1. THAOS Status Update: Phenotypes
Márcia Waddington Cruz

2. 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

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

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

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

6. Distribution of phenotypes
Data as of 01 August 2017

7. Distribution of phenotypes within genotypes
Data as of 01 August 2017

8. 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

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

10. 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
*Median value.
Data as of 01 August 2017 10

11. 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

12. 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

13. 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

14. 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

15. 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