Reflecting on THAOS in 2016, and looking forward to 2017

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1 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 management updates Page 6 Reflecting on THAOS in 2016, and looking forward to 2017 Dear colleagues, I would like to begin by thanking Professor Claudio Rapezzi for all his efforts as acting Chair of the THAOS Scientific Board. Throughout his tenure, the Scientific Board has shaped this registry into what it is today a large-scale, international collaboration that provides a resource of information relating to TTR amyloidosis. It is a pleasure to be part of this growing community, and the resulting increases in understanding and awareness of this disease will ultimately facilitate the provision of the very best care for our patients. It is with great pleasure that I have now accepted the role of Chair of the THAOS Scientific Board, I very much look forward to continuing our collaboration in the future. In this new era of disease awareness and management, it is clear that TTR amyloidosis affects patients in countries across the globe and presents many challenges for physicians. As such, it is indeed an exciting time for the THAOS registry. In 2016 alone we have seen 11 meeting abstracts accepted, two articles published in high-impact factor journals, with a third having been submitted, and the endorsement by the THAOS Scientific Board of two novel projects. We also now have four additional THAOS sites across Europe, Asia and the USA, indicative of the positive growth of this registry. Additionally, we are very pleased to introduce three new members to the THAOS Scientific Board: Martha Grogan, Mayo Clinic, Rochester, Minnesota, USA Jonas Wixner, Umeå University, Umeå, Sweden Fabian aus dem Siepen, University of Heidelberg, Germany I am sure you will join me in welcoming these new members to our community. Thank you all, sincerely, for all your activities and efforts throughout 2016, the continued success of THAOS is a result of all of your hard work and dedication. I now look forward to what 2017 has to offer! 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 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 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.

THAOS Scientific Board Meeting On Saturday 2 nd July 2016, members of the THAOS Scientific Board met in Uppsala, Sweden to discuss updates to the registry and the latest data from various analyses.

2 THAOS Scientific Board Meeting On Saturday 2 nd July 2016, members of the THAOS Scientific Board met in Uppsala, Sweden to discuss updates to the registry and the latest data from various analyses. With the addition of longer term follow-up data and longitudinal assessments, the THAOS registry now represents a mature resource of longitudinal information; allowing for analysis of disease progression over time and a better understanding of the long-term natural history of TTR amyloidosis. The Board continues to focus on and discuss how best to optimize the capture of patient information and improve data quality within the registry in the future. THAOS today The meeting began with an update on the status of the THAOS registry. Highlights included the considerable growth of the registry (>3000 enrolled) thanks to the continued commitment and efforts of the dedicated THAOS investigators and Scientific Board. It was reported that the rate of patient enrolment is everincreasing and a total of 95 mutations have been recorded. Some of the key outcomes of these discussions included: A continuing need to publish manuscripts reporting THAOS data and to develop a standardized timeline for the publication process All investigators are encouraged to submit research proposals to utilize the wealth of data. Proposals can be submitted via where information on the publication process and proposal forms are provided. Recent analyses Analyses of data from the THAOS registry were presented by members of the Scientific Board. These included investigations into the transition from asymptomatic to symptomatic TTR-FAP, the impact of disease-onset on quality of life, and the trajectory of patients treated with tafamidis or liver transplantation compared to those that do not receive treatment. Additional presentations included clues to diagnosing TTR cardiomyopathy, and defining patient characteristics in the United States and Europe. Analyses probing the interactions of genotype and phenotype, as well as the impact of gender on disease status were also presented. Many of these analyses were presented at the International Society of Amyloidosis (ISA) meeting 2016 and will be available on the THAOS website investigator portal. Capturing patient information Discussions took place regarding the importance of capturing patient information upon enrolment and follow-up: For patients with TTR-FAP: Date of diagnosis for subjects with TTR-FAP should be included as a priority For patients with TTR cardiomyopathy: Telephone-based follow-up might facilitate capture of patient status The presence of a pacemaker and occurrence of hospitalizations should be recorded Certain recommendations to optimize THAOS site performance were discussed and included reducing redundancy in the database, improving the ease of data entry, capturing information when patients enter double-blind studies and listing example adverse events (AEs) for untreated patients to give context for treatment-related AEs. Looking to the future At the meeting close, Márcia Waddington Cruz was welcomed as the new Chair of the THAOS Scientific Board. Claudio Rapezzi was sincerely thanked for his significant contributions and successes over the years, and the Scientific Board looked to the future, emphasising the importance of continuing to improve the value of this robust, international disease registry. As patient enrolment continues to increase there is a strong need to gather and input follow-up results and patient status reports to gain long-term follow-up data. Importantly, if patients are not able to attend clinics regularly, we should try to follow up these patients remotely by completing the Status Update page, at least once a year. THAOS Scientific Board and colleagues, Uppsala, Sweden, 2016 From left-to-right; front row: Tomonori Ishii, Isabel Conceição, Teresa Coelho, Márcia Waddington-Cruz, Alejandra González-Duarte, Natália Ferreira, Yoshiki Sekijima; middle row: Fabio Barroso, Marla Sultan, Angela Dispenzieri, Anna Mazzeo, Denise Rill, Yukio Ando, Harmut Schmidt, Damien Simoneau, Violaine Planté-Bordeneuve; back row: Jennifer Schumacher, Michelle Stewart, Mat Maurer, Claudio Rapezzi, Denis Keohane, Thibaud Damy, Ole Suhr, Rajiv Mundayat, Moh-Lim Ong. 2

3 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 the registry in the future. Arnt Kristen works as a Senior Physician at the Heidelberg Heart Center and the Heidelberg Amyloidosis Center at the University of Heidelberg, Germany. His scientific and clinical focus is on cardiomyopathies and rare diseases, including the management and treatment of these disorders through approaches such as heart transplantation. Dr Kristen s particular interests are cardiac amyloidosis and the field of interventional cardiology. What was the most important reason for your center to join THAOS? Heidelberg Amyloidosis Center is a referral center for amyloidosis in Germany. As such, many patients come to us from all over the country, including those with hereditary and wild-type TTR amyloidosis. We feel that the contribution of a German center is most valuable for the registry. How is THAOS organized in your clinic? The THAOS registry is mainly based in the Department of Cardiology, Heidelberg Amyloidosis Center, given the highest proportion of our patients with wild-type TTR amyloidosis first present with cardiac symptoms. During routine assessments and visits at our center, all patients that satisfy the inclusion and exclusion criteria will be informed of the importance of the THAOS registry and asked for permission to be included in the dataset. What do you see as the key value of THAOS for patients and physicians? THAOS is a unique opportunity to collect extensive data across the various fields of TTR amyloidosis. Through using these data, vital information will be available on the heterogeneous presentation of TTR amyloidosis and our patients will benefit from the overall improvement in knowledge of this rare disease. Additionally, there is the potential to establish diagnostic algorithms for TTR amyloidosis. What advantages does THAOS bring to your research? THAOS allows me to access a huge database detailing different aspects of TTR amyloidosis. Currently, I am analyzing the prognostic use of cardiac biomarkers in a large cohort of patients with different genotypes and phenotypes of TTR amyloidosis; a single center is not capable of collecting such volumes of patient data. What do you hope THAOS will contribute over the next five years? Providing further information, not only on the natural course of TTR amyloidosis, but also on predictors of outcome. If you could give one piece of advice to a new THAOS center, what would it be? New centers should make efforts to collect complete datasets including neurologic, cardiologic and laboratorybased assessments. Moreover, they should actively encourage their patients to attend their follow-up visits. Dr Arnt Kristen Heidelberg Heart Center and Heidelberg Amyloidosis Center, University of Heidelberg, Heidelberg, Germany 3

THAOS Today Genotype, phenotype and geography Mutation spectrums in USA and Europe Spectrum of mutations in USA N=460 Spectrum of Mutations in Europe (excluding Portugal, UK and Scandinavia) N=606 3.

0% 2.0% Other 38 mutations affecting 99 patients 32.

Neurologic Phenotype (%) N=1241 Cardiac Phenotype (%) N=453 (84.1) Genotype Thr49Ala (0.7) Thr60Ala (1.2) Wild Type (0.4) Gly47Ala (1.1) Phe64Leu (1.6) Glu89Gln (1.9) Ser50Arg (2.6) Others (7.6) (84.

7) His88Arg (0.7) Glu74Ser (0.7) Sweden (6.4) Brazil (7.0) Spain (2.6) Portugal (58.2) Ile68Leu (2.2) Others Others (11.3) (7.6) Val122Ile (11.3) Sweden (4.4) Wild Type (53.4) (14.8) (94.0) (94.

4 THAOS Today Genotype, phenotype and geography Mutation spectrums in USA and Europe Spectrum of mutations in USA N=460 Spectrum of Mutations in Europe (excluding Portugal, UK and Scandinavia) N= % 3.3% 3.0% 3.0% % 16.3% Other 26 mutations affecting 45 patients 229 Wild Type Leu58His Other mutations 6.1% 19.5% 45 Val122Ile Phe64Leu Val122Ala 2.0% 2.0% 2.0% Other 38 mutations affecting 99 patients 32.5% Thr60Ala Glu74Ser Phe33leu Glu89Gln Val20Ile Ile107Val Wild Type Phe64Leu Gly47Ala Thr49Ala Ile68Leu Ser77Tyr Glu89Lys Other mutations Genotypic and geographic distribution of disease phenotype Neurologic Phenotype (%) N=1241 Cardiac Phenotype (%) N=453 (84.1) Genotype Thr49Ala (0.7) Thr60Ala (1.2) Wild Type (0.4) Gly47Ala (1.1) Phe64Leu (1.6) Glu89Gln (1.9) Ser50Arg (2.6) Others (7.6) (84.1) Geography France (2.6) Mexico (2.7) Argentina (2.8) United States (2.9) Germany (3.1) Spain (3.8) Japan (4.5) Genotype Turkey (0.5) Denmark (0.4) Israel (0.2) Taiwan (0.2) Cyprus (0.1) Thr59Lys (0.7) His88Arg (0.7) Glu74Ser (0.7) Sweden (6.4) Brazil (7.0) Spain (2.6) Portugal (58.2) Ile68Leu (2.2) Others Others (11.3) (7.6) Val122Ile (11.3) Sweden (4.4) Wild Type (53.4) (14.8) (94.0) (94.0) Mixed Phenotype (%) N=668 Genotype Gly47Ala (1.3) Ile107Val (1.2) Ile68Leu (1.5) Ser50Arg (1.8) Ser77Tyr (1.8) Glu89Gln Thr60Ala (4.0) (2.2) Germany (4.2) Mexico (1.9) Argentina (1.3) Denmark (0.7) Japan (5.1) Belgium (0.4) Taiwan (0.3) Sweden (6.4) Others (10.8) Wild Type (12.4) Brazil (6.6) France (8.5) Val122Ile (7.8) Portugal (28.7) Italy (9.0) (54.0) 4 Geography Spain (4.8) Phe64Leu (1.0) United States (21.9) Argentina (0.2) Japan (2.9) Denmark (3.8) Val20Ile (1.3) Leu111Met (1.5) Brazil (0.9) France (2.0) Glu89Lys (0.7) Ser50Arg (1.5) Italy (4.8) Geography Mexico (1.9) Italy (4.8)(6.6) Portugal Sweden (6.4) Italy (12.8) Brazil (7.0) Germany (16.4) United States (47.5) Portugal (58.2)

5 Recent research from THAOS Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey) Maurer MS, Hanna M, Grogan M, et al. J Am Coll Cardiol. 2016;68: TTR amyloidosis is a heterogeneous disease, affecting multiple organs and having both hereditary and nonhereditary etiologies. Using data from the THAOS registry, this study aimed to describe the clinical features of this disease in subjects from the USA (n = 390) versus the rest-of-world (ROW, n = 2140). The influence of genotype on mortality was also studied. Clinical characteristics of TTR amyloidosis in subjects from USA versus ROW ATTR in United States Older (70 ± 11 years) Male (85%) More often African American (25%) ATTRwt common (48%) Val22lle most common mutation Predominately cardiac phenotype ATTR in Rest of the world Younger (46 ± 16 years) Equal male/female More often asymptomatic (28%) most common mutation Especially in Portugal, Sweden and Japan Phenotypes varies by region Predictors of survival in TTR amyloidosis patients from USA From this cohort of THAOS registry subjects from the USA, age and mean arterial pressure were both associated with lower survival, whereas genetic status (Val122Ile carriers versus wild-type TTR subjects) was not. Analysis of data from the THAOS registry allows for the description of disease characteristics of large populations of subjects with TTR amyloidosis. This investigation revealed that TTR amyloidosis in the USA is typically a disorder of older, male subjects with predominantly a cardiologic phenotype and survival was not associated with the presence of the Val122Ile mutation. Univariate and Multivariate Analysis of Predictors of Survival* Univariate Multivariate n Hazard Ratio (95% CI) p Value n Hazard Ratio (95% CI) p Value Age, per 5 yrs ( ) ( ) Female (vs. male) ( ) Val122Ile (vs. wt-attr) ( ) Ejection fraction, per U ( ) Heart rate, per beat/min ( ) Stroke volume, per ml ( ) Myocardial contraction fraction, per U ( ) LV mass index, per g/m ( ) egfr 54 ml/min (vs. reference <54 ml/min) ( ) Low voltage present (vs. absent) ( ) Mean arterial pressure, per mmhg ( ) < ( ) *From registry enrollment in wt-attr and Val122Ile subjects in the United States. CI: confidence interval; egfr: estimated glomerular filtration rate; LV: left ventricular 5

6 Recent research from THAOS Male gender is a risk factor for myocardial involvement in transthyretin-related amyloidosis: A study based on THAOS Clinical Characteristics by Gender Subjects (%) Rapezzi C, Waddington-Cruz M, Lorenzini C, et al. The International Society of Amyloidosis XV th International Symposium on Amyloidosis (ISA), July 3 7, 2016, Uppsala, Sweden All Subjects Symptomatic Cardiac phenotype 1639/ / / / / /822 Using data from the THAOS registry, this study investigated the possible role of gender in TTR amyloidosis disease manifestation. Amyloidotic cardiomyopathy (IV septum >12 mm) Abnormal ECG 447/537 90/ / /766 Data from 2826 subjects were used in this analysis. Data were included from: symptomatic subjects with a TTR gene mutation (n = 1802); asymptomatic TTR mutation carriers (n = 661); and wildtype TTR subjects (n = 363). A multiple linear regression analysis was performed using increasing mean left ventricular (LV) wall thickness and LV mass index as the dependent variables to identify associations of disease manifestations with gender. Among this population of THAOS subjects, gender influenced the clinical phenotype of patients. Cardiologic manifestations, abnormal electrocardiogram and dysautonomia were most common in males. These data support the hypothesis that an as yet unknown phenomena related to gender can moderate disease impact, resulting in a higher severity in males. Future work should focus on identifying this underlying mechanism and consider the implications on innovative therapeutic strategies. Male Female p< Percentages are based on total number of patients with amyloidotic cardiomyopathy. Values in bars: n=number of males or females with characteristic / N=total number of males or females assessed for that characteristic, with the exception of amyloidotic cardiomyopathy, where N includes males + females. Clinical Characteristics by Gender Kidney involvement Sensory abnormalities Autonomic impairment Carpal Tunnel syndrome Subjects (%) / / / / / / / /1096 Male Female *p=0.0009; p< Values in bars: n=number of males or females with characteristic / N=total number of males or females assessed for that characteristic. * ICON Project management updates Serious Adverse Events THAOS is considered a postauthorization safety study. As such, there is an obligation to report serious adverse events (SAEs) and we would therefore like to remind you to report any incidents of SAE. Please contact your ICON site manager if you have any questions regarding SAE reporting. 6 Site payments The next site payments for patient visits will be completed in January Please be sure to input and have all visit data signed by 31 st December to be eligible for January payment cycle. Data management update Database updates reviewed at the Investigator Meeting were included in the database release in October 2016; please refer to the notification from 4 th October Some friendly reminders Protocol training and a collection of study resources are available in Firecrest Information concerning publications and a training video on neurologic assessment are available at THAOS.net

A celebration of 10 years of THAOS

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