Safety and Tolerability of ACP-501, a Recombinant Human Lecithin:Cholesterol Acyltransferase, in a Phase 1 Single-Dose Escalation Study
Rationale: Low high-density lipoprotein cholesterol (HDL-C) in coronary heart disease (CHD) patients may be due to rate-limiting amounts of lecithin:cholesterol acyltransferase (LCAT). Raising LCAT may be beneficial for CHD, as well as for Familial LCAT Deficiency (FLD), a rare disorder of low HDL-C.
Objective: To determine safety and tolerability of recombinant human LCAT (rhLCAT) infusion in subjects with stable CHD and low HDL-C and its effect on plasma lipoproteins.
Methods and Results: A phase 1b, open-label, single-dose escalation study was conducted to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of rhLCAT (ACP-501). Four cohorts with stable CHD and low HDL-C were dosed (0.9, 3.0, 9.0, and 13.5 mg/kg, single 1-hour infusions) and followed for 28 days. ACP-501 was well-tolerated and there were no serious adverse events. Plasma LCAT concentrations were dose-proportional, increased rapidly and declined with an apparent terminal half-life of 42 hours. The 0.9 mg/kg dose did not significantly change HDL-C; however, 6 hours following doses of 3.0, 9.0, and 13.5 mg/kg, HDL-C was elevated by 6%, 36%, and 42%, respectively, and remained above baseline up to 4 days. Plasma cholesteryl esters followed a similar time-course as HDL-C. ACP-501 infusion rapidly decreased small and intermediate-sized HDL, whereas large HDL increased. Preβ-HDL also rapidly decreased and was undetectable up to 12 hours post ACP-501 infusion.
Conclusions: ACP-501 has an acceptable safety profile after a single IV infusion. Lipid and lipoprotein changes indicate that rhLCAT favorably alters HDL metabolism and support rhLCAT use in future clinical trials in CHD and FLD patients.
ClinicalTrials.gov Identifier: NCT01554800
- lecithin:cholesterol acyltransferase
- First-in-human clinical trial
- recombinant enzyme replacement
- LCAT Deficiency
- high-density lipoprotein
- lipids and lipoprotein metabolism
- acute coronary syndrome
- cardiovascular disease
- Received February 9, 2015.
- Revision received November 24, 2015.
- Accepted December 1, 2015.