Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis

Abstract

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by pathologic deposition of immunoglobulin light chains as amyloid fibrils in vital organs, leading to organ impairment and eventual death. That the process is reversible was evidenced in an in vivo experimental model in which fibril-reactive chimeric monoclonal antibody (mAb) 11-1F4 directly targeted human light-chain amyloid deposits and effected their removal via a phagocyte-mediated response. To determine tolerability and potential amyloidolytic effect of this agent (now designated mAb CAEL-101), we conducted a phase 1a/b study involving 27 patients, most of whom had manifestations of organ involvement. This was an open label study in which phase 1a patients received mAb CAEL-101 as a single intravenous infusion, with escalating dose levels from 0.5 mg/m2 to 500 mg/m2 to establish the maximum tolerated dose (MTD). In phase 1b, the antibody was administered as a graded series of four weekly infusions. For both phases, there were no drug-related serious adverse events or dose-limiting toxicities among recipients and the MTD was not reached. Majority of patients had deep hematologic responses but persistent organ disease prior to treatment. Fifteen of 24 patients (63%) who manifested cardiac, renal, hepatic, gastrointestinal, or soft tissue involvement had a therapeutic response to mAb CAEL-101 as evidenced by serum biomarkers or objective imaging modalities with median time to response of 3 weeks. Infusions of mAb CAEL-101 were well-tolerated and, for the majority, resulted in improved organ function, notably for those with cardiac impairment. This trial was registered at www.clinicaltrials.gov as NCT02245867.

Targeting Amyloid Fibrils by Passive Immunotherapy in Systemic Amyloidosis

“…: 56/130 (43.1%) of patients in the NEOD001 arm and 62/130 patients (47.7%) in the placebo arm Time to death or cardiac hosp. (ITT analysis): Log-rank test: p = 0.3300; HR 0.835 (two-sided 95% CI 0.5799–1.2011) SAE in 88/130 (67.7%) patients in the NEOD001 arm and 91/130 (70%) patients in the placebo arm [ 49 ] Anselamimab (CAEL-101) NCT02245867 Phase Ia/b Completed 27 patients Primary: MTD; safety Secondary: PK; organ response DE: 0.5, 5, 10, 50, 100, 250, 500 mg/m 2 until MTD, expansion of the two highest dose levels Phase Ia: single dose; Phase Ib: four weekly injections No DLT up to 500 mg/m 2 ; MTD not achieved in either phase Ia or Ib; half-life of CAEL-101: 10–16 days; cardiac and renal responses in 67% and 20% of evaluable patients, respectively AE grade 3 or higher: pruritus (12.5%), pericardial effusion (5.3%) [ 57 ] PRX004 NCT03336580 Phase I Terminated (COVID-19) DE: 21 patients Long-term extension: 17 patients Primary: MTD; treatment-emergent AEs Secondary: PK; anti-drug Ab DE: 0.1, 0.3, 1, 3, 10, 30 mg/kg IV every 28 days Expansion/long-term extension at RP2D DE: up to 3 infusions Long-term extension: up to 15 infusions PK consistent with IgG1 monoclonal antibodies; pooled data from cohorts >3 mg/kg on 7 evaluable patients; improved GLS in 7 patients and improved NIS in 3 patients No drug-related SAE; AEs (> 10%): fall, anemia, URTI, back pain, constipation, diarrhea, insomnia [ 61 ] AA amyloid A amyloidosis, Ab antibodies, AE adverse event, AF atrial fibrillation, AFib fibrinogen Aα-chain amyloidosis, AL AL amyloidosis, AApoAI apolipoprotein A-I amyloidosis, ATTR transthyretin amyloidosis, CMR cardiac magnetic resonance, CI confidence interval, COVID-19 coronavirus disease 2019, DE dose escalation, DLT dose-limiting toxicity, DPD 3,3-diphosphono-1,2-propanodicarboxylic acid, echo echocardiogram, ECV extracellular volume, expl. exploratory, GLS global longitudinal strain, hosp.…”

“…These results led the National Cancer Institute’s Biological Resource Branch to production of the anti-amyloid fibril chimeric IgG1 antibody anselamimab (CAEL-101). The outcome of the phase Ia/b trial (NCT02245867) has been recently reported [ 57 ]. This was an uncontrolled, open-label, single-center, ‘up-and-down’ dose-escalation study investigating the tolerance, safety, pharmacokinetics, and possible clinical benefit of anselamimab (Table 2 ).…”

“…Pharmacokinetic studies indicated a biphasic disposition of the antibody due to a rapid distribution phase, slower elimination phase, and long half-life of 10–16 days, consistent with the pharmacokinetics of other IgG antibodies, but in contrast with the 4–16 h half-life of dezamizumab (Table 1 ). Excluding three patients without measurable disease, the overall organ response rate was 63%, with a median time to response of 3 weeks [ 57 ]. Organ responses were noted only among evaluable patients receiving > 5 mg/m 2 of anselamimab.…”

Immunoglobulin light chain amyloidosis: 2022 update on diagnosis, prognosis, and treatment

“…There are now three Phase 3 trials underway using antibodies designed to bind to epitopes on the fibril lead to macrophage activation and fibril dissolution. In Phase 1 trial, CAEL‐101 was found to be well tolerated in patients with cardiac AL amyloidosis and led to rapid and sustained organ response in previously treated patients 100 . There are now trials underway for patients with cardiac amyloidosis.…”

Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

“…However, the results from the phase 1a/b study on the anti-LC amyloid fibril antibody CAEL-101 showed good organ response without causing serious adverse events. A sustained decrease in NT-proBNP levels and improvement in global longitudinal strain (GLS) were observed, notably for those with cardiac impairment [ 99 ]. Phase III trials are currently underway in untreated patients with AL amyloidosis who have advanced heart damage (Mayo Stage IIIb) [ 100 ].…”