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Clinical Pharmacokinetics Oct 2023Variants of the transthyretin (TTR) gene cause hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis (v for variant), which results from deposition...
BACKGROUND AND OBJECTIVE
Variants of the transthyretin (TTR) gene cause hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis (v for variant), which results from deposition of misfolded TTR protein as amyloid in organs and tissues. Patisiran is an RNA interference (RNAi) therapeutic that suppresses the hepatic production of TTR protein. Patisiran improves multiple clinical manifestations of hATTR amyloidosis in patients without liver transplantation (LT). Because the liver is the predominant source of circulating TTR, LT has been prescribed to eliminate the production of the variant TTR. However, the continued production of wild-type TTR can contribute to disease progression after LT. Patisiran could potentially address an unmet need in these affected patients. This clinical trial was conducted to evaluate the safety, efficacy, and pharmacokinetics (PK) and pharmacodynamics (PD) of patisiran in patients with hATTR amyloidosis with polyneuropathy progression after LT. In this paper, we describe the PK/PD of patisiran in post-LT patients and compare it with prior patisiran studies in healthy subjects and patients without LT.
METHODS
In an open-label study, patients (N = 23) with hATTR amyloidosis with polyneuropathy progression after LT received 0.3 mg/kg patisiran intravenously every 3 weeks (q3w) for 12 months. As a post hoc analysis, the PK and PD results from the current study were compared with prior patisiran studies in healthy volunteers from a Phase 1 study and in patients with hATTR amyloidosis without LT from Phase 2 and 3 studies.
RESULTS
The PK profile of patisiran siRNA (ALN-18328) and its 2 lipid excipients, DLin-MC3-DMA and PEG2000-C-DMG, in hATTR amyloidosis patients after LT was consistent with prior patisiran studies in non-LT subjects. Plasma PK profiles of ALN-18328 and DLin-MC3-DMA exhibited 2 phases, the first characterized by a short distribution half-life and the second by a minor peak and relatively long elimination half-life. The plasma concentrations of PEG-C-DMG reached C at the end of infusion and declined in a multiphasic manner. There was no appreciable accumulation at steady state. Consistent with prior studies in non-LT subjects, the post-LT patients showed a robust, and sustained TTR reduction; with median TTR reduction from baseline of 91% (average of Month 6 and Month 12). No anti-drug antibodies were observed in any patient.
CONCLUSIONS
The consistency of patisiran PK and PD between patients with and without LT suggests that neither LT nor concomitantly administered immunosuppressants influence hepatic uptake or RNAi activity of patisiran. The patisiran dosing regimen of 0.3 mg/kg q3w is appropriate for hATTR amyloidosis patients with or without LT.
CLINICAL TRIAL REGISTRATION NO
NCT03862807.
Topics: Humans; Liver Transplantation; Prealbumin; RNA, Small Interfering; Amyloidosis
PubMed: 37639169
DOI: 10.1007/s40262-023-01292-w -
Acta Neuropathologica Jan 2023Hereditary transthyretin amyloidosis (ATTRv) is a systemic disease caused by the accumulation of misfolded transthyretin (TTR). It usually presents with an adult-onset...
Hereditary transthyretin amyloidosis (ATTRv) is a systemic disease caused by the accumulation of misfolded transthyretin (TTR). It usually presents with an adult-onset progressive axonal peripheral neuropathy and cardiomyopathy. In the central nervous system (CNS), variant TTR is produced by the choroid plexus and accumulates in the leptomeninges. CNS symptoms have been increasingly recognized in this population, including transient focal neurological episodes and stroke, particularly in patients with the V30M mutation and longstanding disease. The prevalence, pathophysiology, and progression of CNS involvement remain to be clarified. The present work explores if there is a recognizable sequence of CNS TTR deposition in ATTRv. We studied the topographical and severity distribution of TTR deposition in 16 patients with ATTRv, aged 27-69 years and with a mean disease duration of 10.9 years (range: 3-29). Our results suggest that CNS pathological involvement in V30M ATTRv occurs early in the disease course, probably starting in pre-symptomatic phases, and follows a distinct sequence. Leptomeninges and subarachnoid meningeal vessels are affected earlier, then followed by perforating cortical vessels and subpial deposition, and finally by deposition in the subependymal and basal ganglia vessels near the ependymal lining. Brainstem and spinal cord show early and severe involvement, with amyloid subpial deposition already seen in initial stages. Despite massive superficial amyloid deposition, no parenchymal deposition outside subpial or subependymal regions was found. Additionally, vascular lesions or superficial cortical siderosis were not frequent. Future studies with more patients from different populations and TTR mutations will be important to confirm these findings. Defining stages of TTR pathology in the CNS may be useful to better understand pathogenic mechanisms leading to symptoms and to interpret neuroimaging biomarkers.
Topics: Adult; Humans; Prealbumin; Amyloid Neuropathies, Familial; Nervous System Diseases; Mutation; Brain
PubMed: 36198883
DOI: 10.1007/s00401-022-02501-9 -
International Journal of Cardiology Aug 2020
Topics: Amyloid Neuropathies, Familial; Delayed Diagnosis; Humans; Prealbumin
PubMed: 32505334
DOI: 10.1016/j.ijcard.2020.02.072 -
Orphanet Journal of Rare Diseases Jun 2022Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disease caused by the accumulation of variant or wild-type (ATTRwt amyloidosis) transthyretin... (Observational Study)
Observational Study
BACKGROUND
Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disease caused by the accumulation of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in the heart, peripheral nerves, and other tissues and organs.
METHODS
Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal observational study of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This descriptive analysis examines baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2021).
RESULTS
This analysis included 3779 symptomatic patients and 1830 asymptomatic gene carriers. Symptomatic patients were predominantly male (71.4%) and had a mean (standard deviation [SD]) age of symptom onset of 56.3 (17.8) years. Val30Met was the most common genotype in symptomatic patients in South America (80.9%), Europe (55.4%), and Asia (50.5%), and more patients had early- versus late-onset disease in these regions. The majority of symptomatic patients in North America (58.8%) had ATTRwt amyloidosis. The overall distribution of phenotypes in symptomatic patients was predominantly cardiac (40.7%), predominantly neurologic (40.1%), mixed (16.6%), and no phenotype (2.5%). In asymptomatic gene carriers, mean (SD) age at enrollment was 42.4 (15.7) years, 42.4% were male, and 73.2% carried the Val30Met mutation.
CONCLUSIONS
This 14-year global overview of THAOS in over 5000 patients represents the largest analysis of ATTR amyloidosis to date and highlights the genotypic and phenotypic heterogeneity of the disease.
CLINICALTRIALS
gov Identifier: NCT00628745.
Topics: Amyloid Neuropathies, Familial; Female; Genetic Profile; Humans; Male; Phenotype; Prealbumin; Surveys and Questionnaires
PubMed: 35717381
DOI: 10.1186/s13023-022-02359-w -
Giornale Italiano Di Cardiologia (2006) Sep 2022Systemic amyloidosis is a hereditary or acquired disease characterized by deposition of amyloid insoluble fibrils into body organs and tissues, causing structural...
Systemic amyloidosis is a hereditary or acquired disease characterized by deposition of amyloid insoluble fibrils into body organs and tissues, causing structural abnormalities and organ dysfunction, i.e. heart failure. This disease is classified according to the precursor protein involved; immunoglobulin light chains, transthyretin and apolipoprotein A1 underlie the cardiac involvement. Amyloid cardiomyopathy is characterized by symmetric biventricular hypertrophy, preserved systolic function, and pronounced diastolic dysfunction. Although transthyretin-related cardiac amyloidosis has always been considered a rare disease, in the last few years it has been found to be one of the most common causes of hypertrophic cardiomyopathy, thanks to better diagnostic algorithms and considerable improvements in cardiac imaging. Achieving an early diagnosis is a challenge for the modern cardiologist since new disease-modifying therapies have been developed in recent years. This article aims to answer to the main questions about transthyretin-related cardiac amyloidosis: when to suspect it, how to diagnose it and how to treat it.
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Heart Failure; Humans; Prealbumin
PubMed: 36039718
DOI: 10.1714/3860.38451 -
European Heart Journal Aug 2023
Topics: Humans; Prealbumin; Amyloid Neuropathies, Familial
PubMed: 37345642
DOI: 10.1093/eurheartj/ehad411 -
European Journal of Internal Medicine Dec 2020Transthyretin amyloid cardiomyopathy (ATTR-AC) is an under-recognized and underdiagnosed disease. Although traditionally considered a rare condition, the epidemiology of... (Review)
Review
Transthyretin amyloid cardiomyopathy (ATTR-AC) is an under-recognized and underdiagnosed disease. Although traditionally considered a rare condition, the epidemiology of the disease is rapidly changing due to the possibility of non-invasive diagnosis through cardiac scintigraphy with bone tracers and novel disease-modifying treatments providing survival advantages. Nevertheless, many questions and grey areas have to be addressed, such as the natural history of ATTR-AC, the role and implications of genotype-phenotype interactions, the best clinical management, prognostic stratification and the most appropriate treatments, including those already recommended for patients with heart failure. Clinicians have to cope with old beliefs and evolving concepts in ATTR-AC. A wide horizon of possibilities for physicians of many specialties is unfolding and awaits discovery.
Topics: Amyloidosis; Cardiomyopathies; Heart; Heart Failure; Humans; Prealbumin
PubMed: 33032855
DOI: 10.1016/j.ejim.2020.09.025 -
Ugeskrift For Laeger Feb 2020Transthyretin amyloid cardiomyopathy (ATTR-CM) resulting from deposition of transthyretin amyloid fibrils in the heart is an underrecognised cause of heart failure in... (Review)
Review
Transthyretin amyloid cardiomyopathy (ATTR-CM) resulting from deposition of transthyretin amyloid fibrils in the heart is an underrecognised cause of heart failure in the elderly and is associated with a poor life expectancy. The diagnosis can now be made by radionuclide imaging with bone tracers, provided absence of plasma-cell dyscrasia. Recent evidence has suggested a considerable prevalence of ATTR-CM, and effective treatment has become available. This review summarises these new developments, which have ushered a new era in the detection and clinical management of ATTR-CM.
Topics: Aged; Amyloid; Amyloid Neuropathies, Familial; Cardiomyopathies; Heart Failure; Humans; Prealbumin
PubMed: 32089152
DOI: No ID Found -
Future Medicinal Chemistry Dec 2021Transthyretin (TTR) is associated with several human amyloid diseases. Various kinetic stabilizers have been developed to inhibit the dissociation of TTR tetramer and... (Review)
Review
Transthyretin (TTR) is associated with several human amyloid diseases. Various kinetic stabilizers have been developed to inhibit the dissociation of TTR tetramer and the formation of amyloid fibrils. Most of them are bisaryl derivatives, natural flavonoids, crown ethers and carborans. In this review article, we focus on TTR tetramer stabilizers, genetic therapeutic approaches and fibril remodelers. The binding modes of typical bisaryl derivatives, natural flavonoids, crown ethers and carborans are discussed. Based on knowledge of the binding of thyroxine to TTR tetramer, many stabilizers have been screened to dock into the thyroxine binding sites, leading to TTR tetramer stabilization. Particularly, those stabilizers with unique binding profiles have shown great potential in developing the therapeutic management of TTR amyloidogenesis.
Topics: Amyloid; Boron Compounds; Crown Ethers; Drug Development; Flavonoids; Humans; Prealbumin
PubMed: 34633220
DOI: 10.4155/fmc-2021-0248 -
Expert Review of Cardiovascular Therapy Sep 2019: Cardiac amyloidosis is a disorder caused by the accumulation of abnormal protein products, amyloid, in the myocardium which subsequently impairs normal heart function.... (Review)
Review
: Cardiac amyloidosis is a disorder caused by the accumulation of abnormal protein products, amyloid, in the myocardium which subsequently impairs normal heart function. Heart failure with preserved ejection fraction has been increasingly attributed to amyloidosis and the resultant restrictive cardiomyopathy it creates. : Amyloid transthyretin (ATTR) is one of several identified amyloid products that have been pathologically implicated in cardiac amyloidosis through advanced diagnostics. Improvements in nuclear imaging techniques, particularly scintigraphy, have enabled non-invasive diagnosis where previously endomyocardial biopsy was the only option. Despite being considered a rare disease, it is likely that ATTR cardiac amyloidosis is an underdiagnosed condition which has been supported by autopsy findings in heart failure populations. This article will review ATTR cardiac amyloidosis to provide physicians with the tools they need to establish a definitive diagnosis when there is a clinical suspicion of amyloidosis and provide the most appropriate care. : Increased awareness and improved diagnostic techniques will lead to earlier diagnosis and a greater understanding of the clinical presentation. The anticipated increases in the prevalence of this disease due to increased clinical awareness will require, and in-part, facilitate the development of new therapies to manage this patient population.
Topics: Amyloid; Amyloidosis; Heart Failure; Humans; Myocardium; Prealbumin; Radionuclide Imaging
PubMed: 31478389
DOI: 10.1080/14779072.2019.1662723