Darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in diabetic macular edema: a 3-month placebo-controlled study.
OBJECTIVE
To investigate the potential of lipoprotein-associated phospholipase A2 inhibition as a novel mechanism to reduce edema and improve vision in center-involved diabetic macular edema (DME).


METHODS
Prospective, multicenter, randomized, double-masked, placebo-controlled phase IIa study.


METHODS
Fifty-four center-involved DME patients randomized 2:1 to receive darapladib (n = 36) or placebo (n = 18).


METHODS
Darapladib 160 mg or placebo monotherapy was administered orally once daily for 3 months, and patients were followed up monthly for 4 months.


METHODS
Mean change from baseline in best-corrected visual acuity (BCVA) and the center subfield and center point of the study eye at month 3 as determined by spectral-domain optical coherence tomography.


RESULTS
Five patients in the study received intravitreal anti-vascular endothelial growth factor rescue therapy before the day 90 assessment, 2 of 36 (6%) in the darapladib arm and 3 of 18 (17%) in the placebo arm. Administration of 160 mg darapladib for 3 months resulted in statistically significant mean improvements, from baseline to month 3, in BCVA of 4.1 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (95% confidence interval [CI], 2.3-5.8) and of 57 μm in central subfield thickness (95% CI, -84 to -30) in the study eyes. An increase in BCVA of 1.7 ETDRS letters (95% CI, -1.0 to 4.4) and a decrease in center subfield thickness of 34 μm (95% CI, -75 to 6.8) for the placebo group were not significant. No ocular severe adverse events (SAEs) or SAEs considered related to darapladib were reported. One SAE of myocardial infarction, not considered related to darapladib, was reported, and 1 SAE of severe diarrhea was reported in a placebo patient, subsequently withdrawn from the study. Study eye ocular adverse events (AEs) and nonocular AEs were similar between treatment groups.


CONCLUSIONS
Once-daily oral darapladib administered for 3 months demonstrated modest improvements in vision and macular edema that warrant additional investigation of this novel lipoprotein-associated phospholipase A2 inhibitory mechanism for the treatment of DME.
Department of Biomedical and Clinical Science "Luigi Sacco," Sacco Hospital, University of Milan, Milan, Italy. Electronic address: giovanni.staurenghi@unimi.it.
Giovanni
G
Staurenghi
GlaxoSmithKline, King of Prussia, Pennsylvania.
Li
L
Ye
GlaxoSmithKline, King of Prussia, Pennsylvania.
Mindy H
MH
Magee
Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin.
Ronald P
RP
Danis
GlaxoSmithKline, Research Triangle Park, North Carolina.
John
J
Wurzelmann
GlaxoSmithKline, Stevenage, United Kingdom.
Peter
P
Adamson
GlaxoSmithKline, King of Prussia, Pennsylvania.
Megan M
MM
McLaughlin
D000284:Administration, Oral; D001547:Benzaldehydes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008269:Macular Edema / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010091:Oximes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D064801:Phospholipase A2 Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011446:Prospective Studies; D053719:Tandem Mass Spectrometry; D014792:Visual Acuity / Q000502:physiology; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
D001547:Benzaldehydes; D010091:Oximes; D064801:Phospholipase A2 Inhibitors; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides