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      A Review of Tafamidis for the Treatment of Transthyretin-Related Amyloidosis

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          Abstract

          Transthyretin (TTR)-related amyloidosis (ATTR) is a devastating disease which affects a combination of organs including the heart and the peripheral nerves, and which has a fatal outcome if not treated within a average of 10 years. Tafamidis, or 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid, selectively binds to TTR with negative cooperativity and kinetically stabilizes wild-type native TTR and mutant TTR; tafamidis therefore has the potential to halt the amyloidogenic cascade initiated by TTR tetramer dissociation, monomer misfolding, and aggregation. The first tafamidis trial, Fx-005, evaluated the effect of 18 months of tafamidis treatment (20 mg once daily) on disease progression, as well as assessing its safety in TTR-FAP Val30Met patients. The secondary objective of this trial was to study the pharmacodynamic stabilization of mutated TTR. Tafamidis proved effective in reducing the progress of neuropathy, and in maintaining the nutritional status and quality of life of stage 1 (able to walk without support) Val3OMet TTR-FAP patients. Furthermore, TTR stabilization was achieved in more than 90% of patients. An extension study, Fx-006, was conducted to determine the long-term safety and tolerability of tafamidis and to assess the efficacy of the drug on slowing disease progression. No significant safety or tolerability issues were noticed. Taken together, the results from both trials indicated that the beneficial effects of tafamidis were sustained over a 30-month period and that starting treatment early is desirable. Results are expected from an extended open-label study but data that have already been presented show that long-term use of tafamidis in Val30Met patients is associated with reduced progression in polyneuropathy. Tafamidis was initially approved for commercial use in Europe in 2011 and has since been approved for use in Japan, Mexico, and Argentina where it is used as a first-line treatment option for patients with early-stage TTR-FAP. Patients should be carefully followed at referral centers to ascertain the individual response to treatment. In cases of discontinuation, liver transplantation and enrollment in clinical trials of novel drugs aimed mostly toward suppression of TTR production are options.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s40120-015-0031-3) contains supplementary material, which is available to authorized users.

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          Most cited references 29

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          Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort.

          Because there are little satisfactory data on change in severity of diabetic polyneuropathy (DP) over time from study of population-based cohorts of diabetic patients in epidemiologic surveys of DP, it is difficult to predict outcome or morbidity or to identify risk factors; it is also difficult to estimate statistical power for use in controlled clinical trials. In this longitudinal study of almost 200 patients from the Rochester Diabetic Neuropathy Study (RDNS) cohort, we assess which symptoms, clinical examinations, tests, or combinations of examinations and tests (composite scores) are best used as minimal criteria for the diagnosis of DP and as a quantitative measure of severity of DP. An abnormality (> or = 97.5th percentile) of a composite score that included the Neuropathy Impairment Score of the lower limbs plus seven tests (NIS(LL)+7 tests), was a better minimal criteria for DP than clinical judgment alone or previously published minimal criteria. First, it provided a more comprehensive assessment of neuropathic impairment. Second, it avoided the overestimated frequency of DP when the minimal criteria for DP was any one or two abnormalities from multiple measurements. Minimal criteria using nerve conduction and reduced heart beat response to deep breathing identified approximately twice as many patients with DP than did clinical examination and vibration detection threshold using CASE IV. This difference could be used to subclassify state 1 DP. Although various individual measures of DP, for example, vibration detection threshold (as evaluated by CASE IV and the 4, 2, and 1 stepping algorithm [see text]), were good measures of worsening, the composite score NIS(LL)+7 tests (assessing neuropathic impairment) was much better at showing monotone worsening. Using this composite score, the average diabetic patient in the RDNS worsened by 0.34 points per year, whereas patients with diabetic polyneuropathy worsened by 0.85 points per year. On the assumption that a therapeutic agent may prevent worsening of DP but not cause improvement, controlled clinical trials of patients with DP would need to be conducted for a period of 3 years to achieve a meaningful change of 2 NIS points (the level of abnormality considered by a Peripheral Nerve Society consensus group to be clinically meaningful).
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            Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity.

            Several misfolding diseases commence when a secreted folded protein encounters a partially denaturing microenvironment, enabling its self assembly into amyloid. Although amyloidosis is modulated by numerous environmental and genetic factors, single point mutations within the amyloidogenic protein can dramatically influence disease phenotype. Mutations that destabilize the native state predispose an individual to disease; however, thermodynamic stability alone does not reliably predict disease severity. Here we show that the rate of transthyretin (TTR) tetramer dissociation required for amyloid formation is strongly influenced by mutation (V30M, L55P, T119M, V122I), with rapid rates exacerbating and slow rates reducing amyloidogenicity. Although these rates are difficult to predict a priori, they notably influence disease penetrance and age of onset. L55P TTR exhibits severe pathology because the tetramer both dissociates quickly and is highly destabilized. Even though V30M and L55P TTR are similarly destabilized, the V30M disease phenotype is milder because V30M dissociates more slowly, even slower than wild type (WT). Although WT and V122I TTR have nearly equivalent tetramer stabilities, V122I cardiomyopathy, unlike WT cardiomyopathy, has nearly complete penetrance-presumably because of its 2-fold increase in dissociation rate. We show that the T119M homotetramer exhibits kinetic stabilization and therefore dissociates exceedingly slowly, likely explaining how it functions to protect V30MT119M compound heterozygotes from disease. An understanding of how mutations influence both the kinetics and thermodynamics of misfolding allows us to rationalize the phenotypic diversity of amyloid diseases, especially when considered in concert with other genetic and environmental data.
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              Pathology of early- vs late-onset TTR Met30 familial amyloid polyneuropathy.

               N Hattori,  M Sugiura,  K Mori (2004)
              Late-onset type I familial amyloid polyneuropathy (FAP TTR Met30) cases unrelated to endemic foci in Japan show clinical features setting them apart from early-onset cases in endemic foci. To compare pathologic features between the early- and late-onset types. Pathologic findings in FAP TTR Met30 with onset before age 50 in relation to endemic foci (11 cases) were compared with those in 11 later-onset cases unrelated to endemic foci. Sural nerve biopsy specimens showed predominantly small-fiber loss in early-onset cases; variable fiber size distribution, axonal sprouting, and relatively preserved unmyelinated fibers characterized late-onset cases. Autopsy cases representing both groups showed amyloid deposition throughout the length of nerves and in sympathetic and sensory ganglia, but amounts were greater in early-onset cases. Amyloid deposition and neuronal cell loss were greater in sympathetic than dorsal root ganglia in early-onset cases; the opposite was true in late-onset cases. Size assessment of remaining neurons in these ganglia suggested predominant loss of small neurons in early-onset cases but loss of neurons of all sizes in late-onset cases. Transthyretin-positive, Congo red-negative amorphous material was more conspicuous in nerves from late- than early-onset cases. In extraneural sites, amyloid was more conspicuous in thyroid and kidney from early-onset cases and in heart and hypophysis from late-onset cases. In early-onset cases, cardiac amyloid deposition was prominent in the atrium and subendocardium but was conspicuous throughout the myocardium in late-onset cases. The pathology of early- and late-onset FAP TTR Met30 correlated well with differences in clinical findings.
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                Author and article information

                Contributors
                mwaddingtoncruz@gmail.com
                Journal
                Neurol Ther
                Neurol Ther
                Neurology and Therapy
                Springer Healthcare (Cheshire )
                2193-8253
                2193-6536
                15 August 2015
                15 August 2015
                December 2015
                : 4
                : 2
                : 61-79
                Affiliations
                [ ]Amyloidosis Research and Treatment Center (CEPARM), University Hospital (HUCFF), Federal University of Rio de Janeiro, Rio De Janeiro, Brazil
                [ ]Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN USA
                Article
                31
                10.1007/s40120-015-0031-3
                4685869
                26662359
                © The Author(s) 2015
                Categories
                Review
                Custom metadata
                © Springer Healthcare 2015

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