Brolucizumab
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Brolucizumab (Beovu®; manufactured by Novartis, also called RTH258) is a humanized monoclonal single-chain variable fragment (scFv) that binds and inhibits vascular endothelial growth factor A (VEGF-A).1 VEGF is a signal protein that promotes the growth of new blood vessels from pre-existing vessels. Brolucizumab is a single-chain variable fragment with a molecular weight of 26 kD. By attaching to VEGF, brolucizumab inhibits the activation of VEGF receptors, decreasing neovascularization in the eye. Brolucizumab was FDA-approved for treatment of Neovascular Age-related Macular Degeneration (nAMD or wet AMD or wAMD)2 in 2019 and for Diabetic Macular Edema (DME) in 2022.
Background
Vascular endothelial growth factors (VEGFs) are a family of cytokines that are involved in the process of angiogenesis.3 VEGF binds with its receptors leading to proliferation of endothelial cells and growth of new blood vessels from existing vasculature. There are five main ligands in the VEGF family: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PlGF (placental growth factor).4 VEGF-A is the most well-studied member of this family and is the primary target of VEGF suppression therapy.3,4 VEGF-A is organized genetically as eight exons, with nine major isotypes due to alternative splicing identified: VEGF121, VEGF145, VEGF148, VEGF162, VEGF165, VEGF165b, VEGF183, VEGF189 and VEGF206.5,6 VEGF165 has been shown to be the most abundant isotype and has a potent role in angiogenesis, although the VEGF121 isotype has been shown to be more mitogenic than VEGF165.7,8
There are three VEGF receptors, VEGFR-1, VEGFR-2, and VEGFR-3. VEGF-A binds to VEGFR-1 and VEGFR-2 to activate signal transduction cascades that lead to angiogenesis, with VEGFR-2 in particular being thought to be the primary receptor responsible for VEGF signaling in angiogenesis.9 VEGFR-3 primarily binds to VEGF-C and VEGF-D and is involved in lymphangiogenesis.4,10
In the eye, VEGF levels are upregulated in response to hypoxic conditions. VEGF-A has been shown to have a central role in neovascular conditions of the retina, including wet age-related macular degeneration (wAMD) and proliferative diabetic retinopathy (PDR).11–13 Cells of the RPE (retinal pigment epithelium) and retinal tissue release VEGF in response to metabolic stress, inducing the formation of new blood vessels. This neovascularization occurs in the choroid in wAMD as a response to hypoxia14
Mechanism of action
Brolucizumab is a single-chain variable fragment, which is a fusion protein of the variable regions of the heavy and light chain regions of immunoglobulins.15,16 Single-chain fragment variable is the smallest functional unit of an antibody, the Fv region. The small fragments are able to penetrate tissue more rapidly and evenly.17 Because it lacks the Fc region, brolucizumab has a molecular weight of 26 kDa, allowing for a higher molar dosing. Brolucizumab binds VEGF-A in a 2:1 ratio and has been shown to have a higher binding affinity to VEGF-A isoforms than bevacizumab or ranibizumab.1,18 It has been shown experimentally in non-human primates to bind to all isoforms of VEGF-A and have a KD of 28.4 pM for VEGF165. It was shown to inhibit binding of VEGF165 to its receptor VEGFR2 with an IC50 of 0.86 nM.19 It has a half-life of 3.0 days from ocular compartments and was shown to readily penetrate to the RPE and choroid while having minimal serum concentrations (>6000 times less than vitreous concentrations).20,21
Indications
Brolucizumab is FDA-approved (Food and Drug Administration, USA) for treatment of neovascular (wet) age-related macular degeneration and DME.2 It was approved in October 2019 and is currently the only approved single chain antibody fragment. In June 2020, an updated label that included the adverse events of retinal vasculitis and retinal vascular occlusion was included by the FDA.22 In 2022, the FDA approved brolucizumab for DME.
Brolucizumab is currently under preclinical development for use in Kaposi sarcoma and glioblastoma under the name DLX1008.18,23
Dosing, Administration, and Preparation
The recommended dosage of Brolucizuab for treatment of both Neovascular Age-related Macular Degeneration and Diabetic Macular Edema is 6 mg (0.05 mL of solution that is 120 mg/mL).15
Brolucizumab is administered via intravitreal injection into the vitreous cavity. It is recommended to receive injections into the affected eye(s) once per month for the first 3 doses as loading doses for nAMD. Dosing interval after is recommended 8 to 12 weeks based on clinician assessment of disease.15,24,25
For DME, 'the recommended dose for BEOVU is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every six weeks (approximately every 39-45 days) for the first five doses, followed by 6 mg (0.05 mL) by intravitreal injection once every 8-12 weeks.'
Before injection, aseptic cleaning of the eye with betadine, followed by topical or local anesthesia is required. A sterile 5-µm, 18-gauge filter needle should be used to withdraw the entire contents of the vial into a 1-mL syringe. A sterile 30-gauge, ½-inch needle is then used for transconjunctival intravitreal injection via the pars plana with aseptic technique and conditions.15
Brolucizumab is supplied in 6 mg preservative-free, single use vials of clear to slightly opalescent and colorless to slightly brownish-yellow solution that contain 0.05 mL of 120 mg/mL. It should be refrigerated at 2-8 degrees Celsius in the original carton. Unopened vials may be stored at 20-25 degrees Celsius for up to 24 hours prior to use.15,24,25
Clinical Trial Data
HAWK and HARRIER were two-year, randomized, double-masked, multicenter phase 3 trials that assessed the safety and efficacy of brolucizumab intravitreal injections for the treatment of neovascular AMD, compared with aflibercept. HAWK had 3 arms (brolucizumab 6 mg, brolucizumab 3 mg, and aflibercept 2 mg) and HARRIER had 2 arms (brolucizumab 6 mg and aflibercept 2 mg).
A total of 1817 patients with untreated, active choroidal neovascularization due to AMD were randomized to brolucizumab 3 mg (HAWK only), brolucizumab 6 mg, or aflibercept 2 mg. Brolucizumab was administered every 12 weeks after three monthly loading doses and was adjusted to every 8 weeks if disease activity was present. Aflibercept was administered every 8 weeks after 3 monthly loading doses. The primary endpoint was the change from baseline in Best Corrected Visual Acuity (BCVA) at Week 48. Patients were followed for 96 weeks.25–27
Table 1: Efficacy Outcomes in HAWK and HARRIER
| HAWK | HARRIER | ||||||
| Efficacy outcome | At week | Brolucizumab (n=360) | Aflibercept 2 mg (n=360) | Difference (95% CI) brolucizumab – aflibercept | Brolucizumab (n = 370) | Aflibercept 2 mg (n=369) | Difference (95% CI) brolucizumab – aflibercept |
| Mean change in BCVA, ETDRS letters | 48
96 |
6.6
5.9 |
6.8
5.3 |
-0.2
(-2.1, 1.8)
(-1.6, 2.7) |
6.9
6.1 |
7.6
6.6 |
-0.7
(-2.4, 1.0)
(-2.5, 1.6) |
| Proportion of patients who gained visual acuity (%, ≥15 letters) | 48
96 |
33.6
34.2 |
25.4
27 |
8.2
(2.2, 15.0)
(1.4, 13.8) |
29.3
29.1 |
29.9
31.5 |
-0.6
(-7.1, 5.8)
(-8.8, 4.1) |
| Proportion of patients who lost visual acuity (%, ≥15 letters) | 48
96 |
6.4
8.1 |
5.5
7.4 |
0.9
(-2.7, 4.3)
(-3.6, 4.6) |
3.8
7.1 |
4.8
7.5 |
-1.0
(-3.9, 2.2)
(-3.8, 3.3) |
Abbreviations – BCVA: Best Corrected Visual Acuity; ETDRS: Early Treatment Diabetic Retinopathy Study
Adverse Events
Through week 96 of the HAWK and HARRIER studies, the most frequent ocular adverse events (>5% of patients for the overall study population) were conjunctival hemorrhage, reduced visual acuity, cataract, vitreous floaters, dry eye, and eye pain. In the HAWK trial, 61% of patients on brolucizumab experienced at least one ocular adverse event, whereas in the HARRIER trial 47% of patients on brolucizumab experienced at least one ocular adverse event. Adverse events related to intraocular inflammation (IOI) were iritis, uveitis, anterior chamber cell, anterior chamber flare, anterior chamber inflammation, chorioretinitis, eye inflammation, iridocyclitis, keratic precipitates, retinal vasculitis, vitreous haze, and vitritis. The most common were iritis (2.2%) and uveitis (2.2%) with brolucizumab 6 mg (compared to 0.3% and 0% with aflibercept 2mg) in the HAWK study.
The incidence of arterial thromboembolic events (ATEs) in the HAWK study was 1.1% for patients receiving brolucizumab 3 mg, 1.4% for patients receiving brolucizumab 6 mg, and 0.3% for patients receiving aflibercept 2 mg. The incidence of ATEs in the HARRIER study was 1.6% in the brolucizumab 6 mg group and 0.5% in the aflibercept 2 mg group. Overall, adverse events were infrequent and occurred with similar rates across all treatment groups.25–27
Brolucizumab 6 mg was shown to be non-inferior to Aflibercept 2 mg monthly injection for DME in phase 3 KESTREL and KITE trials, and >50% of brolucizumab 6 mg subjects maintained on a q3 month interval at week 52. KESTREL trial had 3 arms (brolucizumab 6 mg, brolucizumab 3 mg, and aflibercept 2 mg) and was done at multiple sites in the USA. The KITE trial had 2 arms (brolucizumab 6 mg and aflibercept 2 mg) at locations outside the USA.
Safety and Precautions
Endophthalmitis and retinal detachment (1%) are events that are at increased risk after any intravitreal injections. Aseptic injection techniques should be used to decrease risk of endophthalmitis. Retinal vasculitis and retinal occlusion, especially retinal arterial occlusions (4%) have been reported at an increased risk with brolucizumab intravitreal injections. Brolucizumab has consistently shown an increased risk of intraocular inflammation (IOI) following intravitreal injection when compared to aflibercept.25,28–30 This IOI was found to be mild and often self-limited.28 This was originally reported in the HAWK and HARRIER trials at a rate of 4%, with severe vision loss being reported. Both acute increases in intraocular pressure (within 30 minutes) and sustained IOP increases (4%) have been reported with brolucizumab. Arterial thromboembolic events (4.5%), including nonfatal stroke, nonfatal myocardial infarction, and vascular death have been seen following use of VEGF inhibitors. Severe vision loss related to brolucizumab use was reported to occur with a rate of 0.5%.25 In Diabetic Macular Edema trials, the incidence of serious ocular adverse events in were 3.7% (brolucizumab 3 mg), 1.1% (brolucizumab 6 mg) in KESTREL; and 2.2% (brolucizumab 6 mg) and 1.7% (aflibercept) in KITE.
It should be noted that on May 28, 2021, Novartis released an announcement regarding results of the Phase III MERLIN study, which is a two-year study assessing the efficacy and safety of brolucizumab 6 mg compared to aflibercept 2 mg given every four weeks following the loading phase in patients with neovascular AMD. The rate of intraocular inflammation following brolucizumab injection every four weeks was 9.3%. Because of this, all clinical trials involving brolucizumab injection with four week dosing intervals were discontinued, including MERLIN as well as RAPTOR and RAVEN, which were assessing the efficacy of brolucizumab in retinal vein occlusion with six monthly injections.31 Novartis promptly recommended against treatment of patients with brolucizumab at intervals less than two months following the first three doses.31
Considerations and Comparisons
Intravitreal brolucizumab is a novel therapeutic option for neovascular AMD, alongside the previous anti-VEGF treatments aflibercept, bevacizumab, and ranibizumab. As mentioned previously, brolucizumab is only comprised of the active binding site of the immunoglobulin, the variable domains of the light and heavy chains. Since it is a single-chain variable fragment, it has a molecular mass of 26 kDA. In comparison, ranibizumab is a Fab fragment, which includes the variable and constant domain of the light and heavy chains. Its molecular mass is larger at 48 kDa and it has been shown to bind to multiple isoforms of VEGF-A. Bevacizumab is larger still as it is a full antibody, with a molecular mass of 147 kDa. Aflibercept has a unique mechanism of action as a soluble decoy receptor that acts as a VEGF trap and binds both sides of the VEGF dimer, preventing binding to its receptor. Aflibercept has a molecular mass of 97-115 kDa and has been shown to bind multiple isoforms of VEGF-A as well as VEGF-B and PlGF.32 Brolucizumab has the lightest molar mass of any treatment currently available for the treatment of neovascular AMD. A lighter molecular mass means a higher concentration of molecules that is delivered to the retinal tissue. In addition, smaller molecules are thought to penetrate the retinal tissue to the choroid more effectively.20,32
The HAWK and HARRIER trials demonstrated noninferiority of brolucizumab to aflibercept in terms of visual outcomes in the treatment of neovascular AMD with no significant difference in BCVA gain at week 48 that was maintained until week 96. In addition, brolucizumab showed superior anatomic outcomes compared to aflibercept, resulting in fewer eyes with intra-retinal fluid (IRF), sub-retinal fluid (SRF), or sub-RPE fluid and an increased reduction in central subfield thickness (CST) on OCT (optical coherence tomography).26,27 Based on recommendations by the European Society of Retina Specialists (EURETINA), fluid on OCT is a sign of active disease and requires treatment with an anti-VEGF agent.33 Other studies have found brolucizumab to have benefit in patients without resolution of subretinal fluid in response to previous anti-VEGF treatments. Brolucizumab was shown to result in more stable CST reductions and increased rates of fluid resolution, indicating a morphological and structural benefit.34,35 This increased fluid control may be due to smaller size and increased molecular concentration, contributing to an increased duration of decreased IRF, SRF, and sub-RPE fluid.36
The KITE and KESTREL trials for DME showed that at week 52, brolucizumab 6 mg was noninferior to aflibercept in mean change in BCVA from baseline (KESTREL: +9.2 letters vs +10.5 letters; KITE: +10.6 letters vs +9.4 letters; P < .001). It also showed that more subjects achieved CST <280 µm with initial five q5 week injections followed by 8-12 week intervals.
A primary benefit of brolucizumab lies in its longer interval between injections, allowing for a decreased injection burden to the patient. Brolucizumab is indicated for 8-12 weeks between injections and may be useful for clinicians looking to have their patients on a longer dosing schedule than other anti-VEGF treatments.1,37 Aflibercept has a recommended treatment schedule of three monthly doses followed by 8 week intervals, ranibizumab is recommended to have monthly intervals or a treat and extend regimen, and bevacizumab is used off-label as monthly injections or pro-re-nata.36,37 Brolucizumab was shown in the HAWK and HARRIER trials to maintain 55.6% and 51.0% of patients on q12w scheduling, respectively, indicating a potential for a substantial decrease in patient burden through less injections per year.
Rates of ocular adverse effects are similar between brolucizumab and aflibercept, with the exception of intraocular inflammation. As previously noted, brolucizumab has been associated with an increased risk of inflammatory events (intraocular inflammation, retinal vasculitis, retinal vascular occlusion ) in 4-10% of injections for nAMD.25,27–30 The incidence of systemic side effects is similar with all four treatments, as is the risk of arterial thromboembolic events.27,38
Brolucizumab has the same cost of aflibercept at $1,418 for a single dose, yet is expected to cost less per year with a longer dosing interval. This is slightly less than ranibizumab, which is $1,575 per dose.39 Bevacizumab is significantly less expensive than the other three options at between $17 and $50 per injection, and though its ocular use is off-label many studies have shown its comparable safety and efficacy to other anti-VEGF agents.40, 41
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