Evolving landscape in the management of transthyretin amyloidosis

Abstract

Transthyretin (TTR) amyloidosis (ATTR amyloidosis) is a multisystemic, multigenotypic disease resulting from deposition of insoluble ATTR amyloid fibrils in various organs and tissues. Although considered rare, the prevalence of this serious disease is likely underestimated because symptoms can be non-specific and diagnosis largely relies on amyloid detection in tissue biopsies. Treatment is guided by which tissues/organs are involved, although therapeutic options are limited for patients with late-stage disease. Indeed, enthusiasm for liver transplantation for familial ATTR amyloidosis with polyneuropathy was dampened by poor outcomes among patients with significant neurological deficits or cardiac involvement. Hence, there remains an unmet medical need for new therapies. The TTR stabilizers tafamidis and diflunisal slow disease progression in some patients with ATTR amyloidosis with polyneuropathy, and the postulated synergistic effect of doxycycline and tauroursodeoxycholic acid on dissolution of amyloid is under investigation. Another therapeutic approach is to reduce production of the amyloidogenic protein, TTR. Plasma TTR concentration can be significantly reduced with ISIS-TTR(Rx), an investigational antisense oligonucleotide-based drug, or with patisiran and revusiran, which are investigational RNA interference-based therapeutics that target the liver. The evolving treatment landscape for ATTR amyloidosis brings hope for further improvements in clinical outcomes for patients with this debilitating disease.

Keywords: Amyloidosis; RNA interference; cardiomyopathies; polyneuropathies; therapeutics; transthyretin.

Figure 1.

Timeline of access to anti-amyloid therapies for patients with hereditary transthyretin amyloidosis with polyneuropathy. OLE = open-label extension; Ph = phase; Vyndaqel = trade name for tafamidis.

Figure 2.

Current treatment pathway for patients with ATTR amyloidosis with polyneuropathy. Disease is classified in stages according to Coutinho et al. (51) at initial diagnosis. ^a First-line anti-amyloid therapy is initiated according to stage of the disease and approval of the medicine in the country, in parallel with symptomatic treatment, to prevent disease progression and improve patient quality of life. Currently approved treatments may stabilize disease (liver transplantation (53)), or slow progression of the disease (tafamidis, diflunisal (52,96)); treatment options are very limited for patients with stage II and III. The pathway described is followed irrespective of TTR gene mutation at stage I, and initiation of treatment for non-neurologic symptoms (renal, cardiac) may also need to be considered in affected patients. ^bMostly performed in patients with early-onset FAP with Val30Met mutation. Approval based on pivotal phase II/III study in patients with FAP stage I with Val30Met mutation (96) and an open-label phase II study in patients with FAP stage I with non-Val30Met mutations (97). ^cDiflunisal should be used with caution in patients with a history of gastrointestinal bleeding or ulceration, renal impairment, or heart failure. ^dPreliminary data from a phase II open-label extension study with patisiran, a RNAi investigational agent, demonstrate a mean 2.5-point decrease in mNIS + 7 score; this treatment has the potential to halt progression of neuropathy (105). Of ongoing recruiting trials, none specify the acceptance of patients with late-stage (FAP stage > II) ATTR amyloidosis with polyneuropathy (clinicaltrials.gov, accessed on 15 May 2015). ^eThere are limited published data for diflunisal treatment of patients with FAP stage III (4 patients with PND stage IV received diflunisal in the Diflunisal Trial (52)). ^fLiver transplant is proposed according to eligible criteria (health status, no evolutive cancer, compliance in the anti-rejection treatment). Best outcome recorded for early-onset (≤ 50 years of age) Val30Met patients. ATTR = transthyretin amyloidosis; FAP = familial amyloidosis with polyneuropathy; PND = polyneuropathy disability; TTR = transthyretin.