Purchase this article with an account.
Rachel Williams, Shawn Patrick Shearn, Michael Dowd, Greg Cicconetti, Lars Wallentin, Harvey White, Salim Janmohamed, John I Wurzelmann, Megan M McLaughlin; Post-hoc analyses of darapladib, an oral Lp-PLA2 inhibitor, in phase III cardiovascular outcomes trials may inform investigation in diabetic macular edema . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2282.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Inhibition of Lp-PLA2 reduces blood brain and blood retinal barrier permeability in preclinical models. Darapladib, an oral Lp-PLA2 inhibitor, reduced edema and improved vision in a Phase IIa study in subjects with diabetic macular edema (DME). The hypotheses that darapladib reduces the risk of major adverse cardiovascular (CV) and major coronary events was investigated in 2 phase III CV outcome trials, STABILITY (White, NEJM, 2014) and SOLID-TIMI 52 (O’Donoghue, JAMA, 2014) with over 28,000 randomized subjects. Post-hoc analyses may inform further investigation of darapladib for the treatment of DME.
Demographics of subjects with diabetes mellitus (DM) at baseline in phase III CV trials were compared to published anti-VEGF DME registration trials. In the CV trials, safety in subjects with DM were compared to all subjects. To look for potential ocular benefit, adverse events (AEs) for DME or diabetic retinopathy (DR) and DME medications were analyzed to investigate whether an association exists with darapladib treatment in the DM subset.
In the phase III CV trials, 10,638 subjects had DM at baseline and demographics were similar to subjects in DME registration trials. Darapladib non-ocular safety parameters were similar for subjects with and without DM at baseline in both CV trials. There were a small number (n=63) of DME/DR AEs and medications. The DME AEs and medications were not significantly associated with darapladib treatment in SOLID-TIMI 52 or STABILITY, although there were fewer cases reported in the darapladib arm than the placebo arm. There were significantly fewer DR AEs in the darapladib arm (n=4) than in placebo (n=13) of SOLID-TIMI 52 (Relative Risk (RR)=0.30, 90%CI=0.12-0.78). This association was not found in STABILITY (RR=1.00, 90%CI=0.60-1.66).
Because demographics of DM subjects in the Phase III CV trials were similar to anti-VEGF DME registration trials, post-hoc analyses may inform continued investigation of darapladib in DME. Analysis of safety in the DM subset, in addition to the preliminary efficacy observed in Phase IIa, supports further study. Despite the limitations of the post-hoc DME/DR analyses that included lack of baseline ocular information, there were significantly fewer DR AEs in the darapladib arm compared to placebo in SOLID-TIMI 52.
This PDF is available to Subscribers Only