The Novartis humanized single-chain antibody fragment previously showed improved best corrected visual acuity in patients with nAMD versus aflibercept.
Dirk Sauer, PhD
New phase 3 trial data shows that brolucizumab (RTH258) 6 mg results in less instances of detected retinal fluid in treated patients versus those treated with aflibercept. The indication of treatment for the key marker of neovascular age-related macular degeneration (nAMD) lends to the hope that the humanized single-chain antibody fragment (scFv) can reach the market as a first-of-its-kind therapy.
The data—which came from pre-specified secondary endpoint analysis of Novartis’ HAWK and HARRIER trials and were presented at EURETINA 2018 Congress in Vienna, Austria—showed brolucizumab had superior fluid resolution versus aflibercept over 4 visits during study weeks 36-48.
Investigators noted the significance of the superior efficacy during that certain period of time in the study—at a time when maintenance treatment is emphasized for a chronic disease such as nAMD. The analysis also accounted for dosing interval differences between brolucizumab and aflibercept; in both trials, brolucizumab patients were dosed at either eight-week or twelve-week intervals, based on disease activity, while aflibercept patients were dosed at eight-week intervals.
In the secondary analyses for HAWK and HARRIER weeks 36-48, patients treated with brolucizumab had significantly fewer visits in which intraretinal fluid (IRF) or subretinal fluid (SRF) was observed. In HAWK, 47.5% of treated patients on the therapy had no visits involving IRF/SRF detection, while just 42.5% of patients treated with aflibercept had detection-free visits (P = .0012).
Patients treated with brolucizumab 6 mg in HARRIER reported even greater rates of detection-free visits (53%) versus patients on aflibercept (45.5% [P = .0001]). Investigators added that more than half of patients on brolucizumab 6 mg were mainainted on twelve-week interval dosing until week 48.
As the most clinically advanced, humanized scFv to reach this stage of clinical development, brolucizumab is highlighted by its enhanced capabilities in tissue penetration, systemic circulation clearance, and drug delivery. Its structure results in a small molecule with inhibition to all vascular endothelial growth factor (VEGF) isoforms. Brolucizumab was shown in preclinical assessment to inhibit VEGF receptor activation—leading to the limitation of neovascular lesion growth.
Retinal fluid remains a critical marker of nAMD disease activity and an at-need area of treatment, Dirk Sauer, PhD, Development Unit Head of Novartis Ophthalmology, said. The new data gives clinicians more insight into the robustsness of brolucizuman capabilities through 48 weeks.
“These results were noted even while more than half of brolucizumab 6 mg patients were receiving treatment every 12 weeks at week 48, further reinforcing our confidence in brolucizumab's superior fluid resolution and supporting our goal of reimagining care for people with nAMD,” Sauer said in a statement.
Brolucizumab’s safety was comparable to aflibercept’s, with overall adverse event incidence balanced across trials’ treatment groups. The most frequent ocular adverse events were reduced visual acuity, conjunctival hemorrhage, vitreous floaters, and eye pain.
The HAWK and HARRIER trials had previously reached their primary endpoints of non-inferiority in mean change in best corrected visual acuity (BCVA) at week 48 versus aflibercept, as well as its secondary endpoint of non-inferiority in mean change in BCVA between weeks 36-48.