SERUM HBV-RNA LEVELS DECLINE SIGNIFICANTLY IN CHRONIC HEPATITIS B PATIENTS DOSED WITH THE NUCLEIC-ACID POLYMER REP 2139-Ca Louis Jansen 1,2, Andrew Vaillant 3, Karel van Dort 1, Femke Stelma 1,2, Neeltje Kootstra 1, Michel Bazinet 3, Mamun Al-Mahtab, Hendrik Reesink 1,2 1 Experimental Immunology, 2 Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands, 3 REPLICor Inc., Montreal, Canada, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
Disclosures Hendrik W. Reesink Consulting / Research Support : Abbvie, BMS, Boehringer Ingelheim, Gilead, GSK, Janssen-Cilag, Merck/MSD, PRA-International, Regulus, Replicor, Roche, R-Pharm, Santaris. Andrew Vaillant, Michel Bazinet Stockholders (shareholder) and Employees: REPLICor Inc. The following people have nothing to disclose: Louis Jansen, Femke Stelma, Karel van Dort, Neeltje Kootstra, Mamun Al- Mahtab.
Introduction Chronic Hepatitis B Treatment Available therapies for patients with chronic hepatitis B 1 : Peginterferon-α + Potential immune-mediated control of HBV - Significant side-effects Nucleos(t)ide analogues + Potent viral supression - Limited off-therapy response Need for new therapeutic approaches: Enhance loss of HBeAg and HBsAg 1. EASL. J Hepatol 2012. Jansen EASL 2015 3
Hypothesis Serum Hepatitis B RNA levels in NUC treatment? SVP (HBsAg) Hepatocyte cccdna RNA Capsids RT DNA HBeAg Virions? Serum HBV RNA 1,2,3 1. Zhang et al. J Med Virol. 2003 2. Bommel van et al. Hepatology. 201 3. Jansen et al. AASLD 2013; EASL 201 Jansen EASL 2015
Introduction Nucleic Acid Polymers (NAPs) in Hepatitis B NAPs have entry and post entry antiviral effects in HBV infection in vitro 1 The post-entry NAP effect appears to be linked to clearance of serum HBsAg 2 Hypothesis: NAPs prevent subviral particle (SVP) formation REP 2139 = (A,5 MeC)20 PS-ON, fully 2 O-methylated REP 2139-Ca = Calcium chelate complex of REP 2139 (improves administration tolerability) 1. Noordeen et al. Antimicrob Agents Chemother. 2013; 5291-5298 2. Noordeen et al. Antimicrob Agents Chemother. 2013; 5299-5306 Jansen EASL 2015 5
Hypothesis Serum Hepatitis B RNA levels in NAP treatment? Elimination of serum HBsAg cccdna Capsids Virions Restoration of immune response? 1,2 Serum HBV RNA? 1. Wu et al. Hepatology. 2009 2. Boni et al. Gastroenterology. 2012 Jansen EASL 2015 6
Research Question Kinetics of serum HBV-RNA in patients dosed with nucleic acid polymer (NAP) REP 2139-Ca? REP 102 protocol: Phase II proof of concept trial Dr. Mamun Al-Mahtab, (Dhaka, Bangladesh) Dosing: 2011 2012, Follow-up ongoing Jansen EASL 2015 7
Patient Cohort Inclusion criteria REP 102 protocol 12 Chronic Hepatitis B patients HBeAg-positive HBV DNA 10 5 10 8 copies / ml Treatment naive Metavir F3 (fibroscan) ALT < 3 ULN Jansen EASL 2015 8
Patient Cohort Study dosing REP 102 protocol HBsAg non-responders (n = 3) Entecavir n = 12 REP 2139-Ca HBsAg responders (n = 9) Add-on* Follow-up 20-2 Weeks 13-26 Weeks 21 Weeks (range 7-27) REP 2139-Ca 500mg qw 2 hour IV *Add-on: Pegasys 180 ug SC qw and/or Zadaxin (thymosin alpha-1) 1.6mg SC 2qW Jansen EASL 2015 9
Patient Cohort Time points of HBV RNA measurement HBsAg non-responders (n = 3) Entecavir n = 12 REP 2139-Ca HBsAg responders (n = 9) Add-on* Follow-up 20-2 Weeks 13-26 Weeks 21 Weeks (range 7-27) Baseline 12 20-2 IM Add-on Follow-up REP 2139-Ca Serum (-20 C) sent to AMC for HBV RNA measurement Compared to HBV DNA (Cobas), and HBsAg (Architect) Jansen EASL 2015 10
Methods Serum HBV RNA Quantification 1,2 RNA isolation in plasma DNAse treatment Quantitative RT-PCR specific for HBV-RNA 1. Laras et al. Virology 2002. 2. Jansen et al. AASLD 2013; EASL 201. Jansen EASL 2015 11
Results Baseline Serum HBV RNA Levels Baseline HBsAg (Log 10 IU/mL) HBV DNA (Log 10 C/mL) 10 8 6 2 HBV DNA r 2 0.7, p < 0.001 HBsAg r 2 0.33, p = 0.09 6 8 10 HBV RNA (log 10 C/mL) Jansen EASL 2015 12
Results Serum HBV-RNA Decline During REP 2139-Ca Treatment 10 2 Week 20-2 Decline HBV RNA (log 10 C/mL) 8 6 LLD 0 12 2 Weeks of REP 2139-Ca Decline from baseline 0-2 - -6-8 RNA HBsAg NR n = 3 R n = 9 Jansen EASL 2015 13
Results Serum HBV-RNA in REP 2139-Ca Responders (n = 9) 10 10 6 600 HBV DNA 8 6 LLD BL 12 20-2 IM FU 8 6 LLD HBV RNA HBsAg 2 0 LLD BL 12 20-2 IM FU 00 200 0 anti-hbs Mean ± SEM HBV DNA, HBV RNA; log 10 C/mL HBsAg; log 10 IU/mL anti-hbs; U/L At FU: /9 patients HBsAg <0.05 IU/mL + anti-hbs positive Jansen EASL 2015 1
Results Serum HBV-RNA in REP 2139-Ca Non-Responders (n = 3) 10 ETV 10 6 ETV 600 HBV DNA 8 6 LLD 8 6 LLD HBV RNA HBsAg 2 0 LLD 00 200 0 anti-hbs BL 12 20-2 FU BL 12 20-2 FU Mean ± SEM HBV DNA, HBV RNA; log 10 C/mL HBsAg; log 10 IU/mL anti-hbs; U/L Jansen EASL 2015 15
Conclusions Treatment of CHB patients with REP 2139-Ca resulted in a pronounced decline of serum HBV-RNA in 9/12 of patients In 3/12 patients (non-responders) HBV-RNA levels were unaffected, both before and after treatment with entecavir. Related abstracts: Topic Preclinical evaluation of NAPs in vivo HBV in vitro activity of NAPs Clinical cytokine analysis (REP 102) HDV in vitro activity of NAPs HBV / HDV clinical data (REP 301) Abstract Number P052 P0556 P0659 LP26 LO2 Jansen EASL 2015 16