Less Frequent Brolucizumab Non-inferior to Standard Aflibercept for nAMD

MAY 01, 2018
Silas Inman
Glenn J. Jaffe, MDGlenn J. Jaffe, MD
Treatment with the anti-VEGF agent brolucizumab, which could be given every 12 weeks, showed non-inferior improvements in best corrected visual acuity (BCVA) when compared with aflibercept every 8 weeks for patients with neovascular age-related macular degeneration (nAMD), according to findings from the HAWK and HARRIER trials presented at the 2018 ARVO Annual Meeting.

Nearly half of patients in each of the phase 3 trials were maintained on an every-12-week (q12w) dose of 6-mg brolucizumab at week 48 (50% to 57%). Most who switched to an every-8-week (q8w) dose of the medication did so during the first 12-week period. Of those who completed the first q12w interval, 87.1% in the HAWK trial stayed on q12w dosing until week 48, as did 82.5% of those in the HARRIER trial.

"They key result is that brolucizumab met the primary endpoint of non-inferiority for BCVA. The increases were very similar, whether it was HAWK or HARRIER," lead investigator Glenn J. Jaffe, MD, chief of Retinal Ophthalmology, Duke University, said at the ARVO Meeting. "The patients who successfully made it through the first 12-week dosing could then stay on the q12w dosing throughout the study. This has the potential to address the unmet need of high treatment burden of anti-VEGF treatment."

In the HAWK trial, patients were randomized to 2-mg aflibercept or brolucizumab at 3 mg or 6 mg. In HARRIER, patients received either brolucizumab at 6 mg or aflibercept at 2 mg. After 3 loading doses on weeks 0, 4, and 8, if deemed eligible, brolucizumab-treated patients could receive treatment q12w with the options to decrease to q8w at each disease activity assessment (DAA). Aflibercept was given at a fixed q8w dose.

Patient characteristics were balanced across both studies. The mean age was around 74 to 76 years. The mean BCVA at baseline was 60 to 61 letters. Overall, 38% to 46% of patients had a BCVA of 56 to 70 letters. Across groups, there were approximately 4.5 lesions associated with choroidal neovascularization (CNV) in the HAWK trial and 2.6 to 2.9 lesions in the HARRIER study. Central subfield thickness (CST) was approximately 465 µm across studies.

Brolucizumab was found to be non-inferior to aflibercept at the week 48 assessment for BCVA, which was the primary endpoint of the study. In the HAWK study, the mean BCVA increased by 6.8 letters (±0.71) with aflibercept and by 6.6 letters (± 0.71) in the 6-mg brolucizumab group. In the HARRIER study, the BCVA increased by 7.6 letters (±0.61) with aflibercept and by 6.9 letters (±0.61) for 6-mg brolucizumab.

For the first 16 weeks of the study, when the agents were given with matched dosing, there was approximately a 30% reduction in disease activity with brolucizumab at 6 mg compared with aflibercept. In the HAWK trial, 23.6% of patients in the brolucizumab 6-mg arm had active disease compared with 34.4% in the aflibercept group. In the HARRIER trial, 22.2% of patients in the aflibercept group had disease activity at 16 weeks compared with 31.5% for the brolucizumab 6-mg arm.

In the HAWK trial, CST reductions were superior in the brolucizumab arm compared with aflibercept both at 16 weeks (P = .0016) and at the 48-week period (P = .0023). This was also seen in the HARRIER trial for both time points (P <.0001).

In the HAWK trial, there was a 35% reduction in intraretinal fluid (IRF) and/or subretinal fluid (SRF) with brolucizumab 6-mg compared with aflibercept at week 16, which persisted at week 48 (31% reduction). In HARRIER, there was a 33% reduction in IRF/SRF at week 16 with brolucizumab and a 41% reduction at week 48.

"We looked at the anatomic outcomes, we saw similar results, there's a rapid drop early on, and there's a modest favoring of brolucizumab over aflibercept both in the early phase and the maintenance phase," said Jaffe. "The percentage of patients with IRF or SRF, those anatomic markers, were lower for brolucizumab at week 16 and 48."

In the HAWK trial, ocular adverse events (AEs) were experienced by 49.7% of patients in the brolucizumab 6-mg arm compared with 47.2% in the aflibercept group. In the HARRIER trial, ocular AEs were seen in 33% and 32.2% of patients in the brolucizumab and aflibercept arms, respectively. Overall, the safety profiles were comparable between the two groups, Jaffe noted.

"If you look at the safety profiles they're very similar between HAWK and HARRIER," said Jaffe. "The adverse events were similar to what has been reported in previous VEGF studies."

One of the chief concerns with the trial was the methods used for DAA from week 16 to week 52. In this stage of the trial, a simpler assessment of BCVA loss of ≥5 letters was used to determine whether patients in the brolucizumab arm should switch from q12w to the q8w dosing. Prior evaluations, during week 16, had included central foveal thickness values. Another qualm with the study was that aflibercept was not also administered at a similar q12w dose.

Novartis, the developer of brolucizumab, plans to apply for approval with the FDA by the end of 2018, according to Jaffe. He could not comment on the exact timeline or potential costs of the medication, if approved.

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