Brolucizumab: Next-generation of anti-VEGF therapy?


Results from two large, phase III studies (HAWK and HARRIER) have found brolucizumab 6 mg (Novartis) produced better anatomical outcomes than aflibercept-in terms of retinal thickness, intraretinal fluid (IRF), and/or subretinal fluid (SRF) status and in sub-retinal pigment epithelial (RPE) fluid status, said Pravin U. Dugel, MD.

The HAWK and HARRIER studies are the first that "individualize" treatment, explained Dr. Dugel, of Retinal Consultants of Arizona, Phoenix.

"We don't necessarily use the branded anti-vascular endothelial growth factor (VEGF) drugs on-label-we treat based on what the disease itself dictates," he said.

Some patients will require very intensive treatment, while others will not, Dr. Dugel said.

"We do not know how to differentiate them; we don't have a genetic test to follow or biomarkers to follow," he said.

HAWK and HARRIER are (to date) the only phase III studies that attempt to mimic real-world treatment regimens, Dr. Dugel noted.

HAWK and HARRIER details

Brolucizumab is a humanized single-chain antibody fragment (scFv). These fragments are heralded for their small size, enhanced tissue penetration, rapid clearance from systemic circulation, and drug-delivery characteristics. The proprietary innovative structure results in a small molecule (26 kDa) with potent inhibition of, and high affinity to, all VEGF-A isoforms, according to Novartis.

In these studies, patients were randomly assigned 1:1:1 to brolucizumab 3 mg (n = 358), 6 mg (n = 360) or aflibercept 2 mg (n = 360) in HAWK, or 1:1 with brolucizumab 6mg (n = 370) or aflibercept 2 mg (n = 369) in HARRIER.

After three loading doses, brolucizumab patients were treated every 12 weeks (q12w), with the possibility of adjusting to every 8 weeks (q8w) during the first q12w interval and at each scheduled q12w treatment visit. Aflibercept patients were treated on-label, every 8 weeks.

Dr. Dugel said that though Novartis intends to file brolucizumab 6 mg for approval, the FDA requires two different doses of an investigational drug be evaluated in registration trials to determine if there is a dose response (conversely, the European Medicines Agency only requires one dose of an investigational drug be used during registration trials).

"What gives us confidence in any data is the reproducibility and dose dependency," he said.  "If the 3-mg dose worked well, and the 6-mg dose worked better, that gives us confidence."

In the OSPREY phase II study,[1] all patients were extended; in HAWK and HARRIER, only those patients who were appropriate were extended, Dr. Dugel said, which comprised about 50% of the study cohort, but the results were "almost identical."

In HAWK, the mean change in central subfield thickness (CST) from baseline to week 16 in the brolucizumab 6-mg arm was -161.4 μm and for aflibercept 2 mg was -133.6 μm (p = 0.0016).

In HARRIER, the mean CST reduction from baseline to week 16 for brolucizumab 6mg was -174.4 μm and for aflibercept 2 mg was -134.2 μm (p < 0.0001).

At week 16, fewer patients on brolucizumab 6mg had retinal fluid (IRF and/or SRF) relative to aflibercept and the corresponding fluid reduction rates for brolucizumab 6 mg were 35% (HAWK) and 33% (HARRIER) lower as compared with aflibercept (p < 0.0001).

Fewer brolucizumab 6 mg patients had sub-RPE fluid compared with aflibercept patients at week 16, i.e., 30% (p = 0.0021) and 33% (p = 0.0041) less fluid with brolucizumab in HAWK and HARRIER, respectively, relative to aflibercept.
There was no statistically significant difference in terms of visual acuity between the arms, Dr. Dugel said. 

"Week 16 is an important time point for analysis in HAWK and HARRIER, because it allows for matched comparison based on identical dosing," he said. "It is the purest comparison between these two drugs."

After week 16, data will be blended from the group of patients deemed appropriate for extension.

Clinical Relevance

Dr. Dugel said brolucizumab may represent the "next-generation anti-VEGF."

The study design allows for a direct head-to-head comparison that's matched with identical dosing through week 16, he said.

"We wanted to find out whether there was evidence that one drug is superior in an incremental way to another on the validated target of VEGF," Dr. Dugel said. "The data we have at week 16 from HAWK and HARRIER is extremely important, because it answers that question. Anatomic changes were statistically significant in both studies, and dose-dependent in HAWK."

This "pure comparison" is what will determine the most effective drug for VEGF suppression.

"Once we have the drug in our hands, we will use it according to what the disease dictates," he said.

Dr. Dugel will be reporting on the 2-year data outcomes for the first time during Retina Subspecialty Day at the American Academy of Ophthalmology meeting in October. Novartis plans to file brolucizumab for regulatory approval by the end of the year.



Dr. Dugel is a consultant and investigator for Novartis and reports receiving honoraria from Novartis.


1. Dugel PU, Jaffe GJ, Sallstig P, et al. Brolucizumab versus aflibercept in participants with neovascular age-related macular degeneration: A randomized trial. Ophthalmology. 2017;124:1296-1304. doi: 10.1016/j.ophtha.2017.03.057

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