Current and future treatment of amyloid neuropathies

Abstract

Amyloid neuropathies of acquired or genetic origin are disabling and life-threatening, until recently there were few treatment options available. Poor prognosis is related to progressive neuropathy and associated, although often underdiagnosed, cardiac involvement in specific transthyretin (TTR) gene mutations. Recent progress has modified prognosis and management of amyloid neuropathies. In TTR-familial amyloidosis with polyneuropathy, major changes have occurred over the last 30 years: better knowledge concerning genetics, phenotypes and epidemiology, and the advent of possible treatments. Liver transplantation, first performed in 1990, stopped disease progression, thus doubling survival in early onset V30M patients. More recently tetramer stabilizers (Tafamidis and Diflunisal) showed a significant reduction of progression of neuropathic scores; Tafamidis is now recommended in Stage I patients. Two multicentric clinical trials are now ongoing to evaluate TTR gene silencing by antisense Oligonucleotides (ASO) or siRNA. In the near future we should have new therapeutical options for patients with amyloid neuropathy.

Keywords::

• antisense oligonucleotides
• diflunisal
• familial amyloid polyneuropathy
• liver transplantation
• patisiran
• tafamidis
• therapeutic patient education program
• transthyretin
• TTR gene silencing
• TTR tetramer stabilizer

Financial & competing interests disclosure

D Adams received consulting honoraria from Isis, Alnylam, received fees from Pfizer for participating to symposium, is participating as principal investigator for trials with ISIS and Alnylam. C Cauquil received honoraria from Pfizer for participating to Symposium. M Theaudin received honoraria from Pfizer for participating to Symposium. MS Slama received consulting fees from Folder’X/Pfizer, Isis and Alnylam and is part of ongoing Clinical Trials with these firms as CoInvestigator. 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.

Key issues

• Liver transplantation allows to modify natural course of the TTR-FAP. The best results are obtained in V30M patients of early onset by stopping progression of the neuropathy and doubling the survival.

• Liver transplantation has significant limitations including contra-indication in old patients, the progression of the disease and the poor survival in late onset V30M and non-V30M TTR-FAP the morbidity due to immunosuppression and the rate of mortality in the first year after LT.

• Oral TTR tetramer stabilizers tafamidis and diflunisal have shown efficiency in two Phase III clinical trials. Tafamidis showed a reduction of rate of patients progressing Neuropathy score in an 18 months study with early stage of V30M TTR-FAP in efficacy evaluable population allowing Marketing authorization in EMA for stage 1. Diflunisal showed the ability to reduce the rate of progression of composite neuropathy score in a 2 year study among patients with varied mutations and stages of the disease. Both are considered as able to slow down the progression of the disease.

• Preliminary clinical studies with TTR gene silencing by Antisense oligonucleotides, RNAi indicate that they reduce production of both mutant and WT-TTR.

• Long term impact of TTR stabilizer on survival and cardiopathy are required.

• Ongoing research in patients at more advanced stages of the disease should identify the specific clinical applications of TTR gene silencing strategy for TTR-FAP.

• Future research for eyes, should identify the specific clinical applications of medicine developed to reduce burden amyloid and remove amyloid deposits.

Notes