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Birtamimab May Reduce Mortality Risk in Therapy-Naïve Advanced AL Amyloidosis

August 30, 2023

September 2023

Katie Robinson

Katie Robinson is a medical writer based in New York.

A late-stage study of birtamimab plus standard of care (SOC) in patients with newly diagnosed, treatment-naïve amyloid light chain (AL) amyloidosis was discontinued early due to futility analysis. However, a post-hoc all-cause mortality analysis showed benefits with the monoclonal antibody therapy targeting amyloid fibrils in Mayo Stage IV patients with cardiac involvement who are at high risk of early death. The study was published in Blood.

“Newly diagnosed, therapy-naïve patients should be referred for trial enrollment so more patients could benefit from amyloid depleter therapy,” said lead author Morie Gertz, MD, MACP, of Mayo Clinic in Rochester, Minnesota.

Patients with advanced AL amyloidosis have a high mortality risk. Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic light chain aggregates and deplete insoluble organ-deposited amyloid through macrophage-induced phagocytosis. A phase I/II trial in patients with AL amyloidosis with persistent organ dysfunction showed that birtamimab had an acceptable side-effect profile.

In the phase III randomized, double-blind, placebo-controlled VITAL clinical trial, researchers assessed the efficacy and safety of birtamimab plus SOC in 260 patients in all stages (Mayo Stages I-IV) of newly diagnosed, treatment-naïve AL amyloidosis and with cardiac involvement (including N-terminal pro-brain natriuretic peptide [NT-proBNP] ≥650 and ≤8500 pg/mL). Patients received 24 mg/kg intravenous birtamimab plus SOC (n=130; median age = 64.2 years; 63% male) or placebo plus SOC (n=130; median age = 62.6 years; 69% male) every 28 days. The primary composite endpoint was time to all-cause mortality or cardiac hospitalization at 91 days or more after first study drug infusion.

The trial was terminated early. An interim futility analysis showed no significant difference between birtamimab and placebo in the primary composite endpoint (hazard ratio [HR] = 0.826; 95% CI 0.574-1.189; log-rank p=0.303). The authors noted that given the median survival for patients with Mayo Stage I, II, and III of around 94, 40, and 14 months, respectively, the study would have unlikely been able to detect a difference in survival between treatment groups without extending the treatment duration.

A post-hoc analysis of patients with Mayo Stage IV showed significant improvement with birtamimab in time to all-cause mortality at month nine (HR=0.413; 95% CI 0.191-0.895; log-​rank p=0.021). At month nine, 74% of patients treated with birtamimab and 49% of those who received placebo survived. Treatment with birtamimab was associated with significantly less deterioration in quality of life, as measured by SF-36v2 physical component summary, and improved cardiac functioning, per six-minute walking test (6MWT). Treatment with placebo led to a 21.5-meter decline in 6MWT distance over nine months, whereas distance increased by 15.22 meters with birtamimab during the same period.

Rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were similar between groups. The most common grade 3 or higher TEAEs in the overall population included cardiac failure (birtamimab 13%, placebo 20%), pneumonia (birtamimab 11%, placebo 9%), and congestive cardiac failure (birtamimab 10%, placebo 7%). Fatal TEAEs occurred in 15% of the birtamimab group and 22% of the placebo group, most commonly cardiac disorders that occurred in 7% and 14%, respectively.

“This post-hoc analysis serves as the justification for a placebo-controlled, phase III registration trial,” Dr. Gertz said. “We are currently enrolling therapy-naïve Stage IV patients into a placebo control trial and, if positive, would be able to provide this potentially lifesaving therapy to the general amyloidosis population.”

The limitations of the post-hoc analyses include the increased potential for a false-positive result. In this case, post-hoc efficacy analyses were limited to nine months, due to early termination of the trial, with longer-term follow-up for survival not possible.

Any conflicts of interest declared by the authors can be found in the original article.


Gertz MA, Cohen AD, Comenzo RL, et al. Birtamimab plus standard of care in light chain amyloidosis: the phase 3 randomized placebo-controlled VITAL trial [published online ahead of print, 2023 Jun 27]. Blood. doi: 10.1182/blood.2022019406.


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