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Infiltrative Diseases
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Tafamidis is a novel compound that binds to the thyroxine-binding sites of TTR with high affinity, which inhibits tetramer dissociation into monomers. Previous trials illustrated that tafamidis slowed the progression of peripheral neuropathy in hATTR polyneuropathy, leading to its approval in other countries.52 The phase 3 double-blind, placebo-controlled trial Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) assessed tafamidis (20 or 80 mg daily) in patients with wtATTR and hATTR. Tafamidis was associated with lower mortality compared with placebo, with a 13.4% absolute difference in mortality and a 32% relative risk reduction in cardiovascular hospitalizations. The estimated number needed to treat with 2.5 years of treatment is 7.5 to prevent one death. Tafamidis was well tolerated, with no significant adverse events.53 Tafamidis achieved expedited approval by the US Food and Drug Administration (FDA). At a cost of $225,000 per patient per year, tafamidis is currently the most expensive cardiovascular drug, and cost continues to be a concern for future use of this medication.
Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
Typing of the amyloid by immunohistochemistry is essential in all cases since therapy and prognosis depends on type. The median untreated survival time was previously less than 6 months but recent progress in chemotherapy, including immunosuppressive drugs, protease inhibitor with steroid therapy significantly improve survival in AL amyloid. Cardiac amyloidosis is now better with early diagnosis and treatment, in the TTR or familial variants as well as the AL variant. ATTR amyloidosis is caused by deposition of monomers of the protein transthyretin, a transport protein produced by the liver, and is subdivided in hereditary TTR amyloidosis (ATTRm) and wild-type/senile systemic TTR amyloidosis (ATTRwt). ATTRwt is found in the elderly population with the V1221 mutant transthyretin having a higher rate of symptomatic HF. Val30Met, the most common genetic mutation globally, preferentially causes neuropathy dominant phenotype, but cardiac involvement is observed in about a half of Val30Met FAP patients. Conduction disturbances and atrioventricular block rather than wall thickness and HF are characteristics of Val30Met FAP patients. Val122Ile, the highest frequency of genetic mutation in African Americans, preferentially causes hATTR-cardiomyopathy (hATTR-CM) phenotype. Three to four per cent of African Americans have this genetic mutation, but not all carriers develop amyloidosis because of the low clinical penetrance. Liver transplant can be a curative option in hereditary ATTR and, more recently, tafamidis has been shown to reduce mortality and improve quality of life in patients with ATTR (both wild-type and mutant). Tafamidis is an oral medication that binds to transthyretin and prevents tetramer dissociation and amyloid formation. Amyloid-specific therapies such as tafamidis, patisiran, and inotersen have dramatically altered the outcome.
Real-world outcomes in non-endemic hereditary transthyretin amyloidosis with polyneuropathy: a 20-year German single-referral centre experience
Published in Amyloid, 2021
Matthias N. Ungerer, Ernst Hund, Jan C. Purrucker, Laura Huber, Christoph Kimmich, Fabian aus dem Siepen, Selina Hein, Arnt V. Kristen, Katrin Hinderhofer, Jennifer Kollmer, Stefan Schönland, Ute Hegenbart, Markus Weiler
Also in line with previous findings, treatment with tafamidis was very well tolerated and no drug-related adverse events were reported in our study [29,30]. Time to neurologic progression was far longer in our patients with PND score I compared to PND score II (Figure 4) confirming that treatment with tafamidis is most efficacious when initiated as early as possible at Coutinho stage 1 ATTR-PN, that is, when the PND score is still I [31,32]. This finding is noteworthy in that the PND score may be useful in clinical practice to assist therapeutic decision-making in ATTRv-PN stage 1 patients for whom all three approved disease-modifying medications, that is, tafamidis, inotersen and patisiran, can be prescribed now. Regarding our findings, first-line treatment with tafamidis (at 20 mg qd in its meglumine salt form, or 61 mg qd depending on concurrent cardiac involvement) seems justified in patients with a PND score of I, whereas patients with more advanced disease manifestation and a PND score of II tend to qualify for first-line treatment with a TTR gene silencing drug (or tafamidis at 61 mg qd given cardiac comorbidity).
APOE polymorphism in ATTR amyloidosis patients treated with lipid nanoparticle siRNA
Published in Amyloid, 2020
Christoph Niemietz, Oksana Nadzemova, Andree Zibert, Hartmut H.-J. Schmidt
In 1990, liver transplantation was introduced to treat ATTR amyloidosis. Transplantation can however not halt disease progression and is associated with a poor outcome for non-V30M ATTR amyloidosis patients [3]. In 2011, Tafamidis was approved as a small compound for treatment of stage 1 ATTR amyloidosis in the European Union. The mechanism of Tafamidis is based on its binding to TTR, thereby stabilising the tetrameric form of the protein and reducing amyloidogenic monomers [4]. Slowing down of neurologic disease progression was shown in V30M and non-V30M ATTR amyloidosis [5]. In 2018, alternate treatment compounds have been approved by FDA and EMA for treatment of ATTR amyloidosis stage 1 and 2 for silencing of liver TTR expression [6,7]. Patisiran (Onpattro®) is by now the first compound of its class that was introduced to the clinic since the concept of small interfering RNA was discovered (siRNA) [8]. siRNA-mediated gene silencing involves the Watson-Crick binding of the oligonucleotide to the complementary sequence of the target mRNA followed by double-stranded RNA cleavage via cellular dicer enzyme. The resulting single-stranded RNA is recognised by an RNA-induced silencing complex (RISC), consisting of Argonaute 2 (Ago 2), Dicer, and the TAR-RNA binding protein (TRBP) ultimately leading to mRNA degradation [9].
Novel drug therapies for cardiac amyloidosis
Published in Expert Opinion on Investigational Drugs, 2019
Prakash Harikrishnan, Srikanth Yandrapalli, Wilbert S. Aronow, Gregg M. Lanier, Diwakar Jain
Tafamidis is a small benzoxazole-derived molecule that selectively binds to the thyroxine binding site of TTR, stabilizes the tetramer and prevents its disassociation into amyloid forming monomers by acting as a chaperone. Tafamidis is administered as an oral medication and has been approved in Europe for delaying the progress of peripheral neuropathy in hereditary transthyretin amyloid neuropathy. In The Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), a multicenter, double-blind, placebo-controlled, randomized control trial, the efficacy and safety of tafamidis was studied in patients with hereditary and senile TTR amyloid cardiomyopathy [6]. Of the 441 patients enrolled, who had a median age of 75 years, 264 received tafamidis (80 mg or 20 mg) and 177 were given placebo, and they were followed up over 30 months. Patients on tafamidis started showing improvement in survival after 18 months and by about 30 months follow-up had a 30% reduction in all-cause mortality and also a reduction in cardiovascular-related hospitalizations compared to placebo group. There was also lower rate of decline in functional capacity and quality of life in tafamidis group. Subgroup analysis showed the efficacy of 20 mg and 80 mg dose of tafamidis to be similar. Tafamidis patients with New York Heart Association (NYHA) class III symptoms had a higher incidence of cardiovascular hospitalizations compared to placebo. This study also showed that tafamidis is safe with no increase in adverse effects compared to placebo. Tafamidis is not yet approved by the FDA for use in TTR amyloid cardiomyopathy.