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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: • • • • • • - 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 • • • • • • • • - 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 • Patient self-rated symptom scores used as primary measure of efficacy • Symptoms scored on a 4 point scale • • • • • 0: absent • 1: mild, barely noticeable • 2: moderate, annoying / troublesome • 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 8 8 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 0 -2 -4 -6 -8 -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 • >1,400 adult & adolescent subjects • Two Cat-SPIRE active treatment arms, evaluating effect of one and two courses of treatment • Primary endpoint change in Combined Score (Symptoms + Medication Use) measured one year after start of treatment • Includes patients with GINA 1 asthma • 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. • 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 ? 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 6 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) 7 TG002: Grass Pollen 8x6nmol vs. placebo at 24-28wks Change in TRSS (Baseline score minus post treatment challenge) Subjects with mean baseline TRSS >8 9 8 8 x 6nmol 7 Placebo 6 P=0.0346 5 4 3 2 1 0 -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 • • • • • • • 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