The Swedish open-label diflunisal trial (DFNS01) on hereditary transthyretin amyloidosis and the impact of amyloid fibril composition

Wixner, Jonas; Westermark, Per; Ihse, Elisabet; Pilebro, Björn; Lundgren, Hans-Erik; Anan, Intissar

doi:10.1080/13506129.2019.1593133

Cited by 19 publications

(11 citation statements)

References 4 publications

(5 reference statements)

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“…Diflunisal is a nonsteroidal anti-inflammatory (NSAID) medication that has demonstrated TTR stabilization in vitro 46 but has only been studied in small, nonrandomized, mostly noncomparative single-arm prospective cohort trials of predominantly ATTRv-CA. 47 , 48 , 49 , 50 Although these studies suggest stabilization of cardiac biomarkers and echocardiographic parameters, formal randomized controlled trials are needed to confirm these findings and determine an impact on morbidity and mortality. While diflunisal is generally considered safe and well tolerated, as an NSAID it is contraindicated in patients with significant thrombocytopenia and or renal dysfunction (glomerular filtration rate < 40 mL/min/1.73m 2 ) and can cause gastrointestinal intolerance, bleeding, and heart failure exacerbation.…”

Section: Disease-modifying Treatment Of Attr Cardiac Amyloidosismentioning

confidence: 99%

Cardiac Amyloidosis Treatment

Stern

Patel

2022

Methodist DeBakey Cardiovascular Journal

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Cardiac amyloidosis (CA) is a restrictive cardiomyopathy with a traditionally poor prognosis. Until recently, CA treatment options were limited and consisted predominantly of managing symptoms and disease-related complications. However, the last decade has seen significant advances in disease-modifying therapies, increased awareness of CA, and improved diagnostic methods resulting in earlier diagnoses. In this review, we provide an overview of current and experimental treatments for the predominant types of CA: transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain (AL)-mediated CA (AL-CA). The mainstay of AL-CA treatment is proteasome inhibitor-based chemotherapy with daratumumab and, when feasible, autologous stem cell transplantation. For ATTR-CA, the stabilizer tafamidis is the only US Food and Drug Administration (FDA)-approved treatment. However, promising novel therapies on the horizon target various points in the ATTR-CA amyloidogenic cascade. These include transthyretin gene ( TTR) silencing agents to prevent TTR formation, TTR tetramer stabilization and inhibition of oligomer aggregation to prevent fibril formation, anti-TTR fiber antibodies, and amyloid degradation. For end-stage CA, advanced interventions may need to be considered, including heart, heart-kidney, and, for hereditary ATTR-CA, heart-liver transplantation. Despite the evolution of treatment options, CA management remains complex due to patient frailty and therapeutic side effects or intolerance with advanced cardiac disease. This is particularly relevant for those with AL-CA, when active teamwork between the hematologist-oncologist and the cardiologist is critical for treatment success. Often, referral to an expert center is necessary for timely diagnosis, initiation of treatment, and participation in clinical trials.

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Section: Disease-modifying Treatment Of Attr Cardiac Amyloidosismentioning

confidence: 99%

Cardiac Amyloidosis Treatment

Stern

Patel

2022

Methodist DeBakey Cardiovascular Journal

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“…52 A single-center study of 53 ATTR-CA patients treated with doxycycline and bile acid ursodiol showed 90% tolerability, with suggestion of disease stabilization by biomarker and echocardiographic measures and 38% of subjects with improvement by echocardiographic data. 53 Another potential amyloid disruptor agent is epigallocatechin-3gallate (EGCG), the most abundant catechin in green tea, which, as discussed previously, has some stabilization effect on TTR but also may promote amyloid degradation by converting existing fibrils into more soluble nonfibril conformers in vitro. 50 An observational report of 19 patients with hereditary or wild-type ATTR-CA studied a daily intake of approximately 500-700 mg EGCG by either drinking 1.2-2 L of green tea or taking 300-mg green tea capsules.…”

Section: T Tr Amyloid Fib Ril D Is Rup Tor Smentioning

confidence: 99%

Advances in the treatment of transthyretin cardiac amyloidosis: Current and emerging therapies

Warner

2021

Pharmacotherapy

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Transthyretin amyloidosis (ATTR) has been recognized as an underdiagnosed and undertreated cause of cardiomyopathy, as well as noncardiac disorders including polyneuropathy, spinal stenosis, and carpal tunnel syndrome. 1 The evolution of the non-biopsy diagnosis of transthyretin cardiac amyloidosis (ATTR-CA) along with new and emerging therapies has escalated the recognition of this multisystem disorder. 2,3 Once considered rare, recent studies have shown prevalence of ATTR-CA in up to 13% of patients hospitalized with heart failure and preserved ejection fraction 4 ; 16% of patients with aortic stenosis undergoing transcatheter valve replacement 4 ; 7-8% of patients undergoing carpal tunnel release surgery 5 ; and 25% of persons >80 years on an autopsy series. 6 With the increase in recognition and diagnosis of ATTR-CA, the development of targeted treatments has evolved and grown rapidly over the past decade.Amyloidoses are a group of protein misfolding disorders where misfolded proteins form insoluble amyloid fibrils that deposit in the tissues leading to organ damage and dysfunction. Two types of amyloid account for 95% of cardiac amyloidosis: light-chain amyloid (AL) due to immunoglobin light-chain deposition and transthyretin cardiac amyloidosis (ATTR) which can be due to hereditary mutation (hATTR) or wildtype transthyretin (wtATTR). 1 Transthyretin (TTR), previously known as prealbumin, is a 55,000-Dalton protein that is synthesized primarily in the liver, and serves as a serum transport protein for thyroxine and retinol, hence deriving the name transthyretin for TRANSporter of THYroxine and RETINol. Although TTR is the primary serum transport protein for retinol-binding protein, it is only a minor transport protein for thyroxine in plasma, with <1% of TTR thyroxine bound due to a

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“…However, the pre‐existing FDA approval of diflunisal for arthritis has never been extended for ATTRv amyloidosis. High drop‐out rates in the trial and the risk of cardiac and nephrotoxic side effects (Wixner et al., 2019) have further been points of discussion. Several similarly structured drugs were designed and tested (Miller et al., 2004; Razavi et al., 2003), revealing that 2‐(3,5‐dichlorophenyl)‐1,3‐benzoxazole‐6‐carboxylic acid was most effective in stabilizing the tetramer while being deprived of its cyclooxygenase inhibitory properties.…”

Section: Reviewmentioning

confidence: 99%

Targeting transthyretin ‐ Mechanism‐based treatment approaches and future perspectives in hereditary amyloidosis

Dohrn

Ihne

Hegenbart

et al. 2020

Journal of Neurochemistry

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The liver‐derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild‐type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate‐limiting step of amyloidogenesis. Besides destabilizing TTR mutations, other genetic (RBP4, APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) factors influence the type of onset and organ tropism. The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence‐specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo. With enhanced hepatic targeting capabilities, GalNac‐conjugated siRNA and ASOs have recently entered phase III clinical trials. Bivalent TTR stabilizers occupy both binding groves in vitro, but have not been tested in trials so far. Tolcapone is another stabilizer with the potential to cross the blood–brain barrier, but its half‐life is short and liver failure a potential side effect. Amyloid‐directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR‐amyloidosis has become a model disease for pathophysiology‐based treatment. Further understanding of disease mechanisms will help to overcome the remaining limitations, including application burden, side effects, and blood–brain barrier permeability.

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The Swedish open-label diflunisal trial (DFNS01) on hereditary transthyretin amyloidosis and the impact of amyloid fibril composition

Cited by 19 publications

References 4 publications

Cardiac Amyloidosis Treatment

Cardiac Amyloidosis Treatment

Advances in the treatment of transthyretin cardiac amyloidosis: Current and emerging therapies

Targeting transthyretin ‐ Mechanism‐based treatment approaches and future perspectives in hereditary amyloidosis

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