Treatment With Tafamidis Slows Disease Progression in Early-Stage Transthyretin Cardiomyopathy

Sultan, Marla B.; Gundapaneni, Balarama; Schumacher, Jennifer; Schwartz, Jeffrey H.

doi:10.1177/1179546817730322

Cited by 34 publications

(30 citation statements)

References 14 publications

(25 reference statements)

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“…Liver transplantation, and recently, gene silencing have been employed successfully to prevent hepatic production of amyloidogenic transthyretin (25). Drugs that stabilize the tetrameric form of transthyretin have been developed that prevent its dissociation into a monomeric component, thereby lowering the concentration of the amyloidogenic species and slowing further amyloid deposition (26). The use of antiinflammatory drugs, notably colchicine, to manage chronic inflammation reduces the production of the acute-phase reactant serum amyloid protein A, the precursor of AA-associated amyloidosis (27).…”

Section: Discussionmentioning

confidence: 99%

Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy

Wall

Williams

Foster

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Amyloidosis is a malignant pathology associated with the formation of proteinaceous amyloid fibrils that deposit in organs and tissues, leading to dysfunction and severe morbidity. More than 25 proteins have been identified as components of amyloid, but the most common form of systemic amyloidosis is associated with the deposition of amyloid composed of Ig light chains (AL). Clinical management of amyloidosis focuses on reducing synthesis of the amyloid precursor protein. However, recently, passive immunotherapy using amyloid fibril-reactive antibodies, such as 11-1F4, to remove amyloid from organs has been shown to be effective at restoring organ function in patients with AL amyloidosis. However, 11-1F4 does not bind amyloid in all AL patients, as evidenced by PET/CT imaging, nor does it efficiently bind the many other forms of amyloid. To enhance the reactivity and expand the utility of the 11-1F4 mAb as an amyloid immunotherapeutic, we have developed a pretargeting “peptope” comprising a multiamyloid-reactive peptide, p5+14, fused to a high-affinity peptide epitope recognized by 11-1F4. The peptope, known as p66, bound the 11-1F4 mAb in vitro with subnanomolar efficiency, exhibited multiamyloid reactivity in vitro and, using tissue biodistribution and SPECT imaging, colocalized with amyloid deposits in a mouse model of systemic serum amyloid A amyloidosis. Pretreatment with the peptope induced 11-1F4 mAb accumulation in serum amyloid A deposits in vivo and enhanced 11-1F4–mediated dissolution of a human AL amyloid extract implanted in mice.

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Section: Discussionmentioning

confidence: 99%

Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy

Wall

Williams

Foster

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…To further evaluate the effect of tafamidis on survival in earlier-stage ATTR-CM, Sultan et al compared survival data from tafamidis-treated patients in the above-mentioned open-label trial 105 with those from untreated patients with ATTR-CM in the TRACS population, 45 excluding patients with NYHA class ≥III to ensure patients had comparable baseline disease severity. 106 In this post hoc analysis, patients with either wild-type or Val122Ile (p.Val142lle) genotypes treated with tafamidis had a significantly longer time to death than untreated patients. These encouraging findings suggested the need for further exploration of tafamidis in a larger controlled clinical study of patients with ATTR-CM.…”

Section: The Tafamidis Clinical Trial Programmentioning

confidence: 79%

“…In a Phase 2, open-label trial conducted in 35 patients with early-stage wild-type ATTR-CM (ClinicalTrials.gov identifier: NCT00694161), tafamidis 20 mg daily was administered for 12 months to evaluate its safety and efficacy in altering disease progression. 105 , 106 This was the first clinical assessment of tafamidis in patients with ATTR amyloidosis nearly exclusively of the cardiac phenotype. Patients had a median disease duration of 56 months, and 97% had mild-to-moderate heart failure (NYHA class I–II).…”

Section: The Tafamidis Clinical Trial Programmentioning

confidence: 99%

Drug Discovery and Development in Rare Diseases: Taking a Closer Look at the Tafamidis Story

Burton¹,

Castaño²,

Bruno³

et al. 2021

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Rare diseases are increasingly recognized as a global public health priority. Governments worldwide currently provide important incentives to stimulate the discovery and development of orphan drugs for the treatment of these conditions, but substantial scientific, clinical, and regulatory challenges remain. Tafamidis is a first-in-class, disease-modifying transthyretin (TTR) kinetic stabilizer that represents a major breakthrough in the treatment of transthyretin amyloidosis (ATTR amyloidosis). ATTR amyloidosis is a rare, progressive, and fatal systemic disorder caused by aggregation of misfolded TTR and extracellular deposition of amyloid fibrils in various tissues and organs, including the heart and nervous systems. In this review, we present the successful development of tafamidis spanning 3 decades, marked by meticulous laboratory research into disease mechanisms and natural history, and innovative clinical study design and implementation. These efforts established the safety and efficacy profile of tafamidis, leading to its regulatory approval, and enabled post-approval initiatives that further support patients with ATTR amyloidosis.

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“…About 71.4% of patients maintained their NYHA classification at month 12, and no patient progressed to NYHA class IV or dropped ≥2 classes over the trial period. A post hoc analysis was conducted by Sultan et al 20 using the data from an observational study as a control to compare with the findings from Maurer et al A significantly longer time to death ( P value = 0.0004) was found in the patients who received tafamidis therapy compared with untreated patients, regardless of the genotypes.…”

Section: Clinical Efficacymentioning

confidence: 99%

Tafamidis: A First-in-Class Transthyretin Stabilizer for Transthyretin Amyloid Cardiomyopathy

et al. 2019

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Objective: To review the pharmacology, efficacy, and safety of the selective transthyretin inhibitor tafamidis for transthyretin amyloid cardiomyopathy (ATTR-CM). Data Sources: A PubMed (1966 to October 2019) and ClinicalTrials. gov search was conducted using the keywords tafamidis, Fx-1006A, Vyndaqel, and Vyndamax. Additional articles were identified from references. Study Selection and Data Extraction: We included English-language clinical studies evaluating the pharmacology, efficacy, or safety of tafamidis in humans for ATTR-CM. Data Synthesis: Tafamidis binds to the thyroxine-binding sites of the transthyretin tetramer and inhibits its dissociation into monomers, which is the rate-limiting step in the amyloidogenic process. Treatment with tafamidis was significantly associated with a significant reduction in mortality, lowered cardiovascular-related hospitalizations, less functional decline, and improved transthyretin stabilization compared with placebo. Additionally, tafamidis was found to have fewer adverse events, with no difference found compared with placebo. Relevance to Patient Care and Clinical Practice: Historically, symptomatic management for ATTR-CM was the only option, and the treatment of the underlying disease was limited to liver or heart transplantation. Tafamidis is the first medication approved for the treatment of ATTR-CM and the only medication that showed a reduction in all-cause mortality and cardiovascular-related hospitalizations in patients with amyloidosis. However, the role of tafamidis in patients with the New York Heart Association class III/IV heart failure or mutated transthyretin remains unclear. Conclusion: Tafamidis is an effective and safe oral medication for the treatment of the cardiomyopathy of transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.

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Treatment With Tafamidis Slows Disease Progression in Early-Stage Transthyretin Cardiomyopathy

Cited by 34 publications

References 14 publications

Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy

Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy

Drug Discovery and Development in Rare Diseases: Taking a Closer Look at the Tafamidis Story

Tafamidis: A First-in-Class Transthyretin Stabilizer for Transthyretin Amyloid Cardiomyopathy

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