Garadacimab and csl112, page-13

https://www.ahajournals.org/doi/10.1161/JAHA.121.024754


CSL112 COMPARED WITH PREVIOUS APOA‐I INFUSION THERAPIES

Two other apoA‐I infusion therapies, MDCO‐216 (recombinant dimeric mutant apoA‐I Milano) and CER‐001 (recombinant wild‐type apoA‐I), have been investigated in phase 2 clinical trials.^{75, 76} However, the development of MDCO‐216 has since been discontinued because of a lack of efficacy on plaque regression in an imaging study, and similar results were observed in relation to CER‐001.^{76, 77} In comparison to these products, CSL112 stimulates a far more substantial increase in ABCA1‐dependent CEC (as seen in the AEGIS‐I trial) than that achieved in phase 2 studies of MDCO‐216 and CER‐001 (330% versus 80%–90% and 6%, respectively).^{9, 75, 76} Dosing of these 3 agents in clinical studies differed substantially, which may also contribute to the disparate effects on CEC. CSL112 is administered at a total dose of 6 g, corresponding to ≈80 mg/kg based on its pharmacodynamic response, whereas MDCO‐216 and CER‐001 were dosed at 20 and 3 mg/kg, respectively.^{75, 76} In addition, CSL112 is the only apoA‐I–based product that is capable of activating lecithin‐cholesterol acyltransferase (LCAT),⁷ with animal model studies showing CSL112 infusion results in an immediate 1.7‐fold increase in plasma LCAT activity⁷; in contrast, MDCO‐216 and CER‐001 have no or inhibitory effects on LCAT, respectively.^{7, 78, 79, 80, 81}LCAT converts free cholesterol into cholesteryl ester, leading to the formation of larger, mature HDL particles, which are then transported to the liver for clearance.⁶The differences observed between CSL112 and these other apoA‐I–based infusion therapies could be attributed to differences in particle composition determined by apoA‐I and lipid source, and apoA‐I/lipid molar ratio. CSL112 contains human plasma‐derived apoA‐I and soy bean phosphatidylcholine, whereas CER‐001 and MDCO‐216 are both based on recombinant apoA‐I preparations and contain sphingomyelin/dipalmitoylphosphatidylglycerol and palmitoyl oleoyl phosphatidylcholine, respectively.^{7, 80, 82} Although CSL112 has been shown to promote LCAT activation,⁷ the other 2 formulations fail to activate LCAT.⁷ MDCO‐216 contains a disulfide linked homodimer form of apoA‐I (apoA‐I‐Milano), which has a reduced ability to activate LCAT. Lack of LCAT stimulation by CER‐001 is attributed to inhibitory effects of sphingomyelin.^{7, 78, 80, 82} The potential of CSL112 to reduce future cardiovascular events by enhancing cholesterol efflux and thereby reducing cholesterol content and/or instability of atherosclerotic plaque is being evaluated in the phase 3 AEGIS‐II study.⁸³