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International Symposium on Amyloidosis (ISA) 2022

Emerging therapies in advanced AL amyloidosis

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Last updated: 13th Sep 2022
Published:13th Sep 2022
Author: By Simon van Rysewyk, PhD

The second highlight article from the 18th International Symposium on Amyloidosis (ISA) 2022 is an overview of the Satellite Symposium, ‘Addressing the Unmet Need in Advanced AL Amyloidosis: Key insights from a panel of experts,’ presented by Morie Gertz (Mayo Clinic, USA), on Tuesday 6, September 2022, in Heidelberg, Germany.

Investigational anti-amyloid monoclonal antibodies

Professor Morie Gertz begins with a cautionary note against focusing too much attention on anti-amyloid treatments that target production of free light-chain amyloid proteins. He urges the development of more anti-amyloid treatments that reduce or eliminate pre-existing amyloid deposits in bodily tissues.

Two investigational anti-amyloid monoclonal antibodies for amyloid light-chain (AL) amyloidosis in phase 3 trials are:

  • CAEL-101
  • Birtamimab

CAEL-101 is a chimeric mAb that targets AL amyloid deposits4,5. Birtamimab is a fully humanised monoclonal antibody (mAb) that targets soluble AL aggregates, and insoluble AL amyloid deposits6,7. Soluble AL aggregates could be part of the cellular toxicity of free light-chains.

CAEL-101 clinical trials

In an open-label, phase 1a/b trial (N = 27)8, there were no drug-related serious adverse events or dose-limiting toxicities in the participants, and the maximum tolerated dose was not reached in phase 1a or 1b. Fifteen of 24 patients (63%) who showed cardiac, renal, hepatic, gastrointestinal or soft tissue involvement, had a therapeutic response to CAEL-101, shown in serum biomarkers (≥30% N-terminal-pro brain natriuretic peptide [NT-proBNP] decrease from baseline), or objective imaging modalities with a median time to response of 3 weeks. Infusions of CAEL-101 were well tolerated.

In a phase 2, single-arm, open-label trial (N = 25)9, 24 patients had treatment-emergent adverse events (TEAE), but only six had a treatment-related TEAE. Eight patients experienced at least 1 Grade ≥3 TEAE, and seven experienced at least one serious adverse event (SAE). Of the 19 current cardiac evaluable patients, 15 (78.9%) responded (≥30% NT-proBNP decrease from baseline) or were stable on CAEL-101 therapy.

Two phase 3 trials in patients with AL amyloidosis stage-IIIa and IIIb with cardiac involvement, Cardiac Amyloid Reaching for Extended Survival (CARES), are ongoing4,5.

CAEL-101 can lead to rapid and sustained organ responses in patients with AL amyloidosis previously treated with standard therapy4,5,8,9

Birtamimab clinical trials

In vitro evidence in rodents shows that birtamimab induces phagocytosis of aggregated AL amyloidosis deposits in a human macrophage cell line (THP-1). According to Professor Gertz, this evidence suggests that macrophages are activated once birtamimab binds in vitro to the amyloid fibril.

In a phase 1/2, open-label dose-escalation trial (N=27)10, no drug-related SAEs, discontinuations due to drug-related AEs, dose-limiting toxicities, or antidrug antibodies were found. Recommended dosing was 24 mg/kg. Pharmacokinetics support intravenous dosing every 28 days. Of 14 cardiac-evaluable patients, eight (57%) met the criteria for cardiac response (≥30% NT-proBNP decrease from baseline), and six (43%) had stable disease. Of 15 renal-evaluable patients, nine (60%) met the criteria for renal response and six (40%) had stable disease.

Post hoc analysis: VITAL

Post hoc analysis of 9-month all-cause mortality (ACM) data, presented by Professor Gertz at ISA 2022, from the terminated (based on a futility analysis of the primary endpoint) phase 3 VITAL trial11, showed a substantial survival benefit (hazard ratio [HR], 0.413; 95% confidence intervals [CI]: 0.191, 0.895; P=0.025) in patients at high risk for early death (Mayo 2012 Stage IV), for which no approved treatments exist. Post hoc analyses of secondary endpoints in this subgroup revealed meaningful improvements in health-related quality of life (36-Item Short Form Health Survey version 2; SF-36v2) and 6-minute walk test (6MWT) distance with birtamimab + SOC (P<0.05) at 9 months.


Professor Gertz also introduced at ISA 2022 the phase 3, double-blind, placebo-controlled AFFIRM-AL study (NCT04973137), which will enrol up to 150 Mayo stage IV patients with newly diagnosed, untreated AL amyloidosis6. AFFIRM-AL is designed to confirm the survival benefit observed in the VITAL study in patients with Mayo 2012 stage IV AL amyloidosis.

  • Primary efficacy endpoint: time to all-cause mortality
  • Secondary endpoints: change from baseline to month 9 in the physical component summary of the Short Form 36 version 2 (SF-36v2) quality-of-life questionnaire and the 6-Minute Walk Test (6MWT) distance


CAEL-101 and birtamimab are two investigational anti-amyloid monoclonal antibodies for AL amyloidosis that have been assessed in phase 3 clinical trials. The CARES clinical program includes two parallel phase 3 studies (one in patients with Mayo-stage IIIa disease, and one in patients with Mayo-stage IIIb disease) designed to evaluate CAEL-101 in combination with standard-of-care (SoC) therapy. Enrolment is underway in both studies. The primary objective of CARES is to assess overall survival. In the phase 3 VITAL trial, post hoc analysis of all-cause mortality over 9 months revealed a pronounced survival benefit for birtamimab in a subgroup of patients with Mayo stage IV disease. Given the >50% reduction in the risk of all-cause mortality observed in VITAL, the AFFIRM-AL study aims to confirm this effect of birtamimab. Site initiation and patient randomisation are ongoing.


  1. Sanchorawala V, Boccadoro M, Gertz M, Hegenbart U, Kastritis E, Landau H, et al. Guidelines for high dose chemotherapy and stem cell transplantation for systemic AL amyloidosis: EHA-ISA working group guidelines. Amyloid. 2022;29(1):1–7.
  2. Wechalekar AD, Cibeira MT, Gibbs SD, Jaccard A, Kumar S, Merlini G, et al. Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group. Amyloid. 2022:1–15.
  3. Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, et al. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. New Eng J Med. 2021;385(1):46–58.
  4. A Study to Evaluate the Efficacy and Safety of CAEL-101 in Patients With Mayo Stage IIIb AL Amyloidosis. 2022. Available at:
  5. A Study to Evaluate the Efficacy and Safety of CAEL-101 in Patients With Mayo Stage IIIa AL Amyloidosis. 2022. Available at:
  6. A Study to Evaluate the Efficacy and Safety of Birtamimab in Mayo Stage IV Patients With AL Amyloidosis. 2022. Available at:
  7. Gertz MA, Tripuraneni R, Kinney GG. Birtamimab in Patients with Mayo Stage IV AL Amyloidosis: Rationale for Confirmatory Affirm-AL Phase 3 Study Design. Blood. 2021;138:2754.
  8. Edwards CV, Rao N, Bhutani D, Mapara M, Radhakrishnan J, Shames S, et al. Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis. Blood. 2021;138(25):2632–2641.
  9. Valent J, Zonder JA, Liedtke M, Silowsky J, Kurman MR, Daniel E, et al. Safety and Tolerability of Cael-101 in Combination with Anti-Plasma Cell Dyscrasia Therapy in Patients with AL Amyloidosis: 1-Year Results from an Open-Label Phase 2 Trial. Blood. 2021;138:468.
  10. Gertz MA, Landau H, Comenzo RL, Seldin D, Weiss B, Zonder J, et al. First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction. J Clin Oncol. 2016;34(10):1097–1103.
  11. Gertz MA, Cohen AD, Comenzo RL, Du Mond C, Kastritis E, Landau HJ, et al. Results of the phase 3 VITAL study of NEOD001 (Birtamimab) plus standard of care in patients with light chain (AL) amyloidosis suggest survival benefit for mayo stage IV patients. Blood. 2019;134:3166.
  12. FDA. DARZALEX FASPRO® Highlights of Prescribing information. 2022. Available at:
  13. Vaxman L, Gertz M. Recent Advances in the Diagnosis, Risk Stratification, and Management of Systemic Light-Chain Amyloidosis. Acta Haematol. 2019;141(2):93–106.
  14. Ciberia MT, Ortiz-Pérez JT, Quintana LF, Fernádez de Larrea C, Tovar N, Bladé J. Supportive Care in AL Amyloidosis. Acta Haematol. 2020;143(4):335–342.

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