Naïve Exp 16-47% Asunaprevir Daclatasvir O10 C-WORTHY

2b

Naïve No MK 5172 MK 8742 Y/N O61 C-WORTHY

2b

Naïve Exp MK 5172 MK 8742 Y/N

Simeprevir + Sofosbuvir +/- RBV

• COSMOS Cohort 1 (#O7) Cohort 2 (#O165)

Patients With GT1 HCV Cohort 1: Previous null responders F0-F2 (N = 80) Cohort 2: Naives and previous null responders F3-F4 (N = 87) Simeprevir + Sofosbuvir + RBV (n = 30) Simeprevir + Sofosbuvir (n = 16) Wk 12 Wk 24 Simeprevir + Sofosbuvir (n = 14) Simeprevir + Sofosbuvir + RBV (n = 27)

COSMOS

Cohort 1 (F0-F2 Nulls)* Cohort 2 (F3-F4 Naives/Nulls)*

SMV/SOF ± RBV

SVR12 (%)

SMV/SOF + RBV SMV/SOF+ RBV SMV/SOF SMV/SOF

24 Wks 12 Wks Overall

4/ 4 7/ 7 8/ 9 3/ 3 7/ 7 3/ 3 6/ 6 12/ 12 8/ 9 4/ 4 4/ 4 5/ 6

*Excluding patients who discontinued for nonvirologic reasons.

100 100 93 88 95 100 100 88 100 9 6

SMV/SOF ± RBV SMV/SOF + RBV SMV/SOF + RBV SMV/SOF SMV/SOF

24 Wks 12 Wks Overall

6/ 6 11/ 11 11/ 11 4/ 4 7/ 7 4/ 4 5/ 5 13/ 14 7/ 8 3/ 3 7/ 8 3/ 3 18/ 18 38/ 40 25/ 26

100 100 100 100 100

100 80 60 40 20

100 100 89 100 100 100 100 100 89 100 100 83 100 100 89

GT1b GT1a without Q80K GT1a with Q80K

30/ 30 7/ 17 24/ 27

IFN-free regimens for G1

Abstract Phase Rx status Cirrhosis NS3/4A Protease Inhibitor NS5A Inhibitor NS5B nonnucleoside polymerase inhibitor NS5B nucleos(t)ide polymerase inhibitor Ribavirin included

O60 SAPPHIRE-1 3 Naïve No ABT 450/r Ombitasvir Dasabuvir Y O1 SAPPHIRE-2 3 Exp No ABT 450/r Ombitasvir Dasabuvir Y O163 TURQUOISE-2 3 Naïve Exp 100% ABT 450/r Ombitasvir Dasabuvir Y O164 ION-1 3 Naïve 16% Ledipasvir Sofosbuvir Y/N O109 ION-2 3 Exp 20% Ledipasvir Sofosbuvir Y/N O56 ION-3 3 Naïve No Ledipasvir Sofosbuvir Y/N O165 COSMOS (Cohort 2) 2a Naïve Exp F3-4 Simeprevir Sofosbuvir Y/N O7 COSMOS (Cohort 1) 2a Exp F0-2 Simeprevir Sofosbuvir Y/N O166 HALLMARK DUAL 3 Naïve Exp 16-47% Asunaprevir Daclatasvir O10 C-WORTHY

2b

Naïve No MK 5172 MK 8742 Y/N O61 C-WORTHY

2b

Naïve Exp MK 5172 MK 8742 Y/N

Daclatasvir + Asunaprevir in G1b

HALLMARK-DUAL (#O166)

• Double-blinded, placebo-controlled

GT1b HCV Placebo* (n = 102) Daclatasvir + Asunaprevir (n = 203) Daclatasvir + Asunaprevir (n = 235) Daclatasvir + Asunaprevir (n = 205) Wk 24 Treatment-naive (N = 305) Previous null or partial responders (N = 205) Interferon ineligible/intolerant (N = 235) Wk 12

*Patients allocated placebo crossed over into a separate study after 12 wks.

HALLMARK-DUAL

90 82 81 80 91 73 10 20 30 40 50 60 70 80 90 100 SVR12 (% of patients)

• Breakthrough: 9 (4%) treatment

naive, 26 (13%) nonresponders, 20 (9%) IFN ineligible/intolerant

• Relapse: 5 (3%) treatment naive, 7

(4%) nonresponders, 12 (6%) IFN ineligible/intolerant

• 28 of 73 patients with NS5A-L31

and/or Y93 variants at baseline achieved SVR12

IFN-free regimens for G1

Abstract Phase Rx status Cirrhosis NS3/4A Protease Inhibitor NS5A Inhibitor NS5B nonnucleoside polymerase inhibitor NS5B nucleos(t)ide polymerase inhibitor Ribavirin included

O60 SAPPHIRE-1 3 Naïve No ABT 450/r Ombitasvir Dasabuvir Y O1 SAPPHIRE-2 3 Exp No ABT 450/r Ombitasvir Dasabuvir Y O163 TURQUOISE-2 3 Naïve Exp 100% ABT 450/r Ombitasvir Dasabuvir Y O164 ION-1 3 Naïve 16% Ledipasvir Sofosbuvir Y/N O109 ION-2 3 Exp 20% Ledipasvir Sofosbuvir Y/N O56 ION-3 3 Naïve No Ledipasvir Sofosbuvir Y/N O165 COSMOS (Cohort 2) 2a Naïve Exp F3-4 Simeprevir Sofosbuvir Y/N O7 COSMOS (Cohort 1) 2a Exp F0-2 Simeprevir Sofosbuvir Y/N O166 HALLMARK DUAL 3 Naïve Exp 16-47% Asunaprevir Daclatasvir O10 C-WORTHY

2b

Naïve No MK 5172 MK 8742 Y/N O61 C-WORTHY

2b

Naïve Exp MK 5172 MK 8742 Y/N

MK-5172 + MK-8742 +/- RBV in treatment-naïve, non-cirrhotic

• C-WORTHY (#O10)

83 83 94 94 94 98 97 100 20 40 60 80 100 SVR 4-24 1a 1b Response 8w+R 12w+R 12w(no R)

Wk 8 Treatment-naive, noncirrhotic patients with GT1 HCV* (N = 65) MK-5172 100 mg + MK-8742 20 mg + RBV (n = 25) MK-5172 100 mg + MK-8742 50 mg + RBV (n = 27) MK-5172 100 mg + MK-8742 50 mg (n = 13) Wk 12 Part A Treatment-naive, noncirrhotic patients with GT1 HCV† (N = 94) MK-5172 100 mg + MK-8742 50 mg + RBV (n = 30) MK-5172 100 mg + MK-8742 50 mg + RBV (n = 33) MK-5172 100 mg + MK-8742 50 mg (n = 31) Part B *Patients with GT1a randomized 1:1 to RBV arms only; patients with GT1b randomized 1:1:2 into all 3 arms.

†Patients with GT1a randomized 1:1:1 across arms; patients with GT1b assigned to 12-wk RBV arm only.

MK-5172 + MK-8742 +/- RBV in Cirrhotics and Null Responders

• C-WORTHY (#O61)

– Increase total bilirubin (2-5xULN) and anaemia (<10) in RBV arms

Treatment-naive pts with GT1 HCV and cirrhosis (N = 123) MK-5172 + MK-8742 + RBV (n = 31) MK-5172 + MK-8742 (n = 29) MK-5172 + MK-8742 + RBV (n = 32) Wk 12 Pts with GT1 HCV and null response to pegIFN/RBV (N = 130) MK-5172 + MK-8742 + RBV (n = 31) MK-5172 + MK-8742 (n = 33) Wk 18 MK-5172 + MK-8742 (n = 31) MK-5172 + MK-8742 + RBV (n = 33) MK-5172 + MK-8742 (n = 32) 28/ 31 28/ 29 30/ 31* 29/ 30* 30/ 32 30/ 33 32/ 32 * 29/ 30*

SVR4-8 (%) 100 80 60 40 20

Treatment-Naive Pts With Cirrhosis Null Responders ± Cirrhosis

12 wks + RBV 12 wks no RBV 18 wks + RBV 18 wks no RBV

90 97 97 91 94 100 97 97

Difficult-to-treat Patients

Sofosbuvir+Ledipasvir FDC+/-RBV

ELECTRON 2 (#O6)

– Partially randomized, open-label phase II trial

SOF/LDV FDC + RBV (n = 26) SOF/LDV FDC (n = 25) SOF/LDV FDC + RBV (n = 19) SOF/LDV FDC (n = 20) Wk 12 Treatment-naive GT3 (N = 51) GT1 and CTP class B cirrhosis (N = 20) GT1 relapsers after previous SOF-based regimen* (N = 19)

SVR12, %

*Includes 10 patients who received SOF + RBV for 12 wks, 8 patients who received SOF/LDV + RBV for 6 wks, and 1 patient who received SOF + GS-9669 + RBV for 12 wks.

Post-liver transplant

AOD+R in Transplant Recipients

• M12-999 (#O114)

– Open-label phase 2 trial – Inclusion criteria: GT1, liver transplantation resulting from HCV infection within 12 mos of screening, no HCV therapy after transplantation, METAVIR score ≤ F2, no previous steroid-resistant rejection, receiving stable tacrolimus- or cyclosporine-based immunosuppressant regimen

ABT-450/RTV/Ombitasvir + Dasabuvir + RBV Wk 24 Liver transplant recipients with recurrent HCV GT1

(N = 34)

Dosing of calcineurin inhibitors based on phase I PK study. Recommended tacrolimus dose modified to 0.5 mg once wkly or 0.2 mg every 3 days. Recommended cyclosporine dose modified to 20% of daily dose administered before study drugs. Prednisone ≤ 5 mg/day permitted. No use of mTOR inhibitors

M12-999

• 26/34 pts evaluated for SVR12 to

date

• No virologic breakthrough
• 1 relapse occurred at

posttreatment Day 3

– Resistant variants detected at time of relapse (none present at baseline):

• R155K in NS3
• M28T + Q30R in NS5A
• G554S + G557R in NS5B
• AEs occurred in 33 pts (97.1%),

serious AEs in 2 pts, and 1 pt DC-ed study drugs due to AEs

96.2 25/26 SVR12 (%) 100 80 60 40 20

ABT-450/RTV/Ombitasvir + Dasabuvir + RBV

Portal hypertension and decompensation

SOF + RBV in Patients With Cirrhosis and Portal Hypertension ± Decompensation

• Interim results of an open-label phase II trial (#O68)

Observation (n = 25) Sofosbuvir + Ribavirin (n = 25) Wk 72 HCV-infected patients with portal hypertension ± decompensated liver disease* (N = 50) Wk 24 Current analysis Sofosbuvir + Ribavirin (n = 25) Wk 48

HCV RNA < LLOQ (%) 100 80 60 40 20 Wk 2 Wk 4 Wk 8 Wk 12 56 100 94 Wk 24 CTP A CTP B 44 75 100 100 100 94 93

Chronic Hepatitis B - Combination therapy

Adding PIFN to ETV in HBeAg+CHB (#O3)

• HBeAg+CHB, compensated liver disease, ALT>1.3 ULN
• Primary endpoint:

– HBeAg loss and HBV DNA <200 IU/ml at week 48

• Secondary endpoint:

– HBV DNA, HBeAg and HBsAg decline during study – Sustainability of response at w96 ETV 24w ETV 48w PIFN 48w ETV 48w ETV 24w FU ETV 48w ETV 48w ETV 24w FU

Response ?

Yes Yes No No

Randomized

• Genotype A/B/C/D = 7%/19%/42%/32%
• Cirrhosis 5%
• Conclusions:

– PIFNa-2a add-on leads to higher HBeAg and HBsAg response rates compared to ETV montherapy

w48 w96 Sustained response Primary endpoint HBeAg loss & DNA<200 IU/ml HBeAg seroconversio n & DNA <200 IU/ml HBsAg <1000 IU/ml HBeAg loss & DNA<200 IU/ml HBeAg seroconversion & DNA <200 IU/ml HBeAg loss, normal ALT, DNA <2000 IU/ml ETV 10% (9/90) 20 (18/90) 11 (10/90) 14 (13/90) 25 (2/8) 25 (2/8) 25 (2/8) ETV+PIFN 19% (16/85) 31 (26/85) 24 (20/85) 26 (22/85) 64 (9/14) 69 (9/13) 79 (11/14) P-value 0.095 0.107 0.029 0.059 0.076 0.049 0.014

Combination therapy with PIFNa-2a and NA for HBeAg+CHB (#O113)

• Phase 4 randomised placebo-controlled double-blind multicentre study in Taiwan
• Treatment-naïve 60%, prev IFN 20%, prev NA 30%

Placebo ADE Placebo ETV Placebo ADE Placebo ETV ETV ADE PIFN a-2a PIFN a-2a PIFN a-2a FU FU FU

4 8 52 76 100

Arm A N=94 Arm B N=95 Arm C N=91

• EOT w52 (HBeAg seroconversion)

– Arm A vs Arm B = 27.2% vs 22.3%, P=0.382 – Arm A vs Arm C = 27.2% vs 21.1%, P=0.317 – Arm B vs Arm C = 22.3% vs 21.1%, P=0.886

• FU w76

– Arm A vs Arm B = 35.9% vs 28.4%, P=0.268 – Arm A vs Arm C = 35.9% vs 22.7%, P=0.055 – Arm B vs Arm C = 28.4% vs 22.7%, P=0.406

• Conclusions:

– This kind of sequential combination strategy does not increase HBeAg seroconversion rate compared to PIFN a-2a montherapy at EOT and 24w post treatment

Sequential combination with NA and PIFN in HBeAg+CHB with prior long term NA (#O117)

• China study

– Prior NA: LAM (33-61%), ADE (34-26%), ETV (61-30%), LdT (1.2-0.01%)

HBeAg+CHB patient on NA>2yrs without HBeAg loss or seroconversion N= 192 Sequential combination therapy PIFN+NA for 48w N=83 Sequential NA monotherapytherapy for 48w N=109

FU for additional 24 w

60.2 27.7 13.8 10 20 30 40 50 60 70 Complete response HBsAg loss Sequential combination therapy NA monotherapy

P<0.0001 P<0.0001

• Complete response: HBeAg loss + HBV DNA <2000 IU/ml
• All patients with baseline HBsAg level of 1000 IU/ml achieved a complete

response

• Decrease in HBsAg levels (>0.5 log IU/ml) at w12 and w24 strongly predict

treatment response

• Conclusions:

– Sequential combination therapy of NA and PIFN shows favorable treatment response in patients with prior long-term exposure to Nas – Sequential combination therapy can be guided by the baseline level and dynamic pattern of HBsAg in clinical practice

100 91 54 18 10 20 30 40 50 60 70 80 90 100 Complete response HBsAg loss Baseline HBsAg<1000 IU/ml Baseline HBsAg>1000 IU/ml

P<0.0026 P<0.0001

Thank You