CARES Phase III programme misses primary endpoint in overall light chain amyloidosis population, yet positions anselamimab as a potential first anti fibril therapy in kappa light chain amyloidosis

Anselamimab delivered a 62% improvement in survival and a 71% reduction in cardiovascular hospitalisations in a prespecified kappa light chain amyloidosis subgroup. The results have been published in the Journal of Clinical Oncology and will be presented at the 2026 American Society of Clinical Oncology Annual Meeting.

The global CARES Phase III clinical programme showed that anselamimab, a potential first in class anti fibril therapy, produced a nominally statistically significant and highly clinically meaningful benefit in adults with advanced kappa light chain (AL) amyloidosis when used as first line therapy on top of standard of care plasma cell dyscrasia (PCD) treatments, compared with placebo. As previously disclosed, in the overall population of patients with AL amyloidosis, anselamimab did not meet the primary endpoint, which was defined as a hierarchical combination of time to all cause mortality (ACM) and frequency of cardiovascular hospitalisations (CVH).

In a prespecified subgroup analysis of patients with the kappa predominant light chain isotype, anselamimab improved survival by 62%, as measured by all cause mortality (hazard ratio 0.38; 95% confidence interval 0.17 to 0.86; nominal p=0.012), and reduced the frequency of cardiovascular hospitalisations by 71% (incidence risk ratio 0.29; 95% confidence interval 0.10 to 0.87; nominal p=0.028), versus placebo within the kappa AL amyloidosis subgroup.

The reduction in the risk of all cause mortality observed in the kappa subgroup was seen across both trials comprising the CARES Phase III programme, in patients with the kappa isotype and Mayo stage IIIa disease (a 75% reduction) and Mayo stage IIIb disease (a 48% reduction). No differences in all cause mortality or cardiovascular hospitalisations were observed in patients with the lambda predominant light chain isotype.

At 50 weeks, numerical improvements favouring anselamimab were also seen across key secondary endpoints, including quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Overall Score (Hodges Lehmann median difference 10.37; 95% confidence interval -9.38 to 25.56; p=0.113), and functional capacity, as measured by the Six Minute Walk Test (Hodges Lehmann median difference 18.00; 95% confidence interval -71.60 to 95.92; p=0.145), in patients with kappa light chain amyloidosis treated with anselamimab compared with placebo.

AL amyloidosis is a rare, systemic, and progressive disorder driven by defective plasma cells in the bone marrow. In AL amyloidosis, abnormal light chain proteins produced by these plasma cells misfold, aggregate, and form amyloid fibrils that deposit in tissues and organs. Without treatment, the accumulation of these toxic amyloid deposits, especially in the heart and kidneys, can cause progressive organ damage and dysfunction and can lead to premature death, most often due to cardiac failure. Globally, there are an estimated 74,000 people living with AL amyloidosis, of whom around 20% have kappa light chain amyloidosis and around 80% have lambda light chain amyloidosis.

Ashutosh Wechalekar, FRCP, FRCPath, DM, Honorary Consultant Haematologist at University College London Hospitals and Professor of Medicine and Haematology at University College London, and lead principal investigator of the programme, said: “People living with advanced AL amyloidosis often face persistent, progressive and debilitating organ damage with no available options to target and clear existing amyloid fibril deposits. Results from the CARES Phase III programme show that anselamimab, a monoclonal antibody with a novel mechanism of action designed to target and remove amyloid fibrils, improved survival and reduced the frequency of cardiovascular hospitalisations in patients with kappa light chain amyloidosis. Anselamimab has the potential to offer a novel, clinically meaningful therapeutic for this subgroup of patients with kappa AL amyloidosis who can be easily identified by simple, routinely-used diagnostics.”

Gianluca Pirozzi, Senior Vice President, Head of Development, Regulatory and Safety, Alexion, AstraZeneca Rare Disease, said: “The CARES Phase III programme is the first to show that targeting existing deposits of amyloid fibrils could deliver clinically meaningful survival and cardiovascular benefit in adults with kappa light chain amyloidosis, underscoring anselamimab’s potential as a first-line therapy on top of standard of care. With anselamimab and our leading amyloidosis portfolio, we are advancing pioneering science with the goal of addressing critical treatment gaps. We look forward to continued engagement with health authorities to advance this potential first-in-class anti-fibril therapy.”