Treatment of patients with cardiovascular disease with L-4F, an apo-A1 mimetic, did not improve select biomarkers of HDL function.
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.
Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
Catherine E
CE
Watson
Nicole
N
Weissbach
Lise
L
Kjems
Surya
S
Ayalasomayajula
Yiming
Y
Zhang
Ih
I
Chang
Mohamad
M
Navab
Susan
S
Hama
Greg
G
Hough
Srinivasa T
ST
Reddy
Daniel
D
Soffer
Daniel J
DJ
Rader
Alan M
AM
Fogelman
Alison
A
Schecter
D000293:Adolescent; D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis; D003327:Coronary Disease / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D018716:Molecular Mimicry; D010455:Peptides / Q000493:pharmacokinetics / Q000627:therapeutic use*
D016632:Apolipoprotein A-I; D015415:Biomarkers; C472885:L-4F peptide; D010455:Peptides; D002097:C-Reactive Protein