IATI BioMed Presentation 2013

BL-7010:
Polymeric Non-Absorbable
Gliadin-Sequestering Agent for
Celiac Disease
IATI-BioMed, Israel
June 11, 2013
Forward Looking Statements
This presentation contains "forward-looking statements."
These statements include words like "may," "expects,"
"believes," “plans,” “scheduled," and "intends," and describe
opinions about future events. These forward-looking
statements involve known and unknown risks and
uncertainties that may cause the actual results, performance
or achievements of BioLineRx to be materially different from
any future results, performance or achievements expressed or
implied by such forward-looking statements.
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BioLineRx Highlights
• 7 clinical stage assets in a variety of indications, 2 in advanced
clinical stages
• Broad pre-clinical pipeline – providing multiple opportunities
for next generation clinical projects
• Special strategic relationships and access to Israeli technology
• Strong balance sheet - $28 million cash as of March 31, 2013
• Several meaningful value inflection points in 2013 and 2014
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Current Pipeline
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BL-7010
POLYMERIC NON-ABSORBABLE GLIADINSEQUESTERING AGENT FOR CELIAC DISEASE
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Celiac Disease Overview
• Chronic GI immunological, inflammatory disease of the small
intestine
– Characterized by small intestinal damage with loss of absorptive villi and hyperplasia
of the crypts, typically leading to malabsorption
– Symptoms include chronic diarrhea, failure to thrive (in children) and fatigue,
however these symptoms may not always be present
• Caused by immunological reaction to gluten’s gliadins
• Occurs in individuals with genetic predisposition (patients share
heterodimeric HLA class II genes HLA-DQ2 or HLA-DQ8)
• There are no pharmacological agents approved for celiac and the
only treatment option is life-long, strict gluten-free diet (GFD)
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Introduction: Unmet Medical Need for the
treatment of Celiac Disease
• 1%-2% World-Wide Prevalence
• There are no pharmacological agents approved for celiac
– Only treatment option is life-long, strict gluten-free diet (GFD)
– Significant burden on the quality-of-life of patients
– Up to 60% of adult CD patients symptomatic despite GFD
• Patients have persistent mucosal inflammation on GFD
• Research indicates a great demand for alternative
treatment (if available)
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Introduction: Celiac Disease
Celiac Disease Market
• The celiac pharmaceutical market is projected to reach $8B by
2019
• Gluten sensitivity is estimated to be an even larger market than
celiac disease
Compound Name
AT-1001
ALV-003
Vercirnon (CCX-282)
Nexvax2
AN-PEP
ZED-101
Actobiotics for treatment of celiac
disease
Nexvax3
AVX-176
Provid therapy
TNX-832
VAL-514-UM
RTLs
Company
Alba (formerly licensed to Shire and
Cephalon)
Alvine Pharmaceuticals
ChemoCentryx (originator) GSK (current
developer)
ImmusanT /Nexpep
Frits Koning
Zedira (originator) Dr. Falk (licensee)
ActoGeniX
Development Status
Ph IIb, another phase IIb is ongoing
Ph IIb
Ph II for celiac disease
Ph I
Ph I (PD study)
Pre-clinical
Pre-clinical
ImmusanT (originator) BTG (licensee)
Pre-clinical
Avaxia
Pre-clinical
Provid
Pre-clinical
Sunol Molecular (originator) Roche (licensee),
Pre-clinical
Altor Bioscience (licensee)
Univalor
Pre-clinical
Artielle ImmunoTherapeutics
Pre-clinical
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BL-7010: Polymeric Non-Absorbable GliadinSequestering Agent for Celiac Disease
• Indication: Celiac disease (additional potential indication – non-celiac
gluten sensitivity)
• Mode of Action: Neutralization of gliadin in the GI tract
• Development Status: Pre-clinical
• Product Highlights:
– High molecular weight polymer with high affinity for gluten’s gliadin
– Non-absorbable, non-biodegradable, no systemic exposure
– Stable at a wide pH range (2-11)
– Prevents pathological damage to small intestine, helps preserve
integrity of intestinal mucosa and reduces inflammation in vivo
– Non-toxic, no effect on weight
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BL-7010: Mode of Action
Gluten
BL-7010
Polymer & gliadin
excreted
Gliadin
Enterocytes
Gliadin peptides
Cell damage & barrier dysfunction
Inflammatory Cytokines
APC
Lymphocytes
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PRE-CLINICAL DATA
BL-7010 Reduces Enzymatic Formation of
Gliadin Immunogenic Peptides
• In vitro digestion of gluten by incubation with common GI enzymes in
the presence or absence of BL-7010
• Various toxic peptides were quantified using LC/MS/MS
• As shown, BL-7010 significantly reduced the formation of
gliadin’s toxic peptides
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BL-7010 Efficacy
Mouse Model of Celiac Disease Exposed to Chronic Meal
Containing Gluten
• Model: HLA-DQ8/HCD4 transgenic mice sensitized to gliadin
• Objective: To assess BL-7010’s efficacy in preventing intestinal
damage induced by gluten-containing meal
• Experimental Design:
– Meal mixture: Mixture bovine serum albumin (BSA), wheat starch and gluten
– Challenge: Gluten mixture twice a day, 3 times a week for 3 weeks
– Mice (males and females) were treated with BL-7010
• Endpoint:
– Net active transport across the epithelium
– Anti-gliadin IgA antibodies were quantified in intestinal washes
– Histology
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BL-7010 Reduces Intestinal Damage in Celiac
Disease Mice Fed Gluten Containing Meal
Net Active Transport
Control
Gluten
Mixture
*P<0.02
BL-7010
+
Gluten
Mixture
Anti-gliadin antibodies
Control
Gluten
Mixture
BL-7010
+
Gluten
Mixture
*P<0.02
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BL-7010 Attenuates Gluten Induced Enteropathy
Non-sensitized
mice
Villus-to-crypt ratio
5.96 ± 1.23
Gluten-sensitized
mice
2.58 ± 0.43
Gluten-sensitized
mice + BL-7010
4.89 ± 1.51
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BL-7010 has a Good Safety Profile
• High importance for safe treatment – alternative or
adjunctive therapy is GFD
• Toxicity MTD study in male SD rats with once daily
administration for 14 days – MTD is at least
2000mg/kg/day
• No effect on BW, FC, hematology, blood chemistry,
urinalysis, histology and clinical signs
• High specificity to gliadin (Biacore tests):
– Interaction with gliadin: KD (M) = 2.4E-9
– No interaction with tested nutrients and digestive enzyme: pepsin,
pancreatin, B1, B2, B3, B5, B6, B9, B12, D3, E, A, K1 and C
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Preliminary ADME
BL-7010 is Excreted in the Feces
• [3H]-BL-7010 was given orally to SD rats
• Blood, feces and urine samples were collected
• Organs were collected (small intestine, colon, liver, kidneys and
spleen)
• Radioactivity in blood, urine, feces and organs was assessed
Sample
Percent Radioactivity from Oral Dose
Blood*
0.09
Organs**
0.99
Urine**
1.82
Feces**
108
* Average
** Cumulative
• Similar results were obtained in gluten-challenged HLA-DQ8/HCD4
mice
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BL-7010: Clinical Program
BioLineRx plans to initiate two studies in celiac
disease patients in 2013-2014:
1. Safety Study: First-in-man, single and repeated
ascending dose study
–
–
Safety endpoints, no efficacy endpoints
Assessment of systemic exposure using LC/MS/MS method
2. PoC Study: Efficacy study in celiac patients
– 6-week repeated oral administration
– Efficacy endpoints (primary and secondary) and safety endpoints
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Summary
• BL-7010 is a high molecular weight polymer that interacts with
gluten’s gliadin
• BL-7010’s efficacy was demonstrated in vitro and in vivo in animal
model of celiac disease
• Safety studies show BL-7010 is safe at doses above effective dose
level (at least 10 fold)
• BL-7010 has no effect on weight and on GI motility
• Preliminary ADME studies indicate that BL-7010 is not absorbed,
rather it is excreted in the feces
• BioLineRx is currently performing pre-clinical studies to support
clinical studies in the following year
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