Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study

• Published in: BMC cardiovascular disorders Vol. 22; no. 1; pp. 49 - 16
• Main Authors: Wechalekar, Ashutosh, Antoni, Gunnar, Al Azzam, Wasfi, Bergström, Mats, Biswas, Swethajit, Chen, Chao, Cheriyan, Joseph, Cleveland, Matthew, Cookson, Louise, Galette, Paul, Janiczek, Robert L, Kwong, Raymond Y, Lukas, Mary Ann, Millns, Helen, Richards, Duncan, Schneider, Ian, Solomon, Scott D, Sörensen, Jens, Storey, James, Thompson, Douglas, van Dongen, Guus, Vugts, Danielle J, Wall, Anders, Wikström, Gerhard, Falk, Rodney H
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 13-02-2022; BioMed Central; BMC
• Subjects: Aged; Aged, 80 and over; Amyloid; Amyloid beta-protein; Amyloid P component; Amyloidosis; Amyloidosis - blood; Amyloidosis - diagnostic imaging; Amyloidosis - drug therapy; Amyloidosis - immunology; Antibodies; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Biomarkers; Biopsy; Carboxylic Acids - adverse effects; Carboxylic Acids - therapeutic use; Cardiac amyloidosis; Cardiomyopathies - blood; Cardiomyopathies - diagnostic imaging; Cardiomyopathies - drug therapy; Cardiomyopathies - immunology; Care and treatment; Chemotherapy; Computed tomography; Dezamizumab; Dosage; Drug dosages; Drug Therapy, Combination; Electrocardiography; Female; Health aspects; Heart; Heart failure; Humans; Immuno-PET; Intravenous administration; Laboratories; Magnetic Resonance Imaging; Male; Medical prognosis; Methylprednisolone; Miridesap; Monoclonal antibodies; Myocardium - metabolism; Myocardium - pathology; Patient outcomes; Patients; PET imaging; Pharmacodynamics; Pharmacokinetics; Pharmacology; Plasma; Positron emission tomography; Predictive Value of Tests; Proteins; Pyrrolidines - adverse effects; Pyrrolidines - therapeutic use; Risk assessment; Safety; SAP protein; Serum amyloid P component; Serum Amyloid P-Component - antagonists & inhibitors; Serum Amyloid P-Component - immunology; Spleen; Systemic amyloidosis; Time Factors; Treatment Outcome; United Kingdom; United States; Vasculitis; Ventricle; Ventricular Function, Left - drug effects; Ventricular Remodeling - drug effects; Viral antibodies; Vital signs; United States; United Kingdom; Cardiac amyloidosis; Dezamizumab; Serum amyloid P component; Miridesap; Immuno-PET; Positron emission tomography; Systemic amyloidosis
• ISSN: 1471-2261; 1471-2261
• DOI: 10.1186/s12872-021-02407-6

In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis.
Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [
Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [
Zr]Zr-dezamizumab cardiac uptake assessed via PET.
Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [
Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks.
Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).