Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is the current standard of care treatment for neovascular age-related macular degeneration (nAMD). Anti-VEGF therapy has been associated with significant improvements in the visual acuity outcomes of patients,¹ and studies of aflibercept (Eylea; Regeneron), bevacizumab (Avastin; Genentech), and ranibizumab (Lucentis; Genentech) have revealed little difference in their efficacy and safety profiles.^2,3

Intraocular Inflammation With New Drugs

Intraocular inflammation (IOI) has been one of the main concerns regarding the use of intravitreal anti-VEGF therapy. Initial anti-VEGF clinical trials among patients with nAMD reported relatively low rates of IOI. The ANCHOR study, for instance, reported a 1.4% rate of significant IOI in ranibizumab-treated eyes compared to 0% in the photodynamic therapy group,¹ the PIER study reported no difference in the rates of IOI between ranibizumab-treated eyes and the sham injection group,² and an analysis of 10 phase 2 and phase 3 randomized, controlled trials of intravitreal aflibercept compared to a pooled control group (including sham injections, laser, and ranibizumab) reported an IOI rate of 2.06% for aflibercept and 2.37% for the pooled control group.³ In the VIEW studies, between baseline and 96 weeks, IOI was reported in 1.5% of patients receiving ranibizumab and 0.5% to 1.1% of patients in the 3 aflibercept arms.⁴ Although retrospective and prospective data suggest that the rates of IOI following intravitreal injection of bevacizumab may be higher than those associated with aflibercept and ranibizumab injection, a meta-analysis focused only on prospective data found no significant difference in the IOI rates among these 3 agents.⁵ The IOI associated with the 3 aforementioned anti-VEGF agents is typically mild and resolves with corticosteroid eye drops.⁶

Brolucizumab (Beovu; Novartis) is an anti-VEGF agent approved by the United States Food and Drug Administration (FDA) in October 2019 for the treatment of nAMD, and is the first anti-VEGF agent approved for a dosing interval range of 8 to 12 weeks after 3 loading doses. The pivotal trials, HAWK and HARRIER, demonstrated noninferiority of brolucizumab compared to aflibercept with respect to visual acuity outcomes, with reduced dosing frequency and better anatomic outcomes in the brolucizumab-treated patients.⁶ However, soon after FDA approval, reports of occlusive retinal vasculitis associated with IOI and severe vision loss were made to Novartis and to the Research and Safety in Therapeutics (ReST) Committee of the American Society of Retina Specialists (ASRS). In 2020, Baumal et al published a retrospective case series of 15 eyes from 12 patients with occlusive retinal vasculitis and IOI after intravitreal injection of brolucizumab; 60% of these eyes lost 3 or more Early Treatment Diabetic Retinopathy Study (ETDRS) lines of vision.⁷ Shortly thereafter, the ReST Committee reported 26 eyes that developed retinal vasculitis after brolucizumab injection; 12 (46%) of these eyes lost 3 or more lines of visual acuity and 12 (46%) had a visual acuity of 20/200 or worse at final follow-up.⁸ An independent Safety Review Committee sponsored by Novartis performed a detailed review of adverse events in HAWK and HARRIER and reported that the incidence of IOI among brolucizumab-treated eyes was 4.6% and the incidence of IOI associated with occlusive retinal vasculitis was 2.1%.⁹

Abicipar pegol (Allergan), an anti-VEGF molecule based on ankyrin repeat proteins (DARPins) which bind to VEGF-A, was demonstrated in 2 nAMD phase 3 clinical trials (CEDAR and SEQUOIA) to be noninferior to ranibizumab for maintaining stable visual acuity and improving central retinal thickness, with reduced dosing frequency in abicipar-treated patients.¹⁰ The primary outcome of both trials was the proportion of patients with stable visual acuity (loss of fewer than 15 ETDRS) from baseline to 52 weeks. The 2 trials combined enrolled a total of 1,888 patients, and the results demonstrated that, at 52 weeks, 93.2% of patients treated with abicipar every 8 weeks and 91.3% of patients treated with abicipar every 12 weeks were stable compared with 95.8% of patients treated with monthly ranibizumab.¹⁰ However, based on the incidence of IOI (15.4%, 15.3%, and 0.3% in the 3 treatment arms, respectively), the FDA rejected the biologics license application for abicipar in June 2020.

Adeno-associated virus gene therapy vector ADVM-022 (Adverum Biotechnologies) is a gene therapy vector designed for continuous delivery of aflibercept through a single intravitreal injection. The phase 1 OPTIC study is an ongoing phase 1, 2-year multicenter dose-ranging trial including 30 patients with nAMD who were treated with a single intravitreal injection of ADVM-022 7 to 14 days after a screening aflibercept injection with a concurrent 6-week topical or 13-day oral corticosteroid regimen for inflammation control.¹¹ At 92 weeks, mean best-corrected visual acuity was maintained and mean central retinal thickness was either maintained or improved; the majority of patients did not need supplemental anti-VEGF therapy. Intraocular inflammation has been noted in some patients, but it has been well controlled with topical steroids. Although ocular adverse events in the OPTIC study were reported as mild (78%) or moderate 22%),¹¹ Adverum Biotechnologies reported in April 2021 that the treated eye of a patient in the INFINITY trial, which evaluated ADVM-022 in patients with diabetic macular edema (DME), developed an unexpected serious adverse event including hypotony, panuveitis, and loss of vision;¹² this led the company to unmask the INFINITY trial, which revealed rapid, clinically relevant decreases in intraocular pressure in patients who had received the high dose of ADVM-022.¹³ As a result, Adverum Biotechnologies suspended its study of ADVM-022 in DME and, in July 2021, announced that it had revised its ADVM-022 development plan to focus on nAMD.¹³

Summary

Although IOI has been reported with the use of all the current intravitreal anti-VEGF agents employed in the treatment of nAMD, the IOI is typically mild and well controlled with topical steroids when it occurs following aflibercept, bevacizumab, or ranibizumab injection. Retina specialists and their patients will need to consider carefully whether anatomic and durability benefits outweigh the increased risks of IOI, occlusive retinal vasculitis, and severe vision loss associated with the use of brolucizumab. The FDA has determined that the increased risk of IOI associated with the use of abicipar was sufficient to deny its approval. Although the risks of hypotony and panuveitis have led to the suspension of study of ADVM-022 for the treatment of DME, these adverse events have not been observed in the phase I OPTIC study of ADVM-022 in nAMD, and the manufacturer is planning a phase 2 clinical trial of ADVM-022 in patients with nAMD. Intraocular inflammation assessment will remain critical for all prospective therapies for nAMD to ensure that the safety profile matches that of currently available and approved anti-VEGF agents.

References

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2. Plyukhova AA, Budzinskaya MV, Starostin KM, et al. Comparative safety of bevacizumab, ranibizumab, and aflibercept for treatment of neovascular age-related macular degeneration (AMD): a systematic review and network meta-analysis of direct comparative studies. J Clin Med. 2020;9(5):1522. doi:10.3390/jcm9051522
3. van Asten F, Michels CTJ, Hoyng CB, et al. The cost-effectiveness of bevacizumab, ranibizumab and aflibercept for the treatment of age-related macular degeneration—a cost-effectiveness analysis from a societal perspective. PLoS One. 2018;13(5):e0197670. doi:10.1371/journal.pone.0197670
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7. Baumal CR, Spaide RF, Vajzovic L, et al. Retinal vasculitis and intraocular inflammation after intravitreal injection of brolucizumab. Ophthalmology. 2020;127(10):1345-1359. doi:10.1016/j.ophtha.2020.04.017
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9. Monés J, Srivastava SK, Jaffe GJ, et al. Risk of inflammation, retinal vasculitis, and retinal occlusion-related events with brolucizumab: post hoc review of HAWK and HARRIER. Ophthalmology. 2021;128(7):1050-1059. doi:10.1016/j.ophtha.2020.11.011
10. Kunimoto D, Yoon YH, Wykoff CC, et al. Efficacy and safety of abicipar in neovascular age-related macular degeneration: 52-week results of phase 3 randomized, controlled study. Ophthalmology. 2020;127(10):1331-1344. doi:10.1016/j.ophtha.2020.03.035
11. Adverum Biotechnologies. Adverum Biotechnologies announces positive interim data from cohorts 1-4 from OPTIC phase 1 trial of ADVM-022 intravitreal gene therapy for wet AMD. News release. Accessed February 17, 2022. https://www.globenewswire.com/news-release/2020/11/14/2126834/0/en/Adverum-Biotechnologies-Announces-Positive-Interim-Data-from-Cohorts-1-4-from-OPTIC-Phase-1-Trial-of-ADVM-022-Intravitreal-Gene-Therapy-for-Wet-AMD.html
12. Adverum Biotechnologies. Adverum Biotechnologies provides update on the INFINITY trial evaluating ADVM-022 in patients with diabetic macular edema. News release. Accessed February 17, 2022. https://www.globenewswire.com/news-release/2021/04/28/2219019/32452/en/Adverum-Biotechnologies-Provides-Update-on-the-INFINITY-Trial-Evaluating-ADVM-022-in-Patients-with-Diabetic-Macular-Edema.html
13. Adverum Biotechnologies. Adverum provides update on ADVM-022 and the INFINITY trial in patients with diabetic macular edema. News release. Accessed February 17, 2022. https://www.globenewswire.com/news-release/2021/07/22/2267699/32452/en/Adverum-Provides-Update-on-ADVM-022-and-the-INFINITY-Trial-in-Patients-with-Diabetic-Macular-Edema.html