Repurposing Diflunisal for Familial Amyloid Polyneuropathy

Berk, John L.; Suhr, Ole B.; Obici, Laura; Sekijima, Yoshiki; Zeldenrust, Steven R.; Yamashita, Taro; Heneghan, Michael A.; Gorevic, Peter D.; Litchy, William J.; Wiesman, Janice F.; Nordh, Erik; Corato, M. Di; Lozza, Alessandro; Cortese, Andrea; Robinson‐Papp, Jessica; Colton, Theodore; Rybin, Denis; Bisbee, Alice; Ando, Yumiko; Ikeda, Shu Ichi; Seldin, David C.; Merlini, Giampaolo; Skinner, Martha; Kelly, Jeffery W.; Dyck, Peter J.

doi:10.1001/jama.2013.283815

Cited by 576 publications

(492 citation statements)

References 40 publications

(37 reference statements)

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“…Additional support for the disease modifying effects of tafamidis comes from a subgroup analysis of the on-going extension study wherein ATTRV30M patients with very mild ATTR-FAP (NIS-LL 10) at the start of tafamidis treatment showed minimal neurologic disease progression over time with a mean (95% CI) NIS-LL change from baseline to 5.5 years of 5.3 (1.6, 9.1) points [23]. These findings are particularly salient when considering that reported disease progression rates in untreated heterogeneous ATTR-FAP populations range from $4 to 6 points per year in NIS-LL [15,22].…”

Section: Discussionmentioning

confidence: 99%

“…Several pharmacologic compounds are in various stages of development, including TTR gene silencers and amyloid fibril disrupters [7,14]. The non-specific TTR stabilizer diflunisal (a non-steroidal anti-inflammatory drug [NSAID]) has demonstrated effect in slowing ATTR-FAP progression [15]; however, it is not approved to treat ATTR-FAP and safety is a concern given the risk of serious gastrointestinal and renal side effects associated with chronic NSAID use [16]. Tafamidis, a highly specific TTR stabilizer administered orally once daily, is the only medicine approved to delay disease progression in ATTR-FAP, and is approved in the European Union and several South American and Asian countries [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years

Barroso

Judge

Ebede

et al. 2017

Amyloid

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Background: The objective of the present study was to evaluate the long-term safety and efficacy of tafamidis in treating hereditary transthyretin amyloid polyneuropathy. Methods: A prospectively planned interim analysis was conducted on an on-going, phase III, open-label extension study following an 18-month, randomized, controlled study and 12-month, open-label extension study in ATTRV30M patients and a single-arm, open-label study in non-ATTRV30M patients. Thirtyseven ATTRV30M patients received placebo for 18 months, then switched to tafamidis and 38 ATTRV30M patients and 18 non-ATTRV30M patients continuously received tafamidis from day 1, up to 6 years. Results: Long-term tafamidis was associated with a favourable safety/tolerability profile, without any unexpected adverse events. Patients initiating tafamidis at the start of the randomized study had less polyneuropathy progression versus those switching to tafamidis following 18 months of placebo and were less likely to progress to the next ambulatory stage after up to 6 years follow-up. In the patients who switched from placebo to tafamidis, polyneuropathy progression and deterioration in quality of life slowed significantly during long-term tafamidis treatment as compared with the previous placebo treatment. In non-ATTRV30M patients, some polyneuropathy progression was observed across all efficacy measures. Conclusions: These data provide evidence for the long-term (up to 6 years) safety and efficacy of tafamidis. ClinicalTrials.gov: NCT00925002

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years

Barroso

Judge

Ebede

et al. 2017

Amyloid

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“…First, LT may halt the progression of neuropathy in PortMet3047 and markedly increase survival,48 but neuropathy and cardiomyopathy may still progress in LateMet30 and forms due to other mutations, because of wild‐type TTR deposition 49. TTR kinetic stabilizers such as tafamidis17 and diflunisal50 may slow disease progression, and RNAi51 and antisense oligonucleotides52 inhibit hepatic production of TTR by post‐transcriptional gene silencing. These approaches are currently in phase 3 clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France

Mariani¹,

Lozeron

Théaudin

et al. 2015

Annals of Neurology

143

102

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ObjectiveTo compare the natural history of familial transthyretin amyloid polyneuropathies (FAP) due to the Val30Met, Ser77Tyr, and Ile107Val mutations in France with the classical Portuguese Val30Met FAP.MethodsWe compared 84 French patients with a control group of 110 Portuguese patients carrying the Val30Met mutation also living in France, all referred to and followed at the French National FAP Reference Center from 1988 to 2010. Clinical examination, functional and walking disability scores, nerve conduction studies, and muscle biopsies are reported. We also conducted a comprehensive literature review to further determine the range of phenotypic expression.ResultsBy comparison with Portuguese Val30Met FAP, French Ile107Val, Ser77Tyr, and LateVal30Met FAP showed more rapid and severe disease progression; onset of gait disorders was 3 times more rapid (p < 0.0001) and the rate of modified Norris test decline was up to 40 times faster in Ile107Val patients (p < 0.0001). Median survival was much shorter in Ile107Val and in Val30Met mutation with late onset (>50 years; LateMet30) FAP (p = 0.0005). Other distinctive features relative to the Portuguese patients included atypical clinical presentations, demyelination on nerve conduction studies (p = 0.0005), and difficult identification of amyloid deposits in nerve and muscle biopsies.InterpretationIle107Val and LateMet30 mutations are associated with the most debilitating and severe FAP ever described, with rapid onset of tetraparesis and shorter median survival. It could be explained by frequent large‐fiber involvement and associated demyelination and more severe axonal loss. These findings have major implications for genetic counseling and patient management as new therapeutic options are being assessed in clinical trials (TTR gene silencing). Ann Neurol 2015;78:901–916

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“…Multiple mechanisms underlie such a time window in the denervation of PGP 9.5 + and VIP + sudomotor nerves, including decreased synthesis or impaired axonal transport of neuropeptide at the early stage of FAP and progressive axonal degeneration as the disease burden increases 36. Furthermore, this observation raises the possibility of testing whether such alterations of functional marker VIP at the early stage are reversible as new therapeutic clinical trials for FAP are initiated 37, 38, 39…”

Section: Discussionmentioning

confidence: 99%

Sudomotor innervation in transthyretin amyloid neuropathy: Pathology and functional correlates

Chao

Huang

Chiang

et al. 2015

Annals of Neurology

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ObjectiveAutonomic neuropathy is a major component of familial amyloid polyneuropathy (FAP) due to mutated transthyretin, with sudomotor failure as a common manifestation. This study aimed to investigate the pathology and clinical significance of sudomotor denervation.MethodsSkin biopsies were performed on the distal leg of FAP patients with a follow‐up duration of 3.8 ± 1.6 years. Sudomotor innervation was stained with 2 markers: protein gene product 9.5 (PGP 9.5), a general neuronal marker, and vasoactive intestinal peptide (VIP), a sudomotor nerve functional marker, followed by quantitation according to sweat gland innervation index (SGII) for PGP 9.5 (SGIIPGP 9.5) and VIP (SGIIVIP).ResultsThere were 28 patients (25 men) with Ala97Ser transthyretin and late onset (59.9 ± 6.0 years) disabling neuropathy. Autonomic symptoms were present in 22 patients (78.6%) at the time of skin biopsy. The SGIIPGP 9.5 and SGIIVIP of FAP patients were significantly lower than those of age‐ and gender‐matched controls. The reduction of SGIIVIP was more severe than that of SGIIPGP 9.5 (p = 0.002). Patients with orthostatic hypotension or absent sympathetic skin response at palms were associated with lower SGIIPGP 9.5 (p = 0.019 and 0.002, respectively). SGIIPGP 9.5 was negatively correlated with the disability grade at the time of skin biopsy (p = 0.004), and was positively correlated with the interval from the time of skin biopsy to the time of wheelchair usage (p = 0.029).InterpretationThis study documented the pathological evidence of sudomotor denervation in FAP. SGIIPGP 9.5 was functionally correlated with autonomic symptoms, autonomic tests, ambulation status, and progression of disability. Ann Neurol 2015;78:272℃283

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Repurposing Diflunisal for Familial Amyloid Polyneuropathy

Cited by 576 publications

References 40 publications

Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years

Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years

Genotype–phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France

Sudomotor innervation in transthyretin amyloid neuropathy: Pathology and functional correlates

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