Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years

Barroso, Fabio; Judge, Daniel P.; Ebede, Ben; Li, Huihua; Stewart, Michelle; Amass, Leslie; Sultan, Marla B.

doi:10.1080/13506129.2017.1357545

Cited by 99 publications

(106 citation statements)

References 32 publications

(75 reference statements)

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“…The interim analysis of an ongoing open‐label extension (10 years; n = 93) of the two studies discussed above and a single‐arm open‐label study in non‐V30M patients discussed below reinforced these results in V30M patients for a treatment duration of up to 6 years …”

Section: Clinical Efficacy – What Do We Know So Far?mentioning

confidence: 80%

“…If pharmaceuticals are not discussed in this section, no valid clinical data are available at this point to the best of our knowledge. A summary of all trials taken into consideration can be found in Table (polyneuropathy) and Table (cardiomyopathy) …”

Section: Clinical Efficacy – What Do We Know So Far?mentioning

confidence: 99%

“…Other treatment‐related adverse events included falls (and sporadic accounts of ataxia/syncope), pleural effusions and slight renal impairment …”

Section: Clinical Efficacy – What Do We Know So Far?mentioning

confidence: 99%

“…Cardiac events, such as transient ischaemic attacks, atrial fibrillation, cardiac failure, chest pain and dyspnoea, were considered part of the progressive nature of ATTR‐associated cardiomyopathy and not related to tafamidis …”

Section: Clinical Efficacy – What Do We Know So Far?mentioning

confidence: 99%

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Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Müller

Butler

Heidecker

2020

European J of Heart Fail

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Transthyretin amyloidosis (ATTR) is a rare, yet underdiagnosed disease characterized by progressive impairment of neurologic and cardiac function due to deposition of misfolded transthyretin. Despite great efforts, such as the introduction of orthotopic liver transplant, the devastating prognosis for both variant and wild‐type ATTR patients remained unchanged over the last decades, mainly due to a lack of specific therapies. Fortunately, recent years saw the introduction of promising targeted therapies, which aim to interfere with the deposition of misfolded transthyretin (TTR) at various stages of the cascade underlying ATTR progression. These include TTR tetramer stabilizers (tafamidis, diflunisal, epigallocatechin‐3‐gallate), TTR silencers (inotersen, patisiran) and fibril disruptors (monoclonal antibodies, doxycycline and tauroursodeoxycholic acid). In the context of this review we explain their mechanisms of action, analyse their efficacy on neurologic and cardiac function based on all clinical trials conducted to date and discuss their clinical applicability. Eventually suggestions for future clinical research into the field are provided.

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Section: Clinical Efficacy – What Do We Know So Far?mentioning

confidence: 80%

Section: Clinical Efficacy – What Do We Know So Far?mentioning

confidence: 99%

“…Other treatment‐related adverse events included falls (and sporadic accounts of ataxia/syncope), pleural effusions and slight renal impairment …”

Section: Clinical Efficacy – What Do We Know So Far?mentioning

confidence: 99%

Section: Clinical Efficacy – What Do We Know So Far?mentioning

confidence: 99%

See 2 more Smart Citations

Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Müller

Butler

Heidecker

2020

European J of Heart Fail

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“…The efficacy and adverse event profile observed in these studies led to the approval of tafamidis in the European Union in 2011 (Pfizer Ltd, ). Sustained activity and tolerability of tafamidis for up to 6 years have been reported (https://clinicaltrials.gov identifier: NCT00925002) (Barroso et al, ); however, outcomes are mixed for patients with mid‐ to late‐stage Val30Met hATTR and patients with any‐stage non‐Val30Met hATTR. Neuropathy progression and increasing disability in patients with late‐stage Val30Met hATTR (Lozeron et al, ) and worsening in neurologic function in patients with non‐Val30Met hATTR have been demonstrated (Merlini et al, ).…”

Section: Discussion/observationmentioning

confidence: 99%

Advances in the treatment of hereditary transthyretin amyloidosis: A review

et al. 2019

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Introduction Amyloid transthyretin amyloidosis (ATTR) is a progressive and often fatal disease caused by the buildup of mutated (hereditary ATTR [hATTR]; also known as ATTR variant [ATTRv]) or normal transthyretin (wild‐type ATTR) throughout the body. Two new therapies—inotersen, an antisense oligonucleotide therapy, and patisiran, an RNA interference therapy—received marketing authorization and represent a significant advance in the treatment of amyloidosis. Herein, we describe the clinical presentation of ATTR, commonly used procedures in its diagnosis, and current treatment landscape for ATTR, with a focus on hATTR. Methods A PubMed search from 2008 to September 2018 was conducted to review the literature on ATTR. Results Until recently, there have been few treatment options for polyneuropathy of hATTR. Inotersen and patisiran substantially reduce the amyloidogenic precursor protein transthyretin and have demonstrated efficacy in patients with early‐ and late‐stage disease and in slowing or improving neuropathy progression. In contrast, established therapies, such as liver transplantation, typically reserved for patients with early‐stage disease, and tafamidis, indicated for the treatment of early‐stage disease in Europe, or diflunisal, a nonsteroidal anti‐inflammatory drug that is used off‐label, are associated with side effects and/or unclear efficacy in certain patient populations. Thus, inotersen and patisiran are positioned to be the preferred therapeutic modalities. Conclusions Important differences between inotersen and patisiran, including formulation, dosing, requirements for premedications, and safety monitoring, require an understanding and knowledge of each treatment for informed decision making.

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Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy

Coelho,

Marques,

Dasgupta

et al. 2023

JAMA

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ImportanceTransthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.ObjectiveTo evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy.Design, Setting, and ParticipantsNEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013–November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo (“placebo”) group.InterventionsSubcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60).Main Outcomes and MeasuresPrimary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, –22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, –4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights.ResultsAmong 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was −81.7% with eplontersen and −11.2% with placebo (difference, −70.4% [95% CI, −75.2% to −65.7%]; P &lt; .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, −24.8 [95% CI, −31.0 to −18.6; P &lt; .001) and for Norfolk QoL-DN (−5.5 vs 14.2; difference, −19.7 [95% CI, −25.6 to −13.8]; P &lt; .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group.Conclusions and RelevanceIn patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo.Trial RegistrationClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10

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Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years

Cited by 99 publications

References 32 publications

Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Advances in the treatment of hereditary transthyretin amyloidosis: A review

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy

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