Biotec’s Soluble Beta-Glucan (SBG in clinical applications

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

Arctic Biotech Seminar 30th November 2015

CSO Rolf E Engstad

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

Biotec Pharmacon

• Company

• Established 1990

• Listed on OSE ticker: biotec

• About 35 employees

• Two operating subsidiaries:

• Biotec Beta-Glucans AS & ArcticZymes AS

• GMP, ISO-13485, and ISO 9001


• Beta-Glucans

• Development, production and sales of beta-

glucans since 1990

• Proprietary and patented manufacturing

processes

• Product range from feed grade (M-Glucan®)

to pharmaceutical grade (SBG®)

• GMP approved plant in Tromsø

One 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


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 Beta-

glucan 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-

On fighting cells of the body

against invading microbes. Ann.

Inst. Pasteur 1: 32

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


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


CH2OH O

OH

O

OH

O

CH2OH O

OH

OH O

OH CH2OH O

OH

O

OH

CH2OH

O

OH O

OH

CH2OH O

OH

OO

OH

CH2OH O

OH

OH O

OHCH

2OH O

OH

O

OHCH

2OH

O

OH O

OH

CH2 O

OH

O

OHCH

2OH O

OH

O

OHCH

2OH O

OH

O

OHCH

2O

OH

O

OHCH

2OH O

OH

O

OHCH

2OH O

OH

OH

n

n

n

Soluble Beta-GlucanHealing of stalled woundsAdvanced wound care

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


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 KOL support

• Potential clinical studies to get regulatory approval outside Europe


SBG® in wound care – mode of action

• SBG® activates macrophages

to produce signal molecules

and growth factors resulting in:

• Wound contraction

• Cell proliferation

• Angiogenesis

Increased healing

(ref.: Skjæveland & Engstad 2013)


-10

40

90

0 4 8 12 16 20 24

% C

on

tra

cti

on

0

5

10

15

20

25

30

35

Marginal Intermediate Centre

Pro

life

rati

ng

cell

co

un

t(f

ov)

0

20

40

60

80

100

120

140

160

Marginal Intermediate Centre

An

gio

ge

nsis

Co

un

t (f

ov)

Water Woulgan Biogel «Woulgan Biogel» without SBG

Cell proliferation Angiogenesis

Wound contraction

0

10

20

30

40

50

60

0 1 2 3 4 5 6 7 8 9 10 11 12

Duration of therapy (weeks)

Patients with complete healing (%)

SBG® in Diabetic Foot Ulcer – clinical data


SBG

Control

Placebo controlled double blinded study of 60 patients

Statistical significant after 8 weeks (p=0.03)

• Methylcellulose (Placebo control)

• N= 60

• Treatment schedule:• 3 treatments per week

• Up to 12 weeks treatment

• Ulcer size 1-34 cm2

• Complete healing (PP):

8 weeks 12 weeks

SBG 44% 56%

Placebo 17% 31%

SBG® in wound care – clinical data


Several monts

29 %

Up to one week

8 %Several weeks

26 %

Over 1 year

37 %

• 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?

Diabetic ulcer

18 %

Pressure ulcer

22 %

Leg ulcer

28 %

Post-op. Wound

14 %

Burns

4 %

Lacerations

8 %

Unknown

6 %Poor

10 % Quite good

12 %

Good

25 %Very good

27 %

Excellent

20 %

Don't know

6 %

How would you rate Woulgan’s effect?Wound diagnosis

Agenda

• Company

• Soluble beta-glucan (SBG®) as PAMP

• SBG® as platform for immunotherapeutic applications

• Healing of stalled wounds

• Immunotherapy of cancer

• Summary


• 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


Biotec SBG® in cancer therapy -mode of action

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, 345:1578-1589

Biotec SBG® in cancer therapy – animal model

• Biotec’s SBG® has been shown to potentiate

the effect of immuntherapetic cancer regimes:

• Improved anticancer mAb effect

• Improved anticancer vaccine effect

• 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.)


mAB alone

mAB + SBG

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)

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

• Followed up in vaccine trial at MSKCC

Before After

123I-MIBG scan of patient treated with

one cycle of 3F8+SBG (80mg/kg/day)

SBG ® in immunotherapy of cancer

• Investigator driven vaccine trial in children with neuroblastomainitiated by MSKCC using their own developed bi-valent vaccineagainst neuroblastoma antigens (GD2L and GD3L).

• Biotec’s SBG® given p.o. to increase tumor killing activity ofwhite 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: 1375-1382

Outlook

Outlook


• 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 KOL 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

Documents

Biotec’s Soluble Beta-Glucan (SBG in clinical applications