Hepatitis B: Future treatment developments VIII International Update Workshop in Hepatology Curitiba, 27.08.2016 Christoph Sarrazin St. Josefs-Hospital Wiesbaden and Goethe-University, Frankfurt am Main Germany
Disclosures Consultancies / Advisory boards: Abbott, Abbvie, BMS, Gilead, Janssen, Merck/MSD, Roche Research support: Abbott, Gilead, Janssen, Qiagen, Roche, Siemens Speaker: Abbott, Abbvie, Achillion, BMS, Gilead, Janssen, Merck/MSD, Qiagen, Roche, Siemens
HBV Treatment: Future Directions Standard treatment Stop Nuc Combination of existing drugs New drugs in development
Chronic hepatitis B infection Life-long disease with different phases Immune tolerant Immune reactive Inactive carrier state HBeAg-neg. hepatitis B HBV DNA very high high low to neg. elevated HBs antigen pos. pos. pos. pos. HBe antigen pos. pos. neg. neg. Aminotransferases Inflammation liver Fibrosis progression normal/slightly elevated no or mild fluctuating elevated moderate to severe normal elevated Different prevalence of HBV and disease phases, routes of transmission, HBV genotypes and genetic risk factors between Europe and Asia no mild to moderate no or slow rapid no moderate EASL CPG Management of chronic hepatitis B virus infection. J Hepatol 2012
Survival (%) Treatment of chronic hepatitis B Endpoints Retrospective study of 309 cirrhotic patients over mean follow-up of 5.7 years 100 80 60 40 20 P<0.001 With HBsAg clearance No HBsAg clearance 0 2 4 6 8 10 12 14 Time (years) HBe antigen and HBs antigen loss / seroconversion Suppression of replication Fattovich et al. Am J Gastroenterol 1998
Established treatment of chronic hepatitis B Viral suppression and immune control after 1 year HBeAg-negative (12 months treatment / plus 6 months FU for PEG, no head-to head studies) PEG LAM LDT ETV ADV TDF Dose (μg/mg) 180 100 600 0.5 10 245 HBV DNA (<60-80 IU/ml) 19% 72-72% 88% 90% 51-63% 93% ALT normalisation 59% 71-79% 74% 78% 72-77% 76% HBsAg loss 4% 0% 0% 0% 0% 0% PEG, PEG-IFN alfa 2a; LAM, lamivudine; LDT, telbivudine; ETV, entecavir; ADV, adefovir; TDF, tenofovir; μg s.c. for PEG; mg for all others p.o.; different definitions of normalisation of ALT PEG with low rate of HBsAg loss NUC with high HBV DNA suppression and ALT normalisation HBsAg loss is limited with all treatment options EASL CPG Management of chronic hepatitis B virus infection. J Hepatol 2012
Treatment with NUCs Long term efficacy of Nucleos(t)ide treatment ETV TDF Response HBeAg+ Patients Year 5 HBeAg- Patients Year 3 HBeAg+ Patients Year 8 HBeAg- Patients Year 8 HBV DNA undetectable 94% (88/94) 95% (54/57) 98% (n=266) 99.6% (n=375) Resistance 1% NR 0% 0% HBeAg loss (seroconversion) 31% 47% (31%) HBsAg loss (seroconversion) 1.4% (0%) NR 11.5% (8.5%) 1.1% (<1%) Continuation of NUC treatment as long as HBV DNA declines Durability of HBeAg loss / seroconversion? Chang TT et al. Hepatology 2010; Shouval D et al. AASLD 2008; Marcellin P et al. AASLD 2014; Fong et al., Dig Dis Sci 2015
HBV Treatment: Future Directions Standard treatment Stop Nuc Combination of existing drugs New drugs in development
Treatment with NUCs Stop NUC HBeAg negative patients, treatment with ADV, 6 years follow-up Stable disease without retreatment (54%) 39% Hadziyannis et al., Gastroenterology 2012; 143: 629-636
Treatment with NUCs Stop NUC 1:1 Randomization Wk 0 Wk 48 Wk 144 CHB patients HBeAg-negative 4 years TDF therapy TDF-Stop TDF-Continue Week 48 Interim Primary endpoint: HBsAg loss by Week 144 Berg T et al., EASL 2015
ALT (U/L) Treatment with NUCs Stop NUC Patients requiring TDF re-initiation (n=3) Time TDF was restarted TDF-Stop (n=21) TDF-Continue (n=21) 983 U/L 559 U/L Berg et al., EASL 2015 Weeks From Baseline Weeks From Baseline
HBsAg (log 10 IU/mL) Treatment with NUCs Stop NUC HBsAg loss Patients requiring TDF re-initiation Time TDF was restarted TDF-Stop (n=21) TDF-Continue (n=21) HBs antigen loss in 10% of patients by stopping all treatment Weeks From Baseline Weeks From Baseline Berg et al., EASL 2015
HBV Treatment: Future Directions Standard treatment Stop Nuc Combination of existing drugs New drugs in development
New treatment strategies with existing drugs Combination / add-on / switch to PEG-IFN strategies Immunotherapy NUC NUC (for several years) Immuotherapy Immunotherapy NUC (for serveral years) NUC (for several years) Immunotherapy
New treatment strategies with existing drugs NUC plus PEG combination Week 0 16 24 48 72 120 n=186 TDF + PEG n=184 TDF+PEG TDF n=185 TDF n=185 PEG Start TDF during follow-up if prespecified safety criteria met Randomized, controlled, open-label study (N=740) Stratified by screening HBeAg status and HBV genotype Inclusion criteria HBeAg+ and HBV DNA 20,000 IU/mL (58-60%); HBeAg- and HBV DNA 2,000 IU/mL ALT >54 and 400 U/L (men); ALT >36 and 300 U/L (women) No bridging fibrosis or cirrhosis on liver biopsy or by transient elastography P. Marcellin et al., AASLD 2014; A193, Marcellin et al., Gastroenterology 2016
New treatment strategies with existing drugs NUC plus PEG combination Mean Change From Baseline(log 10 IU/mL) HBs antigen decline 0 Study Week 0 10 20 30 40 48 50-0,2-0,4-0,6 TDF 120 wk TDF+PEG 16 wk TDF 32 wk -0.3 log -0.5 log p<.001 p<.001-0,8 PEG 48 wk -0.8 log p=.016-1 -1,2 TDF + PEG 48 wk -1.1 log -1,4 3 patients who were re-treated at Week 48 were excluded from Week 48 calculations. Error bars represent 95% confidence intervals. P. Marcellin et al., AASLD 2014; A193, Marcellin et al., Gastroenterology 2016
Patients with HBsAg Loss, Kaplan-Meier Estimate (%) New treatment strategies with existing drugs NUC plus PEG combination HBs antigen loss at week 72 0.15 0.14 0.13 0.12 0.11 0.10 0.09 0.08 0.07 0.06 0.05 0.04 0.03 0.02 0.01 0.00 48 weeks 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 Week 72 weeks 7 patients had HBsAg seroreversion on or after Week 48 (4 [TDF + PEG 48 wk], 3 [TDF + PEG 16 wk TDF 32 wk]) 5/7 had 1 week of therapy after HBsAg loss TDF + PEG 48 wk 9.0% PEG 48 wk TDF + PEG 16 wk TDF 32 wk TDF 120 wk n=12 (58% HBeAg pos.) 2.8% 2.8% 0% p=0.003 p=ns p=ns P. Marcellin et al., AASLD 2014; A193, Marcellin et al., Gastroenterology 2016
New treatment strategies with existing drugs Add-on Interferon-alfa in HBeAg pos. patients Author Population Study design Follow-up Yu Y et al. (EASL 2016, FRI-151) HBeAg positive (n=157) Retrospective, comparing add-on for 48 weeks (n=81) vs. continued ETV (n=116) End-of-treatment HBeAg-seoconversion (48 vs 8%) and HBsAg loss (10 vs 0%) ARES-Study: HBeAg positive patients randomized n=85 ETV with PEG-IFN add-on versus n=90 ETV alone NUCs PEG-IFN NUCs Remission after ETV Stop n=2 n=11 Brouwer et al., Hepatology 2014 Ning et al., J Hepatol 2014
New treatment strategies with existing drugs Combination / add-on / switch to PEG-IFN strategies Immunotherapy NUC NUC (for several years) Immuotherapy Immunotherapy NUC (for serveral years) NUC (for several years) Immunotherapy
New treatment strategies with existing drugs Add-on Interferon-alfa in HBeAg negative patients Author Population Study design Outcome Bourliere M et al., (EASL 2015, PEGAN) HBeAg-negative, on NUCs, HBV- DNA negative > 1y (n=183) Prospective, randomized, PEG2a versus no tx for 48 weeks End of treatment HBsAg loss 3% (no tx) versus 8% (PEG) Sprinzl MF et al. (EASL 2016, LBP517, PADD-ON) HBeAg negative, on NUCs, HBV- DNA negative > 1y (n=137) Prospective, randomized (2:1), (add-on for 48 weeks) Week 24 on treatment interim analysis with significant HBsAg decline Lampertico P et al. (EASL 2016, LBP521, HERMES) HBeAg-negative, HBV-DNA negative > 1y, HBV GT D (n=70) Prospective, single arm (multicenter) (add-on for 48 weeks) Follow-up week 48 after PEG treatment with significant HBsAg decline but rare HBsAg loss (n=1)
HBV Treatment: Future Directions Standard treatment Stop Nuc Combination of existing drugs New drugs in development New nucleoide analogue New mechanisms
New drugs TAF instead of TDF Tenofovir Disoproxil Fumarate (300mg TDF) Tenofovir Alafenamide lower doses, lower systemic exposure of active Tenofovir Primary Endpoint (25mg TAF) Week 0 48 96 144* e+ n=581 n=292 TAF 25 mg QD TDF 300 mg QD Open-label TAF 25 mg Week 0 48 96 144* e- n=285 n=140 TAF 25 mg QD TDF 300 mg QD Open-label TAF 25 mg Chan et al., EASL 2016, GS12; Buti et al., EASL 2016, GS06
New drugs TAF instead of TDF HBV-DNA <29 IU/mL Week 48 100% 94% 93% TAF TDF 80% 60% 64% 67% 40% 20% N=285 N=140 N=581 N=292 0% HBeAg neg HBeAg pos primary end-point non-inferiority was achieved Chan et al., EASL 2016, GS12; Buti et al., EASL 2016, GS06
Mean (SD) % Change From Baseline New drugs TAF instead of TDF 2 0-2 -4-6 Bone mineral density (BMD) and renal safety through week 48 TAF Spine TDF p <0.001 0.42 2.29 2 0-2 -4 scr change, mg/dl egfr CG change, ml/min No dipstick proteinuria, n/n (%) Confirmed renal events, n (%) Hip TAF n=581 0.009 (0.124) -0.3 (14.5) 419/57 7 (73) TDF n=292 p- value 0.026 0.020 (0.095) p <0.001-4.7 <0.001 (13.5) 0.10 221/28 0.21 6 (77) 1.72 scr 0.5 mg/dl 0 0-6 from baseline 0 24 48 Wks 0 24 48 egfr CG <50 Week 0 5 (2) 0.004 ml/min Fewer TAF patients had >3% decreases in BMD at Week 48 Spine: 18% TAF; 38% TDF (p <0.001) Hip: 8% TAF; 24% TDF (p <0.001) PO 4 <2.0 mg/dl 3 (<1) 1 (<1) 1.0 Chan et al., EASL 2016, GS12; Buti et al., EASL 2016, GS06
HBV Treatment: Future Directions Standard treatment Stop Nuc Combination of existing drugs New drugs in development New nucleoide analogue New mechanisms
New treatment strategies Future developments Replication cycle - Viral factors - Host factors entry inhibitors inhibition of HBsAg secretion immunomodulators Immune system - Innate immune response - Adaptive immune response sirna to HBV mrna nucleocapsid inhibitors Adapted from Grimm D et al. Hepatol Int 2011;5:644 53; Fletcher S, Delaney W. Semin Liver Dis 2013;33:130 7
New treatment strategies for chronic HBV Pre-clinical and first clinical studies Author Substance (Company) Class Phase Yuen M-F et al. (LB06) NVR 3-778 (Novira Therapeutics) Core inhibitor Phase 1b Mani N et al. (THU-198) AB-423 (Arbutus Biopharma) Capsid assembly inhibitor (small molecule) preclinical (mice) Li P-C et al. (FRI-136) Yuen M-F et al. (THU-193) Xu Z et al. (THU-213) Blank A et al. (PS054) CpAMs (Assembly Biosciences) ARC-520 (Arrowhead Pharmaceuticals) ARC-520 (Arrowhead Pharmaceuticals) Myrcludex B (Maxwell Biotech) Core protein assembly modulators sirna sirna preclinical Phase IIa Chimps Entry inhibitor Phase 0/I
Summary Treatment of chronic hepatitis B is indicated in replicative patients with inflammation in the liver proven by biopsy and / or ALT levels, in patients with (decompensated) cirrhosis and according to risk factors Aim of treatment is induction of immune control PEG-Interferon and Nucleos(t)ides with different durations, AE-profiles and efficacies in subgroups Stop NUC may be considered Combination, add-on, switch of PEG plus NUC no standard yet New treatment strategies in clinical development