Combination Therapy with Brolucizumab Appeared Well-Tolerated for nAMD Eyes

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Combination therapy of brolucizumab and monthly aflibercept monthly appeared well-tolerated and may be considered for eyes with macular fluid on every-8-week brolucizumab.

Combination anti-VEGF therapy alternating between intravitreal brolucizumab and monthly aflibercept appeared beneficial and well-tolerated in eyes with neovascular age-related macular degeneration (nAMD), according to data from a real-world retrospective study.1

For a majority of these eyes, brolucizumab treatment was linked to an improvement in macular fluid, stabilization of best-corrected visual acuity (BCVA), and/or an increase in intravitreal treatment interval. The investigative team led by Susanna S. Park, MD, PhD, University of California Davis, noted the few cases of mild intraocular inflammation (IOI) observed in these eyes were not associated with vision loss.

“Depending on the patient’s perspective, the benefit of potentially increasing the treatment interval using intravitreal brolucizumab might offset the risk of IOI on intravitreal brolucizumab,” the team wrote.

The US Food and Drug Administration (FDA) approved brolucizumab in 2019 based on the results of the phase 3 HAWK and HARRIER trials. Results from the 2 trials indicated the therapy administered every 8 or 12 weeks was non-inferior to aflibercept administered every 8 weeks.1 However, there has been limited adoption of brolucizimab due to an increased risk for IOI, retinal vasculitis, and retinal vascular occlusion (RVO) observed in post hoc analyses leading to vision loss.

Park and colleagues conducted a retrospective analysis of eyes with nAMD treated with intravitreal brolucizumab between January 2020 and November 2021, evaluating their visual and anatomic outcomes, to better elucidate the real-world safety and efficacy of the therapy. All patients had previously been treated with intravitreal anti-VEGF therapy for nAMD and were switched to intravitreal brolucizumab for recalcitrant fluid on spectral-domain optical coherence tomography (OCT) or new macular hemorrhage on maximum therapy, desire for the extension of the treatment interval, or both.

The single-center analysis additionally included a subset of eyes that were refractory of intravitreal brolucizumab monotherapy every 8 weeks and received combination therapy consisting of alternating doses of intravitreal brolucizumab and aflibercept every month. For the purpose of analysis, mixed-effect regression models were used to evaluate change from baseline while controlling for the length of follow-up.

A total of 52 eyes with nAMD among 40 patients treated with intravitreal brolucizumab were identified and all had been previously treated with anti-VEGF therapy. Overall, 23 eyes (44.2%) were switched to brolucizumab due to recalcitrant fluid, 18 eyes (34.6%) were switched to brolucizumab to extend the treatment interval, and 11 eyes (21.2%) were switched for a combination of the two. After a mean follow-up of 46.2 ± 27.4 weeks on intravitreal brolucizumab, the mean treatment interval increased to 8.8 ± 2.1 weeks from a baseline of 6.1 ± 3.1 weeks (P <.001).

Macular fluid decreased in 32 eyes (61.5%) from baseline with improvement in intraretinal fluid (IRF) and subretinal fluid (SRF) on intravitreal brolucizumab, according to investigators. Data additionally showed BCVA was stable or improved in 32 eyes (61.5%) on intravitreal brolucizumab. Moreover, of 38 eyes with persistent macular fluid at baseline, 18.4% achieved full resolution of fluid at a median of 14 weeks after starting brolucizumab, and 47% had improved or stable macular fluid on brolucizumab.

To measure the subset of combination therapy, 10 eyes with increased macular fluid on brolucizumab monotherapy when extended to every 8 weeks were treated with combination therapy alternating between brolucizumab and aflibercept every 4 weeks. On the combination therapy, macular fluid improved in 80% of eyes and BCVA was stable or improved in 70% of eyes, according to the data.

Based on the safety signals, 4 eyes (7.6%) of 4 patients developed IOI and intravitreal brolucizumab was stopped. All had occurred on intravitreal brolucizumab monotherapy, and no eyes had associated vision loss, according to investigators. Limitations involved in the study included its retrospective design, limited sample size, and inconsistencies in the initiation and dosing of brolucizumab, but Park and colleagues noted the results provided new insights into the use of the therapy.

“Despite these limitations, this real-world study provides longer follow-up information and new insights regarding the safety and efficacy of intravitreal brolucizumab in treating nAMD,” investigators wrote.


  1. Mehta N, Fong RD, Wilson M, Moussa K, Emami-Naeini P, Moshiri A, Yiu G, Park SS. Real-World Experience Using Intravitreal Brolucizumab Alone or in Combination with Aflibercept in the Management of Neovascular Age-Related Macular Degeneration. Clin Ophthalmol. 2023;17:657-665