overview and clinical development dr. leah klapper, cso
TRANSCRIPT
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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