Birtamimab: a new amyloidosis treatment?

In this issue of Blood, Gertz et al¹ report a post hoc analysis of patients with severe cardiac amyloid light chain (AL) amyloidosis treated in the VITAL trial, a phase 3 randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of standard of care (SOC) chemotherapy plus birtamimab, a humanized antibody designed to eliminate the toxic light chain (LC) oligomers and deposits (see figure). They found reduced all-cause mortality at 9 months for the subset of patients with Mayo stage IV cardiac AL amyloidosis receiving birtamimab compared with the placebo group.^1,2 

AL amyloidosis remains a very serious disease. Staging, especially of cardiac involvement through simple markers (troponin, proBNP), now identifies patients with a high risk of death. Mayo stage IIIB and IV patients have a median overall survival of only a few months.

There are 2 active areas of novel therapeutics for the management of the treatment of patients with amyloidosis. First, the efficacy of chemotherapy has improved. The randomized ANDROMEDA trial demonstrated that the addition of daratumumab, an anti-CD38 immunotherapeutic agent, to chemotherapy (bortezomib, cyclophosphamide, and dexamethasone) in patients with Mayo stage I to IIIA disease increased the hematological response rate (53.3% vs 18.1%) and improved the cardiac and renal response (decrease in proBNP and proteinuria) but without statistical significance on overall survival.³ Kastritis et al tested daratumumab in monotherapy to stage IIIB patients and showed a doubling or more of overall survival compared with a historical control.⁴ Thus, the mortality rate of stage IIIB/IV patients remains high, and there may be a concern that chemotherapy toxicity could actually contribute to the problem by destabilizing organ function. Second is the addition of therapeutics specifically to reduce the formation of deposits or to increase deposit clearance: The first trials date from 1995, when Gianni et al attempted to break down amyloid deposits by cyclin derivatives, without clear success.⁵ Epigallocatechin-3-gallate, a green tea polyphenol, showed some efficacy in reducing the volume of the left ventricle by interfering with amyloid fibrillogenesis in patients with cardiopathy⁶; however, no additional studies were conducted. Recently, Wechalekar et al used a strategy against the serum amyloid P component (SAP). After depletion of serum SAP by miridesap, patients received dezamizumab, a monoclonal antibody against SAP. No improvement was found at 8 weeks of administration of the product, and adverse reactions like vasculitis were found.⁷ NEOD001, or birtamimab, is a humanized monoclonal antibody directed against LC, designed to neutralize toxic soluble LC aggregates⁸ and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis.⁹ It was tested in a phase I/II trial of 27 patients who had already received 1 or more lines of chemotherapy. The tolerance and safety of immunotherapy were excellent, and clinical improvements were noted.¹⁰ The VITAL trial tested the addition of birtamimab to SOC bortezomib-based chemotherapy in a phase 3 randomized double-blind trial in 260 patients who were newly diagnosed. The unpublished trial was prematurely stopped at 9 months of treatment initiation after a futility analysis.

In this study, Gertz et al extracted data from the VITAL trial in a post hoc analysis of 77 stage IV patients (38 birtamimab/39 placebo) and found a difference in overall survival in favor of birtamimab. Admittedly, the statistical analysis must be viewed with great caution, as the VITAL trial was not designed for this analysis. The response to chemotherapy was identical, but disappointing, in both the birtamimab and placebo groups, with only 12 of 38 and 11 of 39 patients, respectively, achieving a hematological response better than or equal to a very good partial response at 3 months. This raises the question of the impact of earlier, more effective chemotherapy on the study outcome.

In the end, this post hoc analysis does suggest for the first time that there may be efficiency to an antideposit molecule. It therefore raises hope for the management of the most serious cases of AL amyloidosis. The small number of patients (77 patients) and the short duration of the study requires further validation for this indication. Indeed, the AFFIRM-AL study, a randomized phase 3 trial (2/1), will test birtamimab against placebo + SOC, including daratumumab, in 150 patients with stage IV amyloidosis and will hopefully prove informative. Finally, it should be noted that another trial (CAEL) is under development to test another immunotherapy antibody, 11-1F4, directed against the amyloidogenic serum light chains in patients with stage IIIA and IIIB AL amyloidosis.

Conflict-of-interest disclosure: The author declares no competing financial interests.