AstraZeneca announced that its Cardiac Amyloid Reaching for Extended Survival (CARES) Phase III clinical programme evaluating anselamimab in patients with Mayo stages IIIa and IIIb light chain (AL) amyloidosis did not meet its primary endpoint. The primary endpoint was defined as a hierarchical combination of time to all-cause mortality and frequency of cardiovascular hospitalizations in the overall patient population.
Despite the overall trial results, anselamimab showed highly clinically meaningful improvement in time to all-cause mortality and frequency of cardiovascular hospitalizations in a prespecified subgroup of patients compared to placebo. All patients in the clinical programme received background standard of care for plasma cell dyscrasia.
Novel Mechanism Targets Amyloid Deposits
Anselamimab is an investigational, potentially first-in-class anti-fibril monoclonal antibody designed to improve organ function by reducing or eliminating amyloid deposits in the tissues and organs of patients living with AL amyloidosis. By binding with specificity to targets within amino acids on misfolded amyloid fibrils, anselamimab promotes destruction and clearance of amyloid deposits while sparing native free light chains from destruction.
"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," said Ashutosh Wechalekar, Consultant Haematologist at University College London Hospitals NHS Foundation Trust, Professor of Medicine and Haematology at University College London and lead principal investigator of the programme. "The potential to extend survival and reduce cardiovascular hospitalisations would represent a practice-changing advancement for this patient group."
Addressing Critical Unmet Need in Rare Disease
Light chain (AL) amyloidosis is a rare, systemic and progressive disorder caused 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. Left untreated, the accumulation of these toxic amyloid deposits, particularly in the heart and kidneys, can cause progressive organ damage and dysfunction and may lead to premature death, most commonly due to cardiac failure.
Worldwide, there are an estimated 74,000 patients living with AL amyloidosis. In the early stages of the disease, people with AL amyloidosis may experience a range of vague signs and symptoms that mimic other diseases, which can often delay the diagnosis.
Largest Prospective Investigation in Cardiac AL Amyloidosis
The CARES clinical programme represents the largest prospective investigation in cardiac AL amyloidosis to date, with a total of 406 patients enrolled from 19 countries globally, including 281 patients with stage IIIa and 125 patients with stage IIIb disease per European modification of the Mayo 2004 staging system.
In CARES, newly diagnosed patients planning first-line plasma cell dyscrasia treatment with cyclophosphamide, bortezomib and dexamethasone were randomised 2:1 to receive either anselamimab or placebo once weekly for the first four weeks and then every two weeks until study completion. Daratumumab was permitted but not required as part of the plasma cell dyscrasia regimen, and approximately 80% of patients in CARES received daratumumab as part of their treatment.
Safety Profile and Next Steps
Anselamimab was well tolerated, with the majority of events balanced between the anselamimab treatment arm and the placebo arm. Following the primary evaluation treatment period, which concluded 18 months after the last patient was randomised, all patients had the option to participate in an open-label extension period receiving anselamimab plus standard of care for up to 24 months.
Marc Dunoyer, Chief Executive Officer of Alexion, AstraZeneca Rare Disease, said: "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."
Evaluation of full results is ongoing to further characterise the efficacy and safety of anselamimab. Alexion plans to share these data with global health authorities and present them at a forthcoming medical meeting. Anselamimab has been granted Fast Track Designation by the US Food and Drug Administration and received Orphan Drug Designation from the US FDA, European Commission and the Ministry of Health, Labour and Welfare of Japan for the treatment of AL amyloidosis.
