Anselamimab Misses Overall Endpoint, Signals Kappa Benefit In CARES

Key Takeaways

• Anselamimab was not associated with a significant advantage on the primary hierarchical composite endpoint in the full randomized population.
• Among patients with kappa isotype, lower mortality, fewer cardiovascular hospitalizations, and better Kansas City Cardiomyopathy Questionnaire-Overall Score were reported.
• No clinical benefit was observed in the lambda population, and tolerability was generally similar between treatment arms.

In the randomized CARES trials, anselamimab added to background antiplasma cell therapy missed the primary endpoint in newly diagnosed advanced cardiac AL amyloidosis. The overall win ratio was 1.11 (95% CI, 0.83 to 1.50; P = .332) in patients with European modification of Mayo 2004 stage IIIa or IIIb disease. A more favorable signal was reported in the kappa subgroup than in the full randomized population. The overall result was neutral, with a different pattern by isotype.

The study randomly assigned 406 patients with newly diagnosed European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis to anselamimab or placebo. Both groups received cyclophosphamide, bortezomib, and dexamethasone, with or without daratumumab, as background antiplasma cell therapy. Investigators described anselamimab as a monoclonal antibody that binds amyloid fibrils and is intended to accelerate their clearance. The primary endpoint combined time to all-cause mortality and frequency of cardiovascular hospitalizations in a hierarchical analysis using the Finkelstein-Schoenfeld test and win ratio estimation. The overall efficacy analysis was neutral.

In the full population, the all-cause mortality hazard ratio was 0.80 (95% CI, 0.57 to 1.13; P = .290). Cardiovascular hospitalization rates were 0.59 (95% CI, 0.42 to 0.83) with anselamimab and 0.89 (95% CI, 0.55 to 1.43) with placebo. The reported difference in hospitalization rates carried a P value of .145. These component measures did not translate into a significant advantage on the hierarchical composite endpoint in the overall population. Directional differences were present, but the main efficacy analysis remained neutral.

Among patients with kappa isotype, a subgroup of 72 patients, the win ratio was 2.06 (95% CI, 0.98 to 4.31; P = .100). Within that subgroup, all-cause mortality had a hazard ratio of 0.38 (95% CI, 0.17 to 0.86; nominal P = .012). Cardiovascular hospitalizations also favored anselamimab, with an incidence rate ratio of 0.29 (95% CI, 0.10 to 0.87; nominal P = .028). Investigators also reported improved Kansas City Cardiomyopathy Questionnaire-Overall Score in the kappa subgroup, while no clinical benefit was observed in the lambda population. The isotype split suggested a subgroup signal rather than a uniform effect across the population.

Anselamimab was generally well tolerated, and safety was comparable between treatment arms overall. Investigators noted that the overall endpoint was not met, but that the kappa signal could support a potential therapeutic role in that isotype. That conclusion rested on subgroup results reported with nominal P values rather than a positive overall primary analysis. Overall, the findings included a neutral trial result, a potentially favorable kappa signal, and broadly similar tolerability.