Disease Course (Progression)

Studies Reporting on Survival in ATTR in Japan

japan

Notes: COD = cause of death; dx = diagnosis; LT = liver transplant

Glossary:

6-minute walk test (6MWT), a performance-based test that evaluates an individual’s functional exercise capacity by measuring the distance walked in 6 minutes over a flat, hard surface

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.
Yamashita T, Ueda M, Nomura T, Okazaki T, Okada M, Tsuda Y, et al. Natural history and long-term effects of variant protein reduction in non-V30M ATTR amyloidosis. Neurology. 2019;93(16):714-6.
Ohya Y, Okamoto S, Tasaki M, Ueda M, Jono H, Obayashi K, et al. Manifestations of transthyretin-related familial amyloidotic polyneuropathy: long-term follow-up of Japanese patients after liver transplantation. Surg Today. 2011;41(9):1211-8.

Tracking Disease Progression: Impact of Atrial Fibrillation

Prevalence and survival impact of atrial fibrillation in patients with transthyretin cardiac amyloidosis; analysis from a large cohort

Patients are living longer with treatment and an increased risk of A-fib due to age
Impact on survival has not been analyzed but should have an impact
A-fib was most frequently treated with beta blockers, calcium antagonists, amiodarone; anticoagulants are used but thrombotic events still occur so patients may be at increased risk due to amyloids

Multivariant analysis

Variables independently associated with death: diabetes, higher age or Nt-proBNP, lower LVEF or eGFR

Results

Baseline characteristics:

N = 1157 patients
87.4% male, mean age 75.7 years, 83% wild-type
Median follow-up 23.2 months
AF at baseline: 574 (49.6%)
No AF at baseline: 583 (51.4%)
- 187 (16.1% developed AF during follow-up
- 396 (34.2%) remained in sinus rhythm

Conclusions:

A-fib is very common in patients with ATTR cardiac amyloidosis (49.7% at diagnosis)
1 in 3 ATTR-CM patients will develop A-fib during a median follow-up of 4 years
Patients with A-fib have worst prognosis, but A-fib is not an independent predictor of mortality
Most frequent strategy to control A-fib is rate control; rhythm control seems to have low success

*Very low numbers, both limits above 1

Notes: A-fib = atrial fibrillation; eGFR = estimated glomerular filtration rate; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal pro b-type natriuretic peptide

ALXN: ISA 2020 Clinical Report_ATTR. Presentation: Adrian Rivas Perez- Prevalence and survival impact of atrial fibrillation in patients with transthyretin cardiac amyloidosis. Analysis from a large cohort.

Tracking Disease Progression: Changes in Amyloid Load

In addition to specific cardiac biomarkers, modern non-invasive imaging techniques such as CMR are available today [1]; CMR is the most sensitive tool to quantify and track changes in amyloid load over time [2]

Notes: AUC = area under the curve; ECV = extracellular volume fraction; eGFR = estimated glomerular filtration rate; NAC = National Amyloidosis Centre (UK); NT-proBNP = N-terminal pro b-type natriuretic peptide; NYHA = New York Heart Association

1 Yilmaz, A., Bauersachs, J., Bengel, F. et al. Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK). Clin Res Cardiol 110, 479–506 (2021). https://doi.org/10.1007/s00392-020-01799-3

2 ALXN: 14_Differentiation workshop Pre-reads.

Tracking Disease Progression: Serum TTR Levels

Robust biomarker to explore the in vivo effects of increased TTR stability, based on:
- Destabilizing mutations are often associated with below‐normal serum TTR concentrations in ATTRv patients;
- ATTRwt patients tend to have low‐normal to below‐normal levels as well;
- In ATTRwt‐CM patients, below‐normal TTR levels (<3.2 μM or 18 mg/dL) are associated with a worse prognosis than normal levels;
- Heterozygous T119M (super‐stabilizing mutation) carriers have 20% higher TTR concentrations compared to the general healthy adult population;
- Treatment with a TTR stabilizer increases circulating TTR concentrations in patients with ATTR amyloidosis
However, TTR concentrations are affected by several factors, including age, gender nutritional status, infections, inflammation—not to be used in isolation
Need of a validation in the general population and better characterization in affected patients (RBP4 and other biomarkers to be investigated)
While TTR stabilizers aim at maintaining / increasing serum TTR levels, TTR Knock-down agents aim at suppressing them, with good results in ATTR-PN

In a review of patients with biopsy-proven ATTRwt (n=101), one study showed that each rise of 1 mg/dL in serum TTR is associated with an up to 11% reduced risk of mortality [2]

Notes: 6MWT = 6-minute walk test, a performance-based test that evaluates an individual’s functional exercise capacity by measuring the distance walked in 6 minutes over a flat, hard surface; RBP4 = retinol binding protein-4

ALXN: 14_Differentiation workshop Pre-reads. Citing: Lane T, et al. Circulation 2019;140:16–26.
Hanson JLS, et al. Use of Serum Transthyretin as a Prognostic Indicator and Predictor of Outcome in Cardiac Amyloid Disease Associated With Wild-Type Transthyretin. Circ Heart Fail. 2018 Feb;11(2):e004000. doi: 10.1161/CIRCHEARTFAILURE.117.004000. PMID: 29449366; PMCID: PMC5819619 & TTR Matters. bridgebio. Available at https://www.ttrmatters.com/?gclid=Cj0KCQiAip-PBhDVARIsAPP2xc3ESnLG0POFCyQa35XQWUIqtwlMY94z7cq1x17zYekoXGv2ZMafGnQaAivEEALw_wcB#attr-cm-disease-progression. Accessed January 13, 2022.