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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 58  |  Issue : 4  |  Page : 268-273

Newer anti-vascular endothelial growth factor agents


Department of Ophthalmology, Lotus Eye Hospital, Salem, Tamil Nadu, India

Date of Submission29-Jul-2020
Date of Acceptance21-Sep-2020
Date of Web Publication16-Dec-2020

Correspondence Address:
Dr. Priya Rasipuram Chandrasekaran
Eye Hospital, Salem, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tjosr.tjosr_98_20

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  Abstract 


Ocular angiogenesis is a major cause of ocular morbidity worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis and vascular permeability with diverse roles both during the development and adulthood. This is believed to be the most powerful mediator of angiogenesis leading to ischemia-induced neovascularization in the retinal and choroidal diseases. Anti-VEGF has revolutionized the treatment of such angiogenic and exudative diseases of the retina and choroid. This article gives a brief view of the newer anti-VEGF agents and their role in retinal diseases.

Keywords: Abicipor pegol, anti-vascular endothelial growth factor, brolucizumab, conbercept, faricimab


How to cite this article:
Chandrasekaran PR. Newer anti-vascular endothelial growth factor agents. TNOA J Ophthalmic Sci Res 2020;58:268-73

How to cite this URL:
Chandrasekaran PR. Newer anti-vascular endothelial growth factor agents. TNOA J Ophthalmic Sci Res [serial online] 2020 [cited 2021 Jan 17];58:268-73. Available from: https://www.tnoajosr.com/text.asp?2020/58/4/268/303676




  Introduction Top


The advent of anti-vascular endothelial growth factor (VEGF) treatments marks a major advancement in the treatment of angiogenic eye disease. Ophthalmologists are faced with the challenges of determining the ideal regimen and duration of treatment, the potential of combination treatments, and safety concerns with long-term VEGF inhibition.

VEGF is a homodimeric glycoprotein and is a growth factor specific for endothelial cells.[1] It is a critical regulator of vasculogenesis and angiogenesis, as well as a potent inducer of vascular permeability.[2],[3],[4] Additional VEGF functions under the study include retinal leukostasis and neuroprotection.[2],[3],[5],[6],[7] Three receptor tyrosine kinases have been identified for VEGF: VEGFR 1, VEGFR2, and VEGFR3. The pathological functions of VEGF-A have received the most attention, culminating in the development of a new class of drugs for neovascular eye disease and cancers.[1],[2],[3],[4],[5],[6],[7],[8]

The VEGF gene family consists of VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF), which have different binding affinities for the three VEGF receptors.[9],[10] VEGF-A is the best studied has been most strongly associated with angiogenesis and is the target of most current anti-VEGF treatments.[11],[12] VEGF-A signals through two receptor tyrosine kinases, VEGFR1 and VEGFR2, and is the only member of the VEGF gene family found to be induced by hypoxia.[13] VEGF-B selectively binds VEGFR1 and has a role in the regulation of extracellular matrix degradation, cell adhesion, and migration.[9] Both VEGF-C and VEGF-D bind VEGFR2 and VEGFR3 and regulate lymphangiogenesis, and VEGF-C may also be involved in wound healing.[9],[10],[11],[12],[13],[14] PlGF selectively binds VEGFR19 and is the most abundantly expressed VEGF family member in endothelial cells.[13] PlGF may potentiate VEGF-A induced endothelial cell proliferation, but on its own PlGF exerts only weak mitogenicity.[13]

Nine isoforms of VEGF-A have been identified. VEGF-A has been implicated in ocular development, vasculogenesis, maintenance of adult vasculature, maintenance of adult ocular vasculature, and ocular pathogenesis.[15]

In 1994, Aiello et al. found a striking correlation between intraocular VEGF concentrations and active proliferative retinopathy in patients with diabetes and ischemic central retinal vein occlusion.[16] Around the same time, Adamis et al. reported increased concentrations of VEGF in the vitreous of patients with diabetic retinopathy.[17] In 1996, it also became clear that increased intraocular levels of VEGF were not limited to ischemic retinal disorders: In a pair of influential studies, the localization of VEGF to choroidal neovascular membranes in patients with neovascular AMD was reported.[18],[19] Proof-of-concept studies then demonstrated that blockade of VEGF, in animal models, led to marked decrease in retinal and iris neovascularization.[20],[21]

We have had many studies showcasing the role of ranibizumab, bevacizumab, and aflibercept in various forms in retinal diseases. In this article, we present the newer anti-VEGF agents and their mode of action.


  Brolucizumab Top


Brolucizumab (RTH258, also previously known as ESBA1008) is a humanized single chain antibody fragment that inhibits all isoforms of VEGF-A. It is the smallest anti-VEGF inhibitor tested in humans with a molecular weight of only 26 kDa compared with 48 kDa for ranibizumab or 115 kDa for aflibercept. Because of its high stability and solubility, it is possible to concentrate up to 120 mg/ml, allowing the administration of 6 mg in a single 50-ml intravitreal injection. It maintains full-binding capacity to its intended target. At a dose of 6 mg, its equivalent molar dose is approximately ten times greater than aflibercept and approximately twenty times greater than bevacizumab and ranibizumab.[22],[23]

This enables the delivery of a much higher molar dose in the same volume as the current VEGF inhibitors in clinical use potentially supporting an early initiation and a prolonged duration of treatment effect. The small size leads to fast systemic clearance, a 4-fold lower systemic exposure, and better tissue penetration.[22],[23]

A Phase I/II trial was conducted to assess for the safety, tolerability, and effect of brolucizumab at range of doses compared to ranibizumab. The present study was conducted in two phases – Dose escalation phase where patients were randomized to receive 0.5 mg, 3.0 mg or 4.5 mg, or ranibizumab 0.5 mg. In the first portion of the dose expansion phase, patients were randomized to receive brolucizumab 4.5 mg or ranibizumab 0.5 mg and in the second portion, either brolucizumab 0.5 mg, 3.0 mg, or 6.0 mg or ranibizumab 0.5 mg. This was a single dose protocol. The primary endpoint was change from baseline to 1 month in central subfield thickness (CSFT). Brolucizumab met its primary endpoint at a dose of 4.5 mg and 6.0 mg and demonstrated noninferiority to ranibizumab 0.5 mg. Overall, there was a trend toward a longer duration of action in the brolicizumab treated eyes, although the time course of improvement in the best-corrected visual acuity (BCVA) was similar between the two groups. There were no significant differences in ocular or systemic adverse effects.[24]

A Phase II (OSPREY) 56-week prospective, randomized, double-masked, multicenter, 2-arm study compared the safety and efficacy of brolucizumab 6.0 mg and aflibercept 2.0 mg for the treatment of neovascular AMD. The primary and the key secondary endpoints were the change in BCVA from baseline to week 12 and week 16. Exploratory endpoints included the presence of subretinal fluid and intraretinal fluid at each follow-up visit. The primary safety evaluation was the incidence of ocular and nonocular adverse events during treatment. The trial demonstrated noninferiority of brolucizumab to aflibercept with respect to visual acuity (VA) outcomes. Brolucizumab was found to be noninferior at both time points (weeks 12 and 16). It was found that brolucizumab had roughly equivalent and possibly very slightly better VA gains than aflibercept. With respect to its drying effect, brolucizumab appeared to be a slightly more potent agent than aflibercept by some measures. There were no clearly attributable adverse systemic effects. There were no cases of endophthalmitis, post injection. However, intraocular inflammation postinjection was comparable between the two groups.[25]

HAWK and HARRIER[26],[27] were both 2-year, randomized, double-masked, multicenter studies comparing the efficacy and safety of brolucizumab versus aflibercept in neovascular AMD. While HAWK examined the two doses of brolucizumab (3 mg and 6 mg) versus aflibercept 2 mg, HARRIER compared brolucizumab 6 mg to aflibercept 2 mg. The primary endpoint for both studies was noninferiority of mean BCVA change at week 48. The secondary endpoints were average change in BCVA from baseline for weeks 36–48, change in BCVA and CSFT from baseline at each postbaseline visit, Sub retinal fluid and Intra retinal fluid (SRF and IRF) at each postbaseline visit, and disease activity status at week 16. Disease activity status was defined as a composite clinical assessment based on multiple indicators, including BCVA, CSFT, and the presence of intraretinal cysts or fluid.

In both HAWK and HARRIER, brolucizumab demonstrated noninferiority with respect to its primary endpoint (BCVA at week 48). In HAWK, with respect to the secondary endpoint of change in BCVA over 36–48 weeks, broluicizumab was also found to be noninferior. Also, fewer brolucizumab 6 milligrams-treated eyes had disease activity versus aflibercept (24% versus 34.5%, P = 0.0001) at week 16. In HARRIER, fewer brolucizumab 6 mg-treated eyes had disease activity than aflibercept (22.7% versus 32.2%, P = 0.002) at week 16. BCVA gains achieved by week 48 in both HAWK and HARRIER were maintained through week 96.

Adverse ocular and systemic events were comparable between brolucizumab and aflibercept in HAWK and HARRIER with the exception of uveitis and endophthalmitis. In both trials, cases of uveitis and endophthalmitis were more in brolucizumab than in aflibercept group. Notably, in both trials, brolucizumab appeared to produce greater average CSFTs reductions than aflibercept eyes at 4, 8, 12, and 16 weeks.

Current evidence suggests that brolucizumab 6.0 mg is a potent intravitreal anti-VEGF agent showing efficacy and safety similar to drugs currently used to treat neovascular AMD. In addition, brolucizuamb may be a more durable drug, primarily due its low-molecular weight allowing for higher molar dosing. Clinical trials have demonstrated that brolucizumab 6.0 mg may be a more potent drying agent than aflibercept 2.0 mg as observed with multiple measures including CSFT and fluid compartment assessments. In summary, brolucizumab appears to offer the potential for less frequent intravitreal injections in eyes treated for neovascular AMD without sacrificing efficacy.


  Abicipar Pegol Top


Abicipar pegol (Abicipar, Allergan, Dublin, Ireland) is a DARPin (design ankyrin repeat proteins) directed to bind all VEGF-A isoforms, similar to ranibizumab. It has a higher affinity and a longer intraocular half-life than ranibizumab (>13 days vs. 7.2 days), making it a potential anti-VEGF therapy with longer duration and need for less frequent injections. It is being evaluated for the treatment of AMD.[28],[29]

The REACH study[30] was a phase II multicenter randomized controlled trial that compared abicipar 1 mg, abicipar 2 mg, and ranibizumab in patients with naïve neovascular AMD. BCVA and CRT improvements were similar in both abicipar groups to those achieved with ranibizumab and were maintained for 3 months following the third abicipar injection.

The phase III SEQUOIA and CEDAR studies included patients with neovascular AMD divided into three arms: Three monthly abicipar 2 mg injections followed by an injection every 8 weeks, two monthly abicipar 2 mg injections followed by an injection after 8 weeks and every 12 weeks thereafter, and monthly ranibizumab injections. Overall abicipar demonstrated noninferiority compared with ranibizumab, with less frequent injections in terms of improving VA.

The BAMBOO (conducted in Japan) and CYPRESS (conducted in the US) studies[31] included 25 patients each, divided into the same three treatments arms and injection schedules as in REACH between Japanese and non-Japanese patients. The results with both dosages of abicipar were comparable between studies, indicating that its efficacy is similar in Japanese and non-Japanese patients.

The results indicate that abicipar has the potential to become an extended-duration anti-VEGF agent, which will possibly allow treating patients in intervals of 12 weeks and reduce the ever-increasing burden of anti-VEGF injections. However, this promise is troubled by a relatively high rate of intraocular inflammation (IOI; uveitis or vitritis) following abicipar injections. Rates of IOI were 10.4% in REACH, 15.3% in CEDAR and SEQUOIA, and 7.5% in BAMBOO and CYPRESS, significantly higher than the near-zero rates with ranibizumab and other anti-VEGF agents.

To reduce the chances of inflammation, a more purified product was introduced. In the MAPLE study, 123 neovascular AMD patients were randomized to treatment by the modified formulation of abicipar 2 mg or sham. Overall rates of IOI were 8.9, with only one case (1.6%) of severe IOI. Additional research and clinical trials are required to improve its safety and validate its efficacy and extended duration compared with the currently available anti-VEGF agents.


  Conbercept Top


Conbercept is a genetically engineered homodimeric protein that inhibits the activity of VEGF-family proteins and is used for the treatment of wet AMD. Similar to VEGF Trap-Eye, conbercept (also named KH902;23,24 Chengdu Kanghong Biotech Co., Ltd., Sichuan, China) is a recombinant, soluble, VEGF-receptor protein that was designed as a receptor decoy composed of the second Ig domain of VEGFR-1, and the third and fourth Ig domains of VEGFR-2, and the constant region (Fc) of the human IgG1. Conbercept has a high affinity for all VEGF isoforms and PlGF. It is produced by Chinese hamster ovary cell lines.[32],[33]

Cui and Lu[34] in their study compared conbercept with ranibizumab, traditional transpupillary thermotherapy (TTT), bevacizumab and triamcinolone for AMD treatment. BCVA and CRT were measured the outcome. They concluded that conbercept exerts more positive effects on the long-term BCVA improvement in AMD patients than triamcinolone (after 3 months) and TTT (after 6 months). Conbercept has a therapeutic effect that is identical to that of ranibizumab, but conbercept reduces the concentration of serum VEGF during the period of treatment (1 month). In addition, conbercept has a therapeutic effect that is identical to that of ranibizumab but is superior to the one of TTT in the long-term treatment of AMD patients. Nonetheless, long-term data on the effectiveness and safety of this treatment method are required to confirm these findings.

Liu et al.[35] in his prospective, double masked, sham controlled randomized (Phase 3 PHOENIX) study used 0.5 mg of conbercept once monthly for the first 3 months, then once quarterly until 12th month in the conbercept group and 3 monthly sham injections followed by 0.5 mg of conbercept quarterly in the sham group. At 3 months, BCVA improved in the conbercept group (+9.2) in contrast to sham group where it was + 2.02 with P < 0.001. At 12 months, it was + 9.98 to + 8.81, respectively, in both the groups. SCH and raised IOP was the adverse effect noted, and hence, the author concluded that 3 monthly dose of conbercept followed by quarterly dosage is highly effective in AMD.


  Faricimab Top


It is the generic name for what was once known as RG7716 is the first bispecific antibody for intra-vitreal administration that targets two key factors that contribute to diabetic retinopathy and diabetic macular edema: VEGF and angiopoietin-2, otherwise known as Ang-2[36] Preclinical data have shown that the dual action of RG7716 has shown greater promise to stabilize the vascular leakage from a spontaneous choroidal neovascularisation (CNV) in a mouse model or a LASER-induced CNV in primates compared to the monotherapy of either agent. It also has shown anti-inflammatory properties in cases of endotoxin-induced uveitis mouse models.[37]

Phase I clinical trial analyzed 24 patients of neovascular age-related macular degeneration (nAMD) refractory to 3 or more anti-VEGF injections in the past 6 months. There was an overall favorable safety profile with evidence of BCVA and anatomical improvement.[37],[38]

The AVENUE trial, a phase 2, 273-patient study, compared treatment with ranibizumab 0.5 mg every 4 weeks, faricimab 1.5 mg every 4 weeks, faricimab 6 mg every 4 weeks, faricimab 6 mg every 8 weeks, and faricimab 6 mg/ranibizumab 0.5 mg combination therapy (three ranibizumab injections every 4 weeks, followed by faricimab every 4 weeks) in treatment-naïve nAMD. The primary outcome was mean change in BCVA from baseline at 36 weeks. 1.5 mg faricimab arm given every 4 weeks demonstrated the best gains of +9.1 letters at 36 weeks.[37],[39]

Phase II clinical trial[37],[40] of faricimab was initiated for both DME and nAMD named as BOULEVARD and STAIRWAY trials, respectively. BOULEVARD was a 36-week, double blind, randomized, active comparator controlled multicentric trial with 229 patients of DME in three treatment cohorts. 168 patients were treatment naïve, whereas 61 patients had received anti-VEGF injections previously. Treatment-naïve patients were randomized into three cohorts who received 6.0 mg of faricimab, 1.5 mg of faricimab, and 0.3 mg of ranibizumab. Previously treated patients were randomized into 6.0 mg of faricimab and 0.3 mg of ranibizumab. The trial showed superiority of 6.0 mg faricimab arm over 0.3 mg ranibizumab arm in terms of letter gains in VA, greater central subfoveal thickness (CST) reduction and diabetic retinopathy severity score improvement. It has also shown to have better durability in terms of less requirement of injections during the follow-up period.

STAIRWAY trial[41] evaluated two extended dosing regimens of faricimab in 76 patients of nAMD. A total of 6.0 mg of faricimab was given in four weekly loading doses followed by two different dosing schedules of q16w and q12w dosing and compared to 0.5 mg of ranibizumab in q4w dosing Faricimab and ranibizumab had comparable reduction of CST in both dosing regimens. Both Phase II trials of faricimab have shown to be safe and effective option for treating DME and nAMD.

RHINE and YOSEMITE Phase III trials will evaluate its effect for DME, whereas its effect on nAMD will be evaluated in TENAYA and LUCERNE trial. Phase III will evaluate the anti-inflammatory properties of the drug.[42],[43],[44],[45]


  OPT–302 Top


OPT-302 (Opthea) targets VEGF-C and VEGF-D, which may play a complementary role in nAMD pathogenesis, in addition to anti-VEGF-A. A phase 1/2a study (NCT02543229) showed that in treatment-naïve patients, intra-vitreal injections of both OPT-302 2 mg and ranibizumab 0.5 mg administered every 4 weeks resulted in meaningful additional VA gain and reduction in macular thickness compared to ranibizumab alone at 12-week follow up. Phase 2B trials comparing ranibizumab monotherapy with OPT-302 2 mg/ranibizumab 0.5 mg, and OPT-302 0.5 mg/ranibizumab 0.5 mg in 351 treatment-naïve patients over 6 months are awaiting results.[46]


  KSI–310 Top


KSI-301 (Kodiak Sciences) has developed a novel anti-VEGF antibody biopolymer conjugate (ABC Platform) for the treatment of nAMD and other retinal vascular diseases. In Phase 1a study for DME, a single dose of KSI-301 was well tolerated and showed the duration of response at 12-week follow-up, with a median of 9 ETDRS letter improvement across all dose groups.[46]


  X-82 Top


X-82 (Tyrogenex) is an oral anti-PDGF and VEGF-A inhibitor. In the Phase 1 dose-escalation study 29% did not complete the 24-week endpoint and 17% withdrawing due to adverse events. The most common adverse events were diarrhea, nausea, fatigue, and elevated transaminase enzymes that reversed with cessation of X-82. Twenty-four of the 25 patients that completed the 24-week trial showed stable or improved VA (mean + 3.8 letters), and 15 of 25 (60%) did so without need for rescue ranibizumab injections. Mean CSFT was reduced by a mean of 50 μm. The Phase 2 APEX study tested X-82 at doses of 50 mg, 100 mg, and 200 mg with as-needed anti-VEGF compared to placebo and as-needed anti-VEGF. The primary outcome was the change in VA from baseline to 52 weeks. The present study was terminated after an interim analysis. Participants in the 200 mg arm gained a mean of 1.7 letters while those in the placebo arm lost a mean of 0.3 letters.[47]


  Conclusion Top


The development of anti-VEGF-A therapy has revolutionized the treatment of retinal diseases like nAMD, vascular occlusion and diabetic retinopathy, and choroidal neovascularization. Landmark trials have demonstrated the superiority of anti-VEGF-A injections over photodynamic therapy for preserving and recovering VA. Various new modalities of treatment such as modulating synergistic targets such as the Tie-2 receptor, Ang-2, and PDGF are also on the pipeline. The various modes of delivery of anti-VEGF agents have shown promising results in terms of their need for less frequent injections and adverse reactions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669-76.  Back to cited text no. 1
    
2.
Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983;219:983-5.  Back to cited text no. 2
    
3.
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989;246:1306-9.  Back to cited text no. 3
    
4.
Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 1989;161:851-8.  Back to cited text no. 4
    
5.
Miyamoto K, Khosrof S, Bursell SE, Moromizato Y, Aiello LP, Ogura Y, et al. Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). Am J Pathol 2000;156:1733-9.  Back to cited text no. 5
    
6.
Azzouz M, Ralph GS, Storkebaum E, Walmsley LE, Mitrophanous KA, Kingsman SM, et al. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 2004;429:413-7.  Back to cited text no. 6
    
7.
Ding XM, Mao BY, Jiang S, Li SF, Deng YL. Neuroprotective effect of exogenous vascular endothelial growth factor on rat spinal cord neurons in vitro hypoxia. Chin Med J (Engl) 2005;118:1644-50.  Back to cited text no. 7
    
8.
Karkkainen MJ, Mäkinen T, Alitalo K. Lymphatic endothelium: A new frontier of metastasis research. Nat Cell Biol 2002;4:E2-5.  Back to cited text no. 8
    
9.
Olofsson B, Korpelainen E, Pepper MS, Mandriota SJ, Aase K, Kumar V, et al. Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc Natl Acad Sci U S A 1998;95:11709-14.  Back to cited text no. 9
    
10.
Bauer SM, Bauer RJ, Liu ZJ, Chen H, Goldstein L, Velazquez OC. Vascular endothelial growth factor-C promotes vasculogenesis, angiogenesis, and collagen constriction in threedimensional collagen gels. J Vasc Surg 2005;41:699-707.  Back to cited text no. 10
    
11.
Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996;380:435-9.  Back to cited text no. 11
    
12.
Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: Therapeutic implications. Semin Oncol 2002;29:10-4.  Back to cited text no. 12
    
13.
Yonekura H, Sakurai S, Liu X, Migita H, Wang H, Yamagishi S, et al. Placenta growth factor and vascular endothelial growth factor B and C expression in microvascular endothelial cells and pericytes. Implication in autocrine and paracrine regulation of angiogenesis. J Biol Chem 1999;274:35172-8.  Back to cited text no. 13
    
14.
Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 2001;7:186-91.  Back to cited text no. 14
    
15.
Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond) 2005;109:227-41.  Back to cited text no. 15
    
16.
Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480-7.  Back to cited text no. 16
    
17.
Adamis AP, Miller JW, Bernal MT, D'Amico DJ, Folkman J, Yeo TK, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 1994;118:445-50.  Back to cited text no. 17
    
18.
Kvanta A, Algvere PV, Berglin L, Seregard S. Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci 1996;37:1929-34.  Back to cited text no. 18
    
19.
Lopez PF, Sippy BD, Lambert HM, Thach AB, Hinton DR. Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci 1996;37:855-68.  Back to cited text no. 19
    
20.
Tolentino MJ, Miller JW, Gragoudas ES, Chatzistefanou K, Ferrara N, Adamis AP. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol 1996;114:964-70.  Back to cited text no. 20
    
21.
Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci U S A 1995;92:10457-61.  Back to cited text no. 21
    
22.
Tietz J, Spohn G, Schmid G, Konrad J, Jampen S, Maurer P, et al. Affinity and potency of RTH258 (ESBA1008), a novel inhibitor of vascular endothelial growth factor a for the treatment of retinal disorders. Invest Ophthalmol Vis Sci 2015;56:1501.  Back to cited text no. 22
    
23.
Gaudreault J, Gunde T, Floyd HS, Ellis J, Tietz J, Binggeli D, et al. Preclinical pharmacology and safety of ESBA1008, a single-chain antibody fragment, investigated as potential treatment for age related macular degeneration. Invest Ophthalmol Vis Sci 2012;53:3025.  Back to cited text no. 23
    
24.
Holz FG, Dugel PU, Weissgerber G, Hamilton R, Silva R, Bandello F, et al. Single-chain antibody fragment VEGF inhibitor RTH258 for neovascular age-related macular degeneration: A randomized controlled study. Ophthalmology 2016;123:1080-9.  Back to cited text no. 24
    
25.
Dugel PU, Jaffe GJ, Sallstig P, Warburton J, Weichselberger A, Wieland M, et al. Brolucizumab versus aflibercept in participants with neovascular age-related macular degeneration: A randomized trial. Ophthalmology 2017;124:1296-304.  Back to cited text no. 25
    
26.
Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, et al. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology 2020;127:72-84.  Back to cited text no. 26
    
27.
Dugel P. Brolucizumab for neovascular AMD: The 2 year HAWK and HARRIER results. Presentation at the American Academy of Ophthalmology, Chicago, IL., October 27, 2018.  Back to cited text no. 27
    
28.
Krohne TU, Liu Z, Holz FG, Meyer CH. Intraocular pharmacokinetics of ranibizumab following a single intravitreal injection in humans. Am J Ophthalmol 2012;154:682-600.  Back to cited text no. 28
    
29.
Rodrigues GA, Mason M, Christie LA, Hansen C, Hernandez LM, Burke J, et al. Functional characterization of abicipar-pegol, an anti-VEGF DARPin therapeutic that potently inhibits angiogenesis and vascular permeability. Invest Ophthalmol Vis Sci 2018;59:5836-46.  Back to cited text no. 29
    
30.
Callanan D, Kunimoto D, Maturi RK, Patel SS, Staurenghi G, Wolf S, et al. Double-masked, randomized, phase 2 evaluation of abicipar pegol (an Anti-VEGF DARPin therapeutic) in neovascular age-related macular degeneration. J Ocul Pharmacol Ther 2018;34:700-9.  Back to cited text no. 30
    
31.
Kunimoto D, Ohji M, Maturi RK, Sekiryu T, Wang Y, Pan G, et al. Evaluation of abicipar pegol (an Anti-VEGF DARPin therapeutic) in patients with neovascular age-related macular degeneration: studies in Japan and the United States. Ophthalmic Surg Lasers Imaging Retina 2019;50:e10-22.  Back to cited text no. 31
    
32.
Li X, Xu G, Wang Y, Xu X, Liu X, Tang S, et al. Safety and efficacy of conbercept in neovascular age-related macular degeneration: Results from a 12-month randomized phase 2 study: AURORA study. Ophthalmology 2014;121:1740-7.  Back to cited text no. 32
    
33.
Zhang M, Zhang J, Yan M, Luo D, Zhu W, Kaiser PK, et al. A phase 1 study of KH902, a vascular endothelial growth factor receptor decoy, for exudative age-related macular degeneration. Ophthalmology 2011;118:672-8.  Back to cited text no. 33
    
34.
Cui C, Lu H. Clinical observations on the use of new anti-VEGF drug, conbercept, in age-related macular degeneration therapy: A meta-analysis. Clin Interv Aging 2018;13:51-62.  Back to cited text no. 34
    
35.
Liu K, Song Y, Xu G, Ye J, Wu Z, Liu X, et al. Conbercept for treatment of neovascular age-related macular degeneration: results of the randomized phase 3 PHOENIX study. Am J Ophthalmol 2019;197:156-67.  Back to cited text no. 35
    
36.
Sharma A, Kumar N, Kuppermann BD, Bandello F, Loewenstein A. Faricimab: Expanding horizon beyond VEGF, Eye 2020;34:802-4.  Back to cited text no. 36
    
37.
Iwata D, von Leithner PL, Ng YS, Hartmann G, Shima DT. Anti-VEGF/Ang2 bi-specific antibody ameliorates endotoxin-induced uveitis in mice. Invest Ophthalmol Vis Sci 2014;55:2354.  Back to cited text no. 37
    
38.
Chakravarthy U, Bailey C, Brown D, Campochiaro P, Chittum M, Csaky K, et al. Phase I trial of anti-vascular endothelial growth factor/anti-angiopoietin 2 bispecific antibody RG7716 for neovascular age-related macular degeneration. Ophthalmol Retina 2017;1:474-85.  Back to cited text no. 38
    
39.
Helzner J. Faricimab shows potential for 16-week dosing. Retina Physician 2018. Available from: https://www.retinalphysician.com/issues/2018/september-2018/faricimab-shows-potential-for-16-week-dosing. [Last accessed on 2019 Jul 17].  Back to cited text no. 39
    
40.
Sahni J, Patel SS, Dugel PU, Khanani AM, Jhaveri CD, Wykoff CC, et al. Simultaneous inhibition of angiopoietin-2 and vascular endothelial growth factor-a with faricimab in diabetic macular edema: BOULEVARD phase 2 randomized trial. Ophthalmology 2019;126:1155-70.  Back to cited text no. 40
    
41.
Khanani AM. Simultaneous inhibition of VEGF and Ang-2 with faricimab in neovascular AMD: STAIRWAY phase 2 results. Presented at the 2018 American Academy of Ophthalmology (AAO) Annual Meeting; 26 October, 2018; Chicago, United States.  Back to cited text no. 41
    
42.
A Study to Evaluate the Efficacy and Safety of Faricimab (RO6867461) in Participants with Diabetic Macular Edema. Available from: https://clinicaltrials.gov/ct2/show/NCT03622593. [Last accessed 2019 Jul 15].  Back to cited text no. 42
    
43.
A Study to Evaluate the Efficacy and Safety of Faricimab (RO6867461) in Participants with Diabetic Macular Edema (YOSEMITE). Available from: https://clinicaltrials.gov/ct2/show/NCT03622580. [Last accessed 2019 Jul 15].  Back to cited text no. 43
    
44.
A Study to Evaluate the Efficacy and Safety of Faricimab in Participants withNeovascular Age-Related Macular Degeneration (TENAYA). Available from: https://clinicaltrials.gov/ct2/show/NCT03823287. [Last accessed 2019 Jul 15].  Back to cited text no. 44
    
45.
A Study to Evaluate the Efficacy and Safety of Faricimab in Participants with Neovascular Age-Related Macular Degeneration (LUCERNE). Available from: https://clinicaltrials.gov/ct2/show/NCT03823300. [Last accessed 2019 Jul 15].  Back to cited text no. 45
    
46.
Al-Khersan H, Hussain RM, Ciulla TA, Dugel PU. Innovative therapies for neovascular age-related macular degeneration. Expert Opin Pharmacother 2019;20:1879-91.  Back to cited text no. 46
    
47.
Jackson TL, Boyer D, Brown DM, Chaudhry N, Elman M, Liang C, et al. Oral tyrosine kinase inhibitor for neovascular age-related macular degeneration: A Phase 1 dose-escalation study. JAMA Ophthalmol 2017;135:761-7.  Back to cited text no. 47
    




 

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Abstract
Introduction
Brolucizumab
Abicipar Pegol
Conbercept
Faricimab
OPT–302
KSI–310
X-82
Conclusion
References

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