tafamidis and Polyneuropathies

Topics: Adult; Amyloid Neuropathies, Familial; Bayes Theorem; Benzoxazoles; Female; Humans; Male; Middle Aged; Network Meta-Analysis; Oligonucleotides; Polyneuropathies; RNA, Small Interfering

Autonomic dysfunction is a very common, early and distressing aspect of hereditary transthyretin (ATTR) amyloidosis leading to significant loss of quality of life and morbidity for patients. Although the clinical variability of ATTR has been well characterized as neuropathic, cardiac or mixed phenotype, the extent of autonomic involvement remains poorly understood. Despite the fact that the autonomic nervous system has not been specifically evaluated in any of the clinical trials of tafamidis, and that, for some primary and secondary endpoints used in these trials, the behavior cannot be separated from non-autonomic items, an attempt was made to use published material to indirectly access the efficacy of tafamidis in treating dysautonomia.. Literature review summarizing the results of primary and secondary endpoints related to the autonomic features used in the original tafamidis trials, the post hoc publications, and real-world data, on the effect of tafamidis on autonomic dysfunction in patients with ATTR amyloidosis.. There is some evidence that indirectly demonstrates that tafamidis is safe and could slow or arrest the progression of autonomic neuropathy in patients with ATTR amyloidosis, in addition to its well-described effects to ameliorate sensory-motor peripheral neuropathy.. Although the current evidence is scarce, tafamidis might be effective in arresting the progression of autonomic neuropathy in patients with ATTR amyloidosis. Tafamidis might be more effective at the early stage of the disease; however, individual responses must be monitored.

Topics: Amyloid Neuropathies, Familial; Autonomic Nervous System Diseases; Benzoxazoles; Humans; Polyneuropathies

Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a progressive, life-threatening disease. Until recently, tafamidis was the only approved pharmacotherapy. Patisiran significantly improved polyneuropathy and quality of life (QoL) in the phase III APOLLO trial. In the absence of direct comparisons, this analysis aimed to evaluate the comparative efficacy of tafamidis and patisiran in hATTR amyloidosis with polyneuropathy.. Randomized controlled trial evidence for tafamidis was identified by systematic literature review. Indirect treatment comparisons were performed using the standard pairwise Bucher method for endpoints used in both APOLLO and the tafamidis Fx-005 trial: change from baseline in Neuropathy Impairment Score-lower limbs (NIS-LL), Norfolk QoL-Diabetic Neuropathy questionnaire (QoL-DN), NIS-LL response, and mBMI vs. placebo. Inter-trial population differences were assessed by sensitivity analysis.. The base-case analysis (FAP Stage 1 APOLLO patients vs. intent-to-treat Fx-005 population) suggested patisiran had a greater treatment effect vs. tafamidis for all endpoints, with significant improvements in mean change in NIS-LL (-5.49) and QoL-DN (-13.10) from baseline to Month 18. Similar trends were observed in all sensitivity analyses.. In the absence of direct comparisons, this analysis suggests patisiran has a greater treatment effect than tafamidis in patients with hATTR amyloidosis with polyneuropathy.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Humans; Polyneuropathies; Quality of Life; Randomized Controlled Trials as Topic; RNA, Small Interfering; Surveys and Questionnaires

Transthyretin amyloidosis with polyneuropathy (ATTR-PN), a rare and progressive hereditary disorder, results from mutations in the gene coding for the transthyretin (TTR) protein that destabilize the protein's tetrameric structure. In over 40 countries worldwide, tafamidis (Vyndaqel

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Clinical Trials as Topic; Disease Progression; Drug Approval; Humans; Mutation; Polyneuropathies; Prealbumin; Quality of Life

Tafamidis, a non-NSAID highly specific transthyretin stabilizer, delayed neurologic disease progression as measured by Neuropathy Impairment Score-Lower Limbs (NIS-LL) in an 18-month, double-blind, placebo-controlled randomized trial in 128 patients with early-stage transthyretin V30M familial amyloid polyneuropathy (ATTRV30M-FAP). The current post hoc analyses aimed to further evaluate the effects of tafamidis in delaying ATTRV30M-FAP progression in this trial.. Pre-specified, repeated-measures analysis of change from baseline in NIS-LL in this trial (ClinicalTrials.gov NCT00409175) was repeated with addition of baseline as covariate and multiple imputation analysis for missing data by treatment group. Change in NIS-LL plus three small-fiber nerve tests (NIS-LL + Σ3) and NIS-LL plus seven nerve tests (NIS-LL + Σ7) were assessed without baseline as covariate. Treatment outcomes over the NIS-LL, Σ3, Σ7, modified body mass index and Norfolk Quality of Life-Diabetic Neuropathy Total Quality of Life Score were also examined using multivariate analysis techniques.. Neuropathy progression based on NIS-LL change from baseline to Month 18 remained significantly reduced for tafamidis versus placebo in the baseline-adjusted and multiple imputation analyses. NIS-LL + Σ3 and NIS-LL + Σ7 captured significant treatment group differences. Multivariate analyses provided strong statistical evidence for a superior tafamidis treatment effect.. These supportive analyses confirm that tafamidis delays neurologic progression in early-stage ATTRV30M-FAP.. NCT00409175.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Disease Progression; Female; Humans; Male; Middle Aged; Polyneuropathies; Prealbumin; Treatment Outcome

TTR aggregation causes hereditary transthyretin (TTR) polyneuropathy (ATTRv-PN) in individuals with destabilised TTR variants. ATTRv-PN can be treated with ligands that bind TTR and prevent aggregation. One such ligand, tafamidis, is widely approved to treat ATTRv-PN. We explore how TTR stabilisation markers relate to clinical efficacy in 210 ATTRv-PN patients taking tafamidis.. TTR concentration in patient plasma was measured before and after tafamidis treatment using assays for native or combined native + non-native TTR. TTR tetramer dissociation kinetics, which are slowed by tafamidis binding, were also measured.. Native TTR levels increased by 56.8% while combined native + non-native TTR levels increased by 3.1% after 24 months of tafamidis treatment, implying that non-native TTR decreased. Accordingly, the fraction of native TTR increased from 0.54 to 0.71 with tafamidis administration. Changes in native and non-native TTR levels were uncorrelated with clinical response to tafamidis. TTR tetramer dissociation generally slowed to an extent consistent with ∼40% of TTR being tafamidis-bound. Male non-responders had a lower extent of binding.. Native and non-native TTR concentration changes cannot be used as surrogate measures for therapeutic efficacy. Also, successful tafamidis therapy requires only moderate TTR stabilisation. Male patients may benefit from higher tafamidis doses.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Humans; Male; Polyneuropathies; Prealbumin

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Humans; Polyneuropathies; Prealbumin; RNA, Small Interfering

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Humans; Polyneuropathies; Prealbumin; RNA, Small Interfering

Hereditary amyloidosis related to transthyretin V30M (hATTR V30M) is a progressive length-dependent sensorimotor axonal neuropathy. We aimed to compare the disease progression of treated [liver transplantation (LT) or tafamidis] versus untreated patients with hATTR V30M.. A total of 81 patients with hATTR V30M were included: 27 untreated, 25 treated with LT and 29 undergoing tafamidis treatment. Neuropathy was assessed at baseline, 12, 24 and 36 months after study entry. We evaluated disease stage, modified polyneuropathy disability (mPND) score and a composite neurophysiological score comprised of sensory and motor conduction parameters. The effect of treatment on disease progression was analysed using linear mixed-effects modelling.. At baseline, patients from the untreated group were older (P < 0.01) and those in the LT group had longer disease duration than those in the tafamidis group (P < 0.05). Gender, mPND and motor scores at study entry were equal in the three groups; however, the untreated group had lower sensory scores compared with the tafamidis group (P < 0.01). During the 3-year follow-up period, progression to stage II of the disease was seen only in the untreated group. The progression on mPND, sensory and motor scores was significantly higher in the untreated patients. When treated groups were compared, the LT group had lower rates of composite neurophysiological score progression. However, the sensory score outcome was similar between tafamidis responders and LT patients.. Both LT and tafamidis therapy modified the natural history of hATTR V30M by reducing neuropathy progression.

Topics: Adult; Aged; Amyloid Neuropathies, Familial; Benzoxazoles; Disease Progression; Female; Humans; Liver Transplantation; Male; Middle Aged; Neural Conduction; Polyneuropathies; Time Factors; Treatment Outcome

Transthyretin is a transport protein for thyroxine and retinol-binding protein, which is mainly produced in the liver. Hereditary transthyretin-related amyloidosis (ATTR) is caused by one of more than 120 point mutations in the transthyretin gene and inherited as an autosomal dominant disorder. The mutations cause a reduction in the stability of the tetrameric structure and dissociation into dimers and monomers as the rate-limiting step in amyloid formation is promoted. Clinical symptoms are related to the specific mutation, the age of onset, the ethnic background and environmental factors. The nerves, heart, eyes and intestines are paticularly affected. In general, two different age peaks are observed. An accumulation occurs at the age of 25-35 years with predominantly neurological symptoms. The second peak occurs between the ages of 55 and 65 years and is commonly associated with cardiac involvement with or without polyneuropathy. Characteristic for the nerve involvement are the symmetrical small fiber polyneuropathy and an autonomous polyneuropathy. The typical picture of cardiac involvement is biventricular hypertrophy with diastolic dysfunction finally resulting in restrictive cardiomyopathy. In addition to the symptomatic treatment for the alleviation of individual organ disorders, for many years liver transplantation was the only causal therapy of ATTR amyloidosis. Since 2011 tafamidis, a highly selective transthyretin stabilizer, has been the first drug approved for treatment of ATTR resulting in reduction of the progression of polyneuropathic symptoms. Other therapeutic approaches to reduce amyloid formation (patisiran and inotersen) effectively reduce transthyretin blood levels, leading to a reduction in polyneuropathy and improved quality of life. The approval is expected in 2018.

Topics: Aged; Amyloid; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Drug Approval; Humans; Middle Aged; Mutation; Polyneuropathies; Prealbumin; Quality of Life