Changing paradigm in the treatment of amyloidosis: From disease-modifying drugs to anti-fibril therapy

Abstract

Cardiac amyloidosis is a rare, debilitating, and usually fatal disease increasingly recognized in clinical practice despite patients presenting with non-specific symptoms of cardiomyopathy. The current standard of care (SoC) focuses on preventing further amyloid formation and deposition, either with anti-plasma cell dyscrasia (anti-PCD) therapies in light-chain (AL) amyloidosis or stabilizers of transthyretin (TTR) in transthyretin amyloidosis (ATTR). The SoC is supplemented by therapies to treat the complications arising from organ dysfunction; for example, heart failure, arrhythmia, and proteinuria. Advancements in treatments have improved patient survival, especially for those whose disease is detected and for whom treatment is initiated at an early stage. However, there still are many unmet medical needs, particularly for patients with severe disease for whom morbidity and mortality remain high. There currently are no approved treatments to reverse amyloid infiltration and deplete the amyloid fibrils already deposited in organs, which can continue to cause progressive dysfunction. Anti-fibril therapies aimed at removing the deposited fibrils are being investigated for safety and efficacy in improving outcomes for patients with severe disease. However, there is no clinical evidence yet that removing deposited amyloid fibrils will improve organ function, thereby improving quality of life or extending life. Nevertheless, anti-fibril therapies are actively being investigated in clinical trials to evaluate their ability to complement and synergize with current SoC.

Renale Amyloidosen

“…In präklinischen und klinischen Studien konnte gezeigt werden, dass mithilfe von Antikörpern wie CAEL-101 (Anselamimab) bei Leichtkettenamyloid und dem gegen das Serum-Amyloid-P gerichtete AT-03 Amyloidablagerungen zumindest teilweise abgebaut werden konnten [46,47]. Einige Substanzen zeigten bisher nur im experimentellen Ansatz, jedoch zunächst nicht in der Klinik, Erfolge (Birtamimab).…”

Risk stratification in transthyretin-related cardiac amyloidosis

“…For this reason, an early diagnosis and a prompt start of this specific treatment allows to obtain a significant benefit in terms of survival and quality of life. On the other hand, patients with delayed diagnosis and advanced disease are unlikely going to benefit from these therapies ( 82 ). This is especially true in older patients with higher risk of competitive non-cardiovascular causes of mortality.…”

Advancing Care for AA Amyloidosis with Biomarker-Based Staging

“…The past decade has been remarkable for the introduction of novel treatments of systemic amyloidosis, and although AA amyloidosis has lagged behind AL and TTR, there are grounds for optimism about further trials. 11 Current approaches with the potential for benefit include passive administration of monoclonal antibodies targeting existing amyloid deposits with a view to enhancing their clearance. One of these agents, birtamimab, is currently undergoing phase 3 trials in AL amyloidosis but theoretically has the potential to be of therapeutic benefit in AA type too because it has been shown to bind to epitopes derived from SAA and cryptic epitopes exposed by misfolding of Ig light chains into AL amyloid.…”