Dezamizumab

The study is intended to evaluate whether monthly repeated courses of administration of GSK2315698 followed by GSK2398852 is associated with a reduction in cardiac amyloid load in patients with cardiac amyloidosis, monitored by cardiac magnetic resonance imaging (CMR) and echocardiography (ECHO), and whether this is associated with an improvement in cardiac function. Cohort 1 is transthyretin cardiomyopathy (ATTR-CM) , cohort 2 is patients with immunoglobulin light chain (AL) systemic amyloidosis at greater than 6 months post chemotherapy, cohort 3 newly diagnosed AL systemic amyloidosis undergoing chemotherapy. Primary objectives for the study are assessment of reduction in cardiac amyloid load after repeated administrations of Anti-SAP treatment as evaluated by CMR in all study groups and assessment of safety & tolerability of repeated administration of Anti-SAP treatment, including compatibility with chemotherapy treatment in patients with AL systemic amyloidosis. This is an open label, non-randomised, three-group, monthly repeat Anti-SAP treatment study in systemic amyloidosis patients with cardiac dysfunction caused by cardiac amyloidosis. Subjects will receive up to 6 courses of Anti-SAP treatment. Maximum total duration for a subject in the study is approximately 18 months.

The study will be conducted in two parts. The first (Part A) will be an open label single dose escalation part beginning with the proposed starting dose level of GSK2398852 as 5 milligram (mg) [approximately equivalent to 0.1 mg/kilogram (kg)]. The next escalation dose levels are proposed as 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg. GSK2315698 will be administered at variable doses until the concentration of the serum amyloid P component monoclonal antibody (SAP mAb) has fallen below 100 nanogram/millilitre (ng/mL). Decisions about these next dose levels will be made following safety review of the prior subjects' data; dose levels may be changed (increased and lowered) and dose levels may be repeated depending on the observed safety such that Part A extension study may be performed. In addition, pharmacokinetics of GSK2315698 (SAP depleter) and GSK2398852 (anti-SAP mAb), and circulating SAP concentrations will be assessed. Dose escalation in Part A will continue to the highest well tolerated dose or the highest allowable dose. Subjects will be closely monitored and will undergo Equilibrium contrast Magnetic Resonance Imaging (EqMRI) including organ volume, Elastography and Liver Biopsy if required.
Part B will be a randomized partially blinded part with the principal objective of assessing the dose response of the GSK2398852 in more detail. Subjects will be assigned to one of approximately 5 dose groups from Part A. The precise selection of numbers of subjects and dose levels will be informed by the results from Part A.