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

Cruz, Márcia Waddington; Benson, Merril D.

doi:10.1007/s40120-015-0031-3

Cited by 63 publications

(40 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our findings that TTR amyloid deposition is highly prevalent in aging and OA‐affected joints (Akasaki et al ., ) and that TTR promotes inflammation and cartilage in mouse models suggest that TTR deposition contributes to the progression of OA. Recent advances in the understanding of mechanisms of TTR aggregation (Eisele et al ., ) led to the discovery of TTR stabilizers such as tafamidis or diflunisal (Adamski‐Werner et al ., ; Obici & Merlini, ) and tafamidis have been approved for the treatment of familial amyloidotic polyneuropathy caused by amyloid formed by mutant TTR (Coelho et al ., ; Waddington Cruz & Benson, ). Evaluation of these drugs in preclinical models of OA will be the next step in establishing proof‐of‐concept that prevention of TTR aggregation is a potential therapeutic approach for OA.…”

Section: Discussionmentioning

confidence: 99%

Transthyretin deposition promotes progression of osteoarthritis

et al. 2017

View full text Add to dashboard Cite

SummaryDeposition of amyloid is a common aging‐associated phenomenon in several aging‐related diseases. Osteoarthritis (OA) is the most prevalent joint disease, and aging is its major risk factor. Transthyretin (TTR) is an amyloidogenic protein that is deposited in aging and OA‐affected human cartilage and promotes inflammatory and catabolic responses in cultured chondrocytes. Here, we investigated the role of TTR in vivo using transgenic mice overexpressing wild‐type human TTR (hTTR‐TG). Although TTR protein was detected in cartilage in hTTR‐TG mice, the TTR transgene was highly overexpressed in liver, but not in chondrocytes. OA was surgically induced by destabilizing the medial meniscus (DMM) in hTTR‐TG mice, wild‐type mice of the same strain (WT), and mice lacking endogenous Ttr genes. In the DMM model, both cartilage and synovitis histological scores were significantly increased in hTTR‐TG mice. Further, spontaneous degradation and OA‐like changes in cartilage and synovium developed in 18‐month‐old hTTR mice. Expression of cartilage catabolic (Adamts4, Mmp13) and inflammatory genes (Nos2, Il6) was significantly elevated in cartilage from 6‐month‐old hTTR‐TG mice compared with WT mice as was the level of phospho‐NF‐κB p65. Intra‐articular injection of aggregated TTR in WT mice increased synovitis and significantly increased expression of inflammatory genes in synovium. These findings are the first to show that TTR deposition increases disease severity in the murine DMM and aging model of OA.

show abstract

Section: Discussionmentioning

confidence: 99%

Transthyretin deposition promotes progression of osteoarthritis

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Until recently there has been no specific therapy for hereditary transthyretin amyloidosis. Progression of the disease has usually lead to death within 5-15 years whether due to the ravages of peripheral and autonomic neuropathy or cardiac arrhythmias or congestive heart failure [12]. In addition the increasing presentation of wild type ATTR with predominately a clinical cardiac phenotype has emphasised the need for specific therapy to prevent or halt the continuous deposition of amyloid.…”

Section: Discussionmentioning

confidence: 99%

“…To date two lines of specific therapy for ATTR have been explored. Small molecule therapeutics (diflunisal and tafamidis) which affect the stability of the serum amyloid fibril precursor TTR have been shown to delay progression of amyloid neuropathy and tafamidis has now been found to alter the progression of ATTR cardiomyopathy as measured by all causes of death or hospitalisation [12][13][14][15].…”

Section: Discussionmentioning

confidence: 99%

Inotersen therapy of transthyretin amyloid cardiomyopathy

Dasgupta

Rissing

Smith

et al. 2019

Amyloid

View full text Add to dashboard Cite

Background: Cardiomyopathy is a major cause of death in patients with systemic transthyretin amyloidosis. Long term effect of therapy designed to inhibit hepatic production of the amyloid precursor has not been established in cardiomyopathy. The purpose of this study was to evaluate the long term safety and efficacy of transthyretin specific antisense oligonucleotide therapy, inotersen, in transthyretin cardiomyopathy. Methods: Patients with hereditary or wildtype transthyretin cardiomyopathy (NYHA I-III) with an LV wall thickness ! 1.3 cm and clinical evidence of congestive heart failure were eligible for this single centre, open label protocol. Safety and cardiac structural and functional parameters were prospectively studied. Results: As of October 2018, 33 subjects have entered the study. Twenty have completed 1 year, 16 have completed 2 years, and 14 have completed three years. At the 2 year time point, mean LV mass decreased by 8.4% as measured by MRI, and exercise tolerance increased by 20.2 metres as measured by 6 minute walk test. Further positive indicators were noted at 3 years, with LV mass decreasing by 11.4% and 6MWT increasing by 16.2 metres. Conclusion: Long term treatment of amyloid cardiomyopathy with inotersen is safe and effective in inhibiting progression and potentially reversing amyloid burden.

show abstract

“…Tafamidis is presently approved in the European Union and several countries in Latin America and Asia, with several hundred patients treated clinically to date [11,12]. …”

Section: Introductionmentioning

confidence: 99%

Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy

Cruz

Amass

Keohane

et al. 2016

Amyloid

Self Cite

View full text Add to dashboard Cite

Transthyretin hereditary amyloid polyneuropathy, also traditionally known as transthyretin familial amyloid polyneuropathy (ATTR-FAP), is a rare, relentless, fatal hereditary disorder. Tafamidis, an oral, non-NSAID, highly specific transthyretin stabilizer, demonstrated safety and efficacy in slowing neuropathy progression in early-stage ATTRV30M-FAP in a 1.5-year, randomized, double-blind, placebo-controlled trial, and 1-year open-label extension study, with a second long-term open-label extension study ongoing. Subgroup analysis of the effectiveness of tafamidis in the pivotal study and its open-label extensions revealed a relatively cohesive cohort of patients with mild neuropathy (i.e. Neuropathy Impairment Score for Lower Limbs [NIS-LL] ≤ 10) at the start of active treatment. Early treatment with tafamidis for up to 5.5 years (≥1 dose of tafamidis meglumine 20 mg once daily during the original trial or after switching from placebo in its extension) resulted in sustained delay in neurologic progression and long-term preservation of nutritional status in this cohort. Mean (95% CI) changes from baseline in NIS-LL and mBMI were 5.3 (1.6, 9.1) points and −7.8 (−44.3, 28.8) kg/m2 × g/L at 5.5 years, respectively. No new safety issues or side effects were identified. These data represent the longest prospective evaluation of tafamidis to date, confirm a favorable safety profile, and underscore the long-term benefits of early intervention with tafamidis. Trial Registration: ClincalTrials.gov Identifier: NCT00409175, NCT00791492, and NCT00925002.

show abstract

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

Cited by 63 publications

References 35 publications

Transthyretin deposition promotes progression of osteoarthritis

Transthyretin deposition promotes progression of osteoarthritis

Inotersen therapy of transthyretin amyloid cardiomyopathy

Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy

Contact Info

Product

Resources

About