Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis.
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ABSTRACT:
SUBMITTER: Merlini G
PROVIDER: S-EPMC3838581 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A phase 2, open-label study in 21 patients with non-Val30Met and non-Val122Ile hereditary transthyretin amyloidosis showed that tafamidis (20 mg daily for 12 months) stabilized these transthyretin variants. We assessed cardiac amyloid infiltration and cardiac abnormalities in this same study population. At baseline, median age was 64.3 years, 11 patients were in NYHA class II, 13 had conduction abnormalities, 14 N-terminal pro-hormone brain natriuretic peptide concentrations >300 pg/ml, and 17 interventricular septal thickness >12 mm. Mean (SD) left ventricular ejection fraction was 60.3% (9.96). Patients with normal heart rate variability increased from 4/19 at baseline to 8/19 at month 12 (p < 0.05). Cardiac biomarkers remained stable. Although four patients had increases in interventricular septal thickness ? 2 mm, the remainder had stable septal wall thickness. There were no clinically relevant changes in mean echocardiographic/electrocardiographic variables and no safety concerns.
| S-EPMC4382536 | biostudies-literature
Project description:IntroductionHereditary transthyretin amyloidosis (ATTRv amyloidosis) is a clinically heterogeneous disease caused by mutations in the transthyretin (TTR) gene. The most common mutation, Val30Met, can manifest as an early- or late-onset disease.MethodsThe Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease and asymptomatic patients with TTR mutations. This is a descriptive analysis of symptomatic patients with ATTRv Val30Met amyloidosis with late- (age at least 50 years) vs. early-onset (age less than 50 years) disease in THAOS (data cutoff August 1, 2019).ResultsOf 1389 patients with ATTRv Val30Met amyloidosis, 491 (35.3%) had late-onset disease. Compared with early-onset, patients with late-onset were more likely to be male (66.2% vs. 53.6%) and have a longer mean (standard deviation [SD]) time from onset to diagnosis (3.8 [3.4] vs. 2.7 [4.1] years). Late-onset disease was associated with more severe neurological impairment at enrollment (median [10th, 90th percentile] derived Neuropathy Impairment Score in the Lower Limbs, 25.0 [4.0, 69.3] vs. 8.0 [0, 54.8]; Neurologic Composite Score, 42.0 [2.0, 155.0] vs. 21.0 [0, 102.0]). Cardiac findings were more prominent in late-onset disease. An overall interpretation of electrocardiogram as abnormal was reported in 72.1% of late-onset patients (vs. 44.3% early-onset). A left-ventricular septal thickness of at least 12 mm was reported in 69.7% of late-onset patients (vs. 14.6% early-onset). All differences were statistically significant (p < 0.001).ConclusionIn THAOS, late-onset ATTRv Val30Met amyloidosis is common, presenting with more severe neurologic and cardiac findings at enrollment. Heterogeneity of disease may make it more difficult to diagnose. Increased recognition of late-onset ATTRv Val30Met amyloidosis could lead to more timely diagnosis and improve patient outcomes.Trial registrationClinicalTrials.gov NCT00628745.
| S-EPMC8571445 | biostudies-literature
Project description:BACKGROUND AND PURPOSE:To better characterize the effects of tafamidis in non-Val30Met patients with transthyretin familial amyloid polyneuropathy, this post hoc analysis compared the neurological results from a 12-month, open-label study of non-Val30Met versus Val30Met patients at month 12 from the 18-month, double-blind, placebo-controlled registration study. A baseline covariate adjusted analysis was used to control for differences in baseline neurological severity. METHODS:Neurological function was assessed using the Neuropathy Impairment Score - Lower Limbs (NIS-LL) in three cohorts: Val30Met tafamidis (n = 64), Val30Met placebo (n = 61) and non-Val30Met tafamidis (n = 21). The change in NIS-LL from baseline to month 12 for Val30Met and non-Val30Met tafamidis-treated patients was compared with the change from baseline at month 12 for Val30Met placebo-treated patients using a mixed-effects model for repeated measures (MMRM). RESULTS:The baseline adjusted mean (standard error) change in NIS-LL values at month 12 was similar for Val30Met [1.60 (0.78)] and non-Val30Met [1.62 (1.43)] tafamidis-treated patients and less than that observed in the Val30Met placebo-treated group [4.72 (0.77); P = 0.0055 for Val30Met and P = 0.0592 for non-Val30Met]. Based on the MMRM, the magnitude of change in both tafamidis-treated cohorts was similar across the range of observed baseline NIS-LL values, and was consistently less than that observed in the Val30Met placebo-treated group at month 12. CONCLUSIONS:This baseline-adjusted analysis demonstrated that tafamidis treatment delayed neurological progression comparably in Val30Met and non-Val30Met patients across a range of baseline NIS-LL values. Neurological progression in these two genotype groups may be more similar than previously considered.
| S-EPMC5838526 | biostudies-literature
Project description:AimsMutant transthyretin (ATTRm) amyloidosis is a systemic disease caused by the deposition of amyloid fibrils derived from mutated transthyretin. Although cardiac involvement impacts the prognosis of patients with ATTRm amyloidosis, the incidence of cardiac events, such as bradyarrhythmia, ventricular tachycardia, and heart failure, has not been fully elucidated. The aim of this study was to evaluate the prognosis and predictors of clinical outcomes, including cardiac events, in patients with ATTRm amyloidosis in Japan.Methods and resultsWe evaluated 90 consecutive patients with ATTRm amyloidosis at Kumamoto University. ATTRm amyloidosis was diagnosed by the observation of both amyloid fibril deposition on tissue biopsy and a transthyretin mutation on sequential analysis. Sympathetic nerve activity was evaluated in 59 patients using 123-iodine metaiodobenzylguanidine (123 I-MIBG) imaging. The endpoint was a composite of all-cause death, hospitalization for heart failure, and implantation of a pacemaker, implantable cardioverter defibrillator, or cardiac resynchronization therapy defibrillator. Sixty-seven patients had the Val30Met mutation (74%). The composite endpoint occurred in 23 patients (26%): all-cause death (n = 6), hospitalization for worsening heart failure (n = 1), and implantation of an implantable cardioverter defibrillator (n = 6), cardiac resynchronization therapy defibrillator (n = 3), or pacemaker (n = 7). The 5-year incident rate for clinical outcomes was 19%. In a multivariate Cox hazard analysis, age [hazard ratio (HR): 1.07, 95% confidence interval (95% CI): 1.01-1.12, P = 0.015], PQ interval (HR: 1.01, 95% CI: 1.00-1.02, P = 0.042), interventricular septum thickness in diastole (HR: 1.25, 95% CI: 1.09-1.42, P = 0.001), and non-Val30Met mutation (HR: 4.31, 95% CI: 1.53-12.16, P = 0.006) were independent predictive factors of clinical outcomes. Kaplan-Meier analysis demonstrated a significantly higher probability of the composite endpoint in the non-Val30Met group than in the Val30Met group (log-rank test: P = 0.002) and in patients with left ventricular hypertrophy than in patients without left ventricular hypertrophy (log-rank test: P < 0.001). In patients who underwent 123 I-MIBG imaging, a delayed heart-to-mediastinum (HM) ratio <1.6 was a significant predictive factor of the composite endpoint (HR: 4.98, 95% CI: 1.73-14.37, P = 0.003) in the univariate Cox hazard analyses. Kaplan-Meier curve analysis showed that a delayed HM ratio <1.6 was associated with a poor prognosis (log-rank test: P = 0.001).ConclusionsNon-Val30Met mutation, septal hypertrophy, and a delayed HM ratio are useful predictors of clinical outcomes in patients with ATTRm amyloidosis in Japan. These results suggest that it is important to evaluate cardiac involvement in terms of morphological (left ventricular hypertrophy) and functional (cardiac denervation) perspectives using echocardiography and 123 I-MIBG imaging, respectively.
| S-EPMC6352919 | biostudies-literature
Project description:Transthyretin (TTR) transports the retinol-binding protein-vitamin A complex and is a minor transporter of thyroxine in blood. Its tetrameric structure undergoes rate-limiting dissociation and monomer misfolding, enabling TTR to aggregate or to become amyloidogenic. Mutations in the TTR gene generally destabilize the tetramer and/or accelerate tetramer dissociation, promoting amyloidogenesis. TTR-related amyloidoses are rare, fatal, protein-misfolding disorders, characterized by formation of soluble aggregates of variable structure and tissue deposition of amyloid. The TTR amyloidoses present with a spectrum of manifestations, encompassing progressive neuropathy and/or cardiomyopathy. Until recently, the only accepted treatment to halt progression of hereditary TTR amyloidosis was liver transplantation, which replaces the hepatic source of mutant TTR with the less amyloidogenic wild-type TTR. Tafamidis meglumine is a rationally designed, non-NSAID benzoxazole derivative that binds with high affinity and selectivity to TTR and kinetically stabilizes the tetramer, slowing monomer formation, misfolding, and amyloidogenesis. Tafamidis is the first pharmacotherapy approved to slow the progression of peripheral neurologic impairment in TTR familial amyloid polyneuropathy. Here we describe the mechanism of action of tafamidis and review the clinical data, demonstrating that tafamidis treatment slows neurologic deterioration and preserves nutritional status, as well as quality of life in patients with early-stage Val30Met amyloidosis.
| S-EPMC4919130 | biostudies-literature
Project description: Not available
| S-EPMC4938000 | biostudies-literature
Project description: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.
| S-EPMC4685869 | biostudies-literature
Project description:IntroductionTransthyretin amyloidosis (ATTR amyloidosis) is primarily associated with a cardiac or neurologic phenotype, but a mixed phenotype is increasingly described.MethodsThis study describes the mixed phenotype cohort in the Transthyretin Amyloidosis Outcomes Survey (THAOS). THAOS is an ongoing, longitudinal, observational survey of patients with ATTR amyloidosis, including both hereditary (ATTRv) and wild-type disease, and asymptomatic carriers of pathogenic transthyretin variants. Baseline characteristics of patients with a mixed phenotype (at enrollment or reclassified during follow-up) are described (data cutoff: January 4, 2022).ResultsApproximately one-third of symptomatic patients (n = 1185/3542; 33.5%) were classified at enrollment or follow-up as mixed phenotype (median age, 66.5 years). Of those, 344 (29.0%) were reclassified to mixed phenotype within a median 1-2 years of follow-up. Most patients with mixed phenotype had ATTRv amyloidosis (75.7%). The most frequent genotypes were V30M (38.9%) and wild type (24.3%).ConclusionsThese THAOS data represent the largest analysis of a real-world mixed phenotype ATTR amyloidosis population to date and suggest that a mixed phenotype may be more prevalent than previously thought. Patients may also migrate from a primarily neurologic or cardiologic presentation to a mixed phenotype over time. These data reinforce the need for multidisciplinary evaluation at initial assessment and follow-up of all patients with ATTR amyloidosis.Trial registrationClinicalTrials.gov: NCT00628745.
| S-EPMC10899146 | biostudies-literature
Project description:IntroductionIn the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT; ClinicalTrials.gov number NCT01994889), tafamidis reduced the risk of all-cause mortality in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) by 30% versus placebo. Median overall survival was not achieved in either treatment arm (57.1 and 70.5% of patients in the placebo and tafamidis groups, respectively, survived at 30 months), limiting assessment of the potential survival benefits of treatment.MethodsA survival extrapolation analysis was conducted following technical support guidelines from the National Institute for Health and Care Excellence. Multiple models (i.e., exponential, Weibull, gamma, log-logistic, log-normal, Gompertz, generalized gamma, and generalized F) were applied to systematically fit different candidate curves to existing patient-level data from the 30-month treatment period in ATTR-ACT. The relative goodness-of-fit for each candidate curve was then tested by Akaike's and Bayesian information criteria to select a single model that was fitted to the placebo and pooled tafamidis treatment arms.ResultsA gamma distribution was selected as best fitting model and fitted to both treatment arms. The resulting estimated median overall survival was 35.16 months for placebo and 52.64 months for tafamidis (difference 17.48 months).ConclusionsThis extrapolation of survival data from ATTR-ACT further supports the efficacy of tafamidis in patients with ATTR-CM. Owing to the limitations of this analysis, these survival estimates should be interpreted with caution; however, they are consistent with recently presented findings from a combined analysis of data from ATTR-ACT and interim data from an ongoing long-term extension study (median follow-up 36 months; ClinicalTrials.gov number NCT02791230).Trial registrationClinicalTrials.gov: NCT01994889.
| S-EPMC7584686 | biostudies-literature
Project description:AimsIn patients with transthyretin amyloid cardiomyopathy (ATTR-CM), the effect of tafamidis on myocardial function using serial speckle tracking echocardiography has not been reported. The purpose of this study was to describe the natural history of myocardial function in untreated ATTR-CM and determine the effect of tafamidis on myocardial functional parameters over 12 months of treatment.Methods and resultsA total of 45 subjects with ATTR-CM were retrospectively studied: 23 treated with tafamidis and 22 untreated. Two-dimensional speckle tracking echocardiography was analysed at baseline and 1 year. Serial longitudinal, circumferential, and radial strain, twist, torsion, and myocardial work were measured. Over 1 year, absolute global longitudinal strain (GLS) deteriorated more in the untreated group by a median of 1.1% [inter-quartile range (IQR) 0.95] compared with 0.3% (IQR 1) in the tafamidis group (P = 0.02). Myocardial work index and efficiency also deteriorated to a greater degree: 142.5 mmHg% (IQR 197) and 4% (IQR 8), respectively, in the untreated group compared with 61.5 mmHg% (IQR 210) and 1% (IQR 7) in the tafamidis group (P = 0.04). There were no significant between group differences in left ventricular ejection fraction (LVEF), tissue Doppler velocities, circumferential or radial strain, LV twist or torsion at 1 year. The stabilization effect of tafamidis on myocardial function at 1 year did not differ according to baseline GLS, LVEF, or National Amyloidosis Centre disease stage.ConclusionsIn ATTR-CM, tafamidis resulted in a lesser deterioration in GLS, myocardial work index, and efficiency over a 12-month period compared with a cohort not treated with tafamidis.
| S-EPMC9303005 | biostudies-literature