Biotec s Soluble Beta-Glucan (SBG ) in clinical applications and its scientific platform

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1 Biotec s Soluble Beta-Glucan (SBG ) in clinical applications and its scientific platform Arctic Biotech Seminar 30 th November 2015 CS Rolf E Engstad

2 Agenda Company Soluble beta-glucan (SBG ) as PAMP SBG as platform for immunotherapeutic applications Healing of stalled wounds Immunotherapy of cancer Summary Biotec Pharmacon ASA 2

3 Biotec Pharmacon Company Established 1990 Listed on SE ticker: biotec About 35 employees Two operating subsidiaries: Biotec Beta-Glucans AS & ArcticZymes AS GMP, IS-13485, and IS 9001 Beta-Glucans Development, production and sales of betaglucans since 1990 Proprietary and patented manufacturing processes Product range from feed grade (M-Glucan ) to pharmaceutical grade (SBG ) GMP approved plant in Tromsø Biotec Pharmacon ASA 3

4 ne source different products Yeast cell walls from yeast extract production (25% BG) M-Glucan Feed ingredient (65% BG) BG Particulate Nutrition (80% BG) BG Cos Cosmetics (90% BG) SBG Soluble Beta-Glucan (Medicinal product) (99% BG) Molecule optimized Biotec Pharmacon ASA 4

5 Innate immunity how is it triggered? The innate immune cells (especially macrophages) has through evolution developed strategies to eliminate pathogenic microbes by recognising conserved structural elements on the surface of each group of pathogens These conserved structural elements on microbes are referred to as PAMPS- «Pathogen Associated Molecular Patterns», and where Betaglucan represents yeast, fungi and a few bacterial species Each PAMP triggers a specific set of reactions in macrophages through selective binding to surface receptors «Training of macrophages by beta-glucan» Saeed et al. Science 2014 Metchnikoff Elia (1887). "Sur la lutte des cellules de l organisme contre l invasion des microbes- n fighting cells of the body against invading microbes. Ann. Inst. Pasteur 1: 32 Biotec Pharmacon ASA 5

6 Biotec SBG trigger innate immune responses Biotec SBG is tailored for optimal binding to white blood cells of the innate immune system, especially the macrophages triggering controlled production of: Production of signal molecules alerting the immune system Production of growth factors supporting cell growth Increased bacterial killing Increased antigen presentation Biotec SBG induces a safe and well regulated response Ideal candidate for many immunotherapeutic applications Biotec Pharmacon ASA 6

7 Uniqueness of SBG The Biotec SBG molecule is tailored to trigger a well regulated innate immune response different from other PAMPs and adjuvants that often have side effects. The SBG having very distinct rheological (gel forming) properties SBG is patent protected by a number of patent families covering production, formulation and application H H H H H H H H H H H H H H n H H H H H H C H 2 H H H H H H Biotec Pharmacon ASA 7 H H H H n H H n H H H H H H C H 2 H H H H

8 Soluble Beta-Glucan Healing of stalled wounds Advanced wound care

9 Regulatory approval of Woulgan Strategic decision to apply for a Medical Device registration of Woulgan Woulgan is approved in the most advanced medical device category in Europe Biotec s SBG is approved as a medicinal substance in Woulgan Woulgan is approved for use in chronic wounds, burns, surgical wounds as well as for more «everyday» wounds Approved main functional claims: moist wound healing properties activation of macrophages Biotec Pharmacon ASA 9

10 Status and strategy for clinical development What we have: Existing Randomised Clinical Trial (double blinded placebo controlled) Surveys in Norway, UK and Germany A comprehensive documentation on mode of action, animal studies etc. What we need: Post Market Clinical Follow-Up ( ongoing) Case study series for local KL support Potential clinical studies to get regulatory approval outside Europe Biotec Pharmacon ASA 10

11 Proliferating cell count (fov) % Contraction SBG in wound care mode of action SBG activates macrophages to produce signal molecules and growth factors resulting in: Wound contraction Wound contraction Cell proliferation Angiogenesis Water Woulgan Biogel «Woulgan Biogel» without SBG 160 Increased healing (ref.: Skjæveland & Engstad 2013) Marginal Intermediate Centre Cell proliferation Marginal Intermediate Centre Biotec Pharmacon ASA 11 Angiogensis Count (fov) Angiogenesis

12 SBG in Diabetic Foot Ulcer clinical data Patients with complete healing (%) SBG Methylcellulose (Placebo control) N= Duration of therapy (weeks) Control Placebo controlled double blinded study of 60 patients Statistical significant after 8 weeks (p=0.03) Treatment schedule: 3 treatments per week Up to 12 weeks treatment Ulcer size 1-34 cm 2 Complete healing (PP): 8 weeks 12 weeks SBG 44% 56% Placebo 17% 31% Biotec Pharmacon ASA 12

13 SBG in wound care clinical data Norwegian survey in 55 patient with mixed wound etiology (most chronic wounds) Woulgan used in practical clinical setting in home care and institutions 72% of clinicians rated the product good to excellent How old is the wound? ver 1 year 37 % Several monts 29 % Up to one week 8 % Several weeks 26 % Wound diagnosis Lacerations Unknown 8 % 6 % Burns 4 % Post-op. Wound 14 % Leg ulcer 28 % Diabetic ulcer 18 % Pressure ulcer 22 % How would you rate Woulgan s effect? Excellent 20 % Don't know 6 % Very good 27 % Poor 10 % Quite good 12 % Good 25 % Biotec Pharmacon ASA 13

14 Agenda Company Soluble beta-glucan (SBG ) as PAMP SBG as platform for immunotherapeutic applications Healing of stalled wounds Immunotherapy of cancer Summary Biotec Pharmacon ASA 14

15 Biotec SBG in cancer therapy -mode of action Enhancing the effector functions of white blood cells SBG shown to induce: Priming/training of phagocytic white blood cells to increased cytokine/ chemokine production Increased recruitment of phagocytic cells to site of mab-labelled cancer cells Increased phagocytic and cytotoxic ability of white blood cells to kill cancer cells Macrophages (monocytes) stimulated with beta-glucan or LPS for 24h and then restimulated 6 days later. Stimulation with beta-glucan results in macrophages in a «Trained Immunity» (A) state giving increased cytokine production (B). Saeed et al 2014, Science, 345: Biotec Pharmacon ASA 15

16 Biotec SBG in cancer therapy animal model Biotec s SBG has been shown to potentiate the effect of immuntherapetic cancer regimes: mab alone Improved anticancer mab effect Improved anticancer vaccine effect mab + SBG SBG enhances the immunepresenting capacity of cells, but more important the effector functions of white blood cells (tumor killing) Biotec s SBG effective when given orally (p.o.) Mice inoculated with human neuroblastoma cancer cells, Treatment with i.v. mab 3F8 with or without p.o. administered SBG. Effect measured as tumor size. (Memorial Sloan Kettering Cancer Center - MSKCC) Biotec Pharmacon ASA 16

17 SBG in immunotherapy of cancer Early phase study performed by Memorial Sloan Kettering Cancer Center in New York Increasing doses of p.o administered SBG combined with i.v. administered monoclonal mab against neuroblastoma in children (45 patients) Combination safe and well tolerated Positive, but transient treatment effects observed Before After Followed up in vaccine trial at MSKCC 123I-MIBG scan of patient treated with one cycle of 3F8+SBG (80mg/kg/day) Biotec Pharmacon ASA 17

18 SBG in immunotherapy of cancer Investigator driven vaccine trial in children with neuroblastoma initiated by MSKCC using their own developed bi-valent vaccine against neuroblastoma antigens (GD2L and GD3L). Biotec s SBG given p.o. to increase tumor killing activity of white blood cells Single arm study Phase I part (safety) of studie (15 patients) finalised in 2013 Combination was safe and positive responses observed Phase II part (efficacy) of study ongoing aiming to recruite 100 patients (115 in total) Kushner et al 2014, Clinical Cancer Research 20: Biotec Pharmacon ASA 18

19 utlook

20 utlook The primary focus of Biotec currently is to secure the full commercial potential of Woulgan Market penetration in Europe Secure the execution of the Post Market Clinical Follow-Up study and local case study series for KL support Develop follow up products for wound healing based the Woulgan technology with SBG The results the ongoing study at Memorial Sloan Kettering Cancer Center will be important references of SBG as an adjuvant for cancer theraphies The Company will assess follow up options for developing SBG within this therapeutic field Biotec Pharmacon ASA 20