Understanding new medicines to treat chronic hepatitis B: toward a cure. October 26, 2016

Transcription

1 Understanding new medicines to treat chronic hepatitis B: toward a cure October 26, 2016

2 Define an HBV cure Functionally (practical): Sustained, off drug response (loss of viremia and antigenemia Clinically: Return an individual to the risk of death and disease due to liver disease to that of an age and gender adjusted uninfected individual Block, Gish et al, AVR, 2015 Liang, Block et al, Hepatology, 2016

3 Categories of HBV therapeutics Direct Acting Antivirals (DAA) Indirect (Host) Acting Antivirals (Hos Ryu, W-S (2015)

4 Timeline of Approved Drugs for Chronic HBV REVEAL Study: The Relationship Between Virus Number and Hepatocirrhosis/Hepatocellular Carcinoma 4006 Study: antiviral therapy could slow down the development of CHB Interferon approved for CHB Lamivudine Adefovir Entecavir PEG-IFN Telbivudine Tenofovir Tenofovir approved in US for HBV, in 2008, but not yet approved in China for HBV All are Direct Acting Antivirals (DAA)

5 Functional cures do occur with current therapeutics, although rarely

6 Failure to cure with NUCs is because

7 Nests of infected cells (cccdna containing) remain; HBsAg continues to be made: T cells exhausted B cells: no detectable HBsAb T cells (exhausted) B cells (No detectable Antibody to HBs)

8 Need Something new that complements current compounds Different mechanism DAA + An immuno-enhancer

9 Categories of Anti-HBV Strategies Direct Acting Antivirals In-Direct Acting Antivirals In Use Polymerase Potential RNaseH RNAi Capsid inhibitors sag eag Virus attachment CRISPR/CAS Immuno-modulatory In Use Interferons Potential Therapeutic vaccines PD-1 blockade Toll R agonists STING, other innate defense Interleukins, other cytokines Essential host functions In Use None for HBV Potential Epigentic modifiers Entry Morphogenesis Exit Glycan processing

10 The HBV Therapeutic Development Landscape as of Jan, 2016 Pre-clinical Human Phase Trials DA A Indirect Host modifier RNase H inhib TTP sag Benza capsid CpAM S capsid GLS-4 capsid cccdn A forma Editope DVR capsid NV100 AGX1009 prodrug ALN- HBV ddrna ihbv CMX157 prodrug Isis HBV antisense? Bay41109 capsid GS734 0 Proten TKM- HBV Brinipri nt SMAC NVR12 21 capsid ARC52 0 RNAi MycB entry* RepA9 sag Indirect Immunomodulator HDAC Chimgen e HBV STING Altrava x HBV Inovio HBV GS4774 vac Roche 7795 GS9620 Toll DV501 Vac *HDV active

11 Entry Heptera Immuno Gilead, Arbutus, Roche,Inovio, Akshaya, Springbank cccdna Novartis, Arbutus Morph Neurovive, Cyclophilin RNAi Alnylam, Arbutus, Arrowhead, IsisBenetec Pol Gilead, Contravir Capsid Arbutis, Gilead, Roche, Novera, Assembly, Jansen Block & Liang, 2016

12 Pol inhibitors: Currently Availabl Ten ADF LAM ETV TEL (FMAU in Korea) In development: TAF CMA157

13 Pol inhibitors: Currently Available Ten ADF LAM ETV TEL (FMAU in Korea) In development: Gilead: TAF Contravir: CMA157 Arbutus (RNaseH inhibit)

14 cccdna: natural source of all viral gene products

15 cccdna: natural source of all viral gene products cccdna

16 Repress cccdna, and repress all natural gene product cccdna

17 But cccdna is a small, tough target Nassal et al, Gut 2015 from Gut

18 Block & Guo, 2015, Gastroeneterology HBV IFN-α IFN-γ LT-β TNF-α NTCP Biologicals Approved: IFNs IFN-induced Antiviral Proteins New: Immunenhancers: Inovia, Gilead: Thera vaccines Pol Gilead, Roche: Toll R Capsid Arbutus: STING Envelop Other: Arbutus (ARB) Cytoplasm Intellia: CRISPR CAS Transcription HBV mrnas pgrnacontaining capsids APOBEC3A and/o 3B ISGs cccdna Nucleus (-) DNA U U (+/-) DNA MVB APOBEC 3A/B Capsid Protein Uracil-DNA Glycosylase AP Endonucleases

19 But some HBV DNA is integrated and not free cccdna, and thus might be missed by drugs acting on cccdna free cccdna cccdna integrated in to the host chromosomes

20 RNAi transcript inhibition In development: Antisense: (Ionis/GSK )* shrna: Alnylam (ALNHBV)* Arrowhead (ARC520,521)* Arbutus (ARB 1467,1740)* Benitec *Human Trials

21 RNAi / sh RNA leads to degradation of HBV RNA transcripts from cccdna and integrated DNA

22 RNAi: Complete shut down: integrated and cccdna cccdna

23 Entry Inhibitors Entry Inhibitor (oilgopeptide) MyrcludexB* Human Trials Liang, Block et al 2016

24 Entry Inhibitors

25 Capsid inhibition Capsid Inhibitors Novira NVR 778* Arbutus ARB423 Sunshine* Assembly ABI H101 *Human trials

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27 sag inhibition sag Inhibitor Replicor Rep2165* Arbutus ARB Roche* *Human Trials sag sag sag sag

28 sag inhibition: antiviral, anti-antigenemic, and?immuno restoration sag sag sag sag

29 Hepatitis Delta Virus Needs co-infecetion with HBV Mycludex B and Eiger s Lornafarnib in human trials for HDV

30 Adaptive & Innate host defense Adaptive Gilead GS4774* Inovio Roche INO1800* Altimmune* Transgene TG1050* Indirect treatment B cells (No detectable Antibody to HBs) T cells (exhausted) Innate Gilead Toll GS9620* Roche Toll RO * SpringBank RIGI SB9200* Arbutus STING A Contravir Cyclophil CPI421 *Human Trials Two cell chamber transfer hepatocyte-derived cells Awaken, stimulate HBV HBV RAW cells

31 Inhibiting the virus life cycle at any step should be equal in eliminating infection Break HBV down in to at least 12 different assayable, targetable steps Grouped in to 6, here Entry/ uncoating Capsid assembly Indirect treatment Innate host Two cell chamber transfer hepatocyte-derived cells cccdna formation cccdna transcript RAW cells HBV HBV Selective elimination Pol/RT inhibitors morphoge nesis

32 Current Guidelines Rx Rec vary Rx recommended Rx Rec varies

33 Hepatitis B Foundation Goal No one will die from HBV by 2030 A cure is possible, necessary, and expected