Effect of open-label infusion of an apoA-I-containing particle (CER-001) on RCT and artery wall thickness in patients with FHA

Reverse cholesterol transport (RCT) contributes to the anti-atherogenic effects of HDL. Patients with the orphan disease, familial hypoalphalipoproteinemia (FHA), are characterized by decreased tissue cholesterol removal and an increased atherogenic burden. We performed an open-label uncontrolled proof-of-concept study to evaluate the effect of infusions with a human apoA-I-containing HDL-mimetic particle (CER-001) on RCT and the arterial vessel wall in FHA. Subjects received 20 infusions of CER-001 (8 mg/kg) during 6 months. Efficacy was assessed by measuring (apo)lipoproteins, plasma-mediated cellular cholesterol efflux, fecal sterol excretion (FSE), and carotid artery wall dimension by MRI and artery wall inflammation by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography scans. We included seven FHA patients: HDL-cholesterol (HDL-c), 13.8 [1.8–29.1] mg/dl; apoA-I, 28.7 [7.9–59.1] mg/dl. Following nine infusions in 1 month, apoA-I and HDL-c increased directly after infusion by 27.0 and 16.1 mg/dl (P = 0.018). CER-001 induced a 44% relative increase (P = 0.018) in in vitro cellular cholesterol efflux with a trend toward increased FSE (P = 0.068). After nine infusions of CER-001, carotid mean vessel wall area decreased compared with baseline from 25.0 to 22.8 mm2 (P = 0.043) and target-to-background ratio from 2.04 to 1.81 (P = 0.046). In FHA-subjects, CER-001 stimulates cholesterol mobilization and reduces artery wall dimension and inflammation, supporting further evaluation of CER-001 in FHA patients. Reverse cholesterol transport (RCT) contributes to the anti-atherogenic effects of HDL. Patients with the orphan disease, familial hypoalphalipoproteinemia (FHA), are characterized by decreased tissue cholesterol removal and an increased atherogenic burden. We performed an open-label uncontrolled proof-of-concept study to evaluate the effect of infusions with a human apoA-I-containing HDL-mimetic particle (CER-001) on RCT and the arterial vessel wall in FHA. Subjects received 20 infusions of CER-001 (8 mg/kg) during 6 months. Efficacy was assessed by measuring (apo)lipoproteins, plasma-mediated cellular cholesterol efflux, fecal sterol excretion (FSE), and carotid artery wall dimension by MRI and artery wall inflammation by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography scans. We included seven FHA patients: HDL-cholesterol (HDL-c), 13.8 [1.8–29.1] mg/dl; apoA-I, 28.7 [7.9–59.1] mg/dl. Following nine infusions in 1 month, apoA-I and HDL-c increased directly after infusion by 27.0 and 16.1 mg/dl (P = 0.018). CER-001 induced a 44% relative increase (P = 0.018) in in vitro cellular cholesterol efflux with a trend toward increased FSE (P = 0.068). After nine infusions of CER-001, carotid mean vessel wall area decreased compared with baseline from 25.0 to 22.8 mm2 (P = 0.043) and target-to-background ratio from 2.04 to 1.81 (P = 0.046). In FHA-subjects, CER-001 stimulates cholesterol mobilization and reduces artery wall dimension and inflammation, supporting further evaluation of CER-001 in FHA patients. The large residual burden of CVD in patients receiving guideline-based medical treatment, underscores the need for additional therapeutic interventions (1Fruchart J-C. Davignon J. Hermans M.P. Al-Rubeaan K. Amarenco P. Assmann G. Barter P. Betteridge J. Bruckert E. Cuevas A. et al.Residual macrovascular risk in 2013: what have we learned?.Cardiovasc. Diabetol. 2014; 13: 26Crossref PubMed Scopus (129) Google Scholar). Strategies aimed at increasing HDL-cholesterol (HDL-c) have been pursued as a promising target in CVD prevention for more than two decades (2Di Angelantonio E. Sarwar N. Perry P. Kaptoge S. Ray K.K. Thompson A. Wood A.M. Lewington S. Sattar N. et al.Emerging Risk Factors Collaboration.Major lipids, apolipoproteins, and risk of vascular disease.JAMA. 2009; 302: 1993-2000Google Scholar, 3Kannel W.B. Castelli W.P. Gordon T. Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham study.Ann. Intern. Med. 1979; 90: 85-91Crossref PubMed Scopus (1000) Google Scholar), albeit without a clear CVD benefit. Both the cholesteryl ester transfer protein (CETP) inhibitors (4Schwartz G.G. Olsson A.G. Abt M. Ballantyne C.M. Barter P.J. Brumm J. Chaitman B.R. Holme I.M. Kallend D. Leiter L.A. et al.Effects of dalcetrapib in patients with a recent acute coronary syndrome.N. Engl. J. Med. 2012; 367: 2089-2099Crossref PubMed Scopus (1554) Google Scholar) and nicotinic acid derivatives (5Boden W.E. Probstfield J.L. Anderson T. Chaitman B.R. Desvignes-Nickens P. Koprowicz K. McBride R. Teo K. Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.N. Engl. J. Med. 2011; 365: 2255-2267Crossref PubMed Scopus (2267) Google Scholar), increasing HDL-c on top of standard-of-care by 25–40%, have failed to reduce CVD risk. The expectation of HDL-c as an anti-atherogenic target was further jeopardized by the Mendelian randomization studies, which revealed that common genetic variations affecting HDL-c levels were not associated with CVD risk (6Voight B.F. Peloso G.M. Orho-Melander M. Frikke-Schmidt R. Barbalic M. Jensen M.K. Hindy G. Hólm H. Ding E.L. Johnson T. et al.Plasma HDL cholesterol and risk of myocardial infarction: A mendelian randomisation study.Lancet. 2012; 380: 572-580Abstract Full Text Full Text PDF PubMed Scopus (1648) Google Scholar). In retrospect, the strongest benefits for HDL-increasing strategies in experimental atherosclerosis were confined to interventions increasing apoA-I levels, the major protein constituent of the HDL particle. apoA-I has been shown to play a key role in the initial step of reverse cholesterol transport (RCT) (7Zhang Y. Zanotti I. Reilly M.P. Glick J.M. Rothblat G.H. Rader D.J. Overexpression of apolipoprotein A-I promotes reverse transport of cholesterol from macrophages to feces in vivo.Circulation. 2003; 108: 661-663Crossref PubMed Scopus (372) Google Scholar, 8Duverger N. Kruth H. Emmanuel F. Caillaud J.M. Viglietta C. Castro G. Tailleux A. Fievet C. Fruchart J.C. Houdebine L.M. et al.Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits.Circulation. 1996; 94: 713-717Crossref PubMed Scopus (213) Google Scholar). Tissue cholesterol efflux was decreased in patients with the orphan disease of genetically-determined low HDL-c, familial hypoalphalipoproteinemia (FHA) (9Holleboom A.G. Jakulj L. Franssen R. Decaris J. Vergeer M. Koetsveld J. Luchoomun J. Glass A. Hellerstein M.K. Kastelein J.J. et al.In vivo tissue cholesterol efflux is reduced in carriers of a mutation in APOA1.J. Lipid Res. 2013; 54: 1964-1971Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar), which coincided with accelerated atherogenesis (10Bochem A.E. van Wijk D.F. Holleboom A.G. Duivenvoorden R. Motazacker M.M. Dallinga-Thie G.M. de Groot E. Kastelein J.J. Nederveen A.J. Hovingh G.K. et al.ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden.Eur. Heart J. 2013; 34: 286-291Crossref PubMed Scopus (58) Google Scholar, 11Duivenvoorden R. Holleboom A.G. van den Bogaard Nederveen A.J. de Groot E. Hovingh G.K. 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R. et al.Effects of high-density lipoprotein infusions on coronary a PubMed Scopus Google Scholar), failed to a of apoA-I infusion on coronary apoA-I infusion was associated with a the the effect of infusion of CER-001 in patients after an compared with baseline without a compared with infusion J-C. Ballantyne C.M. Barter P. Kastelein J.J. C. H. W. et al.Effects of the high-density lipoprotein CER-001 on coronary atherosclerosis in patients with acute coronary a Heart J. 2014; PubMed Scopus Google Scholar). A common in that HDL-c In the proof-of-concept we that infusions with CER-001, a HDL-mimetic particle human apoA-I in a with two cholesterol mobilization from the artery wall in patients with characterized by clear in apoA-I we patients with FHA and low apoA-I levels, received a of 20 infusions during 6 months. The was assessed by measuring plasma-mediated cellular cholesterol efflux, and fecal sterol excretion Both at baseline and after 6 we the effect of CER-001 on arterial wall and study was in with the of and in with and the of the and The study was by the and the and was at the in The The was by the and We of with an HDL-c based on for a mutation affecting at of to HDL-c apoA-I, and were on at 6 study included major and the of The study is in we FHA patients to MRI and emission tomography/computed tomography of the carotid Following the baseline the of a of 20 CER-001 infusions was (8 in apoA-I CER-001 is a of human apoA-I and a of two The apoA-I is in and by a The of and in a The of a in the CER-001 particle has been shown to of CER-001 with the of the CER-001 after infusion C. CER-001, a of HDL and of in vitro and in vivo Scholar). The ratio of protein to in the CER-001 is The is a of the CER-001 in The of CER-001 in the is as the of the apoA-I infusions of CER-001 were 1 after the the to infusion of CER-001 were a after which infusions were the and infusion we to and at and after the of CER-001 infusion to evaluate and lipoprotein Subjects the plasma-mediated cellular cholesterol efflux was in vitro in the after the After the and the MRI of the carotid was The was after the infusion of to of FSE was at baseline and after the CER-001 infusion in a of to additional In study lipoprotein were by a 6 and for cholesterol and cholesterol as performed by a The area of the to with the of and HDL was Cholesterol ester levels were by the cholesterol from the cholesterol in The of and cholesterol were performed on the The of apoA-I was performed a of was with an of of cellular cholesterol efflux was in vitro to and at the initial of macrophages were with for Following was after with were performed in cellular cholesterol efflux was as the of the from the relative to the in and M. D. B.F. M. Rader D.J. Rothblat G.H. The to efflux the of with high-density lipoprotein cholesterol to cholesterol from PubMed Scopus Google Scholar). and after CER-001 FSE was for a of in a of the of the a and fecal was were to to a to a and to the of the was to for variations in fecal as is not by the T. K. of of on of cholesterol J. PubMed Scopus Google Scholar). the of of fecal and fecal were and with from which 20 was a and were as M. A. S. F. A. for the of fecal Lipid Res. Full Text PDF PubMed Google Scholar, A.M. N. J. for the of of and in Lipid Res. Full Text PDF PubMed Google Scholar). were by The with a and a The was in derivatives by The a The The excretion of and was as relative compared with the excretion of sterol excretion was to sterol excretion during the MRI of carotid were on a MRI The a carotid MRI were to a R. de Groot E. van Kastelein J.J. Nederveen A.J. In vivo of carotid artery wall MRI 2009; PubMed Scopus Google Scholar). In were in from common carotid as In were from common carotid with the the carotid wall were The baseline and were based on vessel wall and from the carotid performed and wall were in after which mean vessel wall area was Patients were to at baseline and after the CER-001 of the carotid was performed as A. G.G. S. D. D. G.M. K. S. et al.In vivo emission tomography a of carotid inflammation in PubMed Scopus Google Scholar, S. J. A. M. emission tomography of atherosclerotic inflammation is for atherosclerosis PubMed Scopus Google Scholar). In The of the were after infusion in the and carotid arterial wall was assessed by as at of the artery were the arterial was as the the the and the carotid the mean was by the of The arterial target-to-background ratio was by the mean for the mean in the which was from the of at the The vessel which was as the carotid artery with the at baseline M. Kallend D. Abt M. T. Ballantyne C.M. J.C. et and of dalcetrapib on atherosclerotic disease a 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). were performed directly to and after of the and infusion was in to the and was for of with a of In a for the of was by a the cholesterol efflux to CER-001 in of was as a in cholesterol efflux the of and were at infusion and to for was to and after the on the are as with with of to after treatment, the was In of we the to was a in was were performed the to and the were performed A of was The of the study in apoA-I and included in carotid MRI and and in FSE and were the key are in two were included in the were a mutation in two patients apoA-I and for apoA-I and in and patients with a mutation in two for apoA-I and in coronary artery two from myocardial coronary artery and received coronary interventions for patients were The baseline a HDL-c of 13.8 mg/dl and a apoA-I of 28.7 = artery disease, with in a with the after 1 of CER-001 CER-001 increased apoA-I and HDL-c for at after the of the infusion with a in HDL-c directly after the of the infusion at = 1 16.1 mg/dl = 0.018) and for apoA-I levels after the of the infusion 27.0 mg/dl; = 0.018). cholesterol in the HDL increased mg/dl; = in with a increase of cholesterol in the HDL mg/dl; = 0.018). of and revealed in the cholesterol in not increase of in in lipoprotein and apoA-I levels In vitro plasma-mediated cellular cholesterol efflux increased CER-001 after the of the CER-001 infusion an increase of compared with baseline to a relative increase of (P = FSE was in a of were with in the for apoA-I as and cholesterol not the baseline and infusion After CER-001 treatment, was a trend toward increased FSE to = to an of during after trend was by sterol excretion (P = acid excretion was (P = FSE increased in patients CER-001 and we and effect of CER-001 infusion on FSE carotid was 25.0 mm2 of the patients atherosclerotic at was increased compared with that in R. de Groot E. van Kastelein J.J. 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PubMed Scopus Google Scholar) and the of in in on treatment, at In of the seven were the study In with a apoA-I were to CER-001 with a for in study were at to and after The for a apoA-I for at baseline and was for in study 20 and In of the cholesterol efflux to CER-001, as a of the of In FHA infusion of the HDL-mimetic CER-001 in a increase in apoA-I and HDL-c, with in and cholesterol were by a increase in plasma-mediated cellular cholesterol efflux in with a trend toward increased sterol excretion in the After nine infusions of CER-001 1 month, of the carotid artery decreased compared with which after an additional infusions during the months. The of the carotid arterial wall inflammation, was reduced after nine infusions of the of proof-of-concept study that CER-001 stimulates RCT in FHA to a in arterial wall as as arterial wall Following infusion of CER-001, apoA-I levels increased with a to baseline levels the low The increase in HDL-c levels the increase in apoA-I which is with the of the CER-001 and from apoA-I M. L.A. of fecal excretion after infusion of reverse cholesterol transport in PubMed Scopus Google Scholar, R. F. G. increase in tissue and reverse cholesterol transport in Lipid Res. Full Text Full Text PDF PubMed Google Scholar). 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Sattar N. et al.Emerging Risk Factors Collaboration.Major lipids, apolipoproteins, and risk of vascular disease.JAMA. 2009; 302: 1993-2000Google Scholar, 3Kannel W.B. Castelli W.P. Gordon T. Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham study.Ann. Intern. Med. 1979; 90: 85-91Crossref PubMed Scopus (1000) Google Scholar). we the of low HDL-c on tissue cholesterol efflux, in patients with low HDL-c levels (9Holleboom A.G. Jakulj L. Franssen R. Decaris J. Vergeer M. Koetsveld J. Luchoomun J. Glass A. Hellerstein M.K. Kastelein J.J. et al.In vivo tissue cholesterol efflux is reduced in carriers of a mutation in APOA1.J. 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In the patients were in an in of cholesterol which the from proof-of-concept study further evaluation of the HDL-mimetic CER-001 in patients with FHA a the have a for the to two orphan for the of CER-001 in the of patients with apoA-I The proof-of-concept study that CER-001, a human apoA-I-containing HDL-mimetic stimulates RCT in FHA patients. the in carotid and arterial wall inflammation, that the cholesterol at from the atherosclerotic vessel further evaluation of the effect of CER-001 in larger in patients with FHA.