Transcript Progress with T-cell epitope AIT

Progress with T cell epitope AIT
6th International Symposium on Molecular Allergology
19th-21st Nov 2015, Lisbon, Portugal
Mark Larché
Divisions of Clinical Immunology & Allergy and Respirology,
Dept. Medicine & Firestone Institute for Respiratory Health,
McMaster University,
Hamilton, ON
Canada
Disclosure
In relation to this presentation, I declare the following, real or perceived conflicts of interest:
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Circassia Ltd- co-Founder
Circassia Ltd- Intellectual property rights
Circassia Ltd- Consulting
Circassia Pharmaceuticals plc- Ownership interest
Adiga Life Sciences Inc – Consulting
Adiga Life Sciences Inc – Research contracts
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Canadian Institutes for Health Research: operating grants
NIAID: U19 cooperative agreement U19AI100266
Immune Tolerance Network: subcontract
Scleroderma Society of Ontario: PhD Studentship
Canada Research Chair: salary award
McMaster University/GlaxoSmithKline: endowed Chair
Canada Foundation for Innovation: infrastructure award
AllerGen Network of Centres of Excellence; operating grants
A conflict of interest is any situation in which a speaker or immediate family members have interests, and those may cause a conflict
with the current presentation. Conflicts of interest do not preclude the delivery of the talk, but should be explicitly declared. These
may include financial interests (eg. owning stocks of a related company, having received honoraria, consultancy fees), research
interests (research support by grants or otherwise), organisational interests and gifts.
Outline
Rationale for using peptides (T cell epitopes)
Phase II study results for cat allergy
Mechanisms of action
Results for HDM and grass allergy
Factors that limit the effectiveness of current
immunotherapy approaches
Whole proteins
Conformational B cell epitopes
Cross-linking of allergen-specific IgE
Mast cell/basophil activation
Adverse events (local & systemic)
Dose limitation
Protracted treatment period (poor compliance; <20% completion)
Novel approaches to immunotherapy aim to reduce allergenicity
SAFE - EFFECTIVE - QUICK
Synthetic Peptide Immuno-Regulatory Epitopes
(SPIRE)
• Short, synthetic sequences of amino acids representing immunodominant T cell epitopes
• Chemically defined, standardized
• Lack of tertiary structure
• Markedly reduced capacity to cross-link IgE on effector cells
• Modulation of allergen-specific T cell responses, induction of immuno-regulation
• Short treatment course (improved compliance)
• No dose escalation
• Improved safety
• Enduring efficacy
MHC class II restriction map of Fel d 1: defining epitopes for therapy
Worm et al. JACI 2011
Cat: Study Design CP005
Design CP005A/B/C
Baseline
Challenge
EEC
Screening
4 days
3hrs/day
50ng/m3
Fel d 1
* infill placebo to maintain blind
N=202
Dosing (3 months)
8x3nmol 2 wks apart
4x6nmol 4 wks apart*
8xplacebo wks apart
N=89
N=51
CP005
CP005A CP005B
Post
treatment
challenge
EEC
Post
treatment
challenge
EEC
Post
treatment
challenge
EEC
18-22 wk
50-54 wk
100-104 wk
50ng/m3
Fel d 1
50ng/m3
Fel d 1
50ng/m3
Fel d 1
Total Rhinoconjunctivitis Symptom Scores (TRSS) measured
on 4 nasal and 4 ocular symptoms
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Patient self-rated symptom scores used as primary measure of efficacy
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Symptoms scored on a 4 point scale
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0: absent
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1: mild, barely noticeable
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2: moderate, annoying / troublesome
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3: severe, incapacitating
Ocular symptoms scored on scale 0-3 for itchy eyes, watery eyes, red eyes,
sore eyes
Nasal symptoms scored on scale of 0-3 for running nose, sneezing, blocked
nose, itchy nose
TRSS score of 8 could be 8 “mild / barely noticeable scores”
TRSS score of 12 could be 4 “mild / barely noticeable” and 4 “moderate / annoying” scores
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CP005/5A efficacy and treatment duration study: Phase IIb
Randomized, double-blind, placebo-controlled parallel group trial with Environmental Exposure Chamber (EEC)
50-54wk follow-up
9 months after last
dose
Marked treatment effect evident on day 1 which increases with time
Peak change in TRSS on fourth day almost 6 TRSS points
Median change in TRSS between 8 x 3nmol and 4 x 6nmol almost identical at 18-22wks
Patel et al., JACI 2013
Treatment effect larger in more symptomatic subjects
Baseline All
Baseline >10
Baseline >12
Change from baseline in TRSS at one year
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-2
-4
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-10
-12
-14
4 x 6nmol
Placebo
Baseline >14
Baseline >16
Similar data for grass and HDM
CATALYST – Double blind placebo controlled Phase III
study ongoing
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>1,400 adult & adolescent subjects
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Two Cat-SPIRE active treatment arms, evaluating effect of one and two courses of
treatment
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Primary endpoint change in Combined Score (Symptoms + Medication Use)
measured one year after start of treatment
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Includes patients with GINA 1 asthma
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Exploratory endpoints include evaluating changes in asthma control in asthmatic
subjects and the numbers of subjects developing asthma during the course of the
study to provide a baseline for potential future follow-up.
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Recruitment closed December 2014, last follow-up Jan 2016; results H1 2016
Mechanisms of action
Purpose: to investigate mechanisms of action of peptide
immunotherapy and to
(1) identify biomarkers associated with biological response to
the intervention
(2) identify biomarkers associated with clinical efficacy
(3) Identify novel immunological pathways associated with T
cell tolerance
Key Mechanistic Question
How can targeting rare allergen-specific T cells protect from
acute symptoms in an allergen challenge scenario?
Blocking antibody does not appear to be induced
Mechanism of Action pyramid
Epitope-specific intervention targeting 1/20,000 T cells
Single molecules
direct effects on target T cells
e.g. changing chemokine receptor expression
indirect effects on other cells
e.g. recruitment of eosinophils
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Pathways
? Detectable downstream consequences of peptide intervention in the blood
Significant improvements in clinical outcomes
Adiga/Circassia RES-003/RES-004
Design: Open label mechanistic study
Population: 19 subjects with cat-induced allergic
rhinoconjunctivitis +/- mild asthma
Mark Larché
Helen Neighbour
Nasal Allergen Challenge (NAC) dose finding at screening visit (S)
Bolus NAC pre- and post- Cat-SPIRE therapy
Anne Ellis
Cat-SPIRE 4 x 6nmol intradermal administrations @ 1 month intervals
Clinical outcomes:
Scott Tebbutt
Rod Hafner
Pascal Hickey
Dan Gliddon
Total Nasal Symptom Score (TNSS) over 6 hrs
Peak Nasal Inspiratory Flow (PNIF) over 6 hrs
Mechanistic Outcomes:
Whole blood transcriptomic (770 gene nanostring) 6hrs post NAC
Mechanisms of Action: Transcriptomic analysis
www.nanostring.com
Cat-SPIRE reduces NAC symptoms and down
regulates Th2 pathways
Pathways significantly down regulated by
Cat-SPIRE in response to allergen challenge
IL-7 Signaling Pathway(Mus musculus)
Oncostatin M Signaling Pathway(Homo sapiens)
IL-5 Signaling Pathway(Homo sapiens)
Kit receptor signaling pathway(Homo sapiens)
Chemokine signaling pathway(Mus musculus)
TSLP Signaling Pathway(Homo sapiens)
IL-6 signaling Pathway(Mus musculus)
IL-3 Signaling Pathway(Homo sapiens)
enrichr
IL-3 Signaling Pathway(Mus musculus)
www.wikipathways.org
IL-5 Signaling Pathway(Mus musculus)
IL-4 Signaling Pathway(Homo sapiens)
TH002: House Dust Mite
4x12 nmol versus placebo at 50 weeks
 Primary
endpoint on
days 2 and
3 only
Scale: Delta TRSS 3.0
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5
4
3
 Treatment
effect larger
if day 1
included
2
p =0.02
4x12nmol
1
Placebo
0
Week 50 Day 1
Week 50 Day 2
Data similar to Cat-PAD at 1 year
Week 50 Day 3
4.0hr
3.5hr
3.0hr
2.5hr
2.0hr
1.5hr
1.0hr
0.5hr
0.0hr
4.0hr
3.5hr
3.0hr
2.5hr
2.0hr
1.5hr
1.0hr
0.5hr
0.0hr
4.0hr
3.5hr
3.0hr
2.5hr
2.0hr
1.5hr
1.0hr
0.5hr
-1
0.0hr
Inverse Change from Baseline (Positive Treatment Effect)
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TG002: Grass Pollen
8x6nmol vs. placebo at 24-28wks
Change in TRSS (Baseline score minus post treatment challenge)
Subjects with mean baseline TRSS >8
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8 x 6nmol
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Placebo
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P=0.0346
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2
1
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-1
AAAAI 2014
TG002: Grass Pollen
8x6nmol vs. placebo at 24-28wks
Change in TRSS (Baseline score minus post treatment challenge)
Subjects with mean baseline TRSS >12
P=0.0342
Conclusions
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Four administrations of SPIRE over three months shows
statistically significant improvement in TRSS in EEC/EEU studies
Clinical improvements maintained two years after treatment
Safety profile indistinguishable from placebo
Phase 3 trial completion H1 2016
Activation of multiple Th2 pathways, in response to allergen
challenge, is down-regulated following SPIRE therapy
Pathways include putative mast cell and/or ILC2 growth,
activation and survival
Modulation of these pathways may form the basis for
biomarkers of efficacy and will improve understanding of MoA
Acknowledgements
Steve Harris
Charles Swingland
Rod Hafner
Paul Laidler
Pascal Hickey
Steve Pawsey
Dan Gliddon
Kristen Armstrong
Beth Forbes
Brenda Ahenkorah
Piyush Patel
Anne Marie Salapatek Anne Ellis
Charles W. Frankish
Lisa Steacy
Robyn O’Hehir
Margitta Worm
Hae-Hyuk Lee
Jörg Kleine-Tebbe
Wayne Thomas
Belinda Hales
Wendy-Ann Smith
Bernard Maillère
Catherine Texier
Helen Neighbour
Elena Tonti
Jing Yu Mu
Cheryl Kipling
Chris Rudulier
Dan Moldaver
Mantej Bharhani
Lesley Wiltshire
Elizabeth Simms
Jennifer Wattie
Mark Inman
Sarah Colgan
Liz Johnston
Barbara Baker
Christian Gysin
Deanna French
AB Kay
Scott Tebbutt
Young Woong Kim
Casey P Shannon
Amrit Singh
Bill Kwok
Alkis Togias
Mike Minnicozzi