Key Data: Epidemiology, Demographics, Unmet Needs

Patient Demographics

The prevalence and incidence of ATTRwt are not known; however, ATTRwt is increasing rapidly in recognition and, with an aging population, ATTRwt is likely to become the most common type of cardiac amyloidosis [1]

ATTRwt

Prevalence of ATTRwt increases with age with nearly all affected patients >60 years of age [1]
- However, despite being historically considered a disease of older age, there have been reports of diagnosis of ATTRwt in patients as young as 42 years old [8]
Most commonly, ATTR is reported in men over the age of 75 ²*
- A recent meta-analysis of 28 studies from around the world reported that 86.9% of patients with ATTRwt were men and results from Japan are consistent with this finding [6]

ATTRwt: Cardiac Amyloidosis

Although the exact prevalence of ATTRwt is unknown, it is almost certainly the most common cause of cardiac amyloidosis, particularly in the elderly, potentially accounting for up to 10% of elderly patients with HF [3]

Studies suggest ATTRwt is an underdiagnosed cause of HF, with a prevalence of 13% in a cohort of patients presenting with clinical manifestations of HFpEF, and 16% in a cohort of patients with severe aortic stenosis requiring transcatheter aortic valve implantation [1]
Additionally, autopsy data have shown that ~25% of adults >80 years old have significant TTR amyloid deposits in the myocardium [2]

ATTRv

Hereditary ATTRv is generally rare, but some genetic variants are endemic in specific geographic regions or ethnic groups, e.g.:
- Val30Met variant is endemic in some areas (e.g., Portugal, Sweden, Japan)**
  - However, although endemic in some areas of Japan, overall prevalence is thought to be much lower, ~1 in 1,000,000³
- Val122Ile most commonly affects individuals of Sub-Saharan African ancestry and has an allele prevalence of 3% to 4% among African-Americans [3]
ATTRv likewise often occurs more frequently in males than in females, particularly for late-onset phenotypes [5]

ATTRv: Cardiac Amyloidosis and/or Polyneuropathy

Hereditary amyloidosis caused by mutations in the TTR gene (TTRv, variant) has begun to emerge as a significantly underdiagnosed cause of cardiac failure and polyneuropathy [2]
The worldwide prevalence of ATTRv has been estimated at 40,000 to 50,000 individuals, with varying phenotypic presentations [2,7]

Notes: HF = heart failure; HF with preserved ejection fraction = HFpE

Notes: *With recent advances in non-invasive diagnostic tools, some studies indicate ATTRwt may be more common in females than previously reported; however, the clinical characteristics of female ATTRwt patients have not been determined. In a study of 78 consecutive patients with diagnosed with ATTRwt at Kochi Medical School Hospital between April 2012 and October 2020: 14 (17.9%) were female—and compared with male patients, female patients had smaller LV wall thicknesses (ventricular septum thickness 12.9 vs. 14.2 mm; posterior wall thickness 12.7 vs. 13.6mm, and a higher LV EF). However, the severity of HF, as assessed by HF stage, NYHA functional class and B-type natriuretic peptide concentrations, did not differ between female and male patients. Moreover, LV mass index and relative wall thickness were increased, and the stroke volume index was reduced in both female and male patients.9

Notes: *Val30Met variant is endemic in some areas of Portugal, Sweden, Japan, Brazil, and Spain (Majorca), but recent estimates suggest EU prevalence is <1 in 100,000³

Fontana, Marianna. Jul. 9, 2020. Cardiac amyloidosis: Clinical manifestations and diagnosis. UptoDate. https://www.uptodate.com/contents/cardiac-amyloidosis-clinical-manifestations-and-diagnosis?search=ATTR&source=search_result&selectedTitle=1~30&usage_type=default&display_rank=1.
Picken, MM. The Pathology of Amyloidosis in Classification: A Review. Acta Haematol. 2020;143:322-334. doi: 10.1159/000506696.
Witteles, RM, et al. Screening for Transthyretin Amyloid Cardiomyopathy in Everyday Practice. JACC: Heart Failure. 2019. Vol. 7, Iss. 8, 709-16. https://doi.org/10.1016/j.jchf.2019.04.010.
Rozenbaum MH, et al. Impact of Delayed Diagnosis and Misdiagnosis for Patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM): A Targeted Literature Review. Cardiol Ther. 2021;10(1):141-159. doi:10.1007/s40119-021-00219-5.
Sekijima Y, Ueda M, Koike H, Misawa S, Ishii T, Ando Y. Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm. Orphanet J Rare Dis. 2018;13(1):6.
ALXN: ATTR Amyloidosis: Epidemiology Dossier. Elissa Wilker & Shona Fang. September 2021. 18_ATTR Amyloidosis Epi Dossier. Citing: Kroi F, Fischer N, Gezin A, Hashim M, Rozenbaum MH. Estimating the Gender Distribution of Patients with Wild-Type Transthyretin Amyloid Cardiomyopathy: A Systematic Review and Meta-Analysis. Cardiol Ther. 2021;10(1):41-55.
ALXN: ATTR Amyloidosis: Epidemiology Dossier. Elissa Wilker & Shona Fang. September 2021. 18_ATTR Amyloidosis Epi Dossier.
Inomata T, et al. Diagnosis of wild-type transthyretin amyloid cardiomyopathy in Japan: red-!ag symptom clusters and diagnostic algorithm. ESC Heart Failure. 2021. DOI: 10.1002/ehf2.13473.
Ochi, et al. Circulation Reports 2021 - JAPAN - Wild-Type Transthyretin Amyloidosis in Female Patients.pdf.

Alexion Epidemiology Model

Preliminary Epi DatA - FEB 2022

The prevalence and incidence* of ATTRwt are unknown [1]; underdiagnosis and misdiagnosis have likely contributed to underreporting, but both are rising with increased awareness, an aging population distribution, and non-invasive imaging improvements [2]

Diagnosed Prevalent Cases of CHF, with Preserved Ejection Fraction, ATTRwt and ATTRv; in Males & Females, 20+ Years of Age, 2020 [1]

Note: These estimates aim to establish the upper bound of the number of people with ATTR-CM, including those that are diagnosed and those that are undiagnosed. It is likely that not everyone in these estimates will have their HFpEF attributed to ATTR. [1]

Note: CM = cardiomyopathy; ATTRv = “variant” / hereditary / mutant

Note: *No published data on the incidence rate of ATTR in Japan exist¹

Deep Dive

Methodology

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ALXN: ATTR Amyloidosis: Epidemiology Dossier. Elissa Wilker & Shona Fang. September 2021. 18_ATTR Amyloidosis Epi Dossier.
Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(22):2872-91.

ATTRwt Demographics in Japan

Japan

ATTRwt has been reported predominantly in older men [1,3], but studies focusing on ATTRwt and ATTR-CM are limited*

The following tables summarize the findings from studies of ATTRwt and ATTRv patients in Japan separately, given that much of the literature has sought to differentiate populations based on the endemic nature of ATTRv in some areas

Patients with ATTRwt were mostly men
Mean or median age at symptom onset in studies of ATTRwt in Japan ranged 69 to 74 years of age

Population Characteristics of Patients with ATTRwt Reported from Studies in Japan [a]

*Studies in Japan have historically focused on hereditary ATTRv in endemic areas and on the most common variant, Val30Met. Many studies in Japan were small and located at a single site or within a single region. Several studies identified were conducted at Kumamoto University Hospital, located where ATTRv is endemic (see, e.g., Yamada, 20203). Because a number of studies recruited patients from a single center, the study populations described may not be independent; it is possible that patients participated in one or more of these studies.

ALXN: ATTR Amyloidosis: Epidemiology Dossier. Elissa Wilker & Shona Fang. September 2021. 18_ATTR Amyloidosis Epi Dossier. Citing:

Sekijima Y, Yazaki M, Ueda M, Koike H, Yamada M, Ando Y. First nationwide survey on systemic wild-type ATTR amyloidosis in Japan. Amyloid. 2018;25(1):8-10.
Sekijima Y, Mundayat R, Ishii T, Ando Y. The current status of the Transthyretin Amyloidosis Outcomes Survey (THAOS) in Japan. Amyloid. 2019;26(sup1):61-2.
Yamada T, Takashio S, Arima Y, Nishi M, Morioka M, Hirakawa K, et al. Clinical characteristics and natural history of wild-type transthyretin amyloid cardiomyopathy in Japan. ESC Heart Fail. 2020;7(5):2829-37.

ATTRwt Incidence in Japan

Japan

Population-based studies on the incidence of ATTR are lacking [2]; however, data suggests that the number of newly diagnosed cases are increasing, partially due to better awareness and diagnostic tools [1]

In Japan, no published data on the incidence rate of ATTR exists [1]

At Kumamoto University however, the number of newly diagnosed ATTRwt-CM cases more than tripled from 2016 to 2019 [1]

Method of diagnosis:

Group 1: presence of TTR deposition in the myocardium (i.e., heart biopsy)
Group 2: presence of TTR deposition in extracardiac tissue with positive finding of ⁹⁹ᵐTc-labelled pyrophosphate scintigraphy
Group 3: positive finding of ⁹⁹ᵐTc-labelled pyrophosphate scintigraphy without confirmation of pathological TTR deposition

Kumamoto University:
Number of ATTRwt-CM Diagnosed Cases and Diagnosis Method [2]

Deep Dive

Dx increasing also ex-Japan, e.g., see UK data

Go to Deep Dive

ALXN: ATTR Amyloidosis: Epidemiology Dossier. Elissa Wilker & Shona Fang. September 2021. 18_ATTR Amyloidosis Epi Dossier. Citing:
Yamada T, Takashio S, Arima Y, Nishi M, Morioka M, Hirakawa K, et al. Clinical characteristics and natural history of wild-type transthyretin amyloid cardiomyopathy in Japan. ESC Heart Fail. 2020;7(5):2829-37.

Unmet Needs

Notes: PRO = patient-reported outcomes

Rintell, D., Heath, D., Braga Mendendez, F. et al. Patient and family experience with transthyretin amyloid cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN) amyloidosis: results of two focus groups. Orphanet J Rare Dis 16, 70 (2021). https://doi.org/10.1186/s13023-021-01706-7.
ALXN: 08_210201_ALXN2060_Diagnostic summary; treatment guideline by Japanese Circulation Society. Compare ALXN internal: market research December 2020. 04_ALXN2060_UMN, PROPEL.

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