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BL-7010: NON-ABSORBABLE

POLYMERIC SEQUESTERING

AGENT FOR

CELIAC DISEASE

Overview and Clinical

Development

Dr. Leah Klapper, CSO

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BL-7010: Non-Absorbable Polymeric Binder for

Celiac Disease

• Indication: Celiac Disease (additional potential indication – non-celiac

gluten sensitivity)

• Mode of Action: Neutralization of gliadin in GI tract

• Development Status: Ready for first-in-man

• Product Highlights

– Prevents formation of gliadin toxic peptides

– Prevents pathological damage to small intestine; helps preserve integrity of intestinal

mucosa and reduces inflammation

– High safety profile

– No effect on body weight

– Not absorbed systemically

BL-7010 Prevents the Formation of Gliadin’s

Immunogenic Peptides

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Small intestinal damage with loss of

absorptive villi and hyperplasia of the

crypts, typically leading to malabsorption

BL-7010 Gluten

Gliadin

Enterocytes

Lymphocytes

Inflammatory Cytokines

APC

The polymer and

gliadin are excreted

in feces

Copolymer of sodium

styrene sulfonate (SS)

and 2-hydroxyethyl

methacrylate (HEMA)

Gluten

BL-7010 demonstrates

distinguished specificity

towards gliadin

Prevention of intestinal damage

Stomach

• Interaction is mainly driven by electrostatic

forces between the positively charged

residues of gliadin and BL-7010

Mode of Action- BL-7010 Interaction with Gliadin

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Hydrophobic Electrostatic

Acidic PH

Neutral PH

Small intestine

• Electrostatic interactions become less

prominent due to de-protonation of the

gliadin

• Binding occurs via hydrophobic forces

BL-7010 MOA offers a clean safe approach: • No reliance on pharmacological mechanism

• BL-7010 does not accumulate in the GI track and is secreted via feces

• BL-7010 cannot be absorbed via small intestine due to its high molecular weight

BL-7010’s affinity to various vitamins, proteins and enzymes was assessed using

biotinyliated BL-7010 and Surface Plasmon Resonance Method

BL-7010 Demonstrates Selectivity Towards Gliadin

Tested material KD (M)

Gliadin 2.44E-09

Pepsin No interaction

Pancreatin (mixture of amylase, lipase and protease) No interaction

B1 No interaction

B2 No interaction

B3 No interaction

B5 No interaction

B6 No interaction

B9 No interaction

B12 No interaction

D3 No interaction

E No interaction

A No interaction

K1 No interaction

C No interaction

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BL-7010 Inhibits Gluten-Induced Damage In-Vivo

Model: HLA-DQ8/HCD 4 transgenic male and female mice sensitized to gluten

Challenge: Gluten containing meal, twice daily, three times a week for three weeks

• Study groups:

– Non-sensitized controls

– Sensitized and non-treated

– Sensitized and treated with BL-7010

• Endpoints:

– Paracellular permeability across the epithelium - 51Cr-EDTA

– Anti-gliadin IgA antibodies in intestinal washes

– Histology of small intestine

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BL-7010 Reduces Intestinal Damage and

Antibody Production

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*P<0.02 *P<0.02, #P=0.058

Paracellular permeability Anti-gliadin antibodies

BL-7010

+

Gluten

Mixture

2:1

Gluten

Mixture

Control

BL-7010

+

Gluten

Mixture

2:1

Gluten

Mixture

Control

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BL-7010 Attenuates Gluten Induced Enteropathy

Non-sensitized

mice

Gluten-sensitized

mice

Gluten-sensitized

mice + BL-7010

1:2

5.96 ± 1.23 Villus-to-crypt ratio 2.58 ± 0.43 4.89 ± 1.51

BL-7010 reduces morphologic intestinal abnormalities, measured by V/C ratio,

induced by long-term administration of gluten-containing meal for three weeks

BL-7010 has Proven Effective in a

Variety of In-Vivo End-Points

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• BL-7010 was active against different gliadin regimens

• BL-7010 prevented intestinal damage produced by gluten meals

• BL-7010 reduced level of intestinal anti-gliadin IgA

• Chronic gluten-induced enteropathy was attenuated after co-

administration of BL-7010 (measured by V/C ratio)

• BL-7010 reduced gliadin-depended inflammation of the small

intestine (IELs)

BL-7010 was Shown to be Safe in Pre-Clinical Studies

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• Safety studies enabling FIM clinical trials completed successfully

• BL-7010 was safe when administered for 14 consecutive days at

doses of up to 70-fold the starting clinical dose.

• Endpoints included

– Clinical signs

– Biochemistry

– Hematology

– Macroscopic and microscopic testing

– Irritation

• NOAEL - 3000 mg/kg/day - highest feasible dose

BL-7010 is Not Absorbed Systemically

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• BL-7010 is excreted by feces

• BL-7010 was not detected systemically, in rats, following

14-day repeated administrations of 3000mg/kg

Clinical Trial Plan

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First-in-man study

• Two-part (single and repeated), double-blind, placebo-controlled,

dose escalation study

• Up to 32 patients – well controlled

• A world-leading site for celiac disease research in Finland

• Primary objective of study - to assess safety of single and

repeated ascending doses

• Secondary objectives include assessment of systematic

exposure, if any

Clinical Trial Plan

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Efficacy study

• Six-week repeated dosing

• Placebo controlled

• Gluten challenge

• Primary objective is efficacy