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Brian B Berger, Jeremy Gale, Steven Gilbert, Sergei Popa, Marla Sultan, Ronald Schachar, Rob Webster, Christelle Perros-Huguet; Effect of selective oral inhibition of CCR2/5 chemokine receptors compared to intravitreal ranibizumab on diabetic macular edema (DME). Invest. Ophthalmol. Vis. Sci. 2016;57(12):2109.
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© ARVO (1962-2015); The Authors (2016-present)
Chemokine receptor ligands are elevated in the aqueous and vitreous in diabetics and the MCP-1/CCR2 receptor axis appears to play an important role in alterations to the blood-retinal barrier in diabetes. We hypothesized that combined blockade of CCR2 and CCR5 receptors would improve DME. Hence, the efficacy and safety of a novel, highly specific and long-acting dual CCR2/5 receptor antagonist, PF-04634817, on DME was assessed in a multinational, multicenter, randomized, double-masked, placebo-controlled, parallel group trial of DME patients with Type 1 and 2 diabetes.
DME patients with ETDRS BCVA of 24-78 letters and spectral domain optical coherence tomographic central retinal thickness (CRT) of >250mm in the study eye at baseline were randomly assigned to receive for 12 weeks either PF-04634817 200mg orally once daily plus masked sham therapy given monthly or ranibizumab (0.3 or 0.5mg) intravitreal injection monthly plus daily oral placebo. Change from baseline at 12 weeks in BCVA, CRT, fluorescein angiographic (FA) area of leakage and grades of diabetic retinopathy (DR) were assessed.
199 subjects, with mean (SD) BCVA in the study eye of 62.3 (+11.43) letters and a mean CRT of 453.1 mm (+159.55) were randomized. Following 12 weeks of dosing mean BCVA improved 4.4 (+8.21) and 6.4 (+7.83) letters, and mean CRT decreased 24.5mm (+97.74) and 110.4mm (+130.53) in the PF-04634817 and ranibizumab groups, respectively. The least squares mean difference in BCVA was 2.41 letters (80% CI: – 3.91 to 0.91) in favor of ranibizumab. There were 6.9% and 15.4% 3-line gainers, a mean 0.17mm2 (+4.96) and 7.33mm2 (+9.28) decrease in FA leakage area, and a mean 0.0 (+0.61) and 0.5 (+1.03) reduction in grades of DR with PF-04634817 and ranibizumab, respectively. Adverse events (AEs) following PF-04634817 treatment were mostly mild, with the only treatment-related AE of headache exceeding 1% incidence.
Although there was a mean 4.4 letter improvement in BCVA following oral treatment with PF-04634817, it was unaccompanied by anatomical improvements in the retina of the study or fellow eyes. This suggests that changes in BCVA following monotherapy of selective inhibition of CCR2/5 for DME should be interpreted with caution, but further study in combination with other agents may be of value.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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