Safety and Tolerability of ACP-501, a Recombinant Human Lecithin:Cholesterol Acyltransferase, in a Phase 1 Single-Dose Escalation Study

Abstract

Rationale: Low high-density lipoprotein-cholesterol (HDL-C) in patients with coronary heart disease (CHD) may be caused by rate-limiting amounts of lecithin:cholesterol acyltransferase (LCAT). Raising LCAT may be beneficial for CHD, as well as for familial LCAT deficiency, a rare disorder of low HDL-C.

Objective: To determine safety and tolerability of recombinant human LCAT 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 recombinant human LCAT (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 up 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 after 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 ≤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. Pre-β-HDL also rapidly decreased and was undetectable ≤12 hours post ACP-501 infusion.

Conclusions: ACP-501 has an acceptable safety profile after a single intravenous infusion. Lipid and lipoprotein changes indicate that recombinant human LCAT favorably alters HDL metabolism and support recombinant human LCAT use in future clinical trials in CHD and familial LCAT deficiency patients.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01554800.

Keywords: acute coronary syndrome; cardiovascular diseases; cholesterol; cholesterol, HDL; lecithin cholesterol acyltransferase; lecithin cholesterol acyltransferase deficiency.

© 2015 American Heart Association, Inc.

Figures

Figure 1. Plasma kinetic decay curve of LCAT

(A) ACP-501 was intravenously infused over a 1 hour time point and total LCAT mass was measured at the indicated time points by an ELISA that measures both rhLCAT (ACP-501) and endogenous LCAT. Results represent the mean (N=4) ±1 SEM for each dose cohort. The baseline LCAT mass for each patient at time 0 was subtracted from subsequent time points. (B) Dose-response relationship between ACP-501 dose and change in HDL-C. The maximum HDL-C concentration change from baseline that occurred any time after the infusion was plotted against the plasma level of total LCAT mass after completion of infusion. Results are shown for individual subjects for the indicated dose cohorts.

Figure 1. Plasma kinetic decay curve of LCAT

(A) ACP-501 was intravenously infused over a 1 hour time point and total LCAT mass was measured at the indicated time points by an ELISA that measures both rhLCAT (ACP-501) and endogenous LCAT. Results represent the mean (N=4) ±1 SEM for each dose cohort. The baseline LCAT mass for each patient at time 0 was subtracted from subsequent time points. (B) Dose-response relationship between ACP-501 dose and change in HDL-C. The maximum HDL-C concentration change from baseline that occurred any time after the infusion was plotted against the plasma level of total LCAT mass after completion of infusion. Results are shown for individual subjects for the indicated dose cohorts.

Figure 2. Time course for changes in HDL-C and CE after ACP-501 infusion

(A) Mean absolute change from baseline in plasma HDL-C through day 7. (B) Mean absolute change from baseline in plasma CE through day 7. Results represent mean (N=4) ±1 SEM for each dose cohort.

Figure 2. Time course for changes in HDL-C and CE after ACP-501 infusion

(A) Mean absolute change from baseline in plasma HDL-C through day 7. (B) Mean absolute change from baseline in plasma CE through day 7. Results represent mean (N=4) ±1 SEM for each dose cohort.

Figure 3. Time course for changes in apoA-I and cholesterol levels after ACP-501 infusion

(A) Mean absolute change from baseline in apoA-I levels over time through day 7. Results represent mean (N=4) ±1 SEM for each dose cohort. (B) Mean absolute change from baseline for indicated lipids is shown through day 7. Results represent mean (N=4) ±1 SEM for the 9.0 mg/kg dose cohort.

Figure 3. Time course for changes in apoA-I and cholesterol levels after ACP-501 infusion

(A) Mean absolute change from baseline in apoA-I levels over time through day 7. Results represent mean (N=4) ±1 SEM for each dose cohort. (B) Mean absolute change from baseline for indicated lipids is shown through day 7. Results represent mean (N=4) ±1 SEM for the 9.0 mg/kg dose cohort.

Figure 4. Time course for changes in HDL subfraction distribution after ACP-501 infusion

Mean % change from baseline in small (A), medium (B), and large (C) HDL subfractions over time, determined by Lipoprint electrophoresis followed by staining with Sudan Black. Results represent mean (N=4) ±1 SEM for each dose cohort. (D) Non-denaturing gel electrophoresis of serum from a patient receiving 9.0 mg/kg ACP-501 collected at the indicated time points and immunoblotted for apoA-I.

Figure 4. Time course for changes in HDL subfraction distribution after ACP-501 infusion

Mean % change from baseline in small (A), medium (B), and large (C) HDL subfractions over time, determined by Lipoprint electrophoresis followed by staining with Sudan Black. Results represent mean (N=4) ±1 SEM for each dose cohort. (D) Non-denaturing gel electrophoresis of serum from a patient receiving 9.0 mg/kg ACP-501 collected at the indicated time points and immunoblotted for apoA-I.

Figure 4. Time course for changes in HDL subfraction distribution after ACP-501 infusion

Mean % change from baseline in small (A), medium (B), and large (C) HDL subfractions over time, determined by Lipoprint electrophoresis followed by staining with Sudan Black. Results represent mean (N=4) ±1 SEM for each dose cohort. (D) Non-denaturing gel electrophoresis of serum from a patient receiving 9.0 mg/kg ACP-501 collected at the indicated time points and immunoblotted for apoA-I.

Figure 4. Time course for changes in HDL subfraction distribution after ACP-501 infusion

Mean % change from baseline in small (A), medium (B), and large (C) HDL subfractions over time, determined by Lipoprint electrophoresis followed by staining with Sudan Black. Results represent mean (N=4) ±1 SEM for each dose cohort. (D) Non-denaturing gel electrophoresis of serum from a patient receiving 9.0 mg/kg ACP-501 collected at the indicated time points and immunoblotted for apoA-I.

Figure 5. Time course for changes in HDL-mediated cholesterol efflux and LCAT activity after ACP501 infusion

(A) Mean % change from baseline in non-ABCA1 dependent cholesterol efflux from J774 cells not stimulated with cAMP. (B) Mean % change from baseline in global cholesterol efflux from J774 cells stimulated with cAMP. (C) Mean % change from baseline in ABCA1 dependent cholesterol efflux. (D) Mean % change from baseline in cholesterol esterification during the ex vivo cholesterol efflux study from J774 cells not stimulated with cAMP. Results represent mean (n=4) ±1 SEM for the 9 mg/kg dose cohort. Mean absolute values at baseline ±1 SEM were the following: Non-ABCA1 cholesterol efflux (4.35 ± 0.44 %/4h), Global cholesterol efflux (8.14 ± 1.79 %/4h), ABCA1 cholesterol efflux (3.79 ± 1.71 %/4h), LCAT activity (15.6 ± 3.0 %/4h). (*) Indicates values with P<0.05 compared to baseline.

Figure 5. Time course for changes in HDL-mediated cholesterol efflux and LCAT activity after ACP501 infusion

(A) Mean % change from baseline in non-ABCA1 dependent cholesterol efflux from J774 cells not stimulated with cAMP. (B) Mean % change from baseline in global cholesterol efflux from J774 cells stimulated with cAMP. (C) Mean % change from baseline in ABCA1 dependent cholesterol efflux. (D) Mean % change from baseline in cholesterol esterification during the ex vivo cholesterol efflux study from J774 cells not stimulated with cAMP. Results represent mean (n=4) ±1 SEM for the 9 mg/kg dose cohort. Mean absolute values at baseline ±1 SEM were the following: Non-ABCA1 cholesterol efflux (4.35 ± 0.44 %/4h), Global cholesterol efflux (8.14 ± 1.79 %/4h), ABCA1 cholesterol efflux (3.79 ± 1.71 %/4h), LCAT activity (15.6 ± 3.0 %/4h). (*) Indicates values with P<0.05 compared to baseline.

Figure 5. Time course for changes in HDL-mediated cholesterol efflux and LCAT activity after ACP501 infusion

(A) Mean % change from baseline in non-ABCA1 dependent cholesterol efflux from J774 cells not stimulated with cAMP. (B) Mean % change from baseline in global cholesterol efflux from J774 cells stimulated with cAMP. (C) Mean % change from baseline in ABCA1 dependent cholesterol efflux. (D) Mean % change from baseline in cholesterol esterification during the ex vivo cholesterol efflux study from J774 cells not stimulated with cAMP. Results represent mean (n=4) ±1 SEM for the 9 mg/kg dose cohort. Mean absolute values at baseline ±1 SEM were the following: Non-ABCA1 cholesterol efflux (4.35 ± 0.44 %/4h), Global cholesterol efflux (8.14 ± 1.79 %/4h), ABCA1 cholesterol efflux (3.79 ± 1.71 %/4h), LCAT activity (15.6 ± 3.0 %/4h). (*) Indicates values with P<0.05 compared to baseline.

Figure 5. Time course for changes in HDL-mediated cholesterol efflux and LCAT activity after ACP501 infusion

(A) Mean % change from baseline in non-ABCA1 dependent cholesterol efflux from J774 cells not stimulated with cAMP. (B) Mean % change from baseline in global cholesterol efflux from J774 cells stimulated with cAMP. (C) Mean % change from baseline in ABCA1 dependent cholesterol efflux. (D) Mean % change from baseline in cholesterol esterification during the ex vivo cholesterol efflux study from J774 cells not stimulated with cAMP. Results represent mean (n=4) ±1 SEM for the 9 mg/kg dose cohort. Mean absolute values at baseline ±1 SEM were the following: Non-ABCA1 cholesterol efflux (4.35 ± 0.44 %/4h), Global cholesterol efflux (8.14 ± 1.79 %/4h), ABCA1 cholesterol efflux (3.79 ± 1.71 %/4h), LCAT activity (15.6 ± 3.0 %/4h). (*) Indicates values with P<0.05 compared to baseline.