MDCO-216 Does Not Induce Adverse Immunostimulation, in Contrast to Its Predecessor ETC-216

Abstract

PurposeAim of this study was to demonstrate that MDCO-216 (human recombinant Apolipoprotein A-I Milano) does not induce adverse immunostimulation, in contrast to its predecessor, ETC-216, which was thought to contain host cell proteins (HCPs) that elicited an inflammatory reaction.MethodsData were taken from a clinical trial in which 24 healthy volunteers (HV) and 24 patients with proven stable coronary artery disease (sCAD) received a single intravenous dose of MDCO-216, ranging 5–40 mg/kg. Additionally, whole blood from 35 HV, 35 sCAD patients and 35 patients requiring acute coronary intervention (aCAD group) was stimulated ex vivo with MDCO-216 and ETC-216.ResultsNo inflammatory reaction was observed in HV and sCAD patients following MDCO-216 treatment, judging by body temperature, white cell counts, neutrophil counts, C-reactive protein, circulating cytokines (IL-6, TNF-α), and adverse events. In the ex vivo experiment, the geometric means (SD) of the ratio of MDCO-216 stimulated IL-6 over background levels were 0.8 (1.9), 0.7 (1.5), 1.0 (2.0) for respectively HV, sCAD, aCAD. The corresponding ETC-216 stimulated values were 15.8 (2.9), 9.5 (3.6), 3.8 (4.0). TNF-α results were comparable. Because many ETC-216 stimulated samples had cytokine concentrations >ULOQ, ratios were categorised and marginal homogeneity of the contingency table (MDCO-216 versus ETC-216) was assessed with the Stuart-Maxwell test. P-values were ≤0.0005 for all populations.ConclusionsMDCO-216 did not induce adverse immunostimulation in HV and sCAD patients, in contrast to ETC-216. Results from the ex vivo stimulation suggests the same holds true for aCAD patients.

Advances in HDL: Much More than Lipid Transporters

“…Consequent removal of the contaminant proteins from the nanoconstruct and essential improvements in the downstream manufacturing process led to the development of a recombinant ApoA-I Milano formulation named MDCO-216. MDCO-216 has been tested in healthy volunteers and patients with stable CAD, showing modulation of lipid parameters and an increase of cholesterol efflux with no adverse effects [129,130]. More recently, MDCO-216 has also reported, at an experimental level, to revert heart failure progression in Type 2 diabetic mice as well as restore cardiac function [154], lower myocardial acetyl-coenzyme A carboxylase levels, and decrease myocardial transforming growth factor-β1 [155].…”

Successful treatment of established heart failure in mice with recombinant HDL (Milano)

“…MDCO‐216 is a form of reconstituted HDL that consists of a complex of highly purified recombinant dimeric apoA‐I Milano and POPC and has previously been studied as a predecessor compound ETC‐216 (Kallend et al, ). The safety of MDCO‐216 has been established in clinical studies (Kallend et al, ; Kempen et al, ; Kempen et al, ; Reijers et al, ).…”

Adverse immunostimulation caused by impurities: The dark side of biopharmaceuticals

“…37,52 The same was true for product X, which elicited an IL-6 and TNF-α response that was completely absent after the production process was modified. 29 By contrast, product Y induced no IL-6 or TNF-α release in any of the assays. As many variables can influence the read-out in these assays, and controversy still surrounds the interpretation of the results, cytokine release assays are currently only used as a tool for hazard identification of drug candidates that could induce AI.…”

“…In addition, the incidence of gastrointestinal symptoms occurring 2-4 hours after infusionrose with each dose escalation, as did the incidence of diaphoresis and fever. 29 In the next phase, in patients with an acute coronary syndrome, 30 one patient out of a group of 22 receiving the highest dose level experienced what was described as a hypersensitivity reaction. A second (unpublished) patient trial was quickly suspended after one patient on active treatment developed a severe reaction during infusion, leading to multiorgan failure.…”