REP 2139 monotherapy and combination therapy with pegylated interferon: Safety and potent reduction of HBsAg and HDV RNA in Caucasian Patients with chronic HBV / HDV co-infection M. Bazinet 1, V. Pântea 2, V. Cebotarescu 2, L. Cojuhari 3, P. Jimbei 3 and A. Vaillant 1 1.Replicor Inc., Montreal, Canada. 2.Department of Infectious Diseases, Nicolae Testemițanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova. 3.Toma Ciorbă Infectious Clinical Hospital, Chișinău, Republic of Moldova. The Global Viral Hepatitis Summit 15 th International Symposium on Viral Hepatitis and Liver Disease Presentation O-09 Berlin, Germany June 26 28, 2015
Nucleic Acid Polymers (NAPs) Synthetic, amphipathic polymers (oligonucleotides) NOT antisense (think heparin sulfate.) -> block viral entry Post-entry effects appear critical for antiviral effect in vivo Naturally taken up by hepatocytes with parenteral administration Interfere with apolipoprotein / HBsAg interactions required for HBV subviral particle (SVP) assembly Target the host apolipoprotein H (no resistance) Effect is selective for SVPs (virions not directly targeted) June 26, 2015 2
Particle production in HBV infection Subviral particles (bulk of serum HBsAg) Infected hepatocyte cccdna Capsids HBeAg Virions June 26, 2015 3
The NAP effect in HBV infection Infected hepatocyte cccdna Capsids HBeAg Virions June 26, 2015 4
Potential NAP effect in HDV Subviral particles (bulk of serum HBsAg) HDV virus (SVP-like) Infected hepatocyte cccdna Bonino et al., 1986 J. Virol. 58: 945-950 June 26, 2015 5
REP 2139-Ca + Pegasys in HBV / HDV co-infection (REP 301) Caucasian patients treated in Chisinau, Moldova CRO monitored trial compliant with EU GCP Clinicaltrials # NCT02233075 12 patients enrolled with HBV / HDV co-infection at the start of treatment: Anti-HDAg+ Serum HBsAg > 1000 U / ml HBeAg- compensated liver disease mild to moderate fibrosis, non cirrhotic. Viremia monitored at University of Duisburg-Essen, Germany: Abbott PCR (HBV DNA) Abbott Architect (HBsAg and anti-hbs) Robogene RT-PCR (HDV RNA) Diasorin (anti-hdag) June 26, 2015 6
REP 301 Trial Design REP 2139-Ca 500mg qw IV 15 weeks REP 2139-Ca 250mg qw IV 15 weeks Pegylated interferon α-2a (Pegasys ) 180 μg qw SC 48 weeks Follow up (4, 12 and 24 weeks) REP 2139-Ca qw regimen is well established for this drug class (PS-ONs) June 26, 2015 7
Interim REP 301 Efficacy Data (serum HBsAg) 500mg REP 2139-Ca qw 250 mg REP 2139-Ca qw 180 ug Pegasys qw Serum HBsAg (IU / ml) 1.E+05 1.E+04 1.E+03 1.E+02 1.E+01 1.E+00 1.E-01 001-01 001-02 001-03 001-06 001-09 001-11 001-14 001-17 001-20 001-22 001-24 001-26 LLOQ no HBsAg detected start of dosing start Pegasys 1.E-02 1.E-03 June 26, 2015 8
Interim REP 301 Efficacy Data (serum anti-hbs) Serum anti-hbs (miu / ml) 1,000 800 600 400 200 500mg REP 2139-Ca qw 001-01 001-02 001-03 001-06 001-09 001-11 001-14 001-17 001-20 001-22 001-24 001-26 Protective immunity start of dosing start Pegasys 250 mg REP 2139-Ca qw 180 ug Pegasys qw 0 June 26, 2015 9
Interim REP 301 Efficacy Data (serum HDV RNA) Serum HDV RNA (U / ml) 1.E+08 1.E+07 1.E+06 1.E+05 1.E+04 1.E+03 1.E+02 1.E+01 500mg REP 2139-Ca qw 250 mg REP 2139-Ca qw 180 ug Pegasys qw 001-01 001-02 001-03 001-06 001-09 001-11 001-14 001-17 001-20 001-22 001-24 001-26 LLOQ no target detected start of dosing start Pegasys 1.E+00 1.E-01 June 26, 2015 10
Validation of REP 301 HDV RNA Study site Validation site #1 Validation site #2 Serum HDV RNA (U / ml) 1.E+08 1.E+07 1.E+06 1.E+05 1.E+04 1.E+03 1.E+02 1.E+01 1.E+00 001-01 001-02 001-03 001-06 001-09 001-11 001-14 001-17 001-20 001-22 001-24 001-26 LLOQ no target detected start of dosing start Pegasys Serum HDV RNA (copies / ml) 1.E+10 1.E+09 1.E+08 1.E+07 1.E+06 1.E+05 1.E+04 1.E+03 1.E+02 1.E+01 001-01 001-02 001-03 001-06 001-09 001-11 001-14 001-17 001-20 001-22 001-24 001-26 LLOQ no target detected start of dosing start Pegasys Serum HDV RNA (copies / ml) 1.E+07 1.E+06 1.E+05 1.E+04 1.E+03 1.E+02 1.E+01 1.E+00 001-01 001-02 001-03 001-06 001-09 001-11 001-14 001-17 001-20 001-22 001-24 001-26 LLOQ no target detected start of dosing start Pegasys 1.E-01 1.E+00 1.E-01 DUISBURG-ESSEN NGI TUM GT1 primer set on separate serum samples Independent primer set on RNA from study site June 26, 2015 11
HBsAg versus HDV RNA response HBsAg HDV RNA 1.E+05 1.E+08 1.E+04 1.E+07 Serum HBsAg (IU / ml) 1.E+03 1.E+02 1.E+01 1.E+00 1.E-01 1.E-02 Serum HDV RNA (U / ml) 1.E+06 1.E+05 1.E+04 1.E+03 1.E+02 1.E+01 1.E+00 1.E-03 1.E-01 Multiple antiviral effects may be present June 26, 2015 12
Interim REP 301 Efficacy Data (serum HBV DNA) Serum HBV DNA (U / ml) 1.E+03 1.E+02 1.E+01 500mg REP 2139-Ca qw 250 mg REP 2139-Ca qw 180 ug Pegasys qw 001-01 001-02 001-03 001-06 001-09 001-11 001-14 001-17 001-20 001-22 001-24 001-26 LLOQ start of dosing start Pegasys 1.E+00 June 26, 2015 13 13
REP 2139-Ca safety profile in the REP 301 protocol (interim analysis) All AEs are grade 1-2 (fever, redness or headache) and are associated with IV infusion: typically become less frequent as dosing regimen progresses self-resolve after completion of IV infusion (infrequenty requiring supportive treatment) attributed to the presence of phthalate plasticisers in IV tubing Clinical serology monitored weekly with no clinically significant findings One patient removed from dosing after 10 weeks of Pegasys exposure due to Pegasys -related DILI. June 26, 2015 14
Summary Serum HBsAg clearance previously observed with NAPs in Asian patients is replicated in Caucasian patients. REP 2139-Ca can simultaneously reduce HBsAg and HDV RNA multiple antiviral mechanisms de-repression of serum HBV DNA NUC therapy may be required REP 2139-Ca is well tolerated and does not alter tolerability of Pegasys. may provide an additional productive antiviral response. NAP-based antiviral therapy may become an important new treatment option for patients with HBV / HDV co-infection. June 26, 2015 15
Acknowledgements Validation of HDV RNA test results were performed at: The National Genetics Institute, Los Angeles, USA Dr. Jeffrey Albrecht Dr. Peter Schmid Institute of Virololgy, Technische Universität München, Munich, Germany Dr. Hadi Karimzadeh Dr. Michael Roggendorf June 26, 2015 16