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

Shamburek, Robert D.; Bakker-Arkema, Rebecca; Shamburek, Alexandra M.; Freeman, Lita A.; Amar, Marcelo; Auerbach, Bruce J.; Krause, Brian R.; Homan, Reynold; Adelman, Steve; Collins, Heidi L.; Sampson, Maureen; Wolska, Anna; Remaley, Alan T.

doi:10.1161/circresaha.115.306223

Cited by 74 publications

(51 citation statements)

References 40 publications

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“…Recently, recombinant human LCAT (rhLCAT; ACP-501) was shown to be safe in a phase I study of subjects with stable cardiovascular disease 15 (ClinicalTrials.gov NCT01554800) and is being developed as a potential therapy for acute coronary syndrome. In this report, we describe the first-in-human use of enzyme replacement therapy (ERT) with rhLCAT in a patient with FLD and its effect on lipoprotein metabolism, and hematologic and renal function.…”

Section: Introductionmentioning

confidence: 99%

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

Shamburek

Bakker-Arkema

Auerbach

et al. 2016

Journal of Clinical Lipidology

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BACKGROUND Humans with familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) have extremely low or undetectable 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 i.v. 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 1–2 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 8–12 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. LDL-C increased more slowly than HDL-C. Of note, triglyceride routinely decreased after meals following infusion, in contrast to the usual post-prandial 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.

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Section: Introductionmentioning

confidence: 99%

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

Shamburek

Bakker-Arkema

Auerbach

et al. 2016

Journal of Clinical Lipidology

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“…Finally, to test the feasibility of whether LCAT can be used as a potential therapy for reducing Lp‐X in cholestasis, we injected rhLCAT into WT mice treated with ANIT (Figures and ). Based on observations from previous clinical trials of rhLCAT, we hypothesized that the increased esterification of cholesterol by the infused rhLCAT would remodel Lp‐X into normal lipoproteins, as we observed in the LCAT‐Tg mice experiments. Figure A shows the baseline lipoproteins of WT mice (m1 to m6) by agarose gels stained with Filipin (Figure A, top) or Sudan black (Figure A, bottom), prior to ANIT treatment.…”

Section: Resultsmentioning

confidence: 89%

“…It can acutely lower Lp‐X, leading to the normalization of alkaline phosphatase, total bilirubin and AST. Based on the results of this study, rhLCAT, which has been shown to be safe in early stage clinical trials, could also be a potential therapy. rhLCAT is delivered by intravenous infusion and has a half‐life of several days, so it would be difficult to use as a chronic therapy, but it may be useful for the acute management of cholestatic patients.…”

Section: Discussionmentioning

confidence: 85%

“…Based on the results of this study, rhLCAT, which has been shown to be safe in early stage clinical trials, could also be a potential therapy. rhLCAT is delivered by intravenous infusion and has a half‐life of several days, so it would be difficult to use as a chronic therapy, but it may be useful for the acute management of cholestatic patients. There are also early efforts to develop small molecule activators of LCAT, which could be a future consideration as a therapy for this disorder.…”

Section: Discussionmentioning

confidence: 85%

“…Furthermore, recombinant LCAT can prevent Lp‐X formation and renal disease in a mouse model of LCAT deficiency . Because LCAT has a half‐life of several days, a recombinant form of LCAT has been developed as a potential enzyme replacement therapy for FLD . FLD patients, however, do not typically develop cholestasis so the mechanism for formation of Lp‐X in this disorder is thought to be different than in cholestatic liver disease.…”

Section: Introductionmentioning

confidence: 99%

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LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis

Amar

Freeman

Nishida

et al. 2019

Pharmacology Res & Perspec

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Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease characterized by low HDL‐C levels, low plasma cholesterol esterification, and the formation of Lipoprotein‐X (Lp‐X), an abnormal cholesterol‐rich lipoprotein particle. LCAT deficiency causes corneal opacities, normochromic normocytic anemia, and progressive renal disease due to Lp‐X deposition in the glomeruli. Recombinant LCAT is being investigated as a potential therapy for this disorder. Several hepatic disorders, namely primary biliary cirrhosis, primary sclerosing cholangitis, cholestatic liver disease, and chronic alcoholism also develop Lp‐X, which may contribute to the complications of these disorders. We aimed to test the hypothesis that an increase in plasma LCAT could prevent the formation of Lp‐X in other diseases besides FLD. We generated a murine model of intrahepatic cholestasis in LCAT‐deficient (KO), wild type (WT), and LCAT‐transgenic (Tg) mice by gavaging mice with alpha‐naphthylisothiocyanate (ANIT), a drug well known to induce intrahepatic cholestasis. Three days after the treatment, all mice developed hyperbilirubinemia and elevated liver function markers (ALT, AST, Alkaline Phosphatase). The presence of high levels of LCAT in the LCAT‐Tg mice, however, prevented the formation of Lp‐X and other plasma lipid abnormalities in WT and LCAT‐KO mice. In addition, we demonstrated that multiple injections of recombinant human LCAT can prevent significant accumulation of Lp‐X after ANIT treatment in WT mice. In summary, LCAT can protect against the formation of Lp‐X in a murine model of cholestasis and thus recombinant LCAT could be a potential therapy to prevent the formation of Lp‐X in other diseases besides FLD.

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Novel Missense LCAT Gene Mutation Associated with an Atypical Phenotype of Familial LCAT Deficiency in Two Portuguese Brothers

et al. 2017

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Familial lecithin-cholesterol acyltransferase deficiency (FLD) is a rare recessive disorder of cholesterol metabolism, caused by loss-of-function mutations in the human LCAT gene, leading to alterations in the lipid/lipoprotein profile, with extremely low HDL levels.The classical FLD phenotype is characterized by diffuse corneal opacification, haemolytic anaemia and proteinuric chronic kidney disease (CKD); an incomplete form, only affecting the corneas, has been reported in a few families worldwide.We describe an intermediate phenotype of LCAT deficiency, with CKD preceding the development of corneal clouding, in two Portuguese brothers apparently homozygous for a novel missense LCAT gene mutation. The atypical phenotype, the diagnosis of membranous nephropathy in the proband's native kidney biopsy, the late-onset and delayed recognition of the corneal opacification, the co-segregation with Gilbert syndrome and the late recurrence of the primary disease in kidney allograft all contributed to obscure the diagnosis of an LCAT deficiency syndrome for many years.A major teaching point is that on standard light microscopy examination the kidney biopsies of patients with LCAT deficiency with residual enzyme activity may not show significant vacuolization and may be misdiagnosed as membranous nephropathy. The cases of these two patients also illustrate the importance of performing detailed physical examination in young adults presenting with proteinuric CKD, as the most important clue to the diagnosis of FLD is in the eyes.

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

Cited by 74 publications

References 40 publications

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

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

LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis

Novel Missense LCAT Gene Mutation Associated with an Atypical Phenotype of Familial LCAT Deficiency in Two Portuguese Brothers

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