New treatment endpoints and biomarkers for clinical trials

Transcription

1 New treatment endpoints and biomarkers for clinical trials Jorg Petersen Liver Center IFI Institute for Interdisciplinary Medicine at Asklepios Klinik St. George Hamburg University of Hamburg mail:

2 Goal of antiviral treatment in patients with CHB The goal of therapy for hepatitis B is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensated cirrhosis, end-stage liver disease, hepatocellular carcinoma (HCC) and death EASL Guidelines. J Hepatol 2012;57:

3 Current treatment strategies: Viral suppression and disease control

4 Are we successful in reducing the numbers of expected HCCs in treated HBV patients? World-wide majority of HCCs due to HBV Complex HBV associated pathogenesis Multiple HCC risk factors (host, virus) Heterogenous patients profiles (Asian-Caucasian, eagstatus, cirrhosis - no cirrhosis, genotypes..)

5 HCC in NUC naive CHB patients treated in Europe with TDF HCC/yr in untreated Europeans: 0.3% (CHB), 2.2% (Cirrhotics) Fattovich et al J Hepatology 2008 Papatheodoridis G et al. J Hepatol 2015:62:956-67

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7 HBV treatment: Achievements and ongoing challenges (not complete) suppression of HBV replication No HBV eradication Decrease in inflammation and some histological improvement Hepatitis B treatment Very low rates of HBsAg clearance Some prevention of complications of cirrhosis Long-term therapy - Adverse reactions - remaining HCC risk Liaw YF, et al. N Engl J Med 2004;351: ; Marcellin P, et al. Lancet 2013;381:

8 Time for a new goal: functional cure of patients with CHB Finite treatment duration Cessation of all treatment Persistence of Absence HBsAg should of HBsAg be considered as failure of therapy

9 quantitative HBsAg Tests - total HBsAg Abbott linear range 0, IU/mL Elecsys linear range 0, IU/mL ,000 10, ,000 1,000,000 HBsAg Level (IU/mL) Linear ranges covering clinically relevant HBsAg levels Bonino et al. APASL 2011; Package insert: Architect HBsAg assay; Package insert: Elecsys HBsAg II quant

10 Log cccdna/cell cccdna (log c/geq) Pros and Cons of HBsAg: a surrogate marker for (transcriptionally active) cccdna? P= P= HBeAg+ P<0.001 HBeAg- NS <15 15 <35 35 HBsAg (μg/ml) HBeAg+ (n=42); HBeAg- (n=77) HBsAg (log IU/mL) HBeAg+ (n=71); HBeAg- (n=78) Volz T, et al. Gastroenterology 2007;133:843 52; Adapted from Thompson AJ, et al. Hepatology 2010;51: c/geq: copies per genome equivalent; HBeAg: hepatitis B e antigen; NS: not significant

11 Not all HBsAg fractions react the same way example acute HBV infection Percentage % * 0 BL-LHBS FU-LHBS BL-MHBS FU-MHBS BL-SHBS FU-SHBS Mean with SD, t-test unpaired with Welch s correction *p<0.05 Wiegand, Glebe, Cornberg EASL 2013

12 Process of HBV dsldna integration and theoretical production of HBsAg dsldna integration explains persistent expression of HBsAg despite very low cccdna in HBeAg-chimps Loss of ARC-520 target sites explains lower KD of HBsAg in HBeAg-chimps Yuen MF, EASL 2016, THU-193.

13 Analysis of HBV integrations in HBV-infected chimeric mice Detection of HBV integrations after removing viral replicative intermediates from host genome by gel electrophoresis HBsAg - control Genomic DNA with HBV DNA integrations M qpcr (S-region) Cytokeratin 18 HBsAg HBcAg Cytokeratin rcdna and cccdna Serial passage lead to accumulation of human hepatocytes containing HBV integrations (S-region; average 0.5 HBV DNA integrated sequences/cell). Despite accumulation of HBV integrations in serially passaged human hepatocytes, no detectable production of HBsAg and HBcAg was found. Allweiss, Petersen, Dandri et al, EASL 2014

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15 Patients [n] qhbsag long-term Albatros study (10yrs) inactive HBV carriers and HBsAg loss during the natural course of the disease (n=235) (n=152) (n=91) (n=46) HBsAg seroclearance HBsAg seroconversion Active carrier state 3% per year 2% per year No HBsAg loss if HBsAg >100 IU/ml & HBV-DNA >1000 IU/ml V. Knop, Wedemeyer, Petersen,, C. Sarrazin. EASL 2014, Abstract 698

16 Mean HBsAg (Log 10 IU/mL) HBsAg kinetics in HBeAg-negative patients treated with TDF for 4 years Non-Asians (N = 281) Asians (N = 94) Weeks on treatment Asians have lower baseline levels of HBsAg than non- Asians HBsAg decline: log/4 years In both groups, the overall 192 week declines were modest Fung S, et al. APASL 2012; Poster #PP

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18 Patients(%) Switch to PEG IFN in long-term NUC treated pts Predictors of HBsAg loss at week 48 e+ HBsAg loss at week 48 (n=47 pts) , , P< , P< /124 6/147 Baseline /9 0,6 1/176 HBsAg<200 HBsAg 200 IU/mL IU/mL Week 24 Hong R et al. EASL 2015

19 Add-on PEG-IFN in HBeAg neg NUC responders On-treatment changes in HBsAg levels Mean HBsAg titer log 10 (IU/ml) 3,5 HBsAg loss: 0%* HBsAg loss: 3%** 3,0 2,5 2,0 P= * -0.91* P= * NUC alone (n=93) -0.89* NUC + PEG-IFN (n=90) HBsAg loss: 8% HBsAg loss: 8% 1,5 W0 W12 W24 W36 W48 W60 W72 W84 W96 26/07/2013 * p= ** p= Weeks * Log 10 IU/ml decrease between W0/W48 and W0/W96. Error bars represent 95% confidence intervals. Bourliere M. et al, EASL 2015

20 Patients with HBsAg loss, Kaplan Meier estimate (%) Combination therapy results in higher rates of HBsAg loss than monotherapy weeks 72 weeks 10 TDF + PEG-IFN 48 wk 9.1% P= TDF + PEG-IFN 16 wk PEG-IFN 48 wk TDF 32 wk 2.8% 2.8% P=NS P<0.001 P=NS 0 TDF 120 wk 0% Week 7 patients had HBsAg seroreversion on or after Week 48 (4 patients receiving TDF + PEG-IFN for 48 weeks and 3 with TDF + PEG-IFN for 16 weeks followed by TDF for 32 weeks 5/7 had 1 week of therapy after HBsAg loss Marcellin P, et al. Gastroenterology 2016;150:

21 1:1 Randomization A RCT of stopping TDF after long-term virologic suppression in HBeAg-negative CHB: the FINITE CHB study (Germany) Wk 0 Wk 48 Wk 144 CHB patients HBeAgnegative 4 years TDF therapy TDF-Stop TDF-Continue Interim analysis: Week 48 Primary endpoint: HBsAg loss by Week 144 Open-label, multicenter, randomized, controlled trial HBeAg-negative at TDF initiation and randomization HBV DNA <400 copies/ml for 3.5 years before randomization No cirrhosis (Fibroscan 10 kpa), normal ALT, HBeAg-, anti-hbe+, HBsAg+ No history of decompensated liver disease Berg T et al, EASL 2015

22 HBsAg (log 10 IU/mL) HBsAg Profiles 6 TDF-Stop (n=21) HBsAg loss Patients requiring TDF reinitiation Time TDF was restarted TDF-Continue (n=21) Weeks From Baseline Weeks From Baseline 22

23 qhbsag predicts sustained response after LAM discontinuation among HBeAg neg patients from Taiwan e- HBV DNA relapse* HBsAg loss *defined as serum HBV DNA >2,000 IU/mL in 2 measurements at least 3 months apart Chen CH et al, J Hepatol 2014

24 Conclusions qhbsag as biomarker in trials HBsAg levels depend on: The number of infected hepatocytes The amount of transcriptionally active cccdna The presence of transcriptionally active viral integrated sequences Not a direct marker of cccdna HBsAg elimination is the most important clinical endpoint 2016 Not an ideal surrogate marker, but we have defined a few areas of interest and significance in the past years

25 Novel biomarkers for clinical trials Immunotheraputic interventions Clinical immunology: T Cell responses, NK phenotyping etc Liver biopsies (not new ): repeated biopsies for small proof of concept studies? cccdna, epigenetics, intrahep. immunity, immune cells, ISGs HBcrAg RNA containing particles

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29 Zeisel et al, GUT 2015;64:

30 Back up slides

31 New anti-hbv approaches 1 NTCP-R mini-chromosome Restoration of innate and adaptive immunity ciaps 9 Adapted from Chan, Thompson et al. J Hepatol, 2011 Strategy Candidate Clinical development phase Entry inhibitors 1 Entry inhibitors Myrcludex-B Phase 2 Direct antiviral agents 2 / 3 cccdna inhibitors - Elimination - Silencing LT-βR agonists Zinc finger nucleases TALENs CRISPR-Cas9-based strategies Epi-drugs 4 Capsid inhibitors NVR HAPs Phenylpropenamide Preclinical Preclinical Preclinical Preclinical Preclinical Phase 1/2 Phase 1 Preclinical 5 HBV polymerase inhibitor Tenofovir alafenamide Phase 3 6 HBV RNA interference ARC-520 TKM-HBV ALN-HBV 7 HBsAg release inhibitors REP-9AC REP-2139-Ca Host targeting agents Phase 2 Phase 1 Preclinical Phase 2 8 TLR agonists GS-9620 (TLR7) Phase 2 Anti-PD-1 Therapeutic vaccine Nivolumab Pembrolizumab ABX302 GS-4774 (tarmogen) INO-1800 TS1050 Preclinical * Preclinical * Phase 2b/3 Phase 2 Phase 1 Phase 1 9 ciap inhibitor Birinapant Phase 1 Petersen J, Thompson, A, Levrero M. Clinical trial watch HBV and HDV. J Hepatology Review..

32 Endpoints and biomarkers qhbsag: commercially available test The main endpoint in current trials Most informations gained over the last few years Circulating viral RNAs more characterization needed role in the viral life cycle to be determined (surrogate for cccdna?) monitoring core assembly therapies? HBcrAg more charcterization needed - circulating particles without viral genome, correlation with cccdna? monitoring core assembly therapies?