THAOS Status Update: Phenotypes Márcia Waddington Cruz

Definitions of phenotypes in THAOS Data for classification available for N=2562 (symptomatic) (wild-type and TTR mutation combined) Cardiac phenotype 1. Abnormal ECG due to rhythm disturbance, heart failure or dyspnea AND 2. Do not have more than mild neurologic or GI symptoms (excluding erectile dysfunction, constipation and carpal tunnel) Neurologic phenotype 1. Walking disability of any severity or other neurologic symptoms of any severity or GI symptoms (early satiety, nausea, vomiting, unintentional loss of weight, diarrhea, constipation or fecal incontinence) of any severity 2. Do not have abnormal ECG due to rhythm disturbance or heart failure or dyspnea at baseline Mixed phenotype – the rest *Characterization based on Scientific Board decision Data as of 01 August 2017

Neurologic Phenotype (%) N=1381 Genotype Geography Data as of 01 August 2017

Cardiac Phenotype (%) N=608 Genotype Geography Data as of 01 August 2017

Mixed Phenotype (%) N=573 Genotype Geography Data as of 01 August 2017

Distribution of phenotypes Data as of 01 August 2017

Distribution of phenotypes within genotypes Data as of 01 August 2017

Demography of wild-type disease Male (n = 450) Female (n = 19) All Subjects (N = 469) Age at enrollment (years) n Mean ± SD Median p10, p90 450 75.5 ± 6.84 75.3 66.8, 84.1 19 75.4 ± 10.45 75.8 59.1, 87.2 469 75.5 ± 7.00 66.7, 84.7 Age at onset of ATTR symptom (years) 415 68.1 ± 10.82 69.5 54.1, 80.8 18 68.9 ± 13.07 71.2 50.5, 84.7 433 68.2 ± 10.91 54.1, 81.0 Data as of 01 August 2017

Race / Ethnicity in wild-type disease (N, %) Data as of 01 August 2017

Age and disease duration TTR mutation Wild Type Number of patients 2930 469 Age at THAOS entry (years)* 45.0 75.3 Males (%) 52.3 96.0 Symptomatic (%) 74.4 97.7 Age at onset (years)* 41.1 69.5 Duration of disease (years)* 4.2 4.5 Time from symptom onset to diagnosis (year)* 1.9 3.6 Table 14.1.3.1.1 *Median value. Data as of 01 August 2017 10

Distribution of age at onset in patients with TTR mutation Patients with wild-type versus symptomatic patients with TTR mutation by age group at onset 300 Non-Val30Met Val30Met Wild type 200 Frequency 100 ≤20 24 28 32 36 40 44 48 52 56 60 64 68 72 66 80 84 92 Age at onset (years) Data as of 01 August 2017

Family history Family history Neurologic (N=1381) Cardiologic (N=608) Mixed (N=573) Patient reported family history of symptomatic TTR amyloidosis 87.2% 22.2% 60.7% Patients with family history Father 46.2% 51.9% 46.3% Mother 26.7% 40.8% Both father and mother 0.8% - Unknown 6.4% 20.7% 12.4% Other 0.5% 0.6% Data as of 01 August 2017

Family history Family history Neurologic (N=1381) Cardiologic (N=608) Mixed (N=573) How was diagnosis made in affected family members Unknown 12.6% 23.0% 16.1% Clinical diagnosis (symptoms only) 8.9% 26.1% 19.9% Confirmed diagnosis 79.2% 56.3% 65.8% Biopsy 52 5 30 Genotyping 257 23 63 Both 644 48 136 Missing 0.1% 0.3% Patient did not report any known family history 9.2% 65.3% 28.6% Patient reported unknown family history 3.2% 10.2% 9.6% Patient did not provide an answer – missing response 0.4% 2.3% 1.1% Data as of 01 August 2017

Summary THAOS includes subjects from 21 countries Portugal has enrolled 40% of the subjects 14% are wild-type, 86% have TTR mutation 101 different mutations are represented in THAOS Val30Met is the most common mutation, reported in 2138 (70%) of subjects with TTR mutation Val30Met commonly presents early, but there is a group that presents late Late onset is seen mostly in wild-type and non-Val30Met subjects Data as of 01 August 2017

Summary 4% of wild-type symptomatic subjects presented as neurologic phenotype 5% of symptomatic Val30Met subjects presented as cardiologic phenotype, and 11% of Val122Ile subjects presented as neurologic phenotype 87% of subjects with neurologic phenotype reported positive family history 22% of cardiologic phenotype subjects reported positive family history Data as of 01 August 2017