Disease management strategies for transthyretin familial amyloid polyneuropathy

The management of TTR-FAP has expanded significantly in recent years; with the availability of pharmacotherapeutic alternatives, liver transplantation is no longer the only treatment option [26]. A comprehensive care package and a multidisciplinary approach are required to manage this multisystem disease. Targeted therapy is essential in the first instance to prevent further production of amyloid deposits. Thereafter, symptomatic therapy of sensorimotor and autonomic polyneuropathy and cardiac, renal, and ocular injury is required [6,10]. Finally, genetic counselling to patients and relatives is recommended [37].

Prior to the pharmacotherapy era and as early as 1990, orthotopic liver transplant was the standard of care for patients with TTR-FAP [10,26,38]. A 20-year analysis of survival data from the Familial Amyloidotic Polyneuropathy World Transplant Registry of 2044 liver transplant patients reported a 20-year survival rate of 55.3% after treatment. Multivariate analysis revealed modified body mass index, onset of disease (<50 years of age), disease duration before liver transplant, and TTR mutation type (Val30Met vs non-Val30Met) as independent and significant factors for better survival outcomes (i.e., patients with an early onset, Val30Met mutation and shorter duration of the disease have improved prognosis) [39^▪▪]. In addition, a large cohort study of 215 consecutive patients who were followed up for 18 years at the French NRC identified five pejorative factors for survival after liver transplant: polyneuropathy disability score score not less than III, orthostatic hypotension, New York Heart Association (NYHA) functional class more than I, QRS complex duration at least 120 ms and thickened interventricular septum [40]. Risks can be computed using the online calculator by the French Referral Center for FAP and Other Rare Peripheral Neuropathies (NNERF) [41]. However, liver transplant is not readily accessible to many patients. ATTReuNET members reported an average wait of up to 1 year in France, Spain, Italy, and Sweden, increasing to 2–3 years for patients in Germany, the Netherlands, Portugal, and Cyprus (liver transplant not performed in Turkey).

Whereas liver transplant removes the main source of mutated TTR[42–44], it does not prevent progression of cardiac disease because the wild-type TTR may continue to further expand existing amyloid deposits in the heart [45^▪▪,46]. Therefore, continued scrutiny of the cardiac system is warranted, as some patients will develop atrioventricular blocks or infiltrative cardiomyopathy several years or decades later; a combined heart and liver transplant may be recommended in selected patients with non-Val30Met mutations and cardiomyopathy [47,48▪,49–51]. However, ocular and central nervous system involvements often progress and/or appear after liver transplant due to the local synthesis of mutated TTR in retinal epithelium and coroid plexus [52–54].

Tafamidis is a first-in-class therapy that slows the progression of TTR amyloidogenesis by stabilizing the mutant TTR tetramer, thereby preventing its dissociation into monomers and amyloidogenic and toxic intermediates [55,56]. Tafamidis is currently indicated in Europe for the treatment of TTR amyloidosis in adult patients with stage I symptomatic polyneuropathy to delay peripheral neurological impairment [57].

In an 18-month, double-blind, placebo-controlled study of patients with early-onset Val30Met TTR-FAP, tafamidis was associated with a 52% lower reduction in neurological deterioration (P = 0.027), a preservation of nerve function, and TTR stabilization versus placebo [58^▪▪]. However, only numerical differences were found for the coprimary endpoints of neuropathy impairment [neuropathy impairment score in the lower limb (NIS-LL) responder rates of 45.3% tafamidis vs 29.5% placebo; P = 0.068] and quality of life scores [58^▪▪]. A 12-month, open-label extension study showed that the reduced rates of neurological deterioration associated with tafamidis were sustained over 30 months, with earlier initiation of tafamidis linking to better patient outcomes (P = 0.0435) [59▪]. The disease-slowing effects of tafamidis may be dependent on the early initiation of treatment. In an open-label study with Val30Met TTR-FAP patients with late-onset and advanced disease (NIS-LL score >10, mean age 56.4 years), NIS-LL and disability scores showed disease progression despite 12 months of treatment with tafamidis, marked by a worsening of neuropathy stage in 20% and the onset of orthostatic hypotension in 22% of patients at follow-up [60▪].

Tafamidis is not only effective in patients exhibiting the Val30Met mutation; it also has proven efficacy, in terms of TTR stabilization, in non-Val30Met patients over 12 months [61]. Although tafamidis has demonstrated safe use in patients with TTR-FAP, care should be exercised when prescribing to those with existing digestive problems (e.g., diarrhoea, faecal incontinence) [60▪].

Diflunisal is a nonsteroidal anti-inflammatory drug (NSAID) that, similar to tafamidis, slows the rate of amyloidogenesis by preventing the dissociation, misfolding, and misassembly of the mutated TTR tetramer [62,63]. Off-label use has been reported for patients with stage I and II disease, although diflunisal is not currently licensed for the treatment of TTR-FAP.

Evidence for the clinical effectiveness of diflunisal in TTR-FAP derives from a placebo-controlled, double-blind, 24-month study in 130 patients with clinically detectable peripheral or autonomic neuropathy [64▪]. The deterioration in NIS scores was significantly more pronounced in patients receiving placebo compared with those taking diflunisal (P = 0.001), and physical quality of life measures showed significant improvement among diflunisal-treated patients (P = 0.001). Notable during this study was the high rate of attrition in the placebo group, with 50% more placebo-treated patients dropping out of this 2-year study as a result of disease progression, advanced stage of the disease, and varied mutations.

One retrospective analysis of off-label use of diflunisal in patients with TTR-FAP reported treatment discontinuation in 57% of patients because of adverse events that were largely gastrointestinal [65]. Conclusions on the safety of diflunisal in TTR-FAP will depend on further investigations on the impact of known cardiovascular and renal side-effects associated with the NSAID drug class [66,67].

The management of symptoms associated with sensory-motor neuropathy and autonomic dysfunction should be initiated immediately following diagnosis and should be tailored to the individual patient [10]. Symptomatic treatment may include painkillers, antidiarrhoeal drugs, treatment of symptomatic orthostatic hypotension, diuretics for patients with cardiac failure, prophylactic pacemaker implantation for severe cardiac conduction disorders [32^▪▪], or vitrectomy/trabeculectomy for the treatment for ocular amyloidosis or glaucoma, respectively [10].

A number of new treatments for TTR-FAP are currently in phase II or III development. Posttranscriptional gene silencing is an approach that aims to inhibit the hepatic production of mutant and nonmutant TTR using small interfering RNAs [68^▪▪] or antisense oligonucleotides [6]. Two phase III trials are ongoing, involving ALN-TTR02, an RNA interference ({"type":"clinical-trial","attrs":{"text":"NCT01960348","term_id":"NCT01960348"}}NCT01960348) [69], and ISIS 420915, an antisense oligonucleotide ({"type":"clinical-trial","attrs":{"text":"NCT01737398","term_id":"NCT01737398"}}NCT01737398) [70]. The removal of amyloid deposits has also been demonstrated in mouse models using a synergistic combination of doxycycline and tauroursodeoxycholic acid (TUDCA) [71], with ongoing clinical trials seeking to replicate these findings in patients ({"type":"clinical-trial","attrs":{"text":"NCT01855360","term_id":"NCT01855360"}}NCT01855360, {"type":"clinical-trial","attrs":{"text":"NCT01171859","term_id":"NCT01171859"}}NCT01171859) [72,73]. Preliminary data from the latter, a small phase II study, are promising, showing stabilization of neuropathy scores over 12 months of treatment with no clinical progression of cardiac involvement [74]. Immunotherapy produces a regulated immune response against the specific amyloid protein by enhancing the clearance of these deposits with monoclonal antibodies. Currently, a number of antibodies [e.g., monoclonal antibody NEOD001; the combination of a serum amyloid P (SAP) depleter (GSK2315698) and an anti-SAP antibody (GSK2398852)] are undergoing testing in patients with various forms of amyloidosis ({"type":"clinical-trial","attrs":{"text":"NCT01707264","term_id":"NCT01707264"}}NCT01707264, {"type":"clinical-trial","attrs":{"text":"NCT01777243","term_id":"NCT01777243"}}NCT01777243) [75,76].