Advances in the treatment of hereditary transthyretin amyloidosis: A review

Abstract

Introduction: Amyloid transthyretin amyloidosis (ATTR) is a progressive and often fatal disease caused by the buildup of mutated (hereditary ATTR [hATTR]; also known as ATTR variant [ATTRv]) or normal transthyretin (wild-type ATTR) throughout the body. Two new therapies-inotersen, an antisense oligonucleotide therapy, and patisiran, an RNA interference therapy-received marketing authorization and represent a significant advance in the treatment of amyloidosis. Herein, we describe the clinical presentation of ATTR, commonly used procedures in its diagnosis, and current treatment landscape for ATTR, with a focus on hATTR.

Methods: A PubMed search from 2008 to September 2018 was conducted to review the literature on ATTR.

Results: Until recently, there have been few treatment options for polyneuropathy of hATTR. Inotersen and patisiran substantially reduce the amyloidogenic precursor protein transthyretin and have demonstrated efficacy in patients with early- and late-stage disease and in slowing or improving neuropathy progression. In contrast, established therapies, such as liver transplantation, typically reserved for patients with early-stage disease, and tafamidis, indicated for the treatment of early-stage disease in Europe, or diflunisal, a nonsteroidal anti-inflammatory drug that is used off-label, are associated with side effects and/or unclear efficacy in certain patient populations. Thus, inotersen and patisiran are positioned to be the preferred therapeutic modalities.

Conclusions: Important differences between inotersen and patisiran, including formulation, dosing, requirements for premedications, and safety monitoring, require an understanding and knowledge of each treatment for informed decision making.

Keywords: amyloid; hATTR; inotersen; patisiran; transthyretin amyloidosis.

Figure 1

Diagnostic workup for polyneuropathy (a) and cardiomyopathy (b) when ATTR amyloidosis is suspected (Carvalho et al., 2015; Castano et al., 2016; Coelho et al., 2008; Conceicao et al., 2016; Donnelly & Hanna, 2017; Galat et al., 2016; Geller, Singh, Alexander, Mirto, & Falk, 2017; Gertz, 2017, 2018; Gillmore et al., 2016; Nativi‐Nicolau & Maurer, 2018; Ruberg & Berk, 2012; Sperry et al., 2018). ^99mTc, technetium‐99m; AL, amyloid light chain; ATTR, amyloid transthyretin; CMR, cardiac magnetic resonance imaging; DPD, 3,3‐diphosphono‐1,2‐propanodicarboxylic acid; ECG, electrocardiogram; echo, echocardiogram; hATTR, hereditary amyloid transthyretin; MRI, magnetic resonance imaging; PYP, pyrophosphate; TTR, transthyretin; wtATTR, wild‐type amyloid transthyretin. Panel A: ^a“Red‐flag” manifestations include progressive symmetric peripheral sensorimotor neuropathy plus ≥ 1 of the following: bilateral carpal tunnel syndrome (especially family history), orthostatic hypotension, erectile dysfunction, irregular heartbeat (especially atrial fibrillation), conduction blocks (including bundle branch blocks), ventricular wall thickening with preserved ejection fraction and absence of left ventricular dilation, chronic diarrhea, severe constipation, diarrhea/constipation, unintentional weight loss, albuminuria, mild azotemia, dark floaters, lumbar spinal stenosis, and/or spontaneous distal biceps tendon rupture. Modified with permission from Gertz (2017)

Figure 2

Mechanism of amyloid formation. ^aRate‐limiting step involves dissociation of tetrameric TTR to a pair of dimeric TTRs, which rapidly progresses to monomeric TTR. ^bMisfolded protein can form a variety of toxic intermediates, including amyloid fibrils (shown here); small oligomers; and amorphous aggregates. TTR, transthyretin. Modified with permission from Bulawa et al. (2012)