How is the CARES kappa subgroup data changing your approach to newly diagnosed kappa AL amyloidosis?

The CARES trial was a negative phase 3 trial comparing standard-of-care therapy with or without anselamimab (an anti-amyloid monoclonal antibody) for newly diagnosed amyloidosis.

While the overall results were negative, there was a subgroup analysis that was prespecified that showed a significant survival advantage for patients with kappa-subtype amyloidosis. There is some biological plausibility to this, as the drug is an IgG kappa antibody raised against a misfolded kappa light-chain–derived amyloid-like antigen.

As for the subgroup analysis showing benefit in the kappa subtype, it was prespecified but likely underpowered.

I think the signal is intriguing and potentially meaningful in this rarer amyloid subgroup.

But at present, it can’t poss...

These results are the first to demonstrate the potential impact of an anti-fibril therapy and are clearly an exciting advance for the field. However, clinical use of this approach is dependent on regulatory approval and further clarification of the results regarding its applicability outside of the patient population included in the trial. It is of interest that the proportion of kappa patients in the trial is far lower than what we see in the general population with light chain amyloidosis, likely a reflection of the restriction to stage 3 patients where lambda is over-represented. This also brings up the question of whether it is going to be effective in kappa patients in stage 1 or 2. It is quite plausible that the impact or incremental ...

Anselamimab (originally CAEL-101 & 11-1F4) is a chimeric immunoglobulin IgG1 kappa monoclonal antibody (mAb) directed against the human kappa light chain fibril and has shown preclinical reactivity against both isotypes, even though these preclinical studies seem like nonsense. It targets only the kappa light chain fibril, yet the primary outcome was a composite of all-cause mortality and frequency of cardiovascular hospitalizations in ALL patients.

Cardiac Amyloid Reaching for Extended Survival (CARES) was designed to determine the efficacy and safety of anselamimab in combination with standard of care (SoC) anti-PCD therapy in ALL patients with European modification of Mayo 2004 stage IIIa and IIIb AL amyloidosis.

Anselamimab reduced all-ca...

Agree 100% with @Dr. First Last and @Dr. First Last! The only word of caution I'd add to their excellent answers is that this story (a prespecified subgroup analysis showing a clear benefit in a biologically plausible way with an anti-amyloid fibril) is not new.

With a related anti-amyloid fibril called birtamimab, the original phase III VITAL study was negative but showed a compelling mortality benefit in patients with Mayo IV cardiac involvement.

Gertz et al., PMID 37366170

We then proceeded to the randomized AFFIRM-AL trial in only these patients, which was negative and not yet published. There are, of course, differences between the two scenarios (most notably the point that anselamimab was literally developed for kappa-restricted amyloido...