Brolucizumab: Evolution through Preclinical and Clinical Studies and the Implications for the Management of Neovascular Age-Related Macular Degeneration

Nguyen, Quan Dong; Das, Arup; Diana, V.; Dugel, Pravin U.; Gomes, A.V.; Holz, Frank G.; Koh, Adrian; Pan, Carolyn K.; Sepah, Yasir J.; Patel, Nikhil; MacLeod, Heather; Maurer, Patrik

doi:10.1016/j.ophtha.2019.12.031

Cited by 181 publications

(186 citation statements)

References 50 publications

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“…Although the initial results with brolucizumab have been promising, the drug's safety is currently under review due to reports of clinically significant intraocular inflammation and occlusive retinal vasculitis associated with the study drug in the HAWK and HARRIER studies as well as in patients with neovascular AMD treated with brolucizumab after the drug was approved by the FDA [26][27][28][29][30]. In addition, Novartis, the manufacturer of brolucizumab, has also reported the occurrence of vitritis and retinal vasculitis in subjects with DME being treated with RTH 258 in current studies [31,32].…”

Section: Brolucizumabmentioning

confidence: 99%

RETRACTED ARTICLE: Pharmacological agents in development for diabetic macular edema

et al. 2020

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Background: Diabetic macular edema (DME) is the leading cause of visual loss in patients with diabetic retinopathy. There has been a paradigm shift in the treatment of DME since the advent of anti-vascular endothelial growth factor (anti-VEGF) therapy. The safety and efficacy of anti-VEGF therapy has been well established. Although efficacious, currently approved anti-VEGF agents are associated with certain limitations, which include, among others: frequent need for injections, high treatment cost and variable response to treatment. These challenges have led to an active search for more novel agents that may be able to overcome these limitations. Areas covered: The index review focuses on novel treatment agents that target various pathways in patients with DME. These agents are used either as monotherapy or in combination with other agents in the management of DME. Drugs discussed include novel anti-VEGF inhibitors, TIE-2 receptor modulators, integrin peptide inhibitors, rho kinase inhibitors, and future therapies such as neuroprotection and gene therapy. Conclusions: The future of investigational pharmacological therapy appears promising for patients with DME. Results from early clinical trials indicate that newer agents highlighted in the study may be safe and efficacious treatment options for patients with DME. However, data from large multicenter clinical trials need to be analyzed before these agents can be incorporated into clinical practice.

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Section: Brolucizumabmentioning

confidence: 99%

RETRACTED ARTICLE: Pharmacological agents in development for diabetic macular edema

et al. 2020

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“…The small size and low viscosity of brolocizumab, a recently approved anti-VEGF single-chain variable domain, enables concentration up to 120 mg/ml, and the resulting high molar dose of drug extends the approved dosing interval to 3 months. 60 , 61 Kodiak Sciences has pursued an alternate approach where conjugation of a ~ 800 kDa biocompatible polymer to an anti-VEGF IgG results in a nearly megadalton conjugate with slow diffusion out of the eye resulting in a retinal half-life of 10.5 days in rabbits and durability of up to 6 months in a Phase 1 clinical trial (NCT03790852). 62 Finally, surgical implantation of a port delivery system has allowed ranibizumab to be dosed with a median durability of up to 15 months.…”

Section: Discussionmentioning

confidence: 99%

Targeted IgMs agonize ocular targets with extended vitreal exposure

Chen¹,

Paluch²,

Zorn³

et al. 2020

mAbs

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Treatment of ocular disease is hindered by the presence of the blood-retinal barrier, which restricts access of systemic drugs to the eye. Intravitreal injections bypass this barrier, delivering high concentrations of drug to the targeted tissue. However, the recommended dosing interval for approved biologics is typically 6–12 weeks, and frequent travel to the physician’s office poses a substantial burden for elderly patients with poor vision. Real-world data suggest that many patients are under-treated. Here, we investigate IgMs as a novel platform for treating ocular disease. We show that IgMs are well-suited to ocular administration due to moderate viscosity, long ocular exposure, and rapid systemic clearance. The complement-dependent cytotoxicity of IgMs can be readily removed with a P436G mutation, reducing safety liabilities. Furthermore, dodecavalent binding of IgM hexamers can potently activate pathways implicated in the treatment of progressive blindness, including the Tie2 receptor tyrosine kinase signaling pathway for the treatment of diabetic macular edema, or the death receptor 4 tumor necrosis family receptor pathway for the treatment of wet age-related macular degeneration. Collectively, these data demonstrate the promise of IgMs as therapeutic agonists for treating progressive blindness.

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“…Moreover, a newly developed anti-VEGF agent, brolucizumab (Beovu®, Novartis), has been approved by the U.S. Food and Drug Administration and by the EMA for the treatment of nAMD [47]. The main advantage of Brolucizumab over the other anti-VEGFs would be the longer durability, thus having the potential to reduce the treatment burden [48,49].…”

Section: Current Trends and Future Directionsmentioning

confidence: 99%

Intravitreal Bevacizumab in Neovascular Age-Related Macular Degeneration as First Choice: a New Italian Ruling

Erba¹,

Scialdone²,

Casalino³

2020

Med Hypothesis Discov Innov Ophthalmol

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Background: Intravitreal vascular endothelial growth factor (VEGF) inhibitors represent the mainstay of neovascular age-related macular degeneration (nAMD) treatment. Although bevacizumab has been the first anti-VEGF used in ophthalmology, it is unlicensed for intraocular use. However, the favourable cost-benefit balance has favoured its widespread use. We aimed to present relevant literature regarding the safety profile and the regulatory issues of intravitreal bevacizumab use. Methods: In this narrative review we report relevant studies regarding the safety profile of intravitreal bevacizumab. Expert commentary is provided and an overview of the current scenario and possible future directions discussed. Results: Randomized controlled trials have demonstrated that bevacizumab is not inferior to the licensed anti-VEGF agents showing similar efficacy and safety profiles. However, a significant debate on the regulatory issues of intravitreal bevacizumab used as ‘off label’ first-line treatment in nAMD still persists. Recently, the Regional Health System of Lombardia in Italy decided to only cover the expenses of bevacizumab, forcing clinicians to use bevacizumab as the first choice in the treatment of nAMD. Issues about the practical implications of this decision are discussed. Conclusion: The use of intravitreal bevacizumab as first-line therapy in nAMD remains controversial. Many differences in the regulatory aspects still persist among the European countries and sometimes within the same countries, like Italy. Of note the clinical scenario will be modified in future by the introduction of newly developed anti-VEGF agents and anti-VEGF biosimilars.

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Brolucizumab: Evolution through Preclinical and Clinical Studies and the Implications for the Management of Neovascular Age-Related Macular Degeneration

Cited by 181 publications

References 50 publications

RETRACTED ARTICLE: Pharmacological agents in development for diabetic macular edema

RETRACTED ARTICLE: Pharmacological agents in development for diabetic macular edema

Targeted IgMs agonize ocular targets with extended vitreal exposure

Intravitreal Bevacizumab in Neovascular Age-Related Macular Degeneration as First Choice: a New Italian Ruling

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