International Severe Asthma Registry ISAR Protocol for a

International Severe Asthma Registry (ISAR): Protocol for a global registry David Price, Liam G. Heaney, Mark Hew, Peter Gibson, Andrew Menzies-Gow, Matthew Peters, Trung N. Tran, Jim Zangrilli

Disclosures The presenter has indicated that they have a relationship which in the context of their presentation, could be perceived as a real or apparent conflict of interest but do not consider that it will influence their presentation. The nature of the conflict is listed: Affiliation / Financial interest Commercial Company Grants/research support: Astra. Zeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service Honoraria or consultation fees: Amgen, Astra. Zeneca, Boehringer Ingelheim, Chiesi, Glaxo. Smith. Kline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance Participation in a company sponsored bureau: Amgen, Astra. Zeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals Stock shareholder: AKL Research and Development Ltd which produces phytopharmaceuticals, owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore) Spouse / partner: Other support / potential conflict of interest: Payment for lectures/speaking engagements: Astra. Zeneca, Boehringer Ingelheim, Chiesi, Cipla, Glaxo. Smith. Kline, Kyorin, Mylan, Merck, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals Payment for manuscript preparation: Mundipharma, Teva Pharmaceuticals Payment for the development of educational materials: Mundipharma, Novartis Payment for travel/accommodation/meeting expenses: Astra. Zeneca, Boehringer Ingelheim, Circassia, Mundipharma, Novartis, Teva Pharmaceuticals

The need for a global severe asthma registry Global asthma registry is required National/regional asthma registries • • • Variability in definition of severe asthma Variability in data collected Variability in data quality Variability in access to health care Not connected (lack intra-operability) Small numbers (inadequate statistical power) Data share with local registries and connect them • Reduce variability in data collected o Standardized core variables • Improve data quality • Large numbers (sufficient statistical power) •

ISAR: the first global severe asthma registry • • Collects patient-level, pseduonymized, longitudinal, real-life, standardized, highquality data, using a set of core variables. 1 Local registries retain ownership of their own data, but share their anonymised data with ISAR for approved international research purposes. 2 ISAR is currently collaborating with 29 countries worldwide and is The target for prospective patient recruitment is 13, 150 patients with severe asthma by 2022! continuing to grow 1. Bulathsinhala et al, JACI Pract 2019; 2. ISAR Study Group, Chest 2019; in Press ISAR: International Severe Asthma Registry

ISAR strengths ISAR Study Group, Chest 2019; in press ISAR: International Severe Asthma Registry

Committed to conducting high quality, clinically relevant research Examples of some ISAR projects Core Global Projects 2017: demographics & clinical characteristics of severe asthma patients worldwide 2018: characterization of eosinophilic vs non-eosinophilic phenotypes 2019: comparative effectives across biologic classes Some Prioritized Projects BRISAR: Biomarker relatability in ISAR Biologic availability and utilization in severe asthma Hidden severe asthma Impact of exacerbations on lung function trajectory ISAR: International Severe Asthma Registry

Demographic and clinical characteristics of severe asthma worldwide (I) Severity Co-morbidity burden HCRU Wang et al, Chest 2019; In press SK: South Korea; IT: Italy; SAWD: Severe Asthma Web-based Database; HCRU: healthcare resource utilisation

Demographic and clinical characteristics of severe asthma worldwide: more data! Control status Exacerbation frequency Biomarkers Tx Chest 2019; in press Wang et al, Chest 2019; in press; SK: South Korea, IT: Italy, SAWD: Severe Asthma web-based database; Fe. NO: fractional exhaled nitric oxide; OCS: oral corticosteroid; Ig. E: Immunoglobulin E

High degree of irreversible obstruction* FEV 1/FVC • All: 0. 71 (0. 13) • SK: 0. 62 (0. 17) % patients with FEV 1/FVC<0. 7 o GINA Step 4: 43% o GINA Step 5: 47% Wang et al, Chest 2019; In press FEV 1: forced expiratory volume in 1 second; GINA: Global Initiative fro Asthma; FVC: forced vital capacity; * ERS definition (change from % predicted

BRISAR: Biologic relatability in ISAR Little is known about the overlap and relatability of positive biomarkers in severe asthma. • 1175 adult patients with severe asthma from 10 countries were included • In this large international severe asthma cohort, o most patients were positive for at least one potentially actionable biomarker at baseline. o Overlap was greater between eosinophil and Fe. NO positivity than with Ig. E positivity. • Cut-off points for positivity were pre-defined as follows: Ig. E ³ 75 k. U/L, blood eosinophils ³ 300 cells/u. L, Fe. NO ³ 25 ppb. This considerable overalp in biomarker positivity suggests that >1 targeted therapy may be suitable for many patients with severe asthma ISAR: International Severe Asthma Registry; Fe. NO: fractional exhaled nitric oxide; Ig. E: Immunoglobulin

Biologic availability and utilization Availability Utilization patterns ISAR: International Severe Asthma Registry; IL: interleukin; Ig. E: Immunoglobulin E. Bx: biologic

Conclusions • ISAR aims to offer a rich source of real-life data for scientific research to understand improve disease burden, treatment patterns and patient outcomes in severe asthma. • ISAR will provide an international platform for research collaboration in respiratory medicine, with the overarching aim of improving primary and secondary care of adults with severe asthma globally. Visit the ISAR website for details of how you can get involved ISAR: international severe asthma registry

2019 Prioritised Projects Open for Researchers, Post-docs, and PHD students are welcome to participate in any of the following Projects Project Characteristics of severe asthma patients with inflammatory phenotypes and low-FEV 1 Prof. Arnaud Bourdin Prof. Camille Taillé Objective OCS landscape: Annual consumption, prevalence, outcomes and side-effects of long-term OCS PI BRISAR (Monash University), Socio Economic and Asthma Outcome (University of Belfast); Onset of Asthma (Woolcock Institute) To update the annual accumulative incidence of OCS exposure among severe asthma patients using a global severe asthma cohort. Describe cohort of SA patients with inflammatory indicators • High Blood EOS • High Sputum EOS • High Ig. E • Low-FEV 1 Compare clinical outcomes: treatment effectiveness, exacerbation rates, asthma control, incidence of comorbidities Characterization of health disparities across countries Prof. Eileen Wang Describe inter-country disparities in asthma prevalence, asthma severity, treatment, health resource utilization, morbidity and mortality