Effects of Inarigivir (SB9200) Therapy on Immune Responses in Patients with Chronic Hepatitis B (CHB)

Transcription

1 Effects of (SB9200) Therapy on Immune Responses Patients with Chronic Hepatitis B (CHB) Renae Walsh 1, Rachel Hammond 1, Kathy Jackson 1, Ros Edwards 1, Chelsea Macfarlane 2, Radhakrishnan P. Iyer 2, Man Fung Yuen 3, Henry LY Chan 4, Nezam H. Afdhal 2, Stephen Locarni 1 1 Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia 2 Sprg Bank Pharmaceuticals, Hopkton, MA, United States 3 University of Hong Kong, Hong Kong, Hong Kong 4 Chese University of Hong Kong, Hong Kong, Hong Kong

2 Disclosures Consultg Fees (eg. Advisory Boards) Contract Research (grant) CONFLICT OF INTEREST Stephen A Locarni Clear B Therapeutics Gilead Sciences Inc Arrowhead Research Corp Sprg Bank Pharmaceuticals, Inc. Roche Molecular AusBio Ltd Janssen (J&J) YES YES YES YES YES YES YES YES YES AbbVie

3 CHB Functional Cure (FC) Sustaed, undetectable HBsAg and HBV DNA serum with or without seroconversion (Lok, A et al Hepatol;66:1296) Is lked to improved clical outcome particularly if achieved before 50 years of age (elimated HCC risk, ly reduced chronic liver disease) Is NOT fluenced by current NA drug treatments Is likely fluenced by endogenous immune recovery and an ive anti HBs Is achieved rarely (1 2% per annum) the natural history of CHB There are no approved predictive biomarkers of HBsAg clearance and development There is a need for an immunity marker the defition of FC because of HBV Transmission and/or Reactivation Issues(s)

4 CHB Functional Cure What is the role for HBsAg seroclearance and achievg functional cure? Most patients (> 90%) have or develop co existg durg CHB which is masked by excess HBsAg (Maruyama, T et al J Cl Invest;91:2586) Anti HBs production (B cell function) is not completely hibited or suppressed CHB, but is of low affity and usually directed to a heterologous HBsAg sub type (Zhang, JM et al C.F.D.;44:1161.; Gerlich, WH C.I.D.;44:1170) Hypothesis Indicative of an underlyg/emergg host immune that is adequate or masked (complexed) or both Developed Biomarkers for: HBsAg Epitope Loss or Ga Complexed Anti HBs Assays

5 Assay for HBsAg clearance: Biomarker #1 HBsAg epitope mappg 19plex immunoassay to identify an HBsAg Clearance Profile (CP) HBsAg (viral envelope prote) has highly conformational structure ( a determant) HBsAg profile reported based on epitope display (antigen conformation) and occupancy ( native anti HBs recovery) across the a determant ASSAY HBsAg Epitope Mappg 19 mabs HBsAg clearance profile (CP) HBsAg epitope pressure (reduced recognition) at both loop 1 AND loop 2 epitopes secondary to an antibody that clears fection HBsAg non clearance profile (NCP) change HBsAg epitope profile, OR reduced epitope bdg at only one loop The HBsAg CP is a predictive biomarker for HBsAg clearance, potentially associated with or driven by the selective pressure of an ive Walsh, R et al AASLD (2015; 2016)

6 Clical Cohort A [GS US ]: Validation of Clearance Profile 25 CHB patients (gena) on NA therapy: HBsAg Loss (SL) / FC (n=14) c.f. n Responders (n=11) Development of an HBsAg CP with an outcome of HBsAg loss was also ly correlated to: The level of HBsAg decle (p value to ) An ALT flare / immune (p value 0.017), precedg HBsAg and HBsAg loss Walsh R, et al. AASLD 2015 & 2016

7 Assay for Complexed Anti HBs: Biomarker #2 EIA to detect MASKED (complexed to HBsAg) Standard diagnostic serology detects ONLY free Anti HBs (and free HBsAg) Masked /complexed EIA detects the presence of excess HBsAg Represents underlyg or ongog Potential biomarker for HBV virion and/or HBsAg seroclearance ASSAY Masked Anti HBs Walsh R, et al. EASL 2016 Masked (or complexed) HBsAg/ must be present the tested sample to get reporter bdg (absorbance) Records complete HBsAg clearance, i.e. detects HBsAg the presence of excess maskg/ Masked impacts the defition and confirmation of Functional Cure Reports the detection of TRUE HBsAg clearance vs diagnostic HBsAg clearance

8 Validation of Complexed Anti HBs Cohort A [GS US ]: Walsh R, et al. AASLD 2015 & 2016 Development of masked/complexed may represent: Recovery of the immune Reduction of free HBsAg to crease the ratio of complexed/masked

9 RIG I antiviral function for HBV The RNA sensor RIG I dually functions as an nate sensor and direct antiviral factor for HBV RIG I senses the HBV genotype A, B, and C for the duction of type III IFNs The 5 ε region of HBV pgrna is a key element for the RIG I mediated recognition RIG I counteracts the teraction of HBV P with pgrna to suppress viral replication Type III IFNs are predomantly duced human hepatocytes durg HBV fection is a small molecule ducleotide orally active HBV antiviral Inhibits viral replication: bds RIG I to prevent viral polymerase engagg viral RNA Promotes viral clearance: Activated RIG I duces endogenous IFN production Oral prodrug, active metabolite SB 9000 transported to hepatocytes via OATP1 with 30:1 liver to plasma ratio non specific immune s (preclical or phase1 studies) Sato et al., 2015, Immunity 42,

10 Achieve Trial design Study arms: 20 non cirrhotic HBV subjects per cohort, randomized 4:1 between and placebo Aim of Current Analysis: Cohort 1 (25mg) plus Cohort 2 (50mg) [Low Dose] SB9200, n=30 Placebo, n=8 Assessment of of 12 weeks of SB9200 on the virology and anti HBs antibody s Primary endpots: Other endpots: Safety and antiviral activity at 12 weeks PK, change serum HBV DNA, HBsAg, HBeAg, HBV RNA and HBcrAg from basele to weeks 6, 12, 14, 16 and 24

11 Basele Demographics Cohort 1 and 2 Placebo 25mg HBeAg +ve 25mg HBeAg ve 50mg HBeAg +ve Number Age Gender M:F 6 : 2 5 : 4 3 : 4 9 : 2 5 Basele ALT Basele HBV DNA log Genotype A B C D mg HBeAg ve 3 1 In cohort 2, two patients, one HBeAg +ve, and one HBeAg ve, withdrew at day 1 and day 14 due to patient choice

12 Anti-viral efficacy cohort 1 and 2: Basele to week 12 MEAN Placebo 25mg HBeAg +ve 25mg HBeAg ve 50mg HBeAg +ve 50mg HBeAg ve Basele HBV DNA log Change DNA (BL to week 12) * # 1.05 log 10 Basele HBsAg log Change HBsAg log t-test vs placebo *P < 0.03 # p < $ p < 0.01 & p < 0.01 Basele HBV RNA log $ & Change HBV RNA

13 : CP and Masked Anti HBs Biomarker Analysis #1 HBsAg CP analysis: Biomarker of HBsAg clearance/ [possible functional cure outcome] Study Cohort/Arm CP Detected (to W12) CP Detected (to EOS week 24), Cohort 1 (n=16) 6 (33%) 5 (32%) Placebo, Cohort 1 (n=4) 0 2 (50%), Cohort 2 (n=14) 4 (29%) 5 (36%) Placebo, Cohort 2 (n=4) 1 (25%) 1 (25%) Masked development from W2 [Indicative of underlyg ] Study Cohort/Arm Detected ( W2 to W12) Detected ( W14 to EOS week 24), Cohort 1 (n=16) 2 (11%) 1 (6%) Placebo, Cohort 1 (n=4) 1 (25%) 1 (25%), Cohort 2 (n=14) 7 (50%) 4 (29%) Placebo, Cohort 2 (n=4) 1 (25%) 0 Trend for developg an HBsAg CP and/or masked on vs placebo, but not statistically Dose Response (50mg vs 25mg): HBsAg CP development similar between low dose, but trend for enhanced masked dicative of underlyg activity 50mg cohort vs 25mg

14 Cohort Study arm Masked : Anti HBs and HBV Biomarker Analysis #2 Responses developed to W12 Cohort 1 (25mg), n=20 (n=16) Placebo (n=4) CP Masked 2 (11%) 6 (33%) 1 (17%), HBV DNA 2 (33%), HBV RNA 3 (50%), Masked anti HBs AND HBV DNA 2 (100%), n=2 1 (25%) Cohort 2 (50mg), n=18 Combed Cohorts, n=38 (n=14) Placebo (n=4) (n=30) Placebo (n=8) 7 (50%) 4 (29%) 2 (50%), n=4 4 (100%), n=4 3 (100%), n=3 7 (100%), n=7 1 (25%) 1 (25%) (30%) 10 (33%) 3 (30%), 6 (60%), 6 (67%), 9 (100%), 2 (25%) 1 (12%) Difference: vs placebo

15 Cohort Study arm Masked : Anti HBs and HBV Biomarker Analysis #2 Responses developed to W12 Cohort 1 (25mg), n=20 (n=16) Placebo (n=4) CP Masked 2 (11%) 6 (33%) 1 (17%), HBV DNA 2 (33%), HBV RNA 3 (50%), Masked anti HBs AND HBV DNA 2 (100%), n=2 1 (25%) Cohort 2 (50mg), n=18 (n=14) Placebo (n=4) 7 (50%) 4 (29%) 2 (50%), n=4 4 (100%), n=4 3 (100%), n=3 7 (100%), n=7 1 (25%) 1 (25%) Combed Cohorts, n=38 (n=30) Placebo (n=8) Difference: vs placebo 9 (30%) 10 (33%) 3 (30%), 6 (60%), 6 (67%), 9 (100%), 2 (25%) 1 (12%)

16 Cohort 1 and 2 : Summary Responses developed to W12 Cohort Study arm HBV DNA HBsAg HBeAg HBV RNA (>0.5 log) ALT crease (>0.5 log) HBV DNA AND HBV RNA Masked CP Masked HBV DNA HBV RNA Masked AND HBV DNA Cohort 1 (25mg), n=20 (n=16) 9 (56%) 5 (31%) 1 (11%), 10 (62%) 0 8 (50%) 2 (11%) 6 (33%) 1 (17%), 2 (33%), 3 (50%), 2 (100%), n=2 PL (n=4) (33%), n=3* 1 (25%) 1 (25%) 0 1 (25%) Cohort 2 (50mg), n=18 (n=14) 12 (86%) 1 (7%) 1 (12%), n=8 4 (40%), 1 (7%) 4 (40%), 7 (50%) 4 (29%) 2 (50%), n=4 4 (100%), n=4 3 (100%), n=3 7 (100%), n=7 PL (n=4) 1 (25%) 1 (25%) 1 (50%), n=2 1 (25%) 0 1 (25%) 1 (25%) 1 (25%) All Cohorts n=38 (n=30) 21 (70%) 6 (20%) 2 (12%), n=17 14 (54%), n=26 1 (3%) 12 (46%), n=26 9 (30%) 10 (33%) 3 (30%), 6 (60%), 6 (67%), 9 (100%), PL (n=8) 1 (12%) 1 (12%) 2 (40%), n=5* 2 (25%) 1 (12%) 1 (12%) 2 (25%) 1 (12%) Difference vs placebo 58% pts [p=0.005] 29% pts 34% pts

17 Cohort 1 and 2 : Summary Responses developed to W12 Cohort Study arm HBV DNA HBsAg HBeAg HBV RNA (>0.5 log) ALT crease (>0.5 log) HBV DNA AND HBV RNA Masked CP Masked HBV DNA HBV RNA Masked AND HBV DNA Cohort 1 (25mg), n=20 (n=16) 9 (56%) 5 (31%) 1 (11%), 10 (62%) 0 8 (50%) 2 (11%) 6 (33%) 1 (17%), 2 (33%), 3 (50%), 2 (100%), n=2 PL (n=4) (33%), n=3* 1 (25%) 1 (25%) 0 1 (25%) Cohort 2 (50mg), n=18 (n=14) 12 (86%) 1 (7%) 1 (12%), n=8 4 (40%), 1 (7%) 4 (40%), 7 (50%) 4 (29%) 2 (50%), n=4 4 (100%), n=4 3 (100%), n=3 7 (100%), n=7 PL (n=4) 1 (25%) 1 (25%) 1 (50%), n=2 1 (25%) 0 1 (25%) 1 (25%) 1 (25%) All Cohorts n=38 (n=30) 21 (70%) 6 (20%) 2 (12%), n=17 14 (54%), n=26 1 (3%) 12 (46%), n=26 9 (30%) 10 (33%) 3 (30%), 6 (60%), 6 (67%), 9 (100%), PL (n=8) 1 (12%) 1 (12%) 2 (40%), n=5* 2 (25%) 1 (12%) 1 (12%) 2 (25%) 1 (12%) Difference vs placebo 58% pts [p=0.005] 29% pts 34% pts

18 Cohort 1 and 2 : Summary Responses developed to W12 Cohort Study arm HBV DNA HBsAg HBeAg HBV RNA (>0.5 log) ALT crease (>0.5 log) HBV DNA AND HBV RNA Masked CP Masked HBV DNA HBV RNA Masked AND HBV DNA Cohort 1 (25mg), n=20 (n=16) 9 (56%) 5 (31%) 1 (11%), 10 (62%) 0 8 (50%) 2 (11%) 6 (33%) 1 (17%), 2 (33%), 3 (50%), 2 (100%), n=2 PL (n=4) (33%), n=3* 1 (25%) 1 (25%) 0 1 (25%) Cohort 2 (50mg), n=18 (n=14) 12 (86%) 1 (7%) 1 (12%), n=8 4 (40%), 1 (7%) 4 (40%), 7 (50%) 4 (29%) 2 (50%), n=4 4 (100%), n=4 3 (100%), n=3 7 (100%), n=7 PL (n=4) 1 (25%) 1 (25%) 1 (50%), n=2 1 (25%) 0 1 (25%) 1 (25%) 1 (25%) All Cohorts n=38 (n=30) 21 (70%) 6 (20%) 2 (12%), n=17 14 (54%), n=26 1 (3%) 12 (46%), n=26 9 (30%) 10 (33%) 3 (30%), 6 (60%), 6 (67%), 9 (100%), PL (n=8) 1 (12%) 1 (12%) 2 (40%), n=5* 2 (25%) 1 (12%) 1 (12%) 2 (25%) 1 (12%) Difference vs placebo 58% pts [p=0.005] 29% pts 34% pts

19 Cohort 1 and 2 : Summary Responses developed to W12 Cohort Study arm HBV DNA HBsAg HBeAg HBV RNA (>0.5 log) ALT crease (>0.5 log) HBV DNA AND HBV RNA Masked CP Masked HBV DNA HBV RNA Masked AND HBV DNA Cohort 1 (25mg), n=20 (n=16) 9 (56%) 5 (31%) 1 (11%), 10 (62%) 0 8 (50%) 2 (11%) 6 (33%) 1 (17%), 2 (33%), 3 (50%), 2 (100%), n=2 PL (n=4) (33%), n=3* 1 (25%) 1 (25%) 0 1 (25%) Cohort 2 (50mg), n=18 (n=14) 12 (86%) 1 (7%) 1 (12%), n=8 4 (40%), 1 (7%) 4 (40%), 7 (50%) 4 (29%) 2 (50%), n=4 4 (100%), n=4 3 (100%), n=3 7 (100%), n=7 PL (n=4) 1 (25%) 1 (25%) 1 (50%), n=2 1 (25%) 0 1 (25%) 1 (25%) 1 (25%) All Cohorts n=38 (n=30) 21 (70%) 6 (20%) 2 (12%), n=17 14 (54%), n=26 1 (3%) 12 (46%), n=26 9 (30%) 10 (33%) 3 (30%), 6 (60%), 6 (67%), 9 (100%), PL (n=8) 1 (12%) 1 (12%) 2 (40%), n=5* 2 (25%) 1 (12%) 1 (12%) 2 (25%) 1 (12%) Difference vs placebo 58% pts [p=0.005] 29% pts 34% pts

20 Morphological forms of HBs antigen and number of particles per ml the serum of highly viremic HBV carriers HBV (Dane particles) 10 9 HBV RNA (10 6 ) filaments spheres Kdly provided by Prof W.H. Gerlich

21 Biomarkers and MOA of DAAs EXTRACELLULAR / SERUM HBV Virions (DNA) HBV Virions (RNA) HBsAg plasma membrane CYTOPLASM DSL DNA pgrna HBx RNA subgenomic mrna Fusion transcripts nucleus membrane NUCLEUS RC DNA DSL DNA PF-RC DNA Michromosome cccdna Tu, T et al Viruses; 9(4). pii: E75 Integrated DSL HBV DNA host genome

22 Biomarkers and MOA of DAAs EXTRACELLULAR / SERUM HBV Virions (DNA) HBV Virions (RNA) HBsAg plasma membrane CYTOPLASM DSL DNA pgrna HBx RNA subgenomic mrna Fusion transcripts nucleus membrane NUCLEUS RC DNA DSL DNA PF-RC DNA Michromosome cccdna Tu, T et al Viruses; 9(4). pii: E75 Integrated DSL HBV DNA host genome

23 Biomarkers and MOA of DAAs EXTRACELLULAR / SERUM HBV Virions (DNA) HBV Virions (RNA) HBsAg plasma membrane CYTOPLASM DSL DNA pgrna HBx RNA subgenomic mrna Fusion transcripts nucleus membrane NUCLEUS RC DNA DSL DNA PF-RC DNA Michromosome cccdna Tu, T et al Viruses; 9(4). pii: E75 Integrated DSL HBV DNA host genome

24 Biomarkers and MOA of DAAs CP MASKED

25 Achieve Trial: Conclusions 12 weeks of therapy (low doses) resulted virological reduction both HBV DNA (1.0 log IU/ml) and HBV RNA (~2.0 log IU/ml) but not HBsAg, or HBeAg Effect more enhanced HBeAg ve patients emergence of a Clearance Profile and Complexed Anti HBs over 30% of patients Dose seen markers of s (Clearance Profile and masked ) This dose reflective of both s DAA and RIG I activation which can drive T FH cells formation and antiviral antibody formation (Sprokholt, JK et al PLOS Pathogens;13(11):e ) This study supports further vestigation with higher doses of and combation treatments