TTR kinetic stabilizers and TTR gene silencing: a new era in therapy for familial amyloidotic polyneuropathies

ABSTRACT

Introduction: Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a rare disease with autosomal dominant transmission due to a point mutation of the TTR gene. By removing the main source of systemic mutant TTR, liver transplantation (LT) has become the reference therapy of this severe and fatal polyneuropathy of adult-onset, stopping disease progression in subgroup of patients. Recently, new therapeutic strategies have emerged, which intend to stabilize TTR or to silence the TTR gene. Amongst them, the TTR kinetic stabilizer tafamidis is the first drug approved in the EU.

Areas covered: We shall review the natural history of TTR-FAP and the best indications for LT. Data on the efficacy, safety and tolerability of the TTR kinetic stabilizers, tafamidis and diflunisal, have been reviewed, from the pivotal Phase III clinical trials published in PubMed medical journals or presented at international meetings. We will review the ongoing phase III clinical trials of TTR gene silencing with RNAi therapeutics and ASO published in clinicaltrialgov.

Expert opinion: Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease. Only tafamidis got marketing authorization. We are waiting for results of the 2 phase III clinical trials of TTR gene silencing in varied stages of the disease.

KEYWORDS:

• ALN-TTR02 patisiran
• diflunisal
• familial amyloidotic polyneuropathy
• ISIS TTR-Rx
• liver transplantation
• Mab GSK2398852
• tafamidis
• Transthyretin
• TTR gene silencing
• TTR kinetic stabilizer

Article highlights

• Indications of LT, which is the gold standard therapy for TTR-FAP, have been better defined and restricted to patients without high pejorative risk factors.

• TTR stabilizers tafamidis and diflunisal are disease-modifying therapies allowing slow progression of sensory motor neuropathy.

• Only tafamidis has marketing authorization in Europe and in some other countries and in patients at early stage of the disease (stage 1); diflunisal is off-label.

• TTR gene silencing by RNAi or OAS is being assessed in two clinical trials of phase 3 in TTR-FAP.

• RNAi therapy allows to knock down both mutant and wild-type TTR and to stop progression of the disease in an open label study.

This box summarizes key points contained in the article.

Declaration of Interest

D Adams has been a consultant for Pfizer and Alnylam, been on the speakers bureaus for Pfizer and has received honoraria for advisory board for GSK. C Cauquil has expert testimony from pfizer, and received an invitation to congress from Pfizer. M Théaudin has received speaker honoraria from Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.