AstraZeneca sifts for efficacy crumbs in amyloidosis trial

An antibody being developed by AstraZeneca for the treatment of light chain (AL) amyloidosis has failed to move the needle in a phase 3 trial, although the drugmaker thinks it has seen signs of efficacy in some patients.

The data is the first readout from the CARES trial of anselamimab (formerly CAEL-101), a targeted anti-fibril therapy that stems back to an alliance between AZ's rare disease unit Alexion and Caelum Biosciences in 2019, which saw Alexion take a minority stake in the biotech. After it bought Alexion in 2021, AZ subsequently opted to take full control of Caelum and anselamimab for $150 million plus another $350 million in potential milestone payments.

The CARES programme consists of two parallel phase 3 trials in patients with newly diagnosed, advanced AL amyloidosis (Mayo stage IIIa and Mayo stage IIIb disease, respectively). Top-level results are now available, and show that anselamimab was unable to improve on placebo on the primary endpoint – a combination of the time to all-cause mortality (ACM) and frequency of cardiovascular hospitalisations (CVH), according to AZ.

However, AZ has said that the antibody "showed highly clinically meaningful improvement in time to ACM and frequency of CVH in a prespecified subgroup of patients" compared to placebo, suggesting it remains committed to the programme. A spokesperson for the company said it was not yet ready to disclose the subgroup that has benefitted from the treatment.

AL amyloidosis, an incurable and potentially fatal disease that results in the rogue protein amyloid building up in organs like the heart and kidneys. Median survival is estimated to be 24 and 4 months, respectively, for Mayo Stage IIIa and IIIb patients.

For many years, the only available treatment was aggressive chemotherapy or a stem cell transplantation – the latter option available only to a minority of eligible patients – but that changed in 2021 when Johnson & Johnson's Darzalex Faspro (daratumumab and hyaluronidase) became the first drug to be specifically approved for the disease.

Darzalex Faspro, given as part of a combination regimen with Johnson & Johnson/Takeda's Velcade (bortezomib), cyclophosphamide, and dexamethasone, has quickly become the standard-of-care for newly diagnosed patients.

Lead CARES investigator, Ashutosh Wechalekar of University College London (UCL), 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."

He added: "The potential to extend survival and reduce cardiovascular hospitalisations would represent a practice-changing advancement for this patient group."

AZ said its analysis of the data is ongoing and will be presented at a future medical conference. Meanwhile, the company is talking to regulatory authorities about a possible way forward for the programme.

Each year, an estimated 4,500 people develop AL amyloidosis in the US alone, and there are an estimated 30,000 to 45,000 people living with the disease in the US and Europe, and 74,000 worldwide.