Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial

Adams, David H.; Tournev, Ivailo; Taylor, Mark; Coelho, Teresa; Planté‐Bordeneuve, Violaine; Berk, John L.; González‐Duarte, Alejandra; Gillmore, Julian D.; Low, Soon-Chai; Sekijima, Yoshiki; Obici, Laura; Chen, Chongshu; Badri, Prajakta; Arum, Seth; Vest, John; Polydefkis, Michael

doi:10.1080/13506129.2022.2091985

Cited by 147 publications

(132 citation statements)

References 36 publications

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“…V30M was the most prevalent TTR sequence mutation in patients enrolled in the NEURO-TTRansform study, which is reflective of published literature in this population. In NEURO-TTRansform, the proportion of patients with the V30M variant (60.1%) was somewhat higher than for other phase 3 trials in ATTRv-PN (NEURO-TTR [52%] [23], APOLLO [43%] [24], and HELIOS-A [45%] [25]) and approached the prevalence reported in real-world datasets (e.g., 73% in the THAOS global patient registry) [26]. As expected, the V30M TTR sequence variant was present in both early-onset and late-onset disease.…”

Section: Discussionmentioning

confidence: 89%

Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen

et al. 2022

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Introduction Hereditary transthyretin (ATTRv) amyloidosis is a rare, severe, progressive, debilitating, and ultimately fatal disease caused by systemic deposition of transthyretin (TTR) amyloid fibrils. ATTRv amyloidosis occurs in both males and females. Eplontersen (ION-682884), a ligand-conjugated antisense oligonucleotide designed to degrade hepatic TTR mRNA, is being evaluated for the treatment of ATTRv amyloidosis with polyneuropathy (ATTRv-PN) in the phase 3, international, multicenter, open-label NEURO-TTRansform study (NCT04136184). To describe the study population of this pivotal trial, here we report the baseline characteristics of patients enrolled in the NEURO-TTRansform study. Methods Patients eligible for NEURO-TTRansform were 18–82 years old with a diagnosis of ATTRv-PN and Coutinho stage 1 (ambulatory without assistance) or stage 2 (ambulatory with assistance) disease; documented TTR gene variant; signs and symptoms consistent with neuropathy associated with ATTRv; no prior liver transplant; and New York Heart Association (NYHA) functional class I or II. Results The NEURO-TTRansform study enrolled 168 patients across 15 countries/territories (North America, 15.5%; Europe, 38.1%; South America/Australia/Asia, 46.4%). At baseline, the study cohort had a mean age of 52.8 years, 69.0% of patients were male, and 78.0% of patients were White. The V30M variant was most prevalent (60.1% of patients), and prevalence varied by region. Overall, 56.5% and 17.3% of patients had received previous treatment with tafamidis or diflunisal, respectively. A majority of patients (79.2%) had Coutinho stage 1 disease (unimpaired ambulation) and early (before age 50) disease onset (53.0%). Time from diagnosis to enrollment was 46.6 (57.4) months (mean [standard deviation]). Most patients had a baseline polyneuropathy disability (PND) score of I (40.5%) or II (41.1%), and the mean modified Neuropathy Impairment Score + 7 (mNIS + 7) was 79.0. Conclusion The recruited population in the ongoing NEURO-TTRansform study has global representation characteristic of contemporary clinical practice. Trial Registration ClinicalTrials.gov identifier NCT04136184.

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Section: Discussionmentioning

confidence: 89%

Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen

et al. 2022

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“…As therapeutics that selectively suppress target genes through the mechanism of RNA interference, oligonucleotide drugs have been granted market approval ( Cui et al, 2021 ). For instance, Leqvio ® (inclisiran), GIVLAARI™ (givosiran), Oxlumo™ (lumasiran), and AMVUTTRA™ (vutrisiran) that are approved for clinical usage, can target liver mRNAs for the treatment of hypercholesterolemia, mixed dyslipidemia, acute hepatic porphyria (AHP), primary hyperoxaluria type 1 (PH1) and hATTR amyloidosis ( Lamb, 2021 ; Scott and Keam, 2021 ; Subhan et al, 2021 ; Adams et al, 2022 ). Importantly, more oligonucleotide drugs that target metabolic dysfunction symptoms and subsequent complications are under development, providing hope for more genetic solutions.…”

Section: Challenge and Sirna Delivery Systemmentioning

confidence: 99%

The therapeutic prospects of N-acetylgalactosamine-siRNA conjugates

Zhang

Liang²,

Liang³

et al. 2022

Front. Pharmacol.

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RNA interference has become increasingly used for genetic therapy following the rapid development of oligonucleotide drugs. Significant progress has been made in its delivery system and implementation in the treatment of target organs. After a brief introduction of RNA interference technology and siRNA, the efficiency and stability of GalNAc-siRNA conjugates are highlighted since several oligonucleotide drugs of GalNAc have been approved for clinical use in recent years. The structure and features of GalNAc-siRNA conjugates are studied and the clinical efficiency and limitations of oligonucleotide-based drugs are summarized and investigated. Furthermore, another delivery system, lipid nanoparticles, that confer many advantages, is concluded, includ-ing stability and mass production, compared with GalNAc-siRNA conjugates. Importantly, developing new approaches for the use of oligonucleotide drugs brings hope to genetic therapy.

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“…A phase 3 trial demonstrated that intravenous Patisiran, at 18 months, improved or stabilized multiple neuropathy outcome measures, including both somatic and autonomic function, leading to its FDA approval for the treatment of hATTR-associated polyneuropathy. Most recently, Vutrisiran, a subcutaneously administered RNAi therapy that is given every 3 months, also received FDA approval for the treatment of hATTR-associated polyneuropathy ( 32 ). On the other hand, antisense oligonucleotides (ASOs) are short, single-stranded deoxyribonucleic acids that degrade target RNA by binding primarily to target pre-mRNA in the nucleus (as opposed to the cytoplasm).…”

Section: Overview Of Types Of Amyloidosismentioning

confidence: 99%

Multidisciplinary amyloidosis care in the era of personalized medicine

Bumma

Kahwash²,

Parikh³

et al. 2022

Front. Neurol.

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Amyloidosis refers to a group of conditions where abnormal protein—or amyloid—deposits in tissues or organs, often leading to organ malfunction. Amyloidosis affects nearly any organ system, but especially the heart, kidneys, liver, peripheral nervous system, and gastrointestinal tract. Neuromuscular deficits comprise some of its ubiquitous manifestations. Amyloidosis can be quite challenging to diagnose given its clinical heterogeneity and multi-system nature. Early diagnosis with accurate genetic and serologic subtyping is key for effective management and prevention of organ decline. In this review, we highlight the value of a multidisciplinary comprehensive amyloidosis clinic. While such a model exists at numerous clinical and research centers across the globe, the lack of more widespread adoption of such a model remains a major hindrance to the timely diagnosis of amyloidosis. Such a multidisciplinary care model allows for the timely and effective diagnosis of amyloidosis, be it acquired amyloid light amyloidosis (AL), hereditary transthyretin amyloidosis (hATTR), or wild type amyloidosis (TTR-wt), especially in the current era of personalized genomic medicine. A multidisciplinary clinic optimizes the delivery of singular or combinatorial drug therapies, depending on amyloid type, fibril deposition location, and disease progression. Such an arrangement also helps advance research in the field. We present our experience at The Ohio State University, as one example out of many, to highlight the centrality of a multi-disciplinary clinic in amyloidosis care.

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Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial

Cited by 147 publications

References 36 publications

Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen

Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen

The therapeutic prospects of N-acetylgalactosamine-siRNA conjugates

Multidisciplinary amyloidosis care in the era of personalized medicine

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