Sirolimus/Aflibercept Combo Shows Potential Benefits for Wet AMD

The addition of sirolimus to aflibercept (Eylea) did not significantly improve central subfield thickness (CST) but did show marked reduction in intraretinal and subretinal fluid compared with aflibercept alone for patients with wet age-related macular degeneration (AMD), according to findings from a 20-patient phase 2 study presented at the 2017 American Society of Retina Specialists Annual Meeting.

Although CST was not statistically improved, there was a trend toward better activity with the combination. At the end of 36 weeks, there was a 50 µm decrease in thickness with the addition of sirolimus. There was an 85% reduction in subretinal fluid volume with the combination compared with a 31% reduction with aflibercept alone. Additionally, intraretinal fluid was nearly eliminated with the combination.

"Sirolimus does have a biological effect on choroidal neovascularization," said lead investigator Raj K. Maturi, MD, from the Midwest Eye Institute. "The current study did not meet the primary endpoint, which I believe is likely due to the small sample size."

In the study, 20 patients were randomized to receive sirolimus plus aflibercept (n = 10) or aflibercept alone (n = 10). In the combination arm, sirolimus was administered at 440 µg at baseline and on weeks 4, 12, 20, and 28 with standard-dose aflibercept on weeks 1, 8, and 16, with future doses every 8 weeks if needed based on the presence of fluid. In the single-agent group, aflibercept was given on weeks 8, 16, 24, and 32.

All patients were receiving anti-VEGF therapy for wet AMD at the time of enrollment. In the combination arm, patients had received 43 prior anti-VEGF injections and in the single-agent group 34 prior injections had been administered. Patients in the combination arm were younger than the control (71 vs 77 years), and the last treatment was received 4.8 weeks prior in the combination arm compared with 6.3 weeks prior in the control group.

At baseline, patients in the combination arm had a visual acuity of 63 letters versus 61 letters in the monotherapy group. Best-corrected visual acuity improved by 2.5 letters with the combination compared with 0.75 letters for aflibercept alone. At week 36, there was a -0.04 mm³ reduction in central 1 mm foveal volume for the combination versus single-agent.

"There were no visual acuity changes between the two treatment groups, but I believe that if we had used less chronically diseased eyes, we probably would have gotten a better acuity gain," said Maturi.

Subretinal fluid was present for 9 patients in the combination group and for 10 in the aflibercept alone arm. At baseline, patients in the combination arm had 10.99 mm³ of fluid in their subretinal space versus 9.79 mm³ in the aflibercept alone group. By week 36, this had dropped to 1.68 mm³ and 6.77 mm³, a decline of -9.32 and -3.02 for the combination and monotherapy arms, respectively.

Additionally, drops in intraretinal fluid volume were seen with the combination. At baseline, 3 patients in the combination arm had 4.4 mm³ of intraretinal fluid and 3 in the control arm had 13.2 mm³ of fluid. By week 36 essentially all fluid was gone for those in the combination arm (0.05 mm³ remained). In the aflibercept alone group, 3.25 mm³ of intraretinal fluid remained.

At the time of the analysis, there had not been any treatment-related serious adverse events. "It appears safe, when given 4 weeks apart, as it was during the loading dose, and in combination with VEGF agents."

Maturi RK, Chhablani J, Harless A, et al. Sirolimus in Conjunction With Aflibercept vs Aflibercept Monotherapy for the Treatment of Chronic Exudative AMD. Presented at: 35th Annual Meeting of the American Society of Retina Specialists; August 11-15, 2017; Boston, Massachusetts.