MERLIN: Brolucizumab Linked to Higher Intraocular Inflammation Rates At 2 Years

Arshad Khanani, MD, MA

Credit: Sierra Eye Associates

Two-year results from the Phase 3a MERLIN trial revealed brolucizumab 6 mg dosed every 4 weeks (Q4W) was non-inferior to aflibercept 2 mg in best-corrected visual acuity (BCVA) change from baseline in eyes with neovascular age-related macular degeneration (nAMD).¹

These data were consistent with the 1-year primary efficacy endpoint results demonstrating the non-inferiority of Q4W brolucizumab to the 2 mg aflibercept dose at 52 weeks.² However, despite leading to robust improvements in anatomic outcomes, brolucizumab displayed an increase in intraocular inflammation (IOI) over the 104-week study period.

“After careful evaluation of the individual benefit-risk for a given patient, it is recommended that brolucizumab should not be used more frequently than every 8 weeks (Q8W) after the loading regimen,” wrote the investigative team, led by Arshad M. Khanani, MD, MA, director of clinical research, Sierra Eye Associates.

Brolucizumab is an anti-vascular endothelial growth factor (VEGF) agent approved to treat eyes with nAMD.³ MERLIN was a 2-year study designed to evaluate the safety and efficacy of brolucizmab 6 mg to aflibercept 2 mg Q4W in previously anti-VEGF-treated eyes who experience persistent retinal fluid.²

In MERLIN, improvements in BCVA and reductions in CST were reported during the first year. However, the study was terminated during the second year along with other studies of Q4W-mandated brolucizumab dosing, owing to reports of retinal vasculitis.

All availability efficacy and safety data from the second year of MERLIN were reported up to study termination, or Week 104 for participants who completed the study before termination.¹ This included an analysis of noninferiority in mean BCVA, CST, fluid-free status, and safety data. All P values after Week 52 were considered nominal and reflected the observed data for the efficacy analyses.

Overall, 535 eyes of 535 participants were randomized and treated in MERLIN. After study termination in May 2021, 297 and 161 eyes in the brolucizumab 6 mg and aflibercept 2 mg were treated with the study drug at Week 52 and later.

Upon analysis, brolucizumab 8 mg Q4W was non-inferior to aflibercept 2 mg in mean BCVA change at Week 104 (least-squares mean difference, –0.4 ETDRS letters [95% CI, –3.7 to 3.0; P = .0169). The percentage of eyes with ≥15-letter loss was 6.2% in the brolucizumab and 4.7% in the aflibercept arm.

Moreover, the mean change in CST from baseline was –73.3 µm for brolucizumab and –42.1 µm for aflibercept, for a least-squares mean difference of –31.2 µm (P = .0014). Until study termination, brolucizumab-treated eyes experienced a greater and more sustained reduction in CST than aflibercept.

From Week 52 to Week 104, investigators measured the percentage of eyes that remained without intraretinal or subretinal fluid. At Week 104, a greater proportion of eyes treated with brolucizumab were fluid-free, compared with aflibercept (52.% vs. 28.2%; 95% CI, 11.9–37.3; P <.001).

Safety data showed the incidence of adverse events of special interest in the study eye was higher in the brolucizumab arm than in the aflibercept arm at study termination. The incidence of IOI, including retinal vasculitis and retinal vascular occlusion, occurred in 41 (11.5%) eyes in the brolucizumab group, including 7 after study termination, and 11 (6.1%) in the aflibercept group.

“Consistent with previous clinical studies as well as real-world studies, there were robust anatomical outcomes with brolucizumab that were maintained up to Week 104, including improvements in CST and the proportion of eyes with a fluid-free retina,” Khanani and colleagues wrote. “However, there were an increased incidence of IOI AEs over the 104-week study period, including retinal vasculitis, and increased incidence of retinal vascular occlusion compared with eyes receiving aflibercept treatment.”

References

1. _{Brown DM, Jaffe GJ, Wykoff CC, Adiguzel E, Heier JS, Khanani AM. MERLIN: Two-Year Results of Brolucizumab in Participants With Neovascular Age-Related Macular Degeneration and Persistent Retinal Fluid. Ophthalmology. Published online August 23, 2024. doi:10.1016/j.ophtha.2024.08.022}
2. _{Khanani AM, Brown DM, Jaffe GJ, et al. Merlin: Phase 3a, multicenter, randomized, double masked trial of brolucizumab in participants with neovascular age-related macular degeneration and persistent retinal fluid. Ophthalmology 2022;129(9):974-985.}
3. _{Nguyen QD, Das A, Do DV, et al. Brolucizumab: Evolution through preclinical and clinical studies and the implications for the management of neovascular age-related macular degeneration. Ophthalmology 2020;127(7):963-976.}