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Pharmacology: Pharmacodynamics: Mechanism of action: 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 ofVEGF-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.
Pharmacodynamic effects: Wet AMD: 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 Pagenax 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 Pagenax 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: -175vs. -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 Pagenax 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 Pagenax 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 Pagenax, reductions in CNV lesion size were observed as early as 12 weeks, and at weeks 48 and 96 after treatment initiation.
DME: 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 Pagenax as early as 4 weeks after treatment initiation and up to week 52. These reductions were maintained up to week 100.
Clinical efficacy and safety: Wet AMD: The efficacy and safety of Pagenax were assessed in two randomised, multicentre, double-masked, active-controlled Phase III studies (HAWK and HARRIER) in patients with neovascular (wet) AMD.A total of 1,817 patients were treated in these studies for two years (1,088 on Pagenax and 729 on comparator aflibercept). Patient ages ranged from 50 to 97 years, with a mean age of 76 years.
In both studies, after the first three monthly doses (weeks 0, 4 and 8), brolucizumab patients were treated every 12 weeks, with the option of adjusting to a dosing interval every 8 weeks based on disease activity. Disease activity was assessed by a physician during the first 12-week interval (at weeks 16 and 20) and at each subsequent scheduled 12-weekly treatment visit. Patients who showed disease activity (e.g. decreased visual acuity, increased CST and/or presence of IRF/SRF or sub-RPE fluid) at any of these visits were adjusted to an 8-weekly treatment interval. The comparator aflibercept was administered every 8 weeks after the first 3 monthly doses.
Results: The primary efficacy endpoint for the studies was the change from baseline in best corrected visual acuity (BCVA) to week 48, as measured by the early treatment diabetic retinopathy study (ETDRS) letter score, with the primary objective being to demonstrate non-inferiority of Pagenax versus aflibercept. In both studies, Pagenax (administered in an every 12 weeks or an every 8 weeks regimen) demonstrated non-inferior efficacy to aflibercept 2 mg (administered every 8 weeks). The visual acuity gains observed in the first year were maintained in the second year.
Detailed results of both studies are shown in Table 1 and in Figure 1 as follows. (See Table 1 and Figure 1.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageThese visual acuity gains were achieved with 56% and 51% of patients treated with Pagenax 6 mg on a 12-weekly dosing interval at week 48, and with 45% and 39% of patients at week 96 in HAWK and HARRIER, respectively. Among patients identified as eligible for the 12-weekly regimen during the first 12-week interval, 85% and 82% remained on the 12-weekly dosing interval up to week 48. Of patients on the 12-weekly interval at week 48, 82% and 75% remained on the 12-weekly dosing interval up to week 96.
Treatment effects in evaluable subgroups (e.g. age, gender, race, baseline visual acuity, baseline retinal thickness, lesion type, lesion size, fluid status) in each study were generally consistent with the results in the overall populations.
Disease activity was assessed by changes in visual acuity and/or anatomical parameters, including CST and/or presence of IRF/SRF or sub-RPE. Disease activity was assessed throughout the studies. Anatomical parameters of disease activity were decreased at week 48 and at week 96 for Pagenax compared to aflibercept (see Pharmacology: Pharmacodynamics under Actions).
The percentage difference in patients with disease activity at week 16 was statistically significant on Pagenax versus aflibercept (24% vs 35% in HAWK, p=0.0013; 23% vs 32% in HARRIER, p=0.0021).
In both studies, Pagenax demonstrated clinically meaningful increases from baseline in the pre-specified secondary efficacy endpoint of patient-reported outcomes, reported through the National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in BCVA.
Patient-reported outcome benefits were maintained in the second year.
No clinically meaningful differences were found between Pagenax and aflibercept in changes from baseline to week 48 in NEI VFQ-25 total score and subscales (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, colour vision and peripheral vision).
The results of the Pagenax arms of the HAWK and HARRIER studies, where Pagenax was administered every 4 weeks (monthly) for the first 3 doses (loading) followed by maintenance dosing every 12 or 8 weeks, were replicated in a population pharmacokinetic/pharmacodynamic model simulation study where Pagenax was administered every 6 weeks for the first 2 or 3 doses (loading) followed by maintenance dosing every 12 or 8 weeks.
DME: The efficacy and safety of Pagenax were assessed in two randomised, multicentre, double-masked, active-controlled Phase III studies (KESTREL and KITE) in patients with visual impairment due to diabetic macular oedema. A total of 926 patients were treated in these studies for two years (558 on brolucizumab and 368 on aflibercept 2 mg). Patient ages ranged from 23 to 87 years, with a mean age of 63 years.
In both studies, after the first five doses (weeks 0, 6, 12, 18 and 24), brolucizumab patients were treated every 12 weeks, with the option of adjusting to a dosing interval every 8 weeks based on disease activity. Disease activity was assessed by a physician during the first 12-week interval (at weeks 32 and 36) and at each subsequent scheduled treatment visit. Patients who showed disease activity (e.g. decreased visual acuity, increased CST) at any of these visits were adjusted to an every 8 weeks treatment interval. In year 2 of KITE, patients who showed no disease activity could be extended to a 16-week treatment interval. The comparator aflibercept was administered every 8 weeks after the first 5 monthly doses.
Results: The primary efficacy endpoint for the studies was the change from baseline in BCVA to week 52, as measured by the ETDRS letter score, with the primary objective being to demonstrate non-inferiority of Pagenax versus aflibercept 2 mg. In both studies, Pagenax (administered in an every 12 weeks or an every 8 weeks regimen) demonstrated non-inferior efficacy to aflibercept 2 mg (administered every 8 weeks).
The results of KESTREL and KITE also demonstrated non-inferiority of Pagenax versus aflibercept 2 mg for the key secondary endpoint (average change from baseline in BVCA over the period week 40 to week 52).
The visual acuity gains observed in the first year were maintained in the second year.
Detailed results of both studies are shown in Table 2 and in Figure 2 as follows (See Table 2 and Figure 2.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageThese visual acuity gains were achieved with 55% and 50% of patients treated with Pagenax on a 12-weekly dosing interval at week 52, and 44% and 37% of patients treated with Pagenax on a 12-weekly or 12-weekly/16-weekly dosing interval at week 100 in KESTREL and KITE, respectively. Among patients identified as eligible for the 12-weekly regimen during the first 12-week interval, approximately 70% remained on at least the 12-weekly interval at week 100 in both studies. In KITE, 25% of patients were treated with Pagenax on a 16-weekly dosing interval at week 100.
Treatment effects in evaluable subgroups (e.g. age, gender, baseline HbA1c, baseline visual acuity, baseline central subfield thickness, DME lesion type, duration of DME since diagnosis, retinal fluid status) in each study were generally consistent with the results in the overall populations.
In KESTREL and KITE, disease activity was assessed throughout the studies by changes in visual acuity and/or anatomical parameters, including CST and/or presence of IRF/SRF. The reduction in CST from baseline was maintained up to week 100. At week 100, the proportion of patients with IRF/SRF was lower in patients treated with Pagenax (42% KESTREL and 41% KITE) compared to patients treated with aflibercept 2 mg (54% KESTREL and 57% KITE).
Diabetic retinopathy severity score (DRSS) was assessed in the KESTREL and KITE studies. At baseline, 98.1% of patients in both KESTREL and KITE had gradable DRSS scores. Based on the pooled analysis, Pagenax showed non-inferiority to aflibercept 2 mg in the proportion of subjects with at least a 2-step improvement from baseline in DRSS at week 52, using a non-inferiority margin of 10%. Estimated proportions were 28.9% and 24.9% in Pagenax and aflibercept 2 mg, respectively, resulting in a treatment difference of 4.0% (95% CI: [-0.6, 8.6]). At week 100, the proportion of patients with a ≥2-step improvement from baseline to week 100 in the DRSS score was 32.8% with Pagenax and 29.3% with aflibercept 2 mg in KESTREL and 35.8% with Pagenax and 31.1% with aflibercept 2 mg in KITE.
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Pagenax in all subsets of the paediatric population in neovascular AMD and DME (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: Pagenax is administered directly into the vitreous to exert local effects in the eye.
Absorption and distribution: 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.
Biotransformation and elimination: 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.
Special populations: Elderly: 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.
Renal impairment: 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.
Hepatic impairment: 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.
Toxicology: Preclinical safety data: 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.
