Fontana, Marianna

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy is a progressive, fatal disease characterized by deposition of extracellular misfolded transthyretin (TTR) in the myocardium. Eplontersen is an N-acetylgalactosamine ligand–conjugated antisense oligonucleotide targeting hepatocyte TTR messenger RNA to reduce the production of circulating TTR. METHODS: CARDIO-TTRansform is a Phase 3, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of eplontersen in transthyretin amyloidosis with cardiomyopathy. Key inclusion criteria include histological evidence of amyloid deposits or grade 2 to 3 cardiac uptake on cardiac scintigraphy in the absence of plasma cell dyscrasia, New York Heart Association class I–III, and end-diastolic interventricular septum thickness >12 millimeters. Participants were randomized 1:1 to receive eplontersen 45 mg or placebo, administered subcutaneously every 4 weeks for up to 140 weeks, followed by a 20-week post-treatment evaluation period or open-label extension. Participants received locally available standard of care, including unrestricted use of TTR stabilizers. The primary end point is a composite of cardiovascular mortality and recurrent clinical cardiovascular events through 140 weeks. Secondary end points, in order of testing hierarchy, include changes from baseline in 6-minute walk distance and Kansas City Cardiomyopathy Questionnaire overall summary score, recurrent cardiovascular events, all-cause mortality, the primary end point in the patient subgroup receiving stabilizers at baseline, and cardiovascular mortality. Echocardiography was performed in all participants, with cardiovascular magnetic resonance imaging and technetium scintigraphy in a subset. CONCLUSIONS: CARDIO-TTRansform is fully enrolled, with 1432 randomized participants who were dosed with study drug or placebo. As the largest transthyretin amyloidosis with cardiomyopathy study to date, it will evaluate whether eplontersen improves cardiovascular outcomes in patients receiving locally available standard of care, including TTR stabilizers. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04136171. URL: http://ClinicalTrialsRegister.eu ; Unique identifier: EudraCT number 2019-002835-27.

PURPOSE Outcomes in systemic light chain (AL) amyloidosis have improved with modern therapy limiting utility of existing risk stratification models. We validate a new staging system, incorporating longitudinal strain (LS) to the biomarker-based (NT-proBNP and Troponin-T) staging system in the contemporary treatment era (2015-2024). METHODS AL International Staging System (AL-ISS) was derived from a cohort of patients with AL amyloidosis from the UK National Amyloidosis Centre (2015-2019). The model was validated in patient cohorts from Europe (Greece, Italy, the Netherlands, and Switzerland), the United States (2015-2024), and the United Kingdom (2020-2024). RESULTS In total, 2,493 patients were included (derivation, n = 573; validation n = 1,920). In a multivariable model for the derivation cohort, LS ≥ –9% and cardiac biomarkers at previously validated thresholds (NT-proBNP 332 ng/L and 8,500 ng/L and high-sensitivity troponin T ≥ 50 ng/L) were independent poor prognostic factors stratifying patients into stages I, II, IIIA, IIIB, and IIIC. In the validation cohort, the patient stages were stage I: 317 (17%), II: 782 (41%), IIIA: 551 (29%), IIIB: 174 (9%), and IIIC: 96 (5%), respectively (first-line daratumumab treated: 826; 43%). With a median follow-up of 34 months, median overall survival (OS) was not reached (NR); estimated 1-year, 2-year, and 3-year OS was 82%, 74%, and 70% respectively. The median survival for stages I to II, IIIA, IIIB, and IIIC were NR, 67, 26, and 7 months (1-year OS IIIC 53% v 68% for IIIB in the daratumumab-treated patients), respectively ( P < .001). External validation exhibited good predictive performance: 12-month calibration slope was 1.09, Harrell C 0.69, Royston D 1.19, and R 2 D 0.25. Stage IIIC independently discriminated the poorest outcome across all cohorts. CONCLUSION This defines and validates a new staging system from systemic AL amyloidosis with robust identification of an ultra-poor risk stage (IIIC) in contemporarily treated patients.

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy is a progressive disease caused by the deposition of transthyretin (TTR) as amyloid in the myocardium. Current therapies may slow disease progression but do not clear existing deposits. Coramitug is a humanized monoclonal antibody that targets misfolded transthyretin, designed to promote clearance of transthyretin amyloid through antibody-mediated phagocytosis. METHODS: This phase 2, double-blind, placebo-controlled trial randomized participants with transthyretin amyloidosis with cardiomyopathy to receive infusions every 4 weeks of either coramitug at 2 dosages (10 mg/kg or 60 mg/kg) or placebo in a 1:1:1 ratio for 52 weeks. The primary end points were the change from baseline to week 52 in the 6-minute walk test and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Safety was assessed for up to 64 weeks by assessing treatment-emergent adverse events, all-cause mortality, and number of cardiovascular events (comprising hospitalization caused by cardiovascular events or urgent heart failure visits). RESULTS: In total, 104 participants (median age, 77 years; 93% men; 84% New York Heart Association class II; 13% with variant transthyretin amyloidosis with cardiomyopathy) were randomized and dosed: 34 to 10 mg/kg of coramitug, 35 to 60 mg/kg of coramitug, and 35 to placebo. Median NT-proBNP was 1985 pg/mL (interquartile range, 1224, 3406). In total, 90% of participants were receiving disease-modifying therapy; 84% were treated with tafamidis and 7 (6.7%) with transthyretin silencers (patisiran, n=4; vutrisiran, n=3). From baseline to week 52, 60 mg/kg of coramitug significantly reduced NT-proBNP levels compared with placebo (–48% [95% CI, –65% to –22%]; P =0.0017). The change in 6-minute walk test from baseline to week 52 was not statistically different from placebo with either dose. Coramitug (60 mg/kg) was associated with improved functional echocardiographic parameters and was well tolerated. CONCLUSIONS: This phase 2 trial showed that coramitug, an antibody targeting misfolded transthyretin in transthyretin amyloidosis with cardiomyopathy, was well tolerated and, at a dose of 60 mg/kg, resulted in a statistically significant reduction in NT-proBNP, a validated marker of disease progression, with no statistically significant effect on 6-minute walk test within 52 weeks. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05442047.

BACKGROUND: In the phase 3 randomized controlled study ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy), acoramidis, a transthyretin stabilizer, demonstrated significant efficacy on the primary end point. Participants with transthyretin amyloid cardiomyopathy who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report the efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE. METHODS: Participants who previously received acoramidis through month 30 in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through month 30 were switched to acoramidis (placebo to acoramidis). Participants who received concomitant tafamidis in ATTRibute-CM were required to discontinue it to be eligible to enroll in the OLE. Clinical efficacy outcomes analyzed through month 42 included time to event for all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, first CVH alone, ACM or recurrent CVH, change from baseline in NT-proBNP (N-terminal pro-B-type natriuretic peptide), 6-minute walk distance, serum transthyretin, and Kansas City Cardiomyopathy Questionnaire Overall Summary score. Safety outcomes were analyzed through month 42. RESULTS: Overall, 438 of 632 participants in ATTRibute-CM completed treatment, and 389 enrolled in the ongoing OLE (263 continuous acoramidis and 126 placebo to acoramidis). The hazard ratio for ACM or first CVH was 0.57 (95% CI, 0.46–0.72) at month 42 based on a stratified Cox proportional hazards model ( P <0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with hazard ratios of 0.64 (95% CI, 0.47–0.88) and 0.53 (95% CI, 0.41–0.69), respectively, at month 42. Treatment effects for NT-proBNP and 6-minute walk distance also favored continuous acoramidis. On initiation of open-label acoramidis in the placebo-to-acoramidis arm, there was a prompt increase in serum transthyretin. Quality of life assessed by Kansas City Cardiomyopathy Questionnaire Overall Summary score was well preserved in continuous-acoramidis participants compared with the placebo-to-acoramidis participants. No new clinically important safety issues were identified in this long-term evaluation. CONCLUSIONS: Early initiation and continuous use of acoramidis in the ATTRibute-CM study through month 42 of the ongoing OLE study were associated with sustained clinical benefits in a contemporary transthyretin amyloid cardiomyopathy cohort, with no clinically important safety issues newly identified. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04988386.

Abstract Introduction Transthyretin–mediated (ATTR) amyloidosis is a progressive, multisystem, fatal disease. Patisiran, an IV RNAi therapeutic, is approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy. The safety and efficacy of patisiran in patients with wild–type or hereditary ATTR amyloidosis with cardiomyopathy (CM) is being investigated in the ongoing APOLLO–B study. Methods Patients were 18–85 yrs old with evidence of cardiac amyloidosis by echocardiography, and ATTR amyloid by tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with CM. Medical history of heart failure (HF) due to ATTR amyloidosis with ≥1 prior hospitalization or current clinical evidence of HF was required. Patients were randomized 1:1 to patisiran IV 0.3 mg/kg or placebo Q3W for 12 months. The primary endpoint was change from baseline in 6–MWT at Month 12 (M12) with patisiran vs placebo. Results APOLLO–B enrolled 360 patients (patisiran, n=181; placebo, n=179): median age (range), 76.0 (41, 85) yrs; male, 89%; wtATTR, 80%. Baseline characteristics were consistent between patients on tafamidis at baseline (91/360 [25%]) and those who were not. Patisiran achieved a rapid and sustained reduction in serum TTR, irrespective of baseline tafamidis treatment. At M12, patisiran showed a significant benefit vs placebo in 6–MWT (median [95% CI] change from baseline: patisiran, –8.15 [–16.42, 1.50]; placebo, –21.35 [–34.05, –7.52]; HL estimate of median difference: 14.69 [0.69, 28.69]; p=0.0162) and KCCQ–OS (LS mean [SEM] change from baseline: patisiran, 0.300 [1.263]; placebo, –3.408 [1.277]; LS mean [SEM] difference: 3.709 [1.796]; p=0.0397). Consistent benefits with patisiran in 6–MWT and KCCQ–OS were observed across predefined patient subgroups. Time to first event of all–cause hospitalization, urgent HF visit, or death directionally favored patisiran vs placebo (HR [95% CI], 0.839 [0.557, 1.263]), as did all–cause mortality (HR [95% CI], 0.355 [0.110, 1.138]), but all composite outcomes endpoints did not achieve statistical significance over 12 months. Patisiran was well tolerated; most AEs were mild or moderate in severity, and there were no cardiac safety concerns. Conclusions Benefits at 12 months were observed with patisiran vs placebo in functional capacity, and health status and quality of life, in patients with ATTR amyloidosis with CM. The efficacy and safety of patisiran continues to be studied in the APOLLO–B open–label extension.

Abstract Introduction Transthyretin–mediated (ATTR) amyloidosis is a progressive and fatal disease. Patients with hereditary or wild–type ATTR amyloidosis frequently develop cardiomyopathy (CM). Patisiran, an IV RNAi therapeutic that inhibits synthesis of wt and variant TTR, is approved for the treatment of hATTR amyloidosis with polyneuropathy. Methods In APOLLO–B, patients were 18–85 yrs old with evidence of cardiac amyloidosis by echocardiography, ATTR amyloid deposition on tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with CM, and had prior hospitalization for heart failure (HF) due to ATTR amyloidosis or clinical evidence of HF. Patients were randomized 1:1 to patisiran IV 0.3 mg/kg or placebo Q3W for 12 months. The primary endpoint was change from baseline in 6–MWT at Month 12 (M12) with patisiran vs placebo. Exploratory parameters at M12 included changes in cardiac biomarkers, echocardiography and Tc scintigraphy. Results APOLLO–B enrolled 360 patients (patisiran, n=181; placebo, n=179): median age, 76.0 yrs; male, 89%; wtATTR, 80%; on tafamidis at baseline, 25%. Patisiran showed a significant benefit compared with placebo in 6–MWT (median [95% CI] change from baseline: patisiran, –8.15 [–16.42, 1.50]; placebo, –21.35 [–34.05, –7.52]; HL estimate of median difference: 14.69 [0.69, 28.69]; p=0.0162). Patisiran demonstrated favorable trends in change from baseline of NT–proBNP (mean fold change ratio [95% CI]: 0.80 [0.73, 0.89]; p=1.825×10–5) and troponin I (mean fold change ratio [95% CI]: 0.87 [0.80, 0.95]; p=0.0011) at M12 vs placebo. Patisiran also demonstrated a trend towards benefit in change from baseline of most evaluated echocardiographic parameters at M12 vs placebo. Patisiran–treated patients evaluable for scintigraphy (n=37) experienced a reduction (37.8%) or no change (62.2%) in Perugini grade at M12 compared with baseline. Among placebo patients (n=28) at M12, none experienced a reduction from baseline in Perugini grade, and 1 (3.6%) increased in grade. Patisiran demonstrated an acceptable safety profile; AEs were mostly mild or moderate in severity, and there were no cardiac safety concerns. Conclusions Exploratory analyses after 12 months provide further evidence for the potential benefit of patisiran treatment on cardiac biomarkers and manifestations of cardiac amyloid involvement in patients with ATTR amyloidosis. The long–term impact of patisiran will be assessed in the ongoing APOLLO–B open–label extension.

Abstract Background Transthyretin-mediated (ATTR) amyloidosis is a rapidly progressive, debilitating, and fatal disease caused by misfolded TTR accumulating in multiple organs and tissues. Patients with hereditary (hATTR) amyloidosis (also known as ATTRv amyloidosis) or wild-type (wtATTR) amyloidosis with cardiomyopathy exhibit decreased survival. Patisiran, an IV RNAi therapeutic that inhibits synthesis of wt and variant TTR, was approved for the treatment of hATTR amyloidosis with polyneuropathy. Exploratory analyses of a predefined cardiac subpopulation in the APOLLO study demonstrated the potential for patisiran to improve the manifestations of cardiomyopathy in patients with hATTR amyloidosis with polyneuropathy. Objective To investigate the safety and efficacy of patisiran in patients with ATTR amyloidosis with cardiomyopathy in the ongoing APOLLO-B study (NCT03997383). Material & Methods Patients were 18–85 years of age with evidence of cardiac amyloidosis by echocardiography (end-diastolic interventricular wall thickness &gt;12 mm), and either ATTR amyloid deposition on tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with cardiomyopathy. Patients had a medical history of heart failure (HF) due to ATTR amyloidosis with at least 1 prior hospitalization for HF, or current clinical evidence of HF. Patients were randomized (1:1) to receive patisiran IV 0.3 mg/kg or placebo Q3W for 12 months. After the double-blind, placebo-controlled period, all patients may receive patisiran in an open-label extension period for up to 36 months. The primary endpoint was change from baseline in 6-MWT at Month 12 with patisiran treatment, compared with placebo. Secondary endpoints evaluated the effect of patisiran vs placebo at Month 12 on QOL (KCCQ-OS score) as well as two sets of composite endpoints: 1) All-cause mortality, frequency of CV events (CV hospitalizations and urgent HF visits) and change from baseline in 6-MWT; and 2) All-cause mortality and frequency of all-cause hospitalizations and urgent HF visits. The pharmacodynamic effect of patisiran on serum TTR level (change from baseline through Month 12) was also assessed. Results & Discussion Enrollment completed (359 patients) in May 2021. About 80% of patients have wtATTR amyloidosis. Primary and secondary endpoint data will be presented, including change in 6-MWT and KCCQ-OS score at Month 12, in addition to safety data. Summary & Conclusion The primary results of the APOLLO-B study will inform the potential of patisiran as a treatment for the cardiomyopathy of ATTR amyloidosis. APOLLO-B will continue to investigate the efficacy and safety of patisiran on ATTR amyloidosis in an open-label extension period.

AbstractTransthyretin‐mediated amyloidosis (ATTR) is a rare, under‐recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue‐specific delivery of these nucleic acid‐based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low‐density lipoprotein receptor‐mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N‐acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor‐mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor‐targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.