Updated Evaluation of the Safety, Efficacy and Tolerability of Tafamidis in the Treatment of Hereditary Transthyretin Amyloid Polyneuropathy

Abstract

Hereditary amyloid transthyretin (ATTRv) amyloidosis is a devastating hereditary multisystemic disease affecting predominantly the peripheral and autonomic nervous systems and the heart. ATTRv is caused by mutations in the transthyretin (TTR) gene, leading to extracellular deposition of amyloid fibrils in multiple organs including the peripheral nervous system. If untreated, it is associated with a fatal outcome 10–12 years after disease onset. Different treatments are available for patients with ATTRv polyneuropathy. Tafamidis 20 mg is approved in Europe since 2011 for early stages of ATTRv polyneuropathy (stage I – able to walk without support) and it is recommended as first-line therapy in these patients. Tafamidis is a TTR stabilizer that selectively binds to TTR and kinetically stabilizes both wild-type native TTR and mutant TTR. Consequently, it has the potential to prevent the amyloidogenic cascade initiated by TTR tetramer dissociation into its monomers and subsequent misfolding and aggregation. Tafamidis is an oral drug, taken once per day, with proved efficacy, safety and tolerability in ATTRv-PN patients as demonstrated in different clinical trials and open-label extension studies as well in clinical practice setting with around 10 years of experience. Tafamidis treatment started in the earliest stages of the disease is associated with better neurological outcomes. A multidisciplinary approach in referral centres is also fundamental for monitoring patients to assess individual response to treatment.

Keywords:

• hereditary amyloid transthyretin amyloidosis
• transthyretin
• tafamidis
• familial amyloid polyneuropathy
• amyloidosis
• TTR stabilizer

Abbreviations

ATTReuNet, European Network for ATTR-PN; ATTRv, hereditary amyloid transthyretin (ATTRv) amyloidosis; ATTRv-PN, hereditary amyloid transthyretin amyloidosis with polyneuropathy; CNS, central nervous system; CSF, cerebrospinal fluid; EE, efficacy-evaluable; FAP, familial amyloid polyneuropathy; HRDB, Hear rate deep breathing; ITT, intent to treat; LT, liver transplantation; mBMI, modified body mass index; NIS, Neuropathy Impairment Score; NIS-LL, Neuropathy Impairment Score in the Lower Limbs; Norfolk QOL-DN, Norfolk Quality of Life-Diabetic Neuropathy questionnaire; NYHA, New York Heart Association; P-T, placebo-tafamidis; QST, quantitative sensory test; RNA, ribonucleic acid; THAOS, Transthyretin Amyloidosis Outcome Survey; T-T, tafamidis–tafamidis; TTR, transthyretin; Σ3 NTSF, summated 3 nerve tests that assess small fiber function; Σ5 NCS nds, summated 5 nerve conduction study parameters composite score; Σ7 NTs, summated 7 nerve tests that assess large fiber function.

Disclosure

The authors report no conflicts of interest in this work.