serum hbv-rna levels decline significantly in...
TRANSCRIPT
SERUM HBV-RNA LEVELS DECLINE SIGNIFICANTLY IN CHRONIC HEPATITIS B PATIENTS DOSED WITH
THE NUCLEIC-ACID POLYMER REP 2139-Ca
Louis Jansen1,2, Andrew Vaillant3, Karel van Dort1, Femke Stelma1,2, Neeltje Kootstra1, Michel Bazinet3, Mamun Al-Mahtab4, Hendrik Reesink1,2
1 Experimental Immunology,2 Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands,
3 REPLICor Inc., Montreal, Canada,4 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.
IntroductionChronic Hepatitis B Treatment
1. EASL. J Hepatol 2012.
Available therapies for patients with chronic hepatitis B1:• 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
Jansen EASL 2015 – 3
Hepatocyte
Virions
HBeAg
SVP(HBsAg)
Capsids
cccDNA
1. Zhang et al. J Med Virol. 20032. Bommel van et al. Hepatology. 20143. Jansen et al. AASLD 2013; EASL 2014
HypothesisSerum Hepatitis B RNA levels in NUC treatment?
? Serum HBV RNA1,2,3
Jansen EASL 2015 – 4
DNA
RNART
• NAPs have entry and post entry antiviral effects in HBV infection in vitro1
• The post-entry NAP effect appears to be linked to clearance of serum HBsAg2
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)
IntroductionNucleic Acid Polymers (NAPs) in Hepatitis B
1. Noordeen et al. Antimicrob Agents Chemother. 2013; 5291-5298 2. Noordeen et al. Antimicrob Agents Chemother. 2013; 5299-5306 Jansen EASL 2015 – 5
Serum Hepatitis B RNA levels in NAP treatment?
VirionsCapsids
cccDNA
Restoration ofimmune response?1,2
Elimination ofserum HBsAg
1. Wu et al. Hepatology. 20092. Boni et al. Gastroenterology. 2012
Hypothesis
Serum HBV RNA?
Jansen EASL 2015 – 6
Research Question
• Kinetics of serum HBV-RNA in patients dosed with nucleicacid polymer (NAP) REP 2139-Ca?
REP 102 protocol: Phase II proof of concept trialDr. Mamun Al-Mahtab, (Dhaka, Bangladesh)Dosing: 2011 – 2012, Follow-up ongoing
Jansen EASL 2015 – 7
Patient Cohort
• 12 Chronic Hepatitis B patients• HBeAg-positive• HBV DNA 105 – 108 copies / mL• Treatment naive• Metavir ≤ F3 (fibroscan)• ALT < 3 × ULN
Inclusion criteria REP 102 protocol
Jansen EASL 2015 – 8
Study dosing REP 102 protocol
Patient Cohort
REP 2139-Ca
Follow-up
20-24 Weeks
n = 12
REP 2139-Ca – 500mg qW 2 hour IV
Pegasys™ 180 ug SC qWand/or
Zadaxin™ (thymosin alpha-1) 1.6mg SC 2qW
Add-on*
21 Weeks (range 7-27)
13-26 Weeks
Entecavir
HBsAg non-responders (n = 3)
HBsAg responders (n = 9)
Jansen EASL 2015 – 9
*Add-on:
Patient Cohort
Baseline 20-24 Follow-up
• Serum (-20°C) sent to AMC for HBV RNA measurement• Compared to HBV DNA (Cobas), and HBsAg (Architect)
Time points of HBV RNA measurement
12
REP 2139-Ca
Jansen EASL 2015 – 10
REP 2139-Ca
Follow-up
20-24 Weeks
n = 12
Add-on*
21 Weeks (range 7-27)
13-26 Weeks
Entecavir
HBsAg non-responders (n = 3)
HBsAg responders (n = 9)
IM Add-on
Methods
• 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 2014.
Serum HBV RNA Quantification1,2
Jansen EASL 2015 – 11
4 6 8 10
2
4
6
8
10
HBV RNA (log10C/mL)
HB
sAg
(Log
10IU
/mL)
HBV
DNA
(Log
10C/
mL)
Results
HBV DNAr2 0.74, p < 0.001
HBsAgr2 0.33, p = 0.049
Baseline Serum HBV RNA Levels
Jansen EASL 2015 – 12
Baseline
RNA HBsAg-8
-6
-4
-2
0
2
Dec
line
from
bas
elin
e
Results
0 12 24
4
6
8
10
LLD
Weeks of REP 2139-Ca
HB
V R
NA
(log 1
0C/m
L)
n = 3
n = 9
Week 20-24 Decline
Serum HBV-RNA Decline During REP 2139-Ca Treatment
Jansen EASL 2015 – 13
NR
R
4
6
8
10
4
6
8
10
BL 20-24 FULLD LLD
IM12
HBV
DNA
HBV RNA
0
2
4
6
0
200
400
600
BL 20-24 FULLD
12 IM HB
sAg
anti-HBs
Results
4
6
8
10
4
6
8
10
BL 20-24 FULLD LLD
IM12
HBV
DNA
HBV RNA
0
2
4
6
0
200
400
600
BL 20-24 FULLD
12 IM HB
sAg
anti-HBs
At FU: 4/9 patientsHBsAg <0.05 IU/mL+ anti-HBs positive
Mean ± SEMHBV DNA, HBV RNA; log10 C/mLHBsAg; log10 IU/mLanti-HBs; U/L
Serum HBV-RNA in REP 2139-Ca Responders (n = 9)
Jansen EASL 2015 – 14
Results
0
2
4
6
0
200
400
600
BL 20-24 FULLD
12HB
sAg
anti-HBs
4
6
8
10
4
6
8
10
BL 20-24 FULLD LLD
12
HBV
DNA
HBV RNA
Mean ± SEMHBV DNA, HBV RNA; log10 C/mLHBsAg; log10 IU/mLanti-HBs; U/L
Serum HBV-RNA in REP 2139-Ca Non-Responders (n = 3)
ETV ETV
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:
Jansen EASL 2015 – 16
Topic Abstract NumberPreclinical evaluation of NAPs in vivo P0542
HBV in vitro activity of NAPs P0556Clinical cytokine analysis (REP 102) P0659
HDV in vitro activity of NAPs LP26HBV / HDV clinical data (REP 301) LO2