Familial lecithin:cholesterol acyltransferase deficiency: First-in-human treatment with enzyme replacement

• Published in: Journal of clinical lipidology Vol. 10; no. 2; pp. 356 - 367
• Main Authors: Shamburek, Robert D., MD, Bakker-Arkema, Rebecca, PharmD, Auerbach, Bruce J., PhD, Krause, Brian R., PhD, Homan, Reynold, PhD, Amar, Marcelo J., MD, Freeman, Lita A., PhD, Remaley, Alan T., MD, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2016
• Subjects: Anemia - complications; Cardiovascular; Cholesterol; Cholesterol, HDL - blood; Disease Progression; HDL; Hematologic Tests; Humans; Kidney - drug effects; LCAT; Lecithin cholesterol acyltransferase; Lecithin cholesterol acyltransferase deficiency; Lecithin Cholesterol Acyltransferase Deficiency - blood; Lecithin Cholesterol Acyltransferase Deficiency - complications; Lecithin Cholesterol Acyltransferase Deficiency - drug therapy; Lecithin Cholesterol Acyltransferase Deficiency - enzymology; Lipoprotein-X; Male; Middle Aged; Phosphatidylcholine-Sterol O-Acyltransferase - adverse effects; Phosphatidylcholine-Sterol O-Acyltransferase - pharmacokinetics; Phosphatidylcholine-Sterol O-Acyltransferase - pharmacology; Phosphatidylcholine-Sterol O-Acyltransferase - therapeutic use; Recombinant enzyme replacement; Recombinant Proteins - adverse effects; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; Renal disease; Safety; Triglyceride; HDL; Lecithin cholesterol acyltransferase deficiency; Lipoprotein-X; Lecithin cholesterol acyltransferase; Renal disease; LCAT; Triglyceride; Recombinant enzyme replacement; Cholesterol
• ISSN: 1933-2874; 1876-4789
• DOI: 10.1016/j.jacl.2015.12.007

Background Humans with familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) have extremely low or undetectable high-density lipoprotein cholesterol (HDL-C) levels and by early adulthood develop many manifestations of the disorder, including corneal opacities, anemia, and renal disease. Objective To determine if infusions of recombinant human LCAT (rhLCAT) could reverse the anemia, halt progression of renal disease, and normalize HDL in FLD. Methods rhLCAT (ACP-501) was infused intravenously over 1 hour on 3 occasions in a dose optimization phase (0.3, 3.0, and 9.0 mg/kg), then 3.0 or 9.0 mg/kg every 1 to 2 weeks for 7 months in a maintenance phase. Plasma lipoproteins, lipids, LCAT levels, and several measures of renal function and other clinical labs were monitored. Results LCAT concentration peaked at the end of each infusion and decreased to near baseline over 7 days. Renal function generally stabilized or improved and the anemia improved. After infusion, HDL-C rapidly increased, peaking near normal in 8 to 12 hours; analysis of HDL particles by various methods all revealed rapid sequential disappearance of preβ-HDL and small α-4 HDL and appearance of normal α-HDL. Low-density lipoprotein cholesterol increased more slowly than HDL-C. Of note, triglyceride routinely decreased after meals after infusion, in contrast to the usual postprandial increase in the absence of rhLCAT infusion. Conclusions rhLCAT infusions were well tolerated in this first-in-human study in FLD; the anemia improved, as did most parameters related to renal function in spite of advanced disease. Plasma lipids transiently normalized, and there was rapid sequential conversion of small preβ-HDL particles to mature spherical α-HDL particles.