Novel Bispecific Antibodies for Treating Hepatitis B Virus Infection. Dr. Felix Bohne

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1 Novel Bispecific Antibodies for Treating Hepatitis B Virus Infection Dr. Felix Bohne Munich,

2 Consequences of Hepatitis B Virus 2

3 Global prevalence of Hepatitis B (percentage of population per region) 8% 5-7% 2-4% <2% Ott et al. Vaccine (2012) 3

4 Global prevalence of Hepatitis B The WHO enumerates the infection rate with HBV globally to ~2 billion people million patients with chronic hepatitis B Anual mortality due to HBV-infections ranges globally at ~600,000 people High Medical Need for curative therapeutic approaches 4 World Health Organization (WHO, 2015)

5 Technology BiMAbs activate T cells to eliminate HBV-infected hepatocytes in vitro Cytotoxic T- lymphocyte Bispecific BiMab tetravalent antibody construct HBVinfected target cell HBsAg Apoptosis 5

6 Preliminary in vivo results 6

7 Preliminary in vivo results not treated PBMC PBMC +BiMab BiMabs mediate a 40% reduction of HBV+ tumours in vivo 7

8 Market potential Market- and competition analysis For chronic hepatitis B a global number of 250 million accessible patients is estimated 60 million with therapy indication according to current treatment guidelines Annual costs of standard treatment: 40,000 US$ (Hepatitis B Foundation, 2011) 8

9 Market potential Approved standard medication: 2013 revenue 5 Billion US$ Product Pegasys (Peg-IFNα 2a; Roche) Baraclude (Entecavir; BMS) Viread (Tenofovir; Gilead) revenue 1.4 Billion US$ 1.5 Billion US$ 960 Million US$ Epivir (Lamivudine, Zidovudine; GSK) 510 Million US$ Hepsera (Adefovir dipivoxil; Gilead) 440 Million US$ Sebivo/Tyzeka (Telbivudine; Novartis) 105 Million US$ BiMab have a high commercial potential

10 Competition analysis Pharmaceutical and Biotech companies are developing new therapeutic approaches potential candidates for approval: 10

11 Competition analysis Phase III: New nucleos(t)ide analogues Tenefovir alafenamide (GS-7340; Gilead Sciences) Besifovir (LB80380; LG Life Science) 11

12 Competition analysis Phase II: Entry-inhibitors Myrcludex B (Myr GmbH) 12

13 Competition analysis Phase II: Capsid-inhibitors BAY (Bayer AG) 13

14 Competition analysis Phase II: RNA-interference with HBV-proteins ARC-520 (Arrowhead Corp.) 14

15 Competition analysis Phase II: therapeutic vaccine/svp inhibitors REP 9AC/REP (Replicor Inc.) INO-1800 (Inovio) 15

16 Competition analysis Preclinical: TLR-agonists, checkpointinhibitors TLR-8 stimulation: ssrna40 agonist selectively activates liver resident innate immune cells (Jo et al. (2014), PLoS Pathog) Antibody mediated programmed death (PD) 1 inhibition (Tzeng et al. (2012), PLoS One) No direct competitor developing bispecific antibodies against HBV proteins identified 16

17 Comparison with existing solutions Nucleos(t)ide analogues inhibit virus replication, not curative, escape mutations PEG-INFa 10-15% of viral elimination, very strong side effects (flu-like symptoms, depression) Approved medications mediate only insufficient elimination of HBV 17

18 Development status Status Quo: Solid in vitro proof-of-principle First promising in vivo results Successful acquisition of Helmholtz Validation Funding Next steps: In vivo proof-of-concept in relevant animal models First data on bioavailability and toxicity Partnership/Collaboration with industry 18

19 IP-Status International Patent Application PCT/EP2014/069675, Priority Pending main claim: A polypeptide comprising (a) a first set of six complementarity determining regions (CDRs) configured to bind a first antigen; and (b) (ba) a second set of six CDRs configured to bind a second antigen; or (bb) a ligand capable of binding to a second antigen; wherein (i) said first antigen is selected from Hepatitis B virus (HBV) small surface antigen; HBV medium surface antigen; and HBV large surface antigen; and (ii) said second antigen is selected from surface antigens presented by immune effector cells such as natural killer (NK) cells and cytotoxic T lymphocytes. Positive preliminary international search opinion 19

20 IP-Status Follow up application (EP ), Priority claiming a further product improvement Solid perspective of patent protection 20

21 Need of resources GMP-production 1,2 to 1,5 million Pharmacology/Toxicology 250,000 21

22 Risks and bottlenecks Regulatory aspects of clinical testing Failure of proof-of-principle in relevant preclinical model Toxicity in phase Ib study Manageable risk situation 22

23 Freedom To Operate (FTO) Analysed potential infringement form: first specificity for HBV small surface antigen second specificity for T lymphocytes: CD3/CD28 Comfortable FTO for core products 23

24 Summary Hepatitis B is a global health problem, rapidly expanding market Solid cell culture and preliminary in vivo results demonstrate killing of HBV+ cells and tumours Bispecific antibodies have a high potential to cure hepatitis B 24

25 Prof. Dr. Ulrike Protzer Institute of Virology, HMGU/TUM PD Dr. Frank Momburg National Tumour Center/DKFZ MSc. Oliver Quitt MSc. Julia Hasreiter Dr. Jan-Hendrick Bockmann Dr. Felix Bohne Institute of Virology Helmholtz Center Munich Trogerstr München