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Infiltrative Diseases
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Antisense oligonucleotides (ASOs) are short, synthetic RNAs that inhibit the translation of mRNA. Inotersen is an ASO that inhibits hepatic expression of TTR, suppressing both wild-type and mutant TTR. The NEURO-TTR trial demonstrated that, in hATTR polyneuropathy, subcutaneous injections of inotersen resulted in improvement in symptoms related to polyneuropathy.59 In a study of 22 patients with ATTR-CM, inotersen was associated with stabilization of the disease at 12 months, based on decreased left ventricular mass and improvement in 6-min walk test.60 Side effects for TTR silencers include rare infusion reactions for patisiran and glomerulonephritis, and thrombocytopenia for inotersen. FDA approved both patisiran and inotersen for hATTR polyneuropathy, with the caveat that platelets and renal function should be monitored weekly with inotersen. TTR silencers are not currently being approved for hATTR-CM without neuropathy.
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.
Indirect treatment comparison of the efficacy of patisiran and inotersen for hereditary transthyretin-mediated amyloidosis with polyneuropathy
Published in Expert Opinion on Pharmacotherapy, 2021
Peter Gorevic, Jaclyn Franklin, Jihong Chen, Gautam Sajeev, Jessie C. H. Wang, Hollis Lin
Patisiran and inotersen are two therapies approved for treatment of hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy, a rapidly progressive disease with a substantial clinical burden. Data from the NEURO-TTR study of inotersen and the APOLLO study of patisiran provide the opportunity to indirectly compare the two treatments in terms of efficacy on validated measures of neuropathy and quality of life (QOL). This indirect comparison study found that patisiran demonstrated greater treatment effects on neuropathy and QOL compared with inotersen in patients with hATTR amyloidosis with polyneuropathy. The wide range of analyses described provides a comprehensive evidence base for patients, physicians, and other stakeholders to evaluate the comparative efficacy of patisiran and inotersen to inform treatment decision-making.
TTR gene silencing therapy in post liver transplant hereditary ATTR amyloidosis patients
Published in Amyloid, 2020
Orly Moshe-Lilie, Diana Dimitrova, Stephen B. Heitner, Thomas H. Brannagan, Sasha Zivkovic, Mazen Hanna, Ahmad Masri, Michael Polydefkis, John L. Berk, Morie A. Gertz, Chafic Karam
Our study summarises our observations with TTR silencing therapy in hATTR patients with various TTR mutations POLT. We observed neurologic disease stability, and improvement in some, in a population previously experiencing worsening neurologic deficits. However, we cannot adequately assess the efficacy of this treatment in this report. We also observed a high rate of drug discontinuation due to adverse events which could lead to the conclusion that Inotersen may be unsuitable for OLT patients. However, one can also argue that some of these adverse events, such as in the case of liver rejections, could have been avoided by more effective rejection prophylaxis with tacrolimus or another agent. In patient no. 4 specifically, it is unclear whether his rejection episode was related to discontinuation of his chronic immunosuppressant therapy for 6 months prior to Inotersen initiation or is directly related to Inotersen, or both. The second patient who experienced rejection (no. 9) was asymptomatic. Also, both patients’ liver rejection episodes were reversible and did not warrant treatment with corticosteroids. In addition, the diagnosis of allograft rejection in both patients was based on histopathology, and there were no findings such as cholestasis or necroinflammation to suspect drug-induced-liver-injury. In regard to thrombocytopenia, it is a known, rare complication of Inotersen and is usually reversible by treatment modification. In our patients, thrombocytopenia led to discontinuation of treatment per patients’ requests. Lastly, none of the patients in this report experienced any irreversible side effects from Inotersen.
Amyloid transthyretin cardiac amyloidosis: diagnosis and management
Published in Expert Review of Cardiovascular Therapy, 2019
Bennett Di Giovanni, Dakota Gustafson, Diego Hernan Delgado
Inotersen is an antisense oligonucleotide which inhibits hepatic TTR synthesis by targeting its mRNA. This injectable molecule is specifically designed to bind mRNA for TTR and cleave it. Destruction of mRNA removes the cellular input to produce protein or any subsequent amyloid. It was shown to have a reduction in neuropathic symptoms and decline in quality of life by the 66th week of usage [50]. Serious adverse events included glomerulonephritis and thrombocytopenia. The inotersen group had five deaths in comparison to none in the placebo group, one of which was attributed to severe thrombocytopenia [50]. Through the implementation of enhanced safety monitoring, it was found that issues could be identified earlier and managed accordingly. As a weekly subcutaneous injection, there were some site reactions, occurring at a rate of 1.1% with majority being mild in severity [50]. Data from the 66th week suggest that there is comparable effectiveness in the management of neuropathy in those with or without CM [50]. However, evaluation of the strain and echocardiographic variables showed no difference compared to placebo.