AstraZeneca’s Anselamimab Shows Survival Benefit in Kappa AL Amyloidosis, Missing Phase 3 Primary Endpoint

AstraZeneca reported mixed topline results from the Phase III CARES clinical program evaluating anselamimab in patients with light chain (AL) amyloidosis. While the investigational anti-fibril antibody failed to meet the primary endpoint in the overall study population, it delivered clinically meaningful survival and cardiovascular benefits in a prespecified subgroup of patients with advanced kappa-predominant disease.

AL amyloidosis is a rare and progressive disorder in which misfolded light-chain proteins form amyloid fibrils that accumulate in organs, particularly the heart and kidneys, causing irreversible damage. Current therapies target the plasma cells that produce these proteins but do not remove existing amyloid deposits. Anselamimab aims to address this gap by directly targeting and clearing deposited fibrils.

CARES Misses Primary Endpoint

The Cardiac Amyloid Reaching for Extended Survival (CARES) program (NCT04512235, NCT04504825) consisted of two global Phase III randomized, double-blind, placebo-controlled trials enrolling 406 patients with Mayo stage IIIa or IIIb cardiac AL amyloidosis across 19 countries. Patients received anselamimab or placebo alongside standard plasma cell-directed therapy, with daratumumab included in approximately 80% of treatment regimens.

The primary endpoint combined all-cause mortality (ACM) and cardiovascular hospitalizations (CVH) in a hierarchical analysis. Although the program did not achieve statistical significance in the overall population, subgroup analyses revealed a strong treatment effect in patients with kappa-predominant AL amyloidosis.

Kappa Subgroup Shows Strong Survival Benefit

In this subgroup, anselamimab reduced the risk of all-cause mortality by 62% compared with placebo (HR 0.38; 95% CI, 0.17–0.86; nominal p=0.012) and lowered cardiovascular hospitalization frequency by 71% (IRR 0.29; 95% CI, 0.10–0.87; nominal p=0.028).

The mortality benefit was observed across both Mayo stage IIIa and IIIb disease. No meaningful differences in mortality or cardiovascular hospitalizations were observed among patients with lambda-predominant disease.

At 50 weeks, anselamimab also showed numerical improvements in quality of life and functional capacity, measured by the Kansas City Cardiomyopathy Questionnaire Overall Score and the Six-Minute Walk Test, although these secondary endpoints did not reach statistical significance.

Safety Profile Remains Favorable

Anselamimab was generally well tolerated, with adverse events balanced between treatment groups and consistent with the underlying disease and concomitant therapies.

Regulatory Path Remains Open

Ashutosh Wechalekar, lead principal investigator of the program, said the findings provide evidence that directly targeting amyloid fibrils can improve survival and reduce cardiovascular complications in patients with kappa AL amyloidosis.

Gianluca Pirozzi, Senior Vice President and Head of Development, Regulatory and Safety at Alexion, AstraZeneca Rare Disease, said the results represent the first Phase III evidence that removing existing amyloid deposits may translate into meaningful clinical benefit.

The CARES results were presented at the 2026 ASCO Annual Meeting and published in the Journal of Clinical Oncology. AstraZeneca said it will continue discussions with regulators regarding the future development path for anselamimab, with the findings supporting a potential targeted strategy in kappa AL amyloidosis.

Reference

CARES Phase III clinical programme did not meet primary endpoint in overall light chain amyloidosis population, however, demonstrated anselamimab as potential first anti-fibril therapy in kappa light chain amyloidosis