Anselamimab Misses Primary Endpoint in Phase III CARES Trials for AL Amyloidosis

AstraZeneca has shared an update from its Phase III Cardiac Amyloid Reaching for Extended Survival (CARES) clinical program evaluating anselamimab, a light chain depleter antibody, for the treatment of patients with Mayo stages IIIa and IIIb light chain (AL) amyloidosis. High-level results showed that the therapy did not achieve statistical significance for the primary endpoint compared to placebo.¹

These results are from two Phase III trials evaluating anselamimab: NCT04512235 for Mayo stage IIIa, and NCT04504825 for Mayo stage IIIb. The primary endpoint across both studies was defined as a hierarchical combination of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVH).

Prespecified subgroup shows benefit

While anselamimab did not meet statistical significance, the light chain depleter antibody did demonstrate a highly clinically meaningful improvement in time to ACM and frequency of CVH in a prespecified subgroup of patients, compared to placebo.

In a press release, Ashutosh Wechalekar, MBBS, MD, FRCP, FRCPath, DM, consultant hematologist at University College London Hospitals NHS Foundation Trust (UCLH), professor of medicine and hematology at University College London (UCL), and lead principal investigator of the CARES program, said: “While the study did not meet the primary endpoint in the overall patient population, results from a pre-defined subgroup suggest that anselamimab, by targeting and clearing amyloid deposits, may address a leading cause of organ damage and functional impairment in these patients. The potential to extend survival and reduce cardiovascular hospitalizations would represent a practice-changing advancement for this patient group.”

CARES study design and participant breakdown

As previously mentioned, the CARES program is comprised of two Phase III, parallel, global, randomized, double-blind, placebo-controlled, multicenter trials investigating the efficacy and safety of anselamimab plus standard of care in patients with stage IIIa and stage IIIb AL amyloidosis.

• CARES is the largest prospective study conducted to date in cardiac AL amyloidosis, enrolling 406 newly diagnosed patients across 19 countries.
• Participants included 281 patients with stage IIIa and 125 with stage IIIb disease, based on the European-modified Mayo 2004 staging system.
• Patients initiating first-line therapy with cyclophosphamide, bortezomib, and dexamethasone were randomized 2:1 to receive either anselamimab or placebo.
• Dosing included weekly administration of anselamimab or placebo for the first 4 weeks, followed by biweekly dosing through the end of the study.\Use of daratumumab was allowed but not required; about 80% of participants received it as part of their treatment regimen.
• After the 18-month primary treatment period, participants were eligible to continue into a 24-month open-label extension, receiving anselamimab with standard of care.

In the press release, Marc Dunoyer, chief executive officer, Alexion, AstraZeneca Rare Disease, added: “Alexion is pioneering a novel mechanism of action to address organ damage from existing amyloid deposits in patients with AL amyloidosis, a devastating disease often diagnosed in advanced stages with poor prognosis. Anselamimab is the first and only investigational fibril depleter to show clinical benefit in AL amyloidosis, and these results underscore its potential to address a critical treatment gap in a prespecified subgroup of patients.

Earlier data and regulatory progress

Anselamimab was obtained by AstraZeneca’s Alexion in September 2021 as part of an acquisition of Caelum Biosciences.² Then identified as CAEL-101, anselamimab demonstrated positive results in an earlier Phase II study (NCT04304144). According to data from the study, CAEL-101 administered in combination with cyclophosphamide-bortezomib-dexamethasone plus daratumumab was generally safe and well-tolerated in the first four weeks of treatment.³

This multicenter, open-label, Phase II dose-selection study was divided into two parts:

• Part A used a 3+3 dose-escalation design with CAEL-101 given alongside cyclophosphamide, bortezomib, and dexamethasone at doses of 500, 750, and 1000 mg/m². All Part A participants were later adjusted to 1000 mg/m², the selected Phase III dose.
• Part B evaluated CAEL-101 at 1000 mg/m² in combination with CyBorD plus daratumumab.

The FDA granted Fast Track Designation to anselamimab in June 2021. It has also received Orphan Drug Designation from the FDA, European Commission, and the Ministry of Health, Labor, and Welfare of Japan for the treatment of AL amyloidosis.

References

1. Update on CARES Phase III clinical programme of anselamimab in light chain amyloidosis. News release. AstraZeneca. July 16, 2025. Accessed July 17, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/update-on-anselamimab-in-al-amyloidosis.html#

2. AstraZeneca to fully acquire Caelum Biosciences. News release. AstraZeneca. September 29, 2021. Accessed July 17, 2025. https://www.astrazeneca.com/media-centre/press-releases/2021/astrazeneca-to-fully-acquire-caelum-biosciences.html#

3. Caelum and Alexion Present Additional Phase 2 Data Reinforcing Safety and Tolerability of CAEL-101 in AL Amyloidosis at the European Hematology Association Congress 2021. Alexion Pharmaceuticals. June 11, 2021. Accessed July 17, 2025. https://www.businesswire.com/news/home/20210611005037/en/Caelum-and-Alexion-Present-Additional-Phase-2-Data-Reinforcing-Safety-and-Tolerability-of-CAEL-101-in-AL-Amyloidosis-at-the-European-Hematology-Association-Congress-2021