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JAMA Oct 2023Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.
IMPORTANCE
Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.
OBJECTIVE
To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy.
DESIGN, SETTING, AND PARTICIPANTS
NEURO-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.
INTERVENTIONS
Subcutaneous 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 MEASURES
Primary 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.
RESULTS
Among 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 < .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 < .001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P < .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 RELEVANCE
In 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 REGISTRATION
ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.
Topics: Adult; Humans; Male; Middle Aged; Female; Prealbumin; Quality of Life; Amyloid Neuropathies, Familial; Oligonucleotides, Antisense; Polyneuropathies; Disease Progression
PubMed: 37768671
DOI: 10.1001/jama.2023.18688 -
Global Heart 2023Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal condition that requires early diagnosis, management, and specific treatment. The availability... (Review)
Review
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal condition that requires early diagnosis, management, and specific treatment. The availability of new disease-modifying therapies has made successful treatment a reality. Transthyretin amyloid cardiomyopathy can be either age-related (wild-type form) or caused by mutations in the TTR gene (genetic, hereditary forms). It is a systemic disease, and while the genetic forms may exhibit a variety of symptoms, a predominant cardiac phenotype is often present. This document aims to provide an overview of ATTR-CM amyloidosis focusing on cardiac involvement, which is the most critical factor for prognosis. It will discuss the available tools for early diagnosis and patient management, given that specific treatments are more effective in the early stages of the disease, and will highlight the importance of a multidisciplinary approach and of specialized amyloidosis centres. To accomplish these goals, the World Heart Federation assembled a panel of 18 expert clinicians specialized in TTR amyloidosis from 13 countries, along with a representative from the Amyloidosis Alliance, a patient advocacy group. This document is based on a review of published literature, expert opinions, registries data, patients' perspectives, treatment options, and ongoing developments, as well as the progress made possible via the existence of centres of excellence. From the patients' perspective, increasing disease awareness is crucial to achieving an early and accurate diagnosis. Patients also seek to receive care at specialized amyloidosis centres and be fully informed about their treatment and prognosis.
Topics: Humans; Consensus; Prealbumin; Amyloid Neuropathies, Familial; Cardiomyopathies
PubMed: 37901600
DOI: 10.5334/gh.1262 -
JAMA Mar 2024Systemic amyloidosis from transthyretin (ATTR) protein is the most common type of amyloidosis that causes cardiomyopathy. (Review)
Review
IMPORTANCE
Systemic amyloidosis from transthyretin (ATTR) protein is the most common type of amyloidosis that causes cardiomyopathy.
OBSERVATIONS
Transthyretin (TTR) protein transports thyroxine (thyroid hormone) and retinol (vitamin A) and is synthesized predominantly by the liver. When the TTR protein misfolds, it can form amyloid fibrils that deposit in the heart causing heart failure, heart conduction block, or arrhythmia such as atrial fibrillation. The biological processes by which amyloid fibrils form are incompletely understood but are associated with aging and, in some patients, affected by inherited variants in the TTR genetic sequence. ATTR amyloidosis results from misfolded TTR protein deposition. ATTR can occur in association with normal TTR genetic sequence (wild-type ATTR) or with abnormal TTR genetic sequence (variant ATTR). Wild-type ATTR primarily manifests as cardiomyopathy while ATTR due to a genetic variant manifests as cardiomyopathy and/or polyneuropathy. Approximately 50 000 to 150 000 people in the US have heart failure due to ATTR amyloidosis. Without treatment, heart failure due to ATTR amyloidosis is associated with a median survival of approximately 5 years. More than 130 different inherited genetic variants in TTR exist. The most common genetic variant is Val122Ile (pV142I), an allele with an origin in West African countries, that is present in 3.4% of African American individuals in the US or approximately 1.5 million persons. The diagnosis can be made using serum free light chain assay and immunofixation electrophoresis to exclude light chain amyloidosis combined with cardiac nuclear scintigraphy to detect radiotracer uptake in a pattern consistent with amyloidosis. Loop diuretics, such as furosemide, torsemide, and bumetanide, are the primary treatment for fluid overload and symptomatic relief of patients with ATTR heart failure. An ATTR-directed therapy that inhibited misfolding of the TTR protein (tafamidis, a protein stabilizer), compared with placebo, reduced mortality from 42.9% to 29.5%, reduced hospitalizations from 0.7/year to 0.48/year, and was most effective when administered early in disease course.
CONCLUSIONS AND RELEVANCE
ATTR amyloidosis causes cardiomyopathy in up to approximately 150 000 people in the US and tafamidis is the only currently approved therapy. Tafamidis slowed progression of ATTR amyloidosis and improved survival and prevented hospitalization, compared with placebo, in people with ATTR-associated cardiomyopathy.
Topics: Humans; Amyloidosis; Cardiomyopathies; Heart Failure; Immunoglobulin Light-chain Amyloidosis; Prealbumin; Black or African American; United States; Africa, Western; Protein Folding
PubMed: 38441582
DOI: 10.1001/jama.2024.0442 -
The New England Journal of Medicine Jan 2024Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo.
METHODS
In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level.
RESULTS
A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients.
CONCLUSIONS
In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).
Topics: Humans; Amyloidosis; Cardiomyopathies; Heart; Hospitalization; Prealbumin; Treatment Outcome; Double-Blind Method; Cardiovascular Agents; Natriuretic Peptide, Brain; Functional Status
PubMed: 38197816
DOI: 10.1056/NEJMoa2305434 -
The Lancet. Neurology Nov 2023Hereditary transthyretin (TTR) amyloid polyneuropathy is an autosomal dominant life-threatening disorder. TTR is produced mainly by the liver but also by the choroid... (Review)
Review
Hereditary transthyretin (TTR) amyloid polyneuropathy is an autosomal dominant life-threatening disorder. TTR is produced mainly by the liver but also by the choroid plexus and retinal pigment epithelium. Detailed clinical characterisation, identification of clinical red flags for misdiagnosis, and use of biomarkers enable early diagnosis and treatment. In addition to liver transplantation and TTR stabilisers, three other disease-modifying therapies have regulatory approval: one antisense oligonucleotide (inotersen) and two small interfering RNAs (siRNAs; patisiran and vutrisiran). The siRNAs have been shown to stop progression of neuropathy and improve patients' quality of life. As none of the disease-modifying therapies can cross the blood-brain barrier, TTR deposition in the CNS, which can cause stroke and cognitive impairment, remains an important unaddressed issue. CRISPR-Cas9-based one-time TTR editing therapy is being investigated in a phase 1 clinical study. Identification of the earliest stages of pathogenesis in TTR variant carriers is a major challenge that needs addressing for optimal management.
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Quality of Life; Amyloid Neuropathies; Biomarkers
PubMed: 37863593
DOI: 10.1016/S1474-4422(23)00334-4 -
The New England Journal of Medicine Jul 2023Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there is no available treatment that depletes ATTR from the heart for the amelioration of cardiac dysfunction. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells.
METHODS
In this phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. Patients were sequentially enrolled in six cohorts that received ascending doses (ranging from 0.3 to 60 mg per kilogram of body weight). After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed.
RESULTS
The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro-B-type natriuretic peptide and troponin T levels also seemed to be reduced.
CONCLUSIONS
In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.).
Topics: Humans; Amyloid Neuropathies, Familial; Antibodies; Cardiomyopathies; Heart Failure; Magnetic Resonance Imaging; Prealbumin; Double-Blind Method; Chronic Disease; Recombinant Proteins; Infusions, Intravenous
PubMed: 37212440
DOI: 10.1056/NEJMoa2303765 -
Drugs Apr 2024Eplontersen (Wainua™) is a ligand-conjugated antisense oligonucleotide directed to TTR, which is being developed by Ionis Pharmaceuticals and AstraZeneca for the... (Review)
Review
Eplontersen (Wainua™) is a ligand-conjugated antisense oligonucleotide directed to TTR, which is being developed by Ionis Pharmaceuticals and AstraZeneca for the treatment of TTR-mediated amyloidosis (ATTR). Eplontersen, which is targeted to the liver by a ligand containing three N-acetyl galactosamine residues, binds to wild-type and variant TTR mRNA, thus reducing the levels of circulating TTR protein and amyloid deposition. Subcutaneous eplontersen reduced serum TTR levels, inhibited neuropathy progression and improved health-related quality of life in patients with polyneuropathy of hereditary ATTR (ATTRv-PN; v for variant) in a phase III trial. Based on these results, eplontersen was approved in the USA for the treatment of ATTRv-PN on 21 December 2023 and is currently undergoing regulatory review for a similar indication in the EU, the UK, Switzerland and Canada. Eplontersen is also undergoing phase III development for ATTR cardiomyopathy. This article summarizes the milestones in the development of eplontersen leading to this first approval for ATTRv-PN.
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Drug Approval; Oligonucleotides; Oligonucleotides, Antisense; Quality of Life; Clinical Trials, Phase III as Topic
PubMed: 38413492
DOI: 10.1007/s40265-024-02008-5 -
The New England Journal of Medicine Oct 2023Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin.
METHODS
In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months.
RESULTS
A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group.
CONCLUSIONS
In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).
Topics: Humans; Cardiomyopathies; Prealbumin; RNA, Small Interfering; Amyloidosis, Familial; Liver; Double-Blind Method; Amyloidosis
PubMed: 37888916
DOI: 10.1056/NEJMoa2300757 -
ESC Heart Failure Aug 2023Tafamidis improves prognosis in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, real-world data on the therapeutic effect of tafamidis are... (Observational Study)
Observational Study
AIMS
Tafamidis improves prognosis in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, real-world data on the therapeutic effect of tafamidis are lacking. This study aimed to evaluate the clinical course, outcomes, and effectivity monitoring of the therapeutic effect of tafamidis in patients with ATTR-CM.
METHODS AND RESULTS
This is a single-centre, retrospective observational study. We evaluated the clinical characteristics and outcomes in 125 consecutive patients with wild-type ATTR-CM (ATTRwt-CM) treated with tafamidis (treatment group) and 55 untreated patients (treatment-naïve group). We monitored the therapeutic effect of tafamidis for 12 months by evaluating serial cardiac biomarker and imaging findings. The treatment group had significantly more favourable outcome in all-cause mortality and hospitalization due to heart failure than the treatment-naïve group in both the entire cohort (P < 0.01) and the propensity score-matched cohort (P < 0.05). Kaplan-Meier survival curves showed that tafamidis treatment significantly reduced all-cause mortality (P = 0.03, log-rank test), with the curves diverging after approximately 18 months of treatment in the propensity score-matched cohort. On inverse probability of treatment weighting analysis, tafamidis treatment showed a reduced all-cause mortality [hazard ratio (HR), 0.31; 95% confidence interval (CI), 0.11-0.93; P = 0.04]. High-sensitivity cardiac troponin T (hs-cTnT) > 0.05 ng/mL, B-type natriuretic peptide (BNP) > 250 pg/mL, and estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m scored 1 point each. Multivariate logistic regression analysis revealed that a high score (2-3 points) was a significantly poor prognostic factor of composite clinical outcomes, including all-cause death and hospitalization for heart failure (HR, 1.55; 95% CI, 1.22-1.98; P < 0.01) for patients in the treatment group. After 12 months of tafamidis treatment, hs-cTnT levels decreased significantly [0.054 (0.036-0.082) vs. 0.044 (0.033-0.076); P = 0.002], with no significant changes in BNP levels, echocardiographic parameters, native T1 value, and extracellular volume fraction on cardiac magnetic resonance imaging.
CONCLUSIONS
The prognosis of patients with ATTRwt-CM treated with tafamidis was more favourable than that of untreated patients. Patient stratification combined with biomarkers (hs-cTnT, BNP, and eGFR) predicted clinical outcomes. hs-cTnT may be a useful biomarker for evaluating the therapeutic effect of tafamidis.
Topics: Humans; Prealbumin; Amyloidosis; Heart Failure; Biomarkers; Cardiomyopathies
PubMed: 37073415
DOI: 10.1002/ehf2.14380