Brolucizumab is a humanised monoclonal single chain Fv (scFv) antibody fragment with a molecular weight of ~26 kDa.
Increased levels of signalling through the vascular endothelial growth factor A (VEGF-A) pathway are associated with pathological ocular angiogenesis and retinal oedema. Brolucizumab binds with high affinity to VEGF-A isoforms (e.g. VEGF110, VEGF121, and VEGF165), thereby preventing binding of VEGF-A to its receptors VEGFR-1 and VEGFR-2. By inhibiting VEGF-A binding, brolucizumab suppresses endothelial cell proliferation, thereby reducing pathological neovascularisation and decreasing vascular permeability.
In the HAWK and HARRIER studies, anatomical parameters related to leakage of blood and fluid that characterise choroidal neovascularisation (CNV) were part of the disease activity assessments guiding treatment decisions. Reductions in central subfield thickness (CST) and in presence of intraretinal/subretinal fluid (IRF/SRF) or sub-retinal pigment epithelium (sub-RPE) fluid were observed in patients treated with brolucizumab as early as 4 weeks after treatment initiation and up to week 48 and week 96.
At week 16, the reduction in CST was statistically significant on brolucizumab versus aflibercept in both studies (HAWK: -161 vs. -134 microns; HARRIER: -174 vs. -134 microns). This decrease from baseline in CST was also statistically significant at week 48 (HAWK: -173 vs. -144 microns; HARRIER: -194 vs. -144 microns), and maintained to the end of each study at week 96 (HAWK: -175 vs. -149 microns; HARRIER: -198 vs. -155 microns).
At week 16, the percentage difference in patients with IRF and/or SRF fluid was statistically significant on brolucizumab versus aflibercept in both studies (HAWK: 34% vs. 52%; HARRIER: 29% vs. 45%). This difference was also statistically significant at week 48 (HAWK: 31% vs. 45%; HARRIER: 26% vs. 44%), and maintained to the end of each study at week 96 (HAWK: 24% vs. 37%; HARRIER: 24% vs. 39%).
At week 16, the percentage difference in patients with sub-RPE fluid was statistically significant on brolucizumab versus aflibercept in both studies (HAWK: 19% vs. 27%; HARRIER: 16% vs. 24%). This difference was also statistically significant at week 48 (HAWK: 14% vs. 22%; HARRIER: 13% vs. 22%), and maintained to the end of each study at week 96 (HAWK: 11% vs. 15%; HARRIER: 17% vs. 22%).
In these studies, for patients treated with brolucizumab, reductions in CNV lesion size were observed as early as 12 weeks, and at weeks 48 and 96 after treatment initiation.
In the KESTREL and KITE studies, related anatomical parameters were part of the disease activity assessments guiding treatment decisions. Reductions in CST and in presence of IRF/SRF were observed in patients treated with brolucizumab as early as 4 weeks after treatment initiation and up to week 52. These reductions were maintained up to week 100.
Brolucizumab is administered directly into the vitreous to exert local effects in the eye.
After intravitreal administration of 6 mg brolucizumab per eye to patients with nAMD, the geometirc mean Cmax of free brolucizumab in the plasma was 49.0 ng/ml (range: 8.97 to 548 ng/ml) and was attained in 1 day.
Brolucizumab is a monoclonal antibody fragment and no metabolism studies have been conducted. As a single-chain antibody fragment, free brolucizumab is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF, passive renal elimination and metabolism via proteolysis.
After intravitreal injections, brolucizumab was eliminated with an apparent systemic half-life of 4.3 ± 1.9 days. Concentrations were generally near or below the quantitation limit (<0.5 ng/ml) approximately 4 weeks after dosing in most patients. Brolucizumab did not accumulate in the serum when administered intravitreally every 4 weeks.
There were no relevant differences in systemic pharmacokinetics following intravitreal injection in a study with 22 patients aged 65 to 74 years, 18 patients aged 75 to 84 years and 3 patients aged ≥85 years.
The systemic pharmacokinetics of brolucizumab was evaluated in nAMD patients with normal renal function (≥90 ml/min [n=21]), with mild (60 to <90 ml/min [n=22]) or moderate (30 to <60 ml/min [n=7]) renal impairment. While the mean systemic clearance values for patients with mild or moderate renal impairment were generally lower than patients with normal renal function, no significant impact of mild and moderate renal impairment on the overall systemic exposure to brolucizumab was observed. No patients with severe (<30 ml/min) renal impairment were studied.
Brolucizumab has not been studied in patients with hepatic impairment. Mild to severe hepatic impairment should have no impact on the overall systemic exposure to brolucizumab, because metabolism occurs via proteolysis and does not depend on hepatic function.
No studies have been conducted on the carcinogenic or mutagenic potential of brolucizumab.
In pregnant cynomolgus monkeys, brolucizumab was administered once every 4 weeks by intravitreal injection at dose levels resulting in maximal systemic exposures 6-fold higher than those in humans at the maximum recommended dose (based on serum Cmax). There was no impact on embryofoetal development, pregnancy or parturition, or on the survival, growth or postnatal development of offspring. Nevertheless, based on its pharmacological effect, brolucizumab should be regarded as potentially teratogenic and embryo-foetotoxic.
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