A celebration of 10 years of THAOS

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Allison Stephens
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1 Newsletter December 17 Transthyretin Amyloidosis Outcomes Survey Spotlight Fabio Barroso Page 2 A celebration of 10 years of THAOS This October saw the third THAOS Investigator meeting, along with the 17 THAOS Scientific Board Meeting, take place in Rome, Italy. This was a great opportunity for the over 100 global investigators to meet and share their experiences with the registry and management of subjects with transthyretin amyloidosis. We were extremely thankful for the active participation of attendees and the chance to share the latest data and developments with the database, along with opportunities to develop this valuable resource even further. It is hard to believe that it has now been a decade since the first subject was enrolled (29 December 07)! Since then, many milestones have been reached (see below). Over this time, THAOS has become a treasure trove of global representation of TTR subjects. We have a responsibility to do our best with this valuable resource not only in respect to scientific advancement and new research but also in our daily clinical practice. This was THAOS today Page 3 THAOS Investigator Meeting Page 4 noted at the THAOS Investigator Meeting, THAOS is only as good as its raw data and we need to continue our efforts to complete the minimum data set, input follow-up status and sign completed data, which are essential to maximising the value of THAOS. In October, changes to PcPal were made to the database to increase the ease of use for investigators and this should aid us in keeping the database up to date. It is only with the hard work and commitment of the investigators that the registry has moved in the past decade from being a place to collect data, to one that enables us to better understand the disease and how it progresses in our patients. This ultimately leads to improving how we can manage and care for patients and families affected by ATTR. We recently reminded all investigators that they can submit proposals for abstracts and manuscripts through the THAOS website and I encourage you to capitalise on the wealth of information available in the database in this way. THAOS Scientific Board Meeting Page 5 With all the new research and therapies being evaluated, it is an exciting time to be involved in THAOS and we look forward to improving and utilizing this rich resource over the coming decade. I wish you all the very best for the festive season. Dr Márcia Waddington-Cruz Chair of the THAOS Scientific Board University Hospital of the Federal University of Rio de Janeiro, Brazil 08 First Scientific Board Meeting in London, UK and Launch of the THAOS website and newsletter 13 First THAOS manuscripts published Planté-Bordeneuve V, et al. Current Medical Research and Opinion. 13;29(1):77 84 Coelho T, et al. Current Medical Research and Opinion. 13;29(1):63 76 and ATTR phenotype genotype variations further defined 17 Over 100 publications and presentations based on THAOS data 07 Presentation of the first THAOS poster 4 th European Conference on Rare Diseases, Nov 26 27, Lisbon, Portugal th subject enrolled 14 One of the first reports on markers of disease progression in ATTR was published Rapezzi C, et al. Abstract PC-41 presented at XIV th International Symposium on Amyloidosis, April 27 May 1, Indianapolis, IN, USA All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means electrical, mechanical or photocopying or otherwise, without written permission.

2 Spotlight Each edition of the THAOS newsletter will feature a 5-minute interview with an investigator who will explain their rationale for being part of the registry, how it works within their clinic and their aspirations for THAOS in the future. Fabio Barroso is a Neurologist at the Institute for Neurological Research Raul Carrea (FLENI), in Buenos Aires, Argentina. His main areas of expertise include neuromuscular diseases and neurophysiology, with a special interest in hereditary amyloid neuropathies. Dr Barroso has been the lead PI in a number of trials on familial amyloid neuropathy. Since 10 he has collaborated with the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry and served as an important member of the scientific board. How is THAOS organized in your clinic? FLENI is a specialty hospital for neurological and neurosurgical disorders. Many of our patients come from all over the country seeking specialized care of rare, often undiagnosed, afflictions. Peripheral neuropathies are among such disorders. In our dedicated clinic for peripheral neuropathy cases, we have diagnosed over 100 TTR amyloidosis cases over the past 10 years. With the aim of increasing our understanding of the natural course of the disease, improve our detection strategies and our ability to measure the effects of treatment, we offer patients affected by TTR amyloidosis a follow up program which includes clinical assessments, neurophysiological testing, QST testing and autonomic testing on a periodic basis. What studies and investigations are you interested in conducting using THAOS data? We are interested in the clinical aspects of the neuropathy of TTR amyloidosis, particularly its impact on the autonomic nervous system. We also have an interest in studies that correlate clinical, functional and histological assessments of TTR neuropathy. What do you believe THAOS has contributed to the field of ATTR research and consequently to improvements in patient care over the past decade? THAOS provide us a framework to collaborate with and learn from many experts in the field of amyloidosis. Furthermore, the volume of clinical data collected in THAOS provides a unique opportunity to understand aspects of the disease that would be impossible to acquire from a single institution s experience, due its low prevalence. For instance, genotype phenotype correlations, and characterization of the clinical profile in subjects with uncommon mutations. Additionally, the enthusiastic participation of many investigators from many countries has opened the landscape of the disease in ways we did not envisioned 10 years ago. Our perception of the disease has changed from one that saw TTR-FAP as a disease isolated to a handful of endemic regions to one of a widely disseminated, although still rare, disease. How do you hope to see THAOS develop over the next decade? When THAOS was conceived, relatively few clinicians and investigators around the world were interested in TTR amyloidosis. As the number of professionals interested in TTR amyloidosis grows, our scope of the disease expands, and new treatments for it become available, the registry will probably need to incorporate new data categories to fulfil its purpose of improve our understanding of the disease. Fabio Barroso Institute for Neurological Research Raul Carrea (FLENI), Buenos Aires, Argentina 2

THAOS Today Data as of August 17 55 active sites from 17 countries have subjects enrolled into THAOS Subjects in THAOS as of latest date cut (August 17) Subject distribution at enrollment Val122Ile

7% Cumulative Subject Enrollment 4500 3861 4000 2212 00 1688 17 16 Se p- 15 14 13 11 c 08 07 b 10 This STROBE represents patients with signed data using the 01AUG17 data cut Genetic mutation in the

a 219 27 5 0 09 500 Ile68Leu n=7, 2.7% 1187 809 1000 Heterozygous, non-specificc n=58, 2.0% 2500 1500 Other n=479, 65.3% 3236 2674 Thr60Ala n=69, 27.1% Subjects Non-Val30Met n=734, 25.

5% Global Patient Distribution 147 Asia Pac Americas Europe 1143 Glu89Gln, 1.5% Phe64Leu, 2.1% Ser50Arg,3.0% Heterozygous, 1.3% Thr60Ala, 1.2% Val122Ile, 1.2% Wild Type, 1.2% Japan, 4.

3 THAOS Today Data as of August active sites from 17 countries have subjects enrolled into THAOS Subjects in THAOS as of latest date cut (August 17) Subject distribution at enrollment Val122Ile n=160, 62.7% Cumulative Subject Enrollment Se p c b 10 This STROBE represents patients with signed data using the 01AUG17 data cut Genetic mutation in the gene that codes TTR but which does not lead to a TTR disease. Reported TTR mutation but missing specific genotype details. d Cardiac mutations include: Val122Ile, Leu111Met, Thr60Ala, and Ile68Leu. a Ile68Leu n=7, 2.7% Heterozygous, non-specificc n=58, 2.0% Other n=479, 65.3% Thr60Ala n=69, 27.1% Subjects Non-Val30Met n=734, 25.1% Mutation n=2930, 86.2% b d 12 Cardiac n=255, 34.7% 3500 Val30Met n=2138, 73.0% Wild type n=469, 13.8% All patients enrolled in THAOS N=3399a Leu111Met n=19, 7.5% Global Patient Distribution 147 Asia Pac Americas Europe 1143 Glu89Gln, 1.5% Phe64Leu, 2.1% Ser50Arg,3.0% Heterozygous, 1.3% Thr60Ala, 1.2% Val122Ile, 1.2% Wild Type, 1.2% Japan, 4.5% United States, 5.4% Spain, 4.9% Mexico, 3.4% Argentina, 3.3% Others, 8.0% 2571 Germany, 3.6% France, 4.3% Sweden, 7.4% Brazil, 7.8% Italy, 3.0% Val30Met, 80.6% Portugal, 50.5% Others, 2.0% n= 3861 Denmark, 3.5% Glu89Gln, 1.6% Thr60Ala, 3.0% Val30Met, 12.3% Val122Ile, 13.3% ValIle, 1.3% Leu111Met, 1.0% Sweden, 4.1% Spain, 3.0% Italy, 3.3% Portugal, 4.6% Ser50Arg,1.0% Germany, 12% Others, 9.0% Wild Type, 56.1% United States, 58.2% France, 2.8% Japan, 2.5% Bulgeria, 1.6% Mexico, 1.0% South Korea, 0.7% Brazil, 0.8% Netherlands, 0.7% Belgium, 0.5% Argentina, 0.3% Canada, 0.5% Glu89Gln, 3.1% Thr60Ala, 4.7% Ser50Arg,1.9% Ile107Val, 1.4% Ser77Tyr, 1.2% Val122Ile, 7.9% Wild Type, 12.6% Heterozygous, 1.1% Others, 12.6% Val30Met, 53.4% Bulgeria, Italy, 1.4% Germany, 2.8% South Korea, 5.2% Japan, 1.2% Mexico, 5.2% 2.3% Belgium, 0.9% Spain, Denmark, France, 6.3% 0.5% 7.9% Argentina, Brazil, 8.0% 0.7% Netherlands, Sweden, 8.4% 0.5% Portugal, 24.4% United States, 24.3% Data as of August 17 3

4 THAOS Investigator meeting 17: Reflections on the past decade Rome, Italy, was the setting for the third THAOS Investigator meeting on 7 8 October 17. The bi-annual meeting is an opportunity for investigators from around the world to meet and learn more about updates to the THAOS registry, discuss the available data, and to identify opportunities for further research and collaboration. Over 2 days, speakers presented the latest data extracted from the registry, focusing on a range of topics from the 17 data cut. Sessions tackled the functional aspects of the site and ongoing updates that are being made to increase the usability and usefulness for the investigators. Day one Day one began as a celebration this is the 10 th anniversary of THAOS and THAOS chair, Márcia Waddington Cruz, described how the registry had changed over the past decade. Participating in THAOS, there are now 55 sites from 17 countries with over 3800 subjects enrolled. In addition, a number of sites are in various stages of start-up, including one site in Malaysia, which is a new country for the registry. Bryan Shapiro (Pfizer) noted the impressive enrollment in 17, including over 100 new subjects enrolled at Mayo Clinic, USA this year. Congratulations! Based on data from THAOS, Márcia Waddington Cruz stated: Stereotypes on phenotypes being purely neurologic or purely cardiologic are now being dismissed thanks to data gathered around the world, providing another example of how the data in the registry are constantly expanding our knowledge of the disease. A number of key analysis of the data were shared over the 2 days. Chairman-elect, Arnt Kristen, discussed ATTR cardiac manifestations in patients enrolled in the registry, followed by Alejandra González- Duarte who presented information on the neurological findings of symptomatic subjects. Investigators learned about cardiac amyloidosis impact on renal disease progression, and a descriptive analysis of late-onset (>50 years) subjects in Brazilian patients. Day two Day two highlighted investigator-led research, including a survival analysis of subjects with transthyretin amyloid cardiomyopathy, a global database description of the demographic, genetic, and clinical characteristics of subjects in THAOS, and a regionally specific overview of characteristics of Asian subjects. A key theme throughout the meeting was how to improve data quality. Earlier on day two, Rajiv Mundayat (Pfizer Statistician) discussed data availability, summarizing the data for patients with 1 5, and at least 6 years of follow-up data. Follow-up data remain missing for approximately 1000 subjects; data are also missing for the date of diagnosis in one-third of subjects and discussion amongst the investigators centered around means of improving these follow-up rates. Márcia Waddington Cruz closed the meeting reminding investigators of the importance of accurately inputting data, completing the minimum data set (MDS) and following-up patients to ensure we can use the data in a meaningful way, to help patients and families. Investigator Meeting Rome, Italy, 7 8 October 17 4

5 THAOS Scientific Board meeting 17 The THAOS Scientific Board (SB) met in Rome, Italy, during the most recent THAOS Investigator Meeting. The meeting began with sharing results of a survey of SB members designed to elucidate how Pfizer can improve ease of data collection, completeness of data, its engagement with SB and THAOS clinical sites and value of the registry to patients. The survey results showed an interest in more regular communications to sites and investigators, and provision of a monthly report of the status of the registry. Analyzing the database and publishing results focused on the natural history of ATTR and disease progression were also highlighted as important. It also emerged that one of the major strengths of THAOS is the great size and global reach of the registry, which allows data capture on highly diverse subject populations. Proposals for THAOS research in the future A key objective of the scientific board (SB) is discussion of key areas of research focus and a number of topics for evaluation of the data were discussed. Developing a TTR-FAP severity score The morning s sessions concluded with a discussion on development of a new severity score for TTR-FAP. It was noted that although a number of such severity scales have been developed, what physicians need is a simpler, automated measure based on THAOS registry data. It was proposed that existing severity scales could be reviewed, their limitations identified and a new scale devised that would potentially bridge those gaps. A taskforce comprising four centers was selected to evaluate the potential for development of this novel methodology. Need for a definition of disease onset There are various definitions of disease onset, variously defined as from diagnosis (genetic testing), positive biopsy or onset of symptoms. It was conceded that a definition of disease onset might be beyond the scope of the SB s remit, although THAOS data could certainly be useful and scrutinised to inform an opinion, and that other groups are working on new guidelines for publication. Difficulties in making a diagnosis were highlighted and included observations that in some cases symptoms may appear decades after a positive biopsy result. Furthermore, in some patients, symptoms spontaneously improve over time. It was agreed that it might be useful to investigate how a diagnosis is being reached in different countries or regions in order to inform a standardized definition of disease onset. THAOS Scientific Board Chair: Márcia Waddington-Cruz, Brazil: Yukio Ando, Japan Fabio Barroso, Argentina Teresa Coelho, Portugal Isabel Conceição, Portugal Thibaud Damy, France Angela Dispenzieri, USA Bo-Göran Ericzon, Sweden Natália Ferreira, Portugal Alejandra González-Duarte, Mexico Martha Grogan, USA Denis Keohane, Pfizer, USA Arnt Kristen, Germany Mathew Maurer, USA Anna Mazzeo, Italy Violaine Planté-Bordeneuve, France Claudio Rapezzi, Italy Fabian aus dem Siepen, Germany Hartmut Schmidt, Germany Yoshiki Sekijima, Japan Ole Suhr, Sweden Jonas Wixner, Sweden Scientific Board Meeting Rome, Italy, 7 8 October 17 5

Reflecting on THAOS in 2016, and looking forward to 2017

Reflecting on THAOS in 2016, and looking forward to 2017 Newsletter December 2016 Transthyretin Amyloidosis Outcomes Survey Scientific Board Meeting Summary Page 2 Spotlight Dr Arnt Kristen Page 3 THAOS today Page 4 Recent research from THAOS Page 5 ICON Project