Amyloidosis

BackgroundTransthyretin 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.MethodsThis 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).ResultsIn 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.ConclusionsThis 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.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT05442047.

PurposeOutcomes 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).MethodsAL 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).ResultsIn 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 2D 0.25. Stage IIIC independently discriminated the poorest outcome across all cohorts.ConclusionThis 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 and objectivesBlood-brain barrier (BBB) leakage may be an early step in the pathophysiology of cerebral amyloid angiopathy (CAA), possibly preceding hemorrhages. This exploratory study measured BBB leakage in vivo at the level of the leptomeningeal and small parenchymal vessels in patients with probable CAA. We hypothesized that BBB leakage from leptomeningeal and cortical small vessels would be higher in patients with CAA compared with controls and that leakage would be associated with hemorrhagic manifestations of CAA, that is, cortical superficial siderosis (cSS) and lobar cerebral microbleeds (CMBs).MethodsPatients with probable CAA without previous intracerebral hemorrhage and non-CAA patients with mild cognitive impairment from the memory clinic were recruited in this prospective observational exploratory study. Participants underwent 3T brain MRI with injection of a gadolinium-based contrast agent (Dotarem). Leakage from leptomeningeal vessels was assessed on postcontrast vs precontrast T2-fluid-attenuated inversion recovery as either focal or sulcal CSF enhancements. Dynamic contrast-enhanced scans were analyzed to quantify permeability-surface area product (PS): a measure of leakage from parenchymal small vessels.ResultsFourteen patients with CAA (mean age 67.7 ± 9.0 years; 57% female) and 7 non-CAA patients with mild cognitive impairment (mean age 70.1 ± 6.5 years; 29% female) were recruited. Focal CSF enhancements were observed similarly often in patients with CAA (7 [50%]) and non-CAA controls (4 [57%], p = 0.98), whereas sulcal CSF enhancements were only seen in patients with CAA (5 [36%] vs 0 [0%]). In patients with CAA, focal and sulcal CSF enhancement counts were associated with higher cSS volume (B = 2.61, p = 0.003; B = 1.02, p = 0.02), but not with CMBs. PS was numerically higher in the cortex in patients with CAA (5.08 ± 4.02 × 10-4 min-1) than in non-CAA controls (1.29 ± 4.08 × 10-4 min-1, p = 0.07), but it was not associated with CMB count or cSS volume (p > 0.67).DiscussionLeakage of gadolinium-based contrast agent through the BBB can be measured in vivo in CAA from the leptomeningeal vessels, and findings point to likely leakage from cortical small vessels as well. Leakage from leptomeningeal vessels was associated with cSS. Studies with follow-up data need to determine whether these measures could serve as a predictive biomarker in CAA.