Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Ophthalmologicals, antineovascularisation agents, ATC code: S01LA06 
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 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.

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effects

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 Beovu 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 Beovu 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 Beovu 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 Beovu 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 Beovu, reductions in CNV lesion size were observed as early as 12 weeks, and at weeks 48 and 96 after treatment initiation.

Clinical efficacy and safety

The efficacy and safety of Beovu 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 Beovu 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 Beovu versus aflibercept. In both studies, Beovu (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 2 and in Figure 1 below.


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Table 2        Visual acuity outcomes at weeks 48 and 96 in Phase III - HAWK and HARRIER studies

HAWK                                          HARRIER
Efficacy outcome          Week        Beovu        Aflibercept       Difference         Beovu       Aflibercept   Difference 6 mg            2 mg            (95% CI)          6 mg           2 mg        (95% CI) (n=360)        (n=360)        brolucizumab        (n=370)       (n=369)    brolucizumab – aflibercept                                – aflibercept
Mean change from           48          6.6            6.8                -0.2            6.9            7.6           -0.7 baseline in BCVA                    (SE=0.71)      (SE=0.71)          (-2.1, 1.8)     (SE=0.61)     (SE=0.61)      (-2.4, 1.0) (measured by                                                         P<0.0001 a)                                  P <0.0001 a) ETDRS letters score)      36 –         6.7            6.7                 0.0            6.5            7.7           -1.2 48 b)     (SE=0.68)      (SE=0.68)          (-1.9, 1.9)     (SE=0.58)     (SE=0.58)      (-2.8, 0.4) P<0.0001 a)                                  P=0.0003 a)
96          5.9            5.3                 0.5            6.1            6.6           -0.4 (SE=0.78)      (SE=0.78)          (-1.6, 2.7)     (SE=0.73)     (SE=0.73)      (-2.5,1.6) % of patients who          48          33.6           25.4                8.2            29.3           29.9          -0.6 gained at least                                                      (2.2, 15.0)                                   (-7.1, 5.8) 15 letters of vision       96          34.2           27.0                7.2           29.1            31.5          -2.4 (1.4, 13.8)                                   (-8.8, 4.1)
% of patients who          48           6.4            5.5                0.9            3.8            4.8           -1.0 lost visual acuity (%)                                                (-2.7, 4.3)                                  (-3.9, 2.2) (≥15 letters of BCVA       96           8.1            7.4                   0.7               7.1        7.5          -0.4 loss)                                                                    (-3.6, 4.6)                                (-3.8, 3.3) BCVA: best corrected visual acuity; missing data are imputed using last observation carried forward (LOCF) method ETDRS: early treatment diabetic retinopathy study
SE: standard error a)      P-value referring to the non-inferiority hypothesis with a non-interiority margin of 4.0 letters.
b)      Key secondary endpoint, accounting for differences in timing of Beovu and aflibercept treatments.



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Figure 1                                       Mean change in visual acuity from baseline to week 96 in HAWK and HARRIER studies

HAWK

10
9
VA change from baseline (letters)


8
7
6
5
4
3
2
1
0
0   4   8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 
Time (weeks)

Beovu 6 mg (n=360)           aflibercept 2 mg (n=360)

HARRIER

10
9
VA change from baseline (letters)


8
7
6
5
4
3
2
1
0
0   4   8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 
Time (weeks)

Beovu 6 mg (n=370)          aflibercept 2 mg (n=369)


These visual acuity gains were achieved with 56% and 51% of patients treated with Beovu 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 
BEO API July 24 V4_IL country specific                                        Page 10 of 14 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 Beovu compared to aflibercept (see “Pharmacodynamic effects”).

The percentage difference in patients with disease activity at week 16 was statistically significant on Beovu versus aflibercept (24% vs 35% in HAWK, p=0.0013; 23% vs 32% in HARRIER, p=0.0021).

In both studies, Beovu 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 Beovu 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).

Paediatric population

Beovu is not indicated for use in paediatric population.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Beovu 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 
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[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.