Sarah A. M. Cuddy

Background: Transthyretin-lowering therapies target the underlying cause of transthyretin amyloid cardiomyopathy (ATTR-CM), but their effects on myocardial amyloid burden and cardiac remodelling remain incompletely characterized. We evaluated the myocardial effects of sustained transthyretin suppression with eplontersen using serial multiparametric cardiovascular magnetic resonance (CMR). Methods: This CMR study was a pre-specified, international, prospective study embedded within the randomized, placebo-controlled phase 3 CARDIO-TTRansform trial. Participants underwent CMR at baseline and planned assessments at weeks 25, 49, 97, and 140. The primary imaging analysis evaluated longitudinal changes in CMR parameters using mixed models for repeated measures. Myocardial amyloid regression and progression were defined as ≥5 percentage-point decreases and increases in extracellular volume (ECV), respectively. All other patients were considered stable. Results: We enrolled 120 participants with baseline and ≥1 follow-up CMR assessment (eplontersen, n=58; placebo, n=62; mean age, 76.7±6.5 years; 95% male; baseline stabilizer, 12.5%). At week 140 eplontersen resulted in lower ECV, compared with placebo (least-squares mean difference [95% CI], –6.7 percentage points [ –8.7 to –4.7]; P<0.001) and lower native T1 ( –25.9ms [–41.7 to –10.2 ]; P=0.002) and left ventricular mass (–19.1g [–28.0 to –10.2]; P<0.001). Eplontersen also increased left ventricular ejection fraction (+5.1% [1.8–8.3]; P=0.002), right ventricular ejection fraction (+4.6% [0.6–8.7]; P=0.03), and left ventricular global longitudinal, circumferential, and radial strain and right ventricular longitudinal strain (all P<0.05), compared to placebo. At week-140, myocardial amyloid regression occurred in 12.5% receiving eplontersen versus 0% receiving placebo, whereas progression occurred in 12.5% versus 76%, respectively. Conclusions: Sustained transthyretin suppression with eplontersen resulted in substantially lower myocardial ECV and favorable changes in cardiac structure, biventricular systolic function, and myocardial deformation compared with placebo in a cohort of patients mostly not on background stabilizer at baseline. These findings provide randomized evidence that lowering circulating transthyretin modifies myocardial disease progression in ATTR-CM and support serial multiparametric CMR for characterizing myocardial treatment response.

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive, often fatal disease. TTR stabilizers bind directly to TTR, inhibiting tetramer dissociation and the resulting amyloidogenic process. This comprehensive review synthesizes clinical outcomes data from the ATTRibute-CM study program, including primary analyses, prespecified sensitivity studies, and open-label extension (OLE) follow-up, to characterize the clinical profile of acoramidis, an oral TTR stabilizer approved for ATTR-CM treatment. In clinical trials, acoramidis demonstrated consistent clinical benefits, with statistically significant reductions in the composite of all-cause mortality or first cardiovascular-related hospitalization evident within 3 months and sustained through 30 months. Prespecified analyses confirmed treatment robustness. Efficacy was maintained regardless of the N-terminal pro-B-type natriuretic peptide (NT-proBNP) thresholds (≥500 pg/mL, ≥750 pg/mL, and ≥1000 pg/mL), was unaffected by concomitant tafamidis use, and was similar in high-risk participants with stage 4 chronic kidney disease (CKD), who are typically excluded from clinical trials. OLE studies through 42 months showed sustained benefits with no new safety concerns. Results demonstrate robust clinical benefits of acoramidis across diverse ATTR-CM populations and across NYHA classes and NAC stages, independent of NT-proBNP thresholds, concomitant tafamidis use, or high-risk CKD. An ongoing prevention study in asymptomatic ATTR-CM gene-mutation carriers may further expand its therapeutic range for ATTR management.

Immunoglobulin light-chain (AL) amyloidosis is a plasma cell disorder characterized by progressive organ dysfunction secondary to deposition of organized immunoglobulin light-chain aggregates. Achievement of rapid and deep normalization of involved immunoglobulin free light chains is necessary to maximize chances of reversibility of organ dysfunction, which, in turn, results in improved quality and length of life. There are no US Food and Drug Administration (FDA)–approved therapies for patients with relapsed AL amyloidosis. B-cell maturation antigen–targeting (BCMA)-bispecific T-cell engagers teclistamab and elranatamab have shown high activity and acceptable safety profile in patients with relapsed and/or refractory multiple myeloma, leading to their FDA approval. Herein, we report on safety and efficacy of elranatamab for patients with relapsed and/or refractory AL amyloidosis. We treated 9 consecutive patients with advanced-stage AL amyloidosis with single-agent elranatamab, observing a 100% overall response and 67% complete response rate, including minimal residual disease negativity, with expected toxicities. Median time to hematological response was 9 days (range, 6-24), with deep suppression in involved free light chains observed within 1 cycle of therapy, translating in cardiac and renal responses at 3 to 6 months. These data support prospective studies exploring elranatamab for patients with relapsed AL amyloidosis.