Disease‐modifying pharmacological agents for transthyretin (TTR)‐related familial amyloid polyneuropathy (FAP) have become available in the last decade, but evidence on their efficacy and safety is limited. This review focuses on disease‐modifying pharmacological treatment for TTR‐related and other FAPs, encompassing amyloid kinetic stabilisers, amyloid matrix solvents, and amyloid precursor inhibitors.
To assess and compare the efficacy, acceptability, and tolerability of disease‐modifying pharmacological agents for familial amyloid polyneuropathies (FAPs).
On 18 November 2019, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We reviewed reference lists of articles and textbooks on peripheral neuropathies. We also contacted experts in the field. We searched clinical trials registries and manufacturers’ websites.
We included randomised clinical trials (RCTs) or quasi‐RCTs investigating any disease‐modifying pharmacological agent in adults with FAPs.
Disability due to FAP progression was the primary outcome. Secondary outcomes were severity of peripheral neuropathy, change in modified body mass index (mBMI), quality of life, severity of depression, mortality, and adverse events during the trial.
Data collection and analysis
We followed standard Cochrane methodology.
The review included four RCTs involving 655 people with TTR‐FAP. The manufacturers of the drugs under investigation funded three of the studies. The trials investigated different drugs versus placebo and we did not conduct a meta‐analysis.
One RCT compared tafamidis with placebo in early‐stage TTR‐FAP (128 randomised participants). The trial did not explore our predetermined disability outcome measures. After 18 months, tafamidis might reduce progression of peripheral neuropathy slightly more than placebo (Neuropathy Impairment Score (NIS) in the lower limbs; mean difference (MD) ‐3.21 points, 95% confidential interval (CI) ‐5.63 to ‐0.79; P = 0.009; low‐certainty evidence). However, tafamidis might lead to little or no difference in the change of quality of life between groups (Norfolk Quality of Life‐Diabetic Neuropathy (Norfolk QOL‐DN) total score; MD ‐4.50 points, 95% CI ‐11.27 to 2.27; P = 0.19; very low‐certainty evidence). No clear between‐group difference was found in the numbers of participants who died (risk ratio (RR) 0.65, 95% CI 0.11 to 3.74; P = 0.63; very low‐certainty evidence), who dropped out due to adverse events (RR 1.29, 95% CI 0.30 to 5.54; P = 0.73; very low‐certainty evidence), or who experienced at least one severe adverse event during the trial (RR 1.16, 95% CI 0.37 to 3.62; P = 0.79; very low‐certainty evidence).
One RCT compared diflunisal with placebo (130 randomised participants). At month 24, diflunisal might reduce progression of disability (Kumamoto Score; MD ‐4.90 points, 95% CI ‐7.89 to ‐1.91; P = 0.002; low‐certainty evidence) and peripheral neuropathy (NIS plus 7 nerve tests; MD ‐18.10 points, 95% CI ‐26.03 to ‐10.17; P < 0.001; low‐certainty evidence) more than placebo. After 24 months, changes from baseline in the quality of life measured by the 36‐Item Short‐Form Health Survey score showed no clear difference between groups for the physical component (MD 6.10 points, 95% CI 2.56 to 9.64; P = 0.001; very low‐certainty evidence) and the mental component (MD 4.40 points, 95% CI ‐0.19 to 8.99; P = 0.063; very low‐certainty evidence). There was no clear between‐group difference in the number of people who died (RR 0.46, 95% CI 0.15 to 1.41; P = 0.17; very low‐certainty evidence), in the number of dropouts due to adverse events (RR 2.06, 95% CI 0.39 to 10.87; P = 0.39; very low‐certainty evidence), and in the number of people who experienced at least one severe adverse event (RR 0.77, 95% CI 0.18 to 3.32; P = 0.73; very low‐certainty evidence) during the trial.
One RCT compared patisiran with placebo (225 randomised participants). After 18 months, patisiran reduced both progression of disability (Rasch‐built Overall Disability Scale; least‐squares MD 8.90 points, 95% CI 7.00 to 10.80; P < 0.001; moderate‐certainty evidence) and peripheral neuropathy (modified NIS plus 7 nerve tests ‐ Alnylam version; least‐squares MD ‐33.99 points, 95% CI ‐39.86 to ‐28.13; P < 0.001; moderate‐certainty evidence) more than placebo. At month 18, the change in quality of life between groups favoured patisiran (Norfolk QOL‐DN total score; least‐squares MD ‐21.10 points, 95% CI ‐27.20 to ‐15.00; P < 0.001; low‐certainty evidence). There was little or no between‐group difference in the number of participants who died (RR 0.61, 95% CI 0.21 to 1.74; P = 0.35; low‐certainty evidence), dropped out due to adverse events (RR 0.33, 95% CI 0.13 to 0.82; P = 0.017; low‐certainty evidence), or experienced at least one severe adverse event (RR 0.91, 95% CI 0.64 to 1.28; P = 0.58; low‐certainty evidence) during the trial.
One RCT compared inotersen with placebo (172 randomised participants). The trial did not explore our predetermined disability outcome measures. From baseline to week 66, inotersen reduced progression of peripheral neuropathy more than placebo (modified NIS plus 7 nerve tests ‐ Ionis version; MD ‐19.73 points, 95% CI ‐26.50 to ‐12.96; P < 0.001; moderate‐certainty evidence). At week 65, the change in quality of life between groups favoured inotersen (Norfolk QOL‐DN total score; MD ‐10.85 points, 95% CI ‐17.25 to ‐4.45; P < 0.001; low‐certainty evidence). Inotersen may slightly increase mortality (RR 5.94, 95% CI 0.33 to 105.60; P = 0.22; low‐certainty evidence) and occurrence of severe adverse events (RR 1.48, 95% CI 0.85 to 2.57; P = 0.16; low‐certainty evidence) compared to placebo. More dropouts due to adverse events were observed in the inotersen than in the placebo group (RR 8.57, 95% CI 1.16 to 63.07; P = 0.035; low‐certainty evidence).
There were no studies addressing apolipoprotein AI‐FAP, gelsolin‐FAP, and beta‐2‐microglobulin‐FAP.
Evidence on the pharmacological treatment of FAPs from RCTs is limited to TTR‐FAP. No studies directly compare disease‐modifying pharmacological treatments for TTR‐FAP. Results from placebo‐controlled trials indicate that tafamidis, diflunisal, patisiran, and inotersen may be beneficial in TTR‐FAP, but further investigations are needed. Since direct comparative studies for TTR‐FAP will be hampered by sample size and costs required to demonstrate superiority of one drug over another, long‐term non‐randomised open‐label studies monitoring their efficacy and safety are needed.
Plain language summary
Drug treatment for familial amyloid polyneuropathy
What is the aim of this review?
The aim of this review was to assess whether drugs to treat familial amyloid polyneuropathies (FAPs) reduce disability due to nerve damage, reduce the severity of nerve damage, and improve nutritional status, quality of life, and depression. We also reviewed evidence on side effects.
Studies of drug treatments for people with FAP are so far limited to transthyretin‐FAP (also called TTR‐FAP). Four trials have compared a drug with a placebo (an inactive, dummy compound), but none have directly compared drugs with each other. The studies provided evidence that all four drugs studied (tafamidis, diflunisal, patisiran, and inotersen) are probably of benefit for people with TTR‐FAP, but it remains possible that their true effects are different from these results. As research comparing drugs with each other is limited by study size required to demonstrate the superiority of one drug and costs, studies monitoring their effects for longer are needed.
What was studied in the review?
FAPs are a group of hereditary progressive conditions in which insoluble protein deposits (fibrils) affect mainly peripheral nerves (nerves outside the brain and spinal cord). Fibrils are deposited because they are made up of genetically abnormal protein that does not fold properly. This process also occurs in many other organs including the heart, kidneys, and eyes, thus these disorders are complex. The type of protein fibril deposited and the exact genetic defect determine the type of FAP. TTR‐FAP is the most common FAP by far. Although liver transplantation was the only treatment, done in highly selected cases, drugs which may affect the disease course have recently become available for people with TTR‐FAP.
What are the main results of the review?
The review authors found four relevant studies, which involved 655 adults with TTR‐FAP.
In one study, people with early‐stage TTR‐FAP received tafamidis or placebo for 18 months. Disability was not measured. The evidence suggested that tafamidis may reduce both the proportion of people with progression of peripheral neuropathy and the mean change (worsening) of nerve damage (based on a score of strength and sensation) compared to placebo. It is uncertain whether tafamidis has an effect on quality of life and the number of deaths, dropouts due to harmful effects or any severe side effects.
Evidence from a 24‐month study in people with TTR‐FAP suggested that compared to placebo, diflunisal may slightly decrease disability due to FAP progression and lessen worsening of peripheral neuropathy. It is uncertain whether diflunisal has an effect on quality of life and number of deaths, dropouts due to side effects, and people who experience severe side effects.
Results from an 18‐month study in people with TTR‐FAP suggested that compared to placebo, patisiran probably decreases disability due to FAP progression, and lessens worsening of peripheral neuropathy. Quality of life may decline slightly less with patisiran than placebo. Patisiran may lead to little or no difference in mortality, dropouts due to side effects or number of people experiencing severe side effects.
In the fourth study, people with TTR‐FAP received inotersen or placebo for 66 weeks. Disability was not measured. This study indicated that inotersen probably reduces worsening of peripheral neuropathy, but may have little effect on the change in quality of life compared to placebo. Inotersen may be associated with numbers of adverse events above the placebo rate, illustrated by an increase in the number of dropouts due to side effects compared to placebo. There was little or no difference in mortality or number of people experiencing severe side effects.
The review authors did not find any study addressing drug therapy for people with other types of FAP.
Three of the four studies were funded by the manufacturer of the drug investigated.
How up‐to‐date is this review?
The evidence is current to November 2019.