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

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).

Keywords: Cardiac amyloidosis; Dezamizumab; Immuno-PET; Miridesap; Positron emission tomography; Serum amyloid P component; Systemic amyloidosis.

Conflict of interest statement

AW1 has received consultancy fees from GSK. WA-A, MB, SB, CC, MC, LC, MAL, HM, DR, IS, JS2, RLJ, PG, and DT are employees of or hold stocks/shares in GSK. JC is a fulltime Cambridge University Hospitals NHS Foundation Trust employee who was seconded for 50% of his NHS time to the GSK unit in Cambridge until September 2020. He received no employee benefits from GSK. RHF, RYK received research funding from GSK in support of the work provided by the CMR core laboratory. GW has received lecture fees from Novartis, Orion-Pharma, and Actelion. Outside of office hours Professor Wikström received remuneration from CTC. JS1 has no competing interests. SDS has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, and Theracos, and has consulted for Abbott, Action Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GSK, Ironwood, Lilly, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, and American Regent. GA and AW2: report no conflicts of interest. GvD: received funding from GSK for [89Zr]Zr-dezamizumab development and production. He has an unpaid position of Chief Scientific Officer (CSO) at LinXis biopharmaceuticals. DJV: received funding from GSK for [89Zr]Zr-dezamizumab development and production.

© 2022. The Author(s).

Figures

Fig. 1

Study design for the Phase 2 study (A) and immuno-PET study (B). *Blood SAP depletion could extend beyond Days –2 and –1. Note: for the Phase 2 study the start of anti-SAP monoclonal antibody treatment was denoted as Day 1, whereas for the immuno-PET study the start of miridesap treatment was denoted as Day 1. CMR cardiac magnetic resonance, ECHO echocardiogram, IV intravenous, MRI magnetic resonance imaging, PET positron emission tomography, SAP serum amyloid P component, SC subcutaneous

Fig. 2

Mean (SD) complement C3 concentration over time (Phase 2 study; safety population). A n = 5 on Day 2; B n = 4 at the 4-h time point on Day 1. SD standard deviation

Fig. 3

a Mean (SD) LVM over time; b mean (SD) change from baseline in LVM over time (Phase 2 study; safety population). Vertical bars show SD. LVM left ventricular mass, SD standard deviation

Fig. 4

A Coronal view of cardiac uptake of [89Zr]Zr-dezamizumab and B whole-body standardised uptake values (immuno-PET study; all-treated population)