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

BMC Cardiovascular Disorders

Guus van Dongen¹  Danielle J. Vugts¹  Raymond Y. Kwong²  Rodney H. Falk²  Scott D. Solomon²  Joseph Cheriyan³  Duncan Richards⁴  Matthew Cleveland⁴  Robert L. Janiczek⁴  Ian Schneider⁴  Swethajit Biswas⁴  Mats Bergström⁴  Douglas Thompson⁴  James Storey⁴  Wasfi Al Azzam⁴  Mary Ann Lukas⁴  Louise Cookson⁴  Chao Chen⁴  Paul Galette⁴  Helen Millns⁴  Jens Sörensen⁵  Anders Wall⁵  Gunnar Antoni⁵  Gerhard Wikström⁵  Ashutosh Wechalekar⁶ 

[1] Amsterdam UMC, VU University;Brigham and Women’s Hospital;Cambridge University Hospitals NHS Foundation Trust;GlaxoSmithKline;Institutionen för Medicinska Vetenskaper, Uppsala University;University College London;

关键词: Cardiac amyloidosis;    Miridesap;    Dezamizumab;    Positron emission tomography;    Immuno-PET;    Serum amyloid P component;   

DOI  :  10.1186/s12872-021-02407-6

来源: DOAJ

【 摘 要 】

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).

【 授权许可】

Unknown