Retina specialists are fortunate to work at a time when we are on the cusp of many promising pipeline treatments. Our specialty enjoyed remarkable success starting in the early 2000s with the adoption of anti-VEGF agents, but we have relied on this class of therapeutics as the backbone of treatment for common retinal diseases without any new mechanisms of action of delivery platforms.

While we have improved the potency and refined the dosing pattern of anti-VEGF agents, we have not moved to new targets nor new delivery systems in more than 15 years. We have also failed to deliver a proven safe and effective treatment for atrophic “dry” AMD.

However, our robust pipeline may soon move us into a new and exciting time for retina care. Here’s a review of new tools we may soon have at our disposal to combat the most common and troublesome retinal diseases.

DRY AMD WITH GEOGRAPHIC ATROPHY

Currently, two late-phase programs targeting dry AMD with geographic atrophy (GA) are ongoing. Both programs focus on regulating the complement system, which is part of the immune system and generates an inflammatory response. The complement system consists of a number of small proteins that interact in a downstream cascade, ultimately resulting in a release of cytokines that generate membrane attack, phagocytosis and inflammation. This process has been associated with progression of both wet and dry macular degeneration.^1,2

Inhibition of these small proteins in the complement cascade may reduce the progression of GA, although it is not clear which point(s) of inhibition would be most clinically relevant. Complement inhibition has not succeeded to date, highlighted by the failure in Phase 3 of a complement factor D inhibitor lampalizumab (Genentech) to meaningfully reduce the rate of GA enlargement vs sham.³

However, the basic science is compelling, and two late-phase complement inhibition programs are ongoing. Pegcetacoplan (Apellis) is a complement factor 3 (C3) inhibitor that has shown promising results in Phase 2⁴ and has a fully enrolled Phase 3 trial, which is awaiting read-out of its primary endpoint.

Avacincaptad pegol (Zimura, Iveric Bio) is a complement factor 5 (C5) inhibitor that has shown efficacy in Phase 2/3⁵ and is currently enrolling a second pivotal trial to confirm a clinically significant reduction in GA enlargement.

NEOVASCULAR AMD

Intravitreal anti-VEGF monotherapy has been the backbone of neovascular AMD (nAMD) treatment since its commercial availability, initially with pegaptanib sodium (Macugen, Bausch + Lomb) in 2004 and almost immediately thereafter with off-label intravitreal bevacizumab (Avastin, Genentech). Although retina enjoyed a revolution in treatment with the broad and rapid adoption of intravitreal anti-VEGF monotherapy, the real-world results of nAMD treatment do not mirror those seen in clinical trials. These less compelling real-world results are associated with a relatively lower real-world injection frequency than that observed in protocol-driven clinical trials.

There are a number of reasons for lower real-world injection frequencies, including lack of perceived treatment benefit, distance from the clinic, difficulties with caregiver assistance and cost of treatment.⁶

Retina specialists recognize these shortcomings, and recent ASRS Preferences and Trends survey results have shown that reduced treatment burden and long-acting or sustained delivery are the largest unmet needs in nAMD treatment.⁷ The recent commercial release of brolucizumab (Beovu, Novartis) has added another tool to the anti-VEGF armamentarium against AMD. The registration studies for brolucizumab showed visual equivalency to aflibercept in the first 2 years, but with a less-frequent dosing interval up to 12 weeks in the brolucizumab patients starting in the first year. There has been some hesitancy with the adoption of brolucizumab, due to an increased incidence of intraocular inflammation seen in both the registration trial as well as in real-world settings.⁸

Another approach to extended durability is to find new, clinically relevant mechanisms of action. Faricimab (Genentech) is a bispecific molecule that binds to both VEGF and angiopoietin-2 (ang2), and a Phase 2 study in nAMD has suggested improved treatment durability with this dual inhibition.⁹ The recently completed Phase 3 program for faricimab in nAMD presented initial results at the 2021 Angiogenesis meeting. The molecule showed non-inferiority to aflibercept with a dosing interval of 12-16 weeks in over 70% of subjects, with full results forthcoming.

The Port Delivery System (PDS, Genentech) is a novel approach to treating nAMD, in which a surgically implanted passive delivery device secured in the pars plana is filled with a concentrated form of ranibizumab. In Phase 3 clinical trials, this device has demonstrated efficacy equivalent to monthly intravitreal ranibizumab 0.5 mg in the first year of treatment, with only an initial fill and a single refill at month 6.¹⁰ The combination of longer-lasting agents as well as the novel PDS may meaningfully reduce the burden of treatment in nAMD and improve our real-world results.

DIABETIC MACULAR EDEMA

Similar to nAMD, diabetic macular edema (DME) treatments do not perform as well in the real world as compared to their results in clinical trials.¹¹ There are important differences between the populations of nAMD and DME patients. Patients who have diabetes often have vasogenic, inflammatory, ischemic and tractional factors all affecting their disease state and contributing to their vision loss. The DME population is also younger than the nAMD population, so more familial, employment and access pressures reduce their ability to receive frequent or timely care. These multiple societal pressures reduce the real-world injection frequency for diabetes patients.¹² Fortunately, the late-phase pipeline for DME treatment is robust and also focuses on treatment burden.

KSI-301 (Kodiak Sciences) is an anti-VEGF therapy built around an antibody biopolymer conjugate technology, which is a large molecule designed to achieve sustained anti-VEGF drug levels for an extended duration. An ongoing Phase 1b study including patients with AMD, DME and retinal vein occlusion (RVO) has presented uncontrolled data supporting a longer-term favorable safety and a promising durability profile.¹³

A Phase 3 program in DME has started to enroll patients; it will compare KSI-301 to aflibercept with a dosing interval of up to 24 weeks for the KSI-301 patients.¹⁴ A Phase 3 PDS program for DME treatment is also enrolling, utilizing the same surgically-implanted device that showed success in nAMD with a substantial reduction in treatment burden.¹⁵

Faricimab bispecific VEGF and ang2 inhibition has suggested improved efficacy with regards to durability as well as reduction of central subfield thickness compared with anti-VEGF monotherapy with monthly ranibizumab in Phase 2.¹⁶ Importantly, faricimab completed its Phase 3 program in DME, and initial results were reported at Angiogenesis 2021.

Faricimab showed non-inferiority in visual acuity compared to aflibercept, with faricimab subjects showing an enhanced reduction of retinal swelling early in treatment and more than 70% of faricimab-treated subjects achieving a 12- to 16-week extension in the first year in the personalized treatment arm.

The first new agent to expand its label to include DME is likely to be brolucizumab. Although the complete data has not yet been presented, a recent press release from Novartis promoted favorable Phase 3 safety and efficacy results for brolucizumab, stating visual non-inferiority to aflibercept with enhanced durability up to 12 weeks in the first year of treatment.¹⁷

RVO

Many of the agents currently studied in late-phase clinical trials for nAMD and DME are being investigated for branch RVO and central RVO treatment as well, with a similar goal of improved durability with comparable safety to currently available anti-VEGF monotherapy.

Phase 3 trials comparing brolucizumab,¹⁸ KSI-301¹⁴ and faricimab¹⁹ to commercially available agents are all currently enrolling patients with extended dosing intervals between 12 and 24 weeks for the investigative agents.

WE ARE ABOUT TO LEAP FORWARD

We appear to be on the verge of the next phase of retinal therapeutics. Although anti-VEGF monotherapy has been revolutionary, our field has experienced essentially incremental advancement with a single class of drug since the first off-label bevacizumab injections in the early 2000s.

The robust pipeline we’ve fostered is starting to produce meaningful results, and our patients will benefit from finding a therapeutic for GA and reducing the high treatment burden in common exudative retinal disease.

It is our privilege to make this journey together. OM

REFERENCES

1. Csaky K, Ferris F 3rd, Chew EY, et al. Report From the NEI/FDA Endpoints Workshop on Age-Related Macular Degeneration and Inherited Retinal Diseases [published correction appears in Invest Ophthalmol Vis Sci. 2017 Aug 1;58:3960]. Invest Ophthalmol Vis Sci. 2017;58:3456-3463. doi:10.1167/iovs.17-22339. http://europepmc.org/article/PMC/5961066 . Accessed June 30, 2021.
2. Geerlings MJ, de Jong EK, den Hollander AI. The complement system in age-related macular degeneration: A review of rare genetic variants and implications for personalized treatment. Mol Immunol. 2017;84:65-76.
3. Holz FG, Sadda SR, Busbee B, et al, Chroma and Spectri Study Investigators. Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri Phase 3 randomized clinical trials. JAMA Ophthalmol. 2018; 136:666-677.
4. Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial. Ophthalmology. 2020;127:186-195.
5. Jaffe GJ, Westby K, Csaky KG, et al. C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2/3 Trial. Ophthalmology. 2021;128:576-586.
6. Holz FG, Tadayoni R, Beatty S, et al. Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration. Br J Ophthalmol. 2015;99:220-226. Epub 2014 Sep 5.
7. Singh RP, ed. ASRS 2018 Preferences and Trends Membership Survey. American Society of Retina Specialists website. https://www.asrs.org/content/documents/_2018-pat-survey-results-for-website.pdf . Accessed May 1, 2021.
8. Dugel P, Koh A, Ogura Y, et al. Phase 3, randomized, double-masked, multi-center trials of brolucizumab versus aflibercept for neovascular AMD: 96-week results from the HAWK and HARRIER studies. Presented at: The American Academy of Ophthalmology on October 27, 2018, Chicagom.
9. Khanani AM, Patel SS, Ferrone PJ, et al. Efficacy of every four monthly and quarterly dosing of faricimab vs ranibizumab in neovascular age-related macular degeneration: The STAIRWAY Phase 2 Randomized Clinical Trial. JAMA Ophthalmol. 2020;138:964-972.
10. Holekamp N. Primary analysis results of the phase 3 Archway trial of the Port Delivery System with ranibizumab (PDS) for patients with neovascular AMD (nAMD). Paper presented at: American Academy of Ophthalmology Annual Meeting 2020 Subspecialty Day; Virtual.
11. Holekamp NM, Campbell J, Almony A, et al. Vision Outcomes Following Anti-Vascular Endothelial Growth Factor Treatment of Diabetic Macular Edema in Clinical Practice. Am J Ophthalmol. 2018 Jul;191:83-91. doi: 10.1016/j.ajo.2018.04.010. Epub 2018 Apr 21. Erratum in: Am J Ophthalmol. 2018 Oct;194:192.
12. Ciulla TA, Pollack JS, Williams DF. Visual acuity outcomes and anti-VEGF therapy intensity in diabetic macular oedema: a real-world analysis of 28 658 patient eyes. Br J Ophthalmol. 2021;105:216-221. Epub Apr 7 2020. https://bjo.bmj.com/content/bjophthalmol/early/2020/04/07/bjophthalmol-2020-315933.full.pdf . Accessed June 30, 2021.
13. Khanani A. Extended durability in exudative retinal diseases using the novel intravitreal anti-VEGF antibody biopolymer conjugate KSI-301. Paper presented at: Retina Society 2020; Virtual
14. Kodiak. Kodiak Sciences Treats First Patients in Three Ph. 3 Studies of KSI-301 – Two Studies in DME and One Study in Macular Edema Due to RVO. https://kodiak.com/press-releases/kodiak-sciences-treats-first-patients-in-three-ph-3-studies-of-ksi-301-two-studies-in-dme-and-one-study-in-macular-edema-due-to-rvo/ . Accessed May 1, 2021.
15. Eyewire News. Genentech/Roche Initiate First Diabetic Macular Edema Phase 3 Trial of the Port Delivery System with Ranibizumab. https://eyewire.news/articles/genentech-roche-initiate-first-diabetic-macular-edema-phase-3-trial-of-the-port-delivery-system-with-ranibizumab/ . Accessed May 1, 2021.
16. Sahni J, Patel SS, Dugel PU, 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;126:1155-1170. Epub 2019 Mar 21.
17. Novartis. Novartis reports positive topline results from second Phase III trial of Beovu in patients with diabetic macular edema. https://www.novartis.com/news/media-releases/novartis-reports-positive-topline-results-from-second-phase-iii-trial-beovu-patients-diabetic-macular-edema . Accessed May 01, 2021.
18. ClinicalTrials.gov . Assessing the Efficacy and Safety of Brolucizumab Versus Aflibercept in Patients with Visual Impairment Due to Macular Edema Secondary to Central Retinal Vein Occlusion (RAVEN). https://clinicaltrials.gov/ct2/show/NCT03810313 . Accessed May 1, 2021.
19. Ocular Surgery News. Genentech initiates phase 3 faricimab trials in patients with retinal vein occlusion. Published April 20, 2021. https://www.healio.com/news/ophthalmology/20210420/genentech-initiates-phase-3-faricimab-trials-in-patients-with-retinal-vein-occlusion . Accessed May 1, 2021.

About the Author

David A. Eichenbaum, MD, is a partner and director of research at Retina Vitreous Associates of Florida in St. Petersburg, Fla. He has served as a principal investigator in more than 45 Phase 1 through Phase 4 clinical trials.

Financial disclosures: Dr. Eichenbaum reports relationships with Alimera, Allergan, Apellis, Bausch + Lomb, Genentech, Iveric Bio, Kodiak Sciences, Notal Vision, Novartis, Ocular Therapeutix and Regeneron.