Circulation最新文献

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.

Takayasu arteritis (TAK) is a rare, immune-mediated large-vessel vasculitis that affects predominantly young women and carries a substantial risk of both vascular complications and long-term cardiovascular disease. Although glucocorticoids and conventional immunosuppressive therapies remain the cornerstone of treatment, relapse rates are high, and current strategies fail to adequately mitigate future cardiovascular risk. This review synthesizes evidence on current treatment strategies, unmet clinical needs, and novel approaches, including immunological and vascular-targeted therapies, and argues for a shift in management paradigm toward integrated cardiovascular risk reduction. We discuss advances in understanding the pathogenesis of TAK, highlighting the roles of innate and adaptive immunity in disease progression, and the challenges of early diagnosis and disease monitoring. We critically appraise current treatment paradigms, including glucocorticoids, conventional disease-modifying antirheumatic drugs, and biologics such as tocilizumab and tumor necrosis factor-α inhibitors, and outline emerging therapies targeting novel pathways, including interleukin-17, interleukin-12/23, Janus kinase/signal transducer and activator of transcription, and Notch-1/mammalian target of rapamycin complex signaling. We highlight the increasing recognition of cardiovascular morbidity as a major contributor to mortality in TAK and the need for integrated approaches to risk factor modification. We explore a road map for advancing management of cardiovascular disease in TAK, including comprehensive screening tools that integrate serological and imaging biomarkers to interrogate cardiovascular risk and potential therapeutic cardioprotective strategies such as sodium-glucose cotransporter 2 inhibitors and endothelin receptor antagonists. Despite recent progress, clinical management remains limited by diagnostic uncertainty, heterogeneous treatment approaches, and a paucity of high-quality randomized controlled trials. Future work should focus on interventions that target both immune-mediated vascular injury and cardiovascular disease progression. Achieving long-term disease remission while reducing cardiovascular mortality must become the primary therapeutic goal in TAK.