BL-7010: NON-ABSORBABLE POLYMERIC SEQUESTERING AGENT FOR CELIAC DISEASE
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BL-7010: NON-ABSORBABLE
POLYMERIC SEQUESTERING
AGENT FOR
CELIAC DISEASE
110
Celiac Disease – Unmet Medical
Need and Current Therapies
Prof. Joseph Murray, MD
Mayo Clinic
111
What is Celiac Disease?
• It is a inflammatory
state of the small
intestine that
occurs in
genetically
predisposed
individuals and
resolves with
exclusion of Celiac
dietary gluten. Disease
112
Incidence per 100,000 person years
30
Diagnosis Rate in Olmsted County
25
20 Female
Male
Total
15
10
5
0
1950-1959 1960-1969 1970-1979 1980-1989 1990-1999 2000-2001 2002-2004 2005-2007 2008-2010
Calendar Year
Clinical Gastroenterology and Hepatology; Vol. 1-1
113
USA Prevalence of Celiac Disease
NHANES 2009-2010
Diagnosed CD
Gluten Free Diet Celiac Disease
83%
GFD without 17% Untreated CD
Dx of CD
1.6 million 1.8 million
1% of Caucasians
114
Rubio-Tapia, et al. AJG 2012 .
World Map Indicating Prevalence of Celiac Disease
~1% 1-2% >2%
Clinical Spectrum: it is not just celiac disease
Gluten sensitivity (GS)
IBS Potential CD
Lactose intolerance Latent CD
Food intolerance CD and complications
SIBO
IBS-like symptoms Spectrum of
116
CD
Adapted from Verdu et al., 2009.Non Celiac Gluten Sensitivity “Celiac Lite”
Condition of morphological, immunological,
or functional disorder that responds to
gluten exclusion in the absence of celiac
disease.
Gluten sensitive diarrhea
Immunopathological changes in the SB
mucosa
↑ Intraepithelial lymphocytes (IEL)
↑ IgA deposits intestinal villi
↑ Secreted Ab against gliadin
HLA predicted
Adapted from Verdu EF, et
al. AJG, 2009.
117How good is current treatment?
118
New York Times February 4, 2013Gluten-Free Diet
• The gluten-free diet (GFD) is the only
effective therapy available for celiac
disease. The benefits of a GFD are:
• Improve symptoms
• Normalize antibodies
• Induce mucosal recovery*
• Improve quality-of-life
• Reduce the risk of complications
• Decrease mortality*
Rostom A, et al. Gastroenterology 2006
119Celiac Lesion is Reversible
• Genetic Predisposition • Inflammation
• Permanent intolerance to • Villi destruction
gluten • Crypt hyperplasia
Gluten
Gluten exclusion
Normal histology Total villous atrophy
(Marsh 0) (Marsh 3)
120Challenges to Adherence
• Social occasions
• Isolation
• Being different ( teenagers)
• Family support
• Community support
• Depression/anxiety
“I can resist anything except
temptation” Oscar Wilde 121Intentional and No intentional or
known inadvertent known inadvertent
lapses lapses
28% 30%
Intentional lapses,
but no known
No intentional
inadvertent ones
lapses, some known
12%
inadvertent ones
30%
Reported intentional and inadvertent gluten consumption (n=269)
Hall NJ, Rubin GP, Charnock A. Intentional and inadvertent non-adherence in adult
coeliac disease. A cross-sectional survey. Appetite 68:56-62, 2013.
http://dx.doi.org/10.1016/j.appet.2013.04.016
122Views of Celiac Disease Inexorably Linked to GFD for Patients
– Which Make Them Feel like ‘Outsiders’
Isoloation
Need to explain diet
Can’t join in socially
Patients thoughts & feelings regarding celiac disease appeared closely
linked to the GFD
Not feeling yourself
On consumption of
gluten
Global Qualitative Market Research
Alba Therapeutics and Double Helix
123
Homework 1: What having celiac disease means to you?Women Report a Greater Impact on Quality Of Life than Men
IMPACT OF SYMPTOMS OF CELIAC DISEASE ON
QUALITY OF LIFE PRIOR TO DIAGNOSIS
- Patient Survey: Men vs. Women -
Females
Males
0% 100%
Note: While majority experience significant symptoms, over a third characterize as
minimal or moderate
PT: Q3a. We are interested in understanding how your Celiac symptoms affected the quality of your life prior to being diagnosed.
124Dangers of Non-Compliance
• Increased mortality Holmes et al. 1989 Corrao et
al.
• Osteoporosis Cellier
• Lymphoma Holmes et al.
• Other cancers Green, 2006
• Psychological effects hallert
• Failure to heal RubioTapia, 2010
125Healing
• Up to 95% of children with CD may
have complete mucosal recovery within
2 years after starting a gluten-free diet1
• Mucosal recovery in adults with CD is
less certain2
1 Wahab P, et al. Am J Clin Pathol 2002
2 Rostom A, et al. Gastroenterology 2006
126Histologic Healing in Adults
Author Country “n” % healing Time on
GFD
Grefte J1 Netherlands 22 0% 2 years
Bardella M2 Italy 114 17.5% 2 years
Rubio-Tapia* USA 241 34% 2 years
(present) 66% 5 years
Ciacci C3 Italy 390 44% 7 years
Tursi A4 Italy 42 59.5% 2 years
Collin P5 Finland 65 96% 8 years
1J Clin Pathol 1988; 2 Histopathology 2007; 3Digestion 2002; 4Endoscopy 2006; 5Gastrointest Endosc 2004
* Rubio-Tapia A, et al. Am J Gastro 2010
127Persistent Atrophy may be
Clinically Relevant
• Associated with complications such as
osteoporosis, autoimmune diseases,
lymphoma1,4
• Persistent atrophy and symptoms despite GFD
are major criteria for refractory CD, a rare
condition associated with high mortality2
• Even without symptoms: higher risk of
osteoporosis, development of refractory sprue,
and lymphoma3 1
Rostom A, et al. Gastroenterology 2006
2 Rubio-Tapia A, et al. Gut 2010
3 Kaukinen K, et al. Aliment Pharmacol Ther 2007
128
4Lebowhol et al. Ann Int Med, 2013Clinical Response?
• Clinical response: 82%
• However, 62% patients with clinical
response were found to have
persistent damage at their follow-up
biopsy!
• No association between clinical
response and mucosal recovery
(p=.70)
129Non Responsive Celiac Disease
Primary: no initial response to gluten free
diet
Secondary: relapse following initial
response
17% of celiacs at a support group had
diarrhea1
18.7% of a referral center population2
9.9% of primary patients
35% of referral patients
True refractory celiac disease is rare
1Fine et al. Gastro, 1997 130
2Leffler et al. CGH, 2007Therapeutic Targets Points of Action in Pathogenesis
Toxic Non-toxic A B
A wheat wheat
IEL
Toxic
+ wheat
Additional Probiotics
gluten
B + E
Stress
Enzymes Gluten Tissue
peptide B C damage
fragments Toxic and
non-toxic Stimulate
C + Digestion by gluten B-cells
gastric and peptides
Protease pancreatic proteases Inflammatory
supplement markers
IL-15
D Pass through
lumen F
T-cell
Gluten
D H
Polymeric
binder G
Paracellular
E Probiotics Transcytosis passage
F Anti IL-15 Stress
TTG
G Anti-Zonulin
Enterocytes Deamidation
H Engineered probiotics of gluten
MHC II TCR
©2013 MFMER | 3249362-131 131
©2013 MFMER | 3249362-131Multiple innate immune gluten-mediated effects
Stress pathways Receptors pathways
Gluten
gliadin p31-43
LGQQQPFPPQQPY FQQPQQQYPSSQ SQQPYLQLQ QQQQQQQQQQQQILQQILQQ
Tryptic digested gliadin
QVLQQSTYQLLQELCCAHLW
MIC IL-15 ? HLA-E CXCR3
TLR-4 ?
EGFR pMAPK
MyD88
HLA-E
Epithelial activation
Upregulation of IL-15 and EGFR HLA-E surface expression APC activation
Upregulation of stress-induced and stabilization Inflammatory cytokines
MHC-Ib IL-15?
IFN-?
APC maturation Increased
Inflammatory cytokines intestinal permeability 132
IFN-Current Therapies
• Larazotide acetate ( Alba/Teva)
Phase 2b complete
• Alv-1003, Phase 2 B underway
• An-Pep going OTC
• Chemocentryx drug: Clinical trial
completed 2010 ( no report assume
failure)
• Nex-Pep: safety study in humans
• BL-7010 – Phase 1/2 underway
133Conclusions
Celiac disease is Common
The GFD stinks:
– Hard to follow
– Less than optimal adherence
Many don’t heal
Many have symptoms
Precedence of trials in celiac disease
Track record with FDA and EMEA
Clinical trials are feasible
Outcome measures: objective and subjective ( PRO)
134
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