Treatment of patients with cardiovascular disease with L-4F, an apo-A1 mimetic, did not improve select biomarkers of HDL function

Abstract

L-4F, an apolipoprotein A-I (apoA-I) mimetic peptide (also known as APL180), was administered daily by either intravenous (IV) infusion for 7 days or by subcutaneous (SC) injection for 28 days in patients with coronary heart disease in two distinct clinical studies. L-4F was well tolerated at all doses tested. Despite achieving plasma levels (mean maximal plasma concentration of 2,907 ng/ml and 395 ng/ml, following IV infusion and SC injection, respectively), that were effective in previously published animal models, treatment with L-4F, as assessed by biomarkers of HDL function such as HDL-inflammatory index (HII), and paraoxonase activity, did not improve. Paradoxically, there was a 49% increase in high-sensitivity C-reactive protein (hs-CRP) levels after seven IV infusions of 30 mg L-4F (P < 0.05; compared with placebo) and a trend for hs-CRP increase in subjects receiving 30 mg SC injection for 28 days. In a subsequent, ex vivo study, addition of L-4F at concentrations of 150, 375, or 1,000 ng/ml to plasma from subjects prior to L-4F treatment resulted in significant dose-dependent HII improvement. In conclusion, in vivo L-4F treatment, delivered by either SC injection or IV infusion, did not improve HDL functional biomarkers despite achieving plasma levels that improved identical biomarkers ex vivo and in animal models. L-4F, an apolipoprotein A-I (apoA-I) mimetic peptide (also known as APL180), was administered daily by either intravenous (IV) infusion for 7 days or by subcutaneous (SC) injection for 28 days in patients with coronary heart disease in two distinct clinical studies. L-4F was well tolerated at all doses tested. Despite achieving plasma levels (mean maximal plasma concentration of 2,907 ng/ml and 395 ng/ml, following IV infusion and SC injection, respectively), that were effective in previously published animal models, treatment with L-4F, as assessed by biomarkers of HDL function such as HDL-inflammatory index (HII), and paraoxonase activity, did not improve. Paradoxically, there was a 49% increase in high-sensitivity C-reactive protein (hs-CRP) levels after seven IV infusions of 30 mg L-4F (P < 0.05; compared with placebo) and a trend for hs-CRP increase in subjects receiving 30 mg SC injection for 28 days. In a subsequent, ex vivo study, addition of L-4F at concentrations of 150, 375, or 1,000 ng/ml to plasma from subjects prior to L-4F treatment resulted in significant dose-dependent HII improvement. In conclusion, in vivo L-4F treatment, delivered by either SC injection or IV infusion, did not improve HDL functional biomarkers despite achieving plasma levels that improved identical biomarkers ex vivo and in animal models. Epidemiologic data support that elevated levels of HDL cholesterol are associated with an improvement in cardiovascular risk (1Gordon T. Castelli W.P. Hjortland M.C. Kannel W.B. Dawber T.R. High density lipoprotein as a protective factor against coronary heart disease.Am. J. Med. 1977; 62: 707-714Abstract Full Text PDF PubMed Scopus (4082) Google Scholar). HDL particles provide atherosclerosis protection by way of their role in reverse cholesterol transport and potentially their direct anti-inflammatory, antioxidant, and antithrombotic properties. However, there is an increasing body of literature that not all HDL particles are equal in their cardioprotective effects and that certain properties of the HDL particle itself confer either pro- or anti-inflammatory effects (2Navab M. Reddy S.T. Van Lenten B.J. Anantharamaiah G.M. Fogelman A.M. The role of dysfunctional HDL in atherosclerosis.J. Lipid Res. 2009; 50: 145-149Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). Thus, HDL function, rather than the absolute level of HDL-cholesterol, may be a more accurate indicator for risk of developing atherosclerosis and of manifesting its clinical sequelae (2Navab M. Reddy S.T. Van Lenten B.J. Anantharamaiah G.M. Fogelman A.M. The role of dysfunctional HDL in atherosclerosis.J. Lipid Res. 2009; 50: 145-149Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). This hypothesis has led to investigation of HDL as a for cardiovascular risk and a to be M. Anantharamaiah G.M. Reddy S.T. Van Lenten B.J. Fogelman A.M. HDL as a and 2009; PubMed Scopus Google Scholar). the plasma concentrations of the apolipoprotein in apolipoprotein A-I intravenous (IV) has an However, treatment with HDL or is the of is not and with prior to IV that or as M. Anantharamaiah G.M. Reddy S.T. Van Lenten B.J. Fogelman A.M. and function of HDL PubMed Scopus Google Scholar). The mimetic and L-4F in a of animal M. Anantharamaiah G.M. Reddy S.T. Van Lenten B.J. Fogelman A.M. and function of HDL PubMed Scopus Google and in with B.J. M. Fogelman A.M. and of mimetic peptide in cardiovascular Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). The of of has to be to their to and with to of as compared with Lenten B.J. M. Anantharamaiah G.M. mimetic with than Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). in mimetic to improve the of HDL to by as by in and as the HDL-inflammatory index Lenten B.J. M. Anantharamaiah G.M. mimetic with than Lipid Res. 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In of HDL anti-inflammatory and of in the plasma of patients with disease by an mimetic 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). with by treatment and as the was from in data at for the IV and SC The hypothesis the hypothesis the an L-4F and treatment, was at the from days were was the the of HII all data were prior to and biomarkers for subjects in the IV were the two mg L-4F and and were the of in the mg to the of subjects The and for subjects in the SC were were more patients in the mg of IV by (mean (mean (mean (mean disease (mean (mean apolipoprotein body high-sensitivity C-reactive in a of SC by (mean (mean (mean (mean disease (mean (mean in a apolipoprotein body high-sensitivity C-reactive L-4F was well tolerated administered IV for seven daily doses the mg the patients in the IV study, patients the were and for two patients the and were the an after of daily doses of mg This was to be to the by the of the in the were and were in and subjects of subjects at compared with of In the were and compared with in compared with in placebo) and and compared with in the of in subjects with mg L-4F was all of by body in IV and SC body and and and and and and and and and and subcutaneous the IV study, the infusion was at the of infusion in compared with in In the SC study, the injection subjects were and in and were in a the IV study, the infusion was at the of infusion in compared with in In the SC study, the injection subjects were and in and were L-4F was well tolerated administered SC for 28 daily doses and 30 the subjects in the SC study, the were mg L-4F was for an and subjects were the mg L-4F was to the for and days after receiving the of was by the to be to the of subjects at compared with of In the were and compared with in placebo) and compared with in in and with increasing were by and of 30 and were by and of 30 and patients receiving 30 mg daily SC after did not the as the for the there was for in the in the SC the of a and clinical in or were compared with in either of against the peptide was after 28 days of SC treatment not IV infusion of L-4F, and in a the mg and levels from ng/ml, and ng/ml, were and and of L-4F was following IV L-4F is with a of the of with IV and SC of in patients in a SC injection, L-4F was concentrations with in and in a the and 30 mg and levels from ng/ml, and ng/ml, were and and of L-4F was following SC L-4F was with a of of with were in plasma HDL-cholesterol, or subjects with or L-4F in either not was a trend levels of compared with for placebo) and compared with for placebo) following and IV doses of 30 mg compared with at and 7 and 7 not In was compared with its IV infusion of L-4F did not improve HII compared with despite achieving plasma levels of L-4F that following daily IV doses of or 30 mg L-4F, the level of HII was compared with and and to be than the following was not from at daily SC treatment with L-4F at or 30 there was significant in HII or compared with In at HII was not compared with despite achieving plasma levels of ng/ml and ng/ml for the and 30 there were a significant in the the were compared with the of previously with B.J. 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