A Survival Analysis of Subjects With Transthyretin Amyloid Cardiomyopathy from the Transthyretin Amyloidosis Outcomes Survey Martha Grogan, Martin Carlsson, Michelle Stewart, Jennifer Schumacher, Angela Dispenzieri

Conflicts of interest and acknowledgements MG and AD are members of the Scientific Board of THAOS. MC, JS, and MS are employees of Pfizer. The authors thank all THAOS patients and investigators for their important contributions to this study. The THAOS registry and this analysis were sponsored by Pfizer. Medical writing support was provided by David Wateridge, PhD, of Engage Scientific Solutions and was funded by Pfizer.

Background Patients with the rare, progressive, and debilitating disease of transthyretin (TTR) amyloidosis can develop a fatal cardiomyopathy caused by the accumulation of amyloid fibrils composed of misfolded TTR monomers TTR cardiomyopathy is increasingly recognized as an important cause of heart failure and atrial arrhythmias, especially in older men. TTR amyloid fibrils can develop in patients with a wild-type TTR genotype as part of the natural aging process (ATTRwt), and can also form due to amyloidogenic TTR mutations that destabilize the structure of native TTR tetramers Grogan M, et al. Poster presented at the 21st Annual Meeting of the HFSA, September 16–19, 2017, Grapevine, TX, USA

Rapezzi et al. European Heart Journal (2013) 34, 520–528

To characterize the survival of subjects with ATTRwt or Objectives To characterize the survival of subjects with ATTRwt or ATTRm, restricted to mutations considered to be associated with a primarily cardiac phenotype: Val122Ile, Thr60Ala, Leu111Met, Ile68Leu Grogan M, et al. Poster presented at the 21st Annual Meeting of the HFSA, September 16–19, 2017, Grapevine, TX, USA

Methods All symptomatic subjects enrolled in THAOS with a diagnosis of ATTR amyloidosis meeting following criteria ATTRwt or ATTRm (limited to Val122Ile, Thr60Ala, Leu111Met, or Ile68Leu mutations) At least 1 follow-up visit prior to January 30, 2017 No disease-modifying therapies allowed Non-parametric Kaplan–Meier delayed-entry methodology was used to estimate median survival from the time of diagnosis. What happened to those who did not have a follow-up visit? Grogan M, et al. Poster presented at the 21st Annual Meeting of the HFSA, September 16–19, 2017, Grapevine, TX, USA

Characteristics of the study population Results Characteristics of the study population A total of 421 subjects were included: 275 with ATTRwt 37 Thr60Ala 81 Val122Ile Compare to Mauer publication, his n for overall population was 166 WT and 77 Val122Ilewas for overall survival 119 WT and 60 ValI22Ile J A C C V O L . 6 8 , NO . 2 , 2 0 1 6 Maurer et al. J U L Y 1 2 , 2 0 1 6 : 1 6 1 – 7 2 146 with ATTRm 9 Leu111Met 19 Ile68Leu Grogan M, et al. Poster presented at the 21st Annual Meeting of the HFSA, September 16–19, 2017, Grapevine, TX, USA

*Val122Ile, Thr60Ala, Leu111Met, or Ile68Leu. Clinical characteristic at enrollment ATTRwt ATTRm* N 275 146 Age at diagnosis, years† 75 (47, 89) 67 (35, 85) Male gender, % 95 76 Race, % White 92.7 46.6 Black 2.9 42.5 Other 3.6 6.2 Missing 0.7 4.8 NYHA Class, % No heart failure reported 10 17 I / II 6 / 46 7 / 27 III IV 29 / 4 23 / 5 5.1 21.2 Time from symptom onset to diagnosis, years† 3.8 (0.9, 9.9) 3.0 (0.6, 8.4) *Val122Ile, Thr60Ala, Leu111Met, or Ile68Leu. †Values are presented as median (Interquartile range). NYHA, New York Heart Association. Overall, age at diagnosis was higher in the ATTRwt group vs the ATTRm group, but time from symptom onset to diagnosis was similar between groups. Compare to Mauer publication, his n was 119 WT and 60 ValI22Ile Grogan M, et al. Poster presented at the 21st Annual Meeting of the HFSA, September 16–19, 2017, Grapevine, TX, USA

*Val122Ile, Thr60Ala, Leu111Met, or Ile68Leu. Clinical characteristic at enrollment ATTRwt ATTRm* Age < 70 ≥ 70 N 67 208 92 54 Age at diagnosis, years† 66 (47, 70) 77 (70, 89) 61 (35, 70) 74 (70, 85) Male gender, % 92.5 95.7 79.3 70.4 Race, % White 91.0 93.3 55.4 31.5 Black 3.0 2.9 33.7 57.4 Other 4.5 3.4 5.5 7.4 Missing 1.5 0.5 5.4 3.7 NYHA Class, % No heart failure reported 11.3 9.8 31.0 6.3 I / II 5 / 45 7 / 42 7 / 13 4 / 39 III / IV 23 / 5 30 / 3 15 / 7 40 / 0 11 8 26 10 Time from symptom onset to diagnosis, years† 4.0 (0.8, 10.2) 3.8 (0.9, 9.1) 2.2 (0.4, 6.6) (1.3, 10.2) *Val122Ile, Thr60Ala, Leu111Met, or Ile68Leu. †Values are presented as median (Interquartile range). NYHA, New York Heart Association. For wt 24% under age 70 vs, 63% of mut under age 70 Grogan M, et al. Poster presented at the 21st Annual Meeting of the HFSA, September 16–19, 2017, Grapevine, TX, USA

Age at diagnosis and time from symptom onset to diagnosis varied according to the specific TTR mutation carried Grogan M, et al. Poster presented at the 21st Annual Meeting of the HFSA, September 16–19, 2017, Grapevine, TX, USA

Survival from time of diagnosis, stratified according to TTR genotype Median survival from diagnosis in the ATTRwt and ATTRm groups was 3.1 and 3.7 years, respectively ATTRwt N=421 N=275 N=146 ATTRwt Grogan M, et al. Poster presented at the 21st Annual Meeting of the HFSA, September 16–19, 2017, Grapevine, TX, USA

Survival from time of diagnosis, stratified according to TTR genotype and age at diagnosis Survival from time of diagnosis was more dependent on age at diagnosis than whether patients were ATTRwt or ATTRm < 70 y: ATTRm, n=92 < 70 y: ATTRwt, n=67 ≥ 70 y: ATTRwt, n=208 ≥ 70 y: ATTRm, n=54 Median OS 6.7 years 4.4 years 2.9 years 3.0 years Grogan M, et al. Poster presented at the 21st Annual Meeting of the HFSA, September 16–19, 2017, Grapevine, TX, USA

Published THAOS Data Maurer JACC 68 (2), 2016;161-72

Conclusions Symptomatic subjects with ATTR amyloidosis due to either ATTRwt or ATTRm predisposing to a cardiac phenotype had a median delay ≥3.0 years from symptom onset to diagnosis. The majority of subjects diagnosed with ATTRm at age ≥70 years were black; whereas the majority diagnosed with ATTRm aged <70 years were white. In general, median survival estimates from diagnosis were similar for subjects with ATTRwt or ATTRm predisposing to a cardiac phenotype when stratified according to age at diagnosis. Grogan M, et al. Poster presented at the 21st Annual Meeting of the HFSA, September 16–19, 2017, Grapevine, TX, USA

Limitations Short follow-up Exclusion of lost to follow-up patients