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.


Type
Article
Change log
Authors
Wechalekar, Ashutosh  ORCID logo  https://orcid.org/0000-0002-4406-7237
Antoni, Gunnar 
Al Azzam, Wasfi 
Bergström, Mats 
Biswas, Swethajit 
Abstract

BACKGROUND: 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. METHODS: 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 [89Zr]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 [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: 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 [89Zr]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. CONCLUSIONS: 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).

Description
Keywords
Cardiac amyloidosis, Dezamizumab, Immuno-PET, Miridesap, Positron emission tomography, Serum amyloid P component, Systemic amyloidosis, Aged, Aged, 80 and over, Female, Humans, Male, Amyloidosis, Antibodies, Monoclonal, Carboxylic Acids, Cardiomyopathies, Drug Therapy, Combination, Magnetic Resonance Imaging, Myocardium, Positron-Emission Tomography, Predictive Value of Tests, Pyrrolidines, Serum Amyloid P-Component, Time Factors, Treatment Outcome, United Kingdom, United States, Ventricular Function, Left, Ventricular Remodeling
Journal Title
BMC Cardiovasc Disord
Conference Name
Journal ISSN
1471-2261
1471-2261
Volume Title
22
Publisher
Springer Science and Business Media LLC
Sponsorship
National Institute for Health and Care Research (IS-BRC-1215-20014)