Safety and efficacy of a TTR specific antisense oligonucleotide in patients with transthyretin amyloid cardiomyopathy

Benson, Merrill D.; Dasgupta, Noel R.; Rissing, Stacy M.; Smith, Jessica; Feigenbaum, Harvey

doi:10.1080/13506129.2017.1374946

Cited by 68 publications

(59 citation statements)

References 19 publications

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“…Examples are the approved ASO mipomersen and PCSK9 mAbs versus the siRNA-based drug incli-siran, now in phase 3 trials, all three designed to lower cholesterol by targeting the same enzyme 69,105,106 , and the Ionis ASO inotersen versus Alnylam patisiran, both targeting TTR to treat amyloidosis (J. Gollob (Alnylam), personal communication and ref. 107 ). For gene knockdown strategies, siRNAs will probably be more effective drugs than ASOs, provided that they can be effectively delivered to the tissue or cell of interest.…”

Section: Advantages Of Rna-based Drugsmentioning

confidence: 99%

Tapping the RNA world for therapeutics

Lieberman

2018

Nat Struct Mol Biol

159

127

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A recent revolution in RNA biology has led to the identification of new RNA classes with unanticipated functions, new types of RNA modifications, an unexpected multiplicity of alternative transcripts and widespread transcription of extragenic regions. This development in basic RNA biology has spawned a corresponding revolution in RNA-based strategies to generate new types of therapeutics. Here, I review RNA-based drug design and discuss barriers to broader applications and possible ways to overcome them. Because they target nucleic acids rather than proteins, RNA-based drugs promise to greatly extend the domain of ‘druggable’ targets beyond what can be achieved with small molecules and biologics.

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Section: Advantages Of Rna-based Drugsmentioning

confidence: 99%

Tapping the RNA world for therapeutics

Lieberman

2018

Nat Struct Mol Biol

159

127

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“…A single-center, investigator-initiated, open-label phase 2 study was conducted to evaluate inotersen in biopsy-proven hereditary or wild-type ATTR patients with moderate-to-severe cardiomyopathy [54]. Subjects were treated with SC inotersen 300 mg, administered once weekly for up to 3 years.…”

Section: Investigator-initiated Trialmentioning

confidence: 99%

“…In the investigator-initiated phase 2 trial, inotersen was well tolerated by all 15 patients who had received 12 months of inotersen [54]. AEs included pruritus (n = 2), localized injection site reactions (erythema, itching, and induration; n = 5), and transient fatigue (n = 2).…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

Inotersen for the treatment of adults with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis

Gertz

Scheinberg

Waddington-Cruz

et al. 2019

Expert Review of Clinical Pharmacology

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Introduction: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is an underdiagnosed, progressive, and fatal multisystemic disease with a heterogenous clinical phenotype that is caused by TTR gene mutations that destabilize the TTR protein, resulting in its misfolding, aggregation, and deposition in tissues throughout the body. Areas covered: Inotersen, an antisense oligonucleotide inhibitor, was recently approved in the United States and Europe for the treatment of the polyneuropathy of ATTRv based on the positive results obtained in the pivotal phase 3 trial, NEURO-TTR. This review will discuss the mechanism of action of inotersen and its pharmacology, clinical efficacy, and safety and tolerability. A PubMed search using the terms 'inotersen,' 'AG10,' 'antisense oligonucleotide,' 'hereditary transthyretin amyloidosis,' 'familial amyloid polyneuropathy,' and 'familial amyloid cardiomyopathy' was performed, and the results were screened for the most relevant English language publications. The bibliographies of all retrieved articles were manually searched to identify additional studies of relevance. Expert opinion: Inotersen targets the disease-forming protein, TTR, and has been shown to improve quality of life and neuropathy progression in patients with stage 1 or 2 ATTRv with polyneuropathy. Inotersen is well tolerated, with a manageable safety profile through regular monitoring for the development of glomerulonephritis or thrombocytopenia. ARTICLE HISTORYand wild-type TTR by targeting its mRNA. This article will review inotersen, an antisense oligonucleotide (ASO) inhibitor, for the treatment of polyneuropathy caused by ATTRv, focusing on the mechanism of action of inotersen and its pharmacology, clinical efficacy, and safety and tolerability.

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“…For example, inherited connective tissue disease due to variants in ACTA2, MYH11, or TGFBR2 might prompt consideration of surgical intervention at a smaller aortic aneurysm diameter 38) ; and 4) identify patients for targeted therapies: targeted medical therapies, including antibody-based therapeutics, gene editing, and silencing technologies, are available or under development for several genetic diseases, including LQTS, DMD, TTR cardiac amyloidosis, and Fabry disease. [38][39][40]…”

Section: Genomics In CV Precision Medicinementioning

confidence: 99%

Challenges and Future in Precision Cardiovascular Medicine

Baek

2019

Cardiovasc Prev Pharmacother

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Cardiovascular disease (CVD) still remains the global leading cause of mortality and also impose major burdens on morbidity, quality of life, and societal costs despite of the remarkable progress of cardiovascular (CV) treatment over the past 50 years. CVD therapy improves CV outcomes in less than half of patients. Precision medicine is an attractive and advancing strategy to enhance for disease prevention, diagnosis, and tailored treatment and allocate limited resources more wisely and effectively. We are now in the middle of fourth industrial revolution by a robust confluence of biotechnology, physical science and information technologies. This approach is in its premature so far, but has begun to yield useful information that moves from the conventional 'average response' approach to more specific and targeted approaches governed by individual variability. This review aims to how precision medicine, genomics, and epigenetics work together to create a new era of CV precision medicine.

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Safety and efficacy of a TTR specific antisense oligonucleotide in patients with transthyretin amyloid cardiomyopathy

Abstract: ASO treatment of patients with moderate to advanced ATTR cardiomyopathy shows indication of stabilization of disease progression and may therefore contribute to enhanced life expectancy.

Cited by 68 publications

References 19 publications

Tapping the RNA world for therapeutics

Tapping the RNA world for therapeutics

Inotersen for the treatment of adults with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis

Challenges and Future in Precision Cardiovascular Medicine

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