At least 38 different human protein precursors of amyloid fibrils are known—some are produced at the site of amyloid formation (localized), and some circulate in the blood to deposit in a variety of tissues and organs (systemic). [2]

Exclusively localized amyloid deposits have been associated with at least 19 protein types, while at least 14 protein types (and many more variants) appear to be consistently associated with systemic amyloidosis. [1]

Interestingly, however, at least 3 protein types (most notably AL/AH, amyloidosis derived from immunoglobulin light or heavy chain, respectively, amyloidosis derived from β2 microglobulin, Aβ2M), and ATTR can occur as either localized or systemic deposits. [1]

• Amyloid deposits are formed from globular, soluble proteins, which undergo misfolding and, subsequently, aggregate into insoluble fibrils, leading to progressive organ damage [2]
• Amyloid formation involves a combination of several factors, including: a sustained increase in the concentration of proteins with an acquired or hereditary mutation, or wild-type proteins with an intrinsic propensity to misfold, or a proteolytic remodeling of a wild-type protein into an amyloidogenic fragment [2]
• Protein folding is under the control of quality control systems, which operate at the cellular (as well as extracellular) level and promptly eliminate misfolded proteins—it is only when these quality control systems are overwhelmed by the conditions listed above, or are reduced in their capacity by aging, that amyloidogenesis occurs [2]
• Several amyloidoses are associated with aging, including systemic (ATTRwt, AApoAIV) and localized forms (atrial and seminal vesicle amyloid); development of these amyloidoses may be associated with age-related reduced effectiveness of the protein folding quality control systems [2]
• With aging, the TTR tetramer becomes less stable, resulting in the release of misfolded intermediates that ultimately form amyloid deposits, mainly in the heart; ATTRwt is most commonly reported in men >age 75, and autopsy data have shown TTR deposits in the myocardium of ~25% of individuals >80 years old; while extracardiac amyloid deposits are largely limited to the vasculature, amyloid associated with carpal tunnel syndrome and lumbar spine stenosis may also be detected [2]
   

To estimate the number of total prevalent cases of ATTR-CM, the number of people diagnosed with CHF was first determined using the following sources, as cited in the DRG Chronic Heart Failure Epidemiology Report

• US: CDC, 2018 (NHANES, 2013-2016)
• France: Peretti, 2013 (DHNS, 2008-2009)
• Germany: Stork, 2017 (German SHI, 2011)
• Italy: Maggioni, 2016 (ARNO study, 2008-2012)
• Spain: Farre, 2016
• United Kingdom: Conrad, 2017 (CPRD, 2014)
• Japan: Okura, 2008 (Sado Heart Failure Study, 2003)
• China: Guo, 2016; Zhang, 2017

The number of diagnosed CHF patients with preserved ejection fraction (HFpEF) were then determined using the following sources, as cited in the DRG Chronic Heart Failure Epidemiology Report

• US: Steinberg, 2012 (2005-2010)
• EU5: Piccini, 2017 (Italian GP database study, 2002-2013); Gasperoni, 2017 (2015)
• Japan: Tsuji, 2017 (CHART-2 study 2015-2016)
• China: Guo, 2016; Zhang, 2017

Data from a Spanish study was used to estimate the proportion of HFpEF patients that had ATTRwt identified on ⁹⁹ᵐTc-DPD scintigraphy

• All markets: Gonzalez-Lopez, 2015

The ratio of ATTRwt to ATTRm in a Japanese study was used to estimate the number of HFpEF patients that had ATTRm

• All markets: Winburn, 2019 (Japan Medical Data Vision Database, 2010-2018)

• The diagnosed prevalence of CHF with preserved ejection fraction is well established in the markets under study leading to a robust base population from which to further estimate the ATTR-CM population.
• Estimates include diagnosed prevalent cases of HFpEF that have been diagnosed with ATTR-CM and those that have not been diagnosed with ATTR-CM. While not all of the estimated number of people with ATTR-CM will ever be diagnosed and treated as such, the advancements in diagnostic techniques and emerging TTR-modifying treatments will certainly lead to an increase in the number of diagnosed and treated ATTR-CM patients over time.
• The study used to estimate the number of HFpEF patients with ATTRwt was based in a hospitalized patient population. It was assumed that the proportion of hospitalized HFpEF patients with ATTRwt would be the same as non-hospitalized HFpEF patients.

Estimated ATTR-CM prevalence due to either ATTRwt or ATTRv from Jan. 2010-Sept. 2018 using the Japan MDV database, which includes inpatient/outpatient hospital records [2]
 

• ATTR-CM definitions were based on ≥1 ICD-10 code(s) and no specific ATTR code; a less conservative approach vs. other studies requiring ≥2 codes and thus it may include some patients who were evaluated but ultimately not diagnosed with ATTR-CM
• Alexion interpreted the representativeness of these results with caution, given the lack of a specific ATTR code, no information on tissue biopsy and demographics, and clinical characteristics that were inconsistent with prior information on ATTRwt patients

a. Broad includes familial amyloidosis, secondary amyloidosis, amyloid CM, generalized amyloidosis, CA, senile amyloidosis, senile TTR amyloidosis, amyloidosis, primary amyloidosis, and primary systemic amyloidosis

b. Narrow includes ICD-10 codes for CA, senile amyloidosis, senile TTR amyloidosis, amyloidosis, primary amyloidosis, and primary systemic amyloidosis

US estimates of ATTR-CM are likewise limited; using IBM MarketScan Commercial data and Medicare Supplemental databases, US prevalence and incidence are estimated as follows:

The proportion of ATTRwt increased from less than 3% of all cases in the period 1987–2009 to 14% in the period 2010–2015 and to 25% from 2016-2019, with an increasing number of cases over time