AMD is a major public health concern and a leading cause of blindness in people aged 60 and older.¹ Neovascular AMD (nAMD) is an advanced form of the disease that can lead to severe and possibly irreversible vision loss.

During the past two decades, anti-VEGF therapies have revolutionized the management of nAMD and other VEGF-driven ocular diseases, significantly improving visual outcomes.

Unfortunately, treatment burden continues to be a major concern for patients, caretakers and the health-care system, with current standard of care requiring eye injections as frequently as every month. In addition, the real-world data suggest patients in clinical practice receive fewer injections, which correlates with worse visual outcomes over time² and emphasizes the unmet need for longer acting and durable therapies.

With that in mind, we provide a summary of the latest nAMD therapies that may reduce that burden for practices and patients.

FARICIMAB

Prior to the approval of faricimab for the treatment of nAMD, intravitreal injectable therapies primarily targeted vascular endothelial growth factor (VEGF). Faricimab (Vabysmo, Genentech) is the first-in-class bispecific monoclonal antibody that acts through a dual simultaneous and potent inhibition of VEGF-A and angiopoietin-2, which play an important role in vascular stability and permeability.³

In a Phase 2 randomized controlled clinical trial, AVENUE, faricimab demonstrated safety and efficacy in treating nAMD at dosing intervals every 4 or 8 weeks comparable with monthly ranibizumab.⁴ STAIRWAY, a Phase 2 randomized controlled trial, compared extended dosing with faricimab to monthly ranibizumab in treating patients with nAMD. At week 52, faricimab given every 12 and 16 weeks resulted in maintenance of initial vision and anatomic improvements comparable to monthly ranibizumab.⁵ This was the first trial to demonstrate extended dosing to every 16 weeks with anti-VEGF monotherapy when treating nAMD, suggesting a potential to provide sustained efficacy through extended durability and reduced treatment burden.⁵

Following this, two multicenter double-masked Phase 3 randomized controlled trials, TENAYA and LUCERNE, compared faricimab given up to every 16 weeks to aflibercept 2 mg given every 8 weeks in patients with nAMD. In both trials, faricimab met its primary efficacy endpoints of noninferiority to aflibercept in the average change of BCVA compared with baseline averaged over weeks 40, 44 and 48.⁶ Treatment with faricimab resulted in central subfield thickness (CST) reductions from baseline at all timepoints up to week 48, comparable to aflibercept every 8 weeks. Faricimab was also well-tolerated with favorable safety profile in both trials.⁶

The trials showed an impressive durability effect in the faricimab group. By week 48, about 80% of the patients treated with faricimab were on either every 12- or 16-week dosing, and about 45% of patients treated with faricimab were extended to 4 months between treatments within the first year. Observed extended durability effect, likely driven by the dual inhibition of VEGF and Ang-2 pathway, may have the potential to improve visual outcomes while decreasing treatment burden. Two-year data from the TENAYA and LUCERNE studies has confirmed the efficacy and durability of faricimab with 63% of patients on Q16W and approximately 80% on ≥Q12W dosing at week 112.⁷ No new safety signals were seen in the second year of the study. The data from the extension study AVONELLE-X will provide further insight into faricimab’s long-term effects and patients’ quality of life.

Real-world data showing potential benefits of faricimab has been emerging in recent months. A small retrospective series of 11 eyes treated with faricimab showed significant improvement in BCVA and anatomic parameters.⁸ The TRUCKEE study 6-month results reported that faricimab demonstrated improvement or maintenance of visual acuity along with rapid improvement of anatomical parameters in 376 eyes with nAMD. It was well-tolerated with low incidence of intraocular inflammation.⁹

HIGH-DOSE AFLIBERCEPT

Anti-VEGF therapy has dramatically improved visual outcomes for patients with nAMD; however, a subset of population exhibits an incomplete response despite monthly anti-VEGF treatments. High-dose anti-VEGF agents have been trialed for the resistant cases, and recent clinical studies have shown promising results.

A small study by You et al. demonstrated that eyes resistant to standard doses of ranibizumab or bevacizumab, who were first switched to 2 mg monthly aflibercept and then switched to 4 mg monthly aflibercept due to continued resistance, achieved significant anatomical improvement and maintained visual acuity.¹⁰ In another retrospective analysis of 37 eyes with nAMD who received 3 mg aflibercept, 0.75 or 1.0 mg ranibizumab, and 1.8mg or 2.5 mg bevacizumab, a significant decrease in central retinal thickness was observed for all three agents upon initiation of high-dose anti-VEGF treatment compared to baseline. Higher dose therapy was able to sustain visual acuity, though no significant reduction in injection frequency was noted.¹¹

In a retrospective analysis of 318 eyes who had suboptimal response to aflibercept 2 mg given monthly or who showed increased activity with extension while on aflibercept 2 mg and then were switched to high-dose aflibercept (3 mg or 4 mg), high-dose aflibercept demonstrated maintenance of BCVA gains, improved anatomic outcomes, and decreased injection burden over 12 months of follow-up. In eyes with nAMD with activity despite monthly 2 mg aflibercept, the mean injection interval increased from 29.5 to 55.4 days after switching to high-dose aflibercept. In eyes with increased disease activity on extension treated with 2 mg aflibercept, the mean injection interval increased from 45.3 days to 59 days over the study period.¹²

Subsequently, even higher doses of aflibercept have been trialed to intensify and potentially prolong the effect of anti-VEGF therapy. CANDELA, a Phase 2, randomized, single-masked, open label 44-week clinical trial, assessed the safety and efficacy of intravitreal aflibercept 8 mg compared to intravitreal aflibercept 2 mg in treatment-naíve nAMD in 106 eyes with subfoveal CNV. Preliminary results shared at the ARVO meeting in 2022 showed the high-dose aflibercept group demonstrated a greater numerical reduction in central subfield thickness at 16 weeks; however, it did not reach statistical significance. The overall safety profile was comparable to that of standard dose aflibercept.¹³

Promising and exciting results from the PULSAR trial suggest potential future utility in using high-dose aflibercept for patients with nAMD. In this Phase 3 multicenter randomized double-masked trial, 1,009 treatment-naíve nAMD patients were randomized to 2 mg every 8 weeks, 8 mg every 12 weeks and 8 mg every 16 weeks after three initial monthly aflibercept injections. At 48 weeks, both high-dose treatment arms met the primary endpoint of noninferior BCVA gains compared to aflibercept 2 mg. PULSAR also met its key secondary endpoint, demonstrating superiority of high-dose aflibercept in improving anatomic outcomes of retinal fluid. At week 16, 63% patients had no retinal fluid in central subfield in all 8 mg groups compared to 52% in standard dose aflibercept group (P=.0002). With respect to treatment burden, overall, 83% (n=628) of patients receiving aflibercept 8 mg maintained ≥12-week treatment intervals. In the 8q12 group, 79% (n=316) of patients maintained 12-week treatment intervals, and 77% (n=312) of patients in the 8q16 group maintained 16-week treatment intervals through 48 weeks. The safety profile of high- and standard-dose aflibercept was comparable. The results of the trial support the potential use of high-dose aflibercept for treatment of nAMD to maintain visual acuity, provide longer duration of action thereby potentially decreasing treatment burden while maintaining an acceptable safety profile.¹⁴

Studies have raised concerns regarding short- and long-term effects of IOP elevation that may be associated with delivering high doses of intravitreal drugs.¹⁵ While long-term implications warrant future investigation, current data suggests no difference in incidence of IOP increase between standard and high aflibercept dosing.^11,12,14 There has also been a debate raising a concern that anti-VEGF therapy may potentially contribute to the development of macular atrophy.^16-18 While the existence of such association is uncertain, future research may be warranted on this topic in the setting of high-dose anti-VEGF use.

TYROSINE KINASE INHIBITORS

Overview

Tyrosine kinases are enzymes involved in activating proteins via signal transduction cascades. Modifying this signal pathway by inhibiting the tyrosine kinase receptor can have powerful effects downstream, thus leading to significant attention to tyrosine kinase inhibitors (TKIs) throughout medicine — particularly oncology. While anti-VEGF therapies target VEGF molecules in the extracellular space, selective TKIs can work intracellularly to stop the downstream effects of all the isoforms of VEGF as well as platelet-derived growth factor (PDGF), potentially improving therapeutic efficacy by inhibiting multiple components of angiogenesis. The various TKIs and their early, promising results have warranted continued interest, not only into the drug molecule itself but also their delivery platforms used to promote sustained delivery. Several TKIs are in development for nAMD, which we will briefly outline here.

Sunitinib

Sunitinib maleate (GB-102, GrayBug Vision) is a TKI that targets both VEGF receptors and PDGF receptors (PDGFR) and is contained in a biodegradable polymer allowing for sustained delivery. Sunitinib is a small molecule that already has FDA approval for renal cell carcinoma and gastrointestinal stromal tumor. ALTISSIMO is a Phase 2b clinical trial assessing sunitinib delivered as an intravitreal injection twice a year.¹⁹ Results showed a similar central subfield thickness but lower BCVA than patients treated with bimonthly aflibercept. There were events of particle dispersion in the anterior chamber as well as 4 of 21 patients with intraocular inflammation that resolved with topical steroid therapy. The program has been terminated at this stage.

Vorolinib

Vorolinib (EYP-1901, Eyepoint Pharmaceuticals) is a TKI that also targets all VEGFRs and PDGFRs and utilizes the company’s sustained delivery platform Durasert. The Phase 1 DAVIO trial enrolled 17 patients to receive the sustained delivery bioerodible intravitreal implant (already utilized in YUTIQ), with 53% and 35% of patients not requiring a rescue anti-VEGF injection at 6 and 12 months, respectively. There were no significant safety concerns, and drug release was essentially depleted past 8 months. DAVIO2, a Phase 2 randomized study with two different doses comparing to aflibercept, is currently ongoing.

Axitinib

Axitinib is a selective TKI for both VEGFR and PDGFR. It is the most potent TKI available and is currently being investigated via an intravitreal route (OTX-TKI, Ocular Therapeutix) and a suprachoroidal route (CLS-AX, Clearside Biomedical).

OTX-TKI is a hydrogel depot (similar to the company’s implant DEXTENZA) that resorbs by bulk hydrolysis and should not result in a buildup of intraocular particle fragments. The Phase 1b OTX-TKI trial compares a single 600 ug implant of OTX-TKI followed by an aflibercept injection 4 weeks later to aflibercept injections every 8 weeks. Interim 10-month results were reported earlier this year, which demonstrated stable and sustained BCVA and CST, 73% of subjects were rescue-free at 10 months, and an overall 92% reduction in treatment burden.²⁰

A single dose of CLS-AX in the Phase 1/2a OASIS trial met its primary endpoint at 3 months with a 73% reduction in treatment burden, and recent extension to 6 months showed a 77-85% reduction in treatment burden.²¹ ODYSSEY, a Phase 2b study evaluating efficacy, safety and durability of CLS-AX, is currently ongoing.

VEGF-C/-D BLOCKADE

All currently available anti-VEGF monotherapies, such as ranibizumab, aflibercept and off-label bevacizumab, primarily block VEGF-A, which binds to VEGF receptor 2 (VEGFR-2). Other VEGF receptors, such as VEGF receptor 3 (VEGFR-3), bind other isoforms of VEGF such as VEGF-C and VEGF-D, which are not targeted by currently available therapies. Because VEGFR-3 is also involved in angiogenesis, VEGF-C/-D blockade is a valuable approach to increase drug efficacy, particularly in patients with sub-optimal response.²²

OPT-302 (Opthea) is a first-in-class biologic that specifically targets and sequesters VEGF-C and VEGF-D. A Phase 2b study of 366 treatment-naïve patients with nAMD who received a combination of OPT-302 and ranibizumab experienced a statistically significant superior gain in visual acuity compared to ranibizumab alone at week 24.

Two Phase 3 clinical trials, ShORe (OPT-302 plus ranibizumab) and COAST (OPT-302 plus aflibercept) are ongoing with a primary endpoint of superiority in visual gains at 12 months for the combination therapy compared to monotherapy. (For more, see page 49.)

GENE THERAPY FOR NEOVASCULAR AMD

Perhaps one of the most exciting avenues for nAMD treatment is sustained VEGF suppression with gene therapy. This approach utilizes a non-integrating viral vector that carries an encoded genetic message to make a novel protein, specifically an anti-VEGF protein. Once the cells produce their own anti-VEGF protein, this would effectively allow for a more permanent therapeutic effect compared to other long-lasting delivery platforms. The options currently being investigated range in route delivery (intravitreal, suprachoroidal, subretinal) and are in different phases of the clinical trial pathway. (For more, see page 42.)

CONCLUSION

The recent nAMD treatments currently available and in the pipeline are pushing the boundaries of durability and reducing treatment burden for our patients. In this article, we highlighted several treatments in various stages of development, which underscores that the future is promising in finding better solutions for nAMD. This is an ever expanding and competitive space with many Phase 1 trials not mentioned here that will one day challenge current paradigms. OM

REFERENCES

1. GBD 2019 Blindness and Vision Impairment Collaborators; Vision Loss Expert Group of the Global Burden of Disease Study. Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the Right to Sight: an analysis for the Global Burden of Disease Study. Lancet Glob Health. 2021 Feb;9(2):e144-e160. doi: 10.1016/S2214-109X(20)30489-7. Epub 2020 Dec 1. Erratum in: Lancet Glob Health. 2021 Apr;9(4):e408.
2. Ciulla TA, Huang F, Westby K, Williams DF, Zaveri S, Patel SC. Real-world outcomes of anti–vascular endothelial growth factor therapy in neovascular age-related macular degeneration in the United States. Ophthalmol Retina. 2018;2(7):645-653.
3. Regula JT, Lundh von Leithner P, Foxton R, et al. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol Med. 2019;11(5):e10666.
4. Sahni J, Dugel PU, Patel SS, et al. Safety and efficacy of different doses and regimens of faricimab vs ranibizumab in neovascular age-related macular degeneration: the AVENUE phase 2 randomized clinical trial. JAMA Ophthalmol. Published online July 30, 2020. doi: 10.1001/jamaophthalmol.2020.2685
5. Khanani AM, Patel SS, Ferrone PJ, Osborne A, Sahni J, Grzeschik S, Basu K, Ehrlich JS, Haskova Z, Dugel PU. 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 Sep 1;138(9):964-972.
6. Heier JS, Khanani AM, Quezada Ruiz C, et al; TENAYA and LUCERNE Investigators. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet. Published January 24, 2022. doi:10.1016/S0140-6736(22)00010-1
7. Khanani AM, Demetriades A, Kotecha A et. al. Faricimab in Neovascular Age-Related Macular Degeneration: Year 2 Efficacy, Safety, and Durability Results From the Phase 3 TENAYA and LUCERNE Trials. Presented at American Society of Retina Specialists 2022 meeting, New York.
8. Stanga PE, Valentín-Bravo FJ, Stanga SEF, Reinstein UI, Pastor-Idoate S, Downes SM. Faricimab in neovascular AMD: first report of real-world outcomes in an independent retina clinic. EyeLond 2023.
9. Khanani AM, Aziz AA, Khan H, Gupta A, Mojumder O, Saulebayeva A, Abbey AM, Almeida DRP, Avery RL, Banda HK, Barakat MR, Bhandari R, Chang EY, Haug SJ, London NJS, Mein L, Sheth VS, Wolfe JD, Singer MA, Danzig CJ. The real-world efficacy and safety of faricimab in neovascular age-related macular degeneration: the TRUCKEE study - 6 month results. Eye (Lond). 2023 May 12.
10. You QS, Gaber R, Meshi A, et al. High-dose high-frequency aflibercept for recalcitrant neovascular age-related macular degeneration. Retina. 2018;38(6):1156-1165.
11. Broadhead GK, Keenan TDL, Chew EY, Wiley HE, Cukras CA. Comparison of agents using higher dose anti-VEGF therapy for treatment-resistant neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2022 Jul;260(7):2239-2247.
12. Nielsen JS, Roberts CL, Saggau DD, Alliman KJ. High-Dose Aflibercept for Neovascular AMD and DME in Suboptimal Responders to Standard-Dose Aflibercept. Journal of VitreoRetinal Diseases. 2023;7(2):116-124.
13. Brown DM. Evaluation of 8 mg intravitreal aflibercept injection for neovascular age-related macular degeneration: results from the Phase 2 CANDELA study. Invest Ophthalmol Vis Sci. 2022;63(7):1345–F0179
14. Regeneron. Aflibercept 8 mg positive pivotal results in diabetic macular edema and wet age-related macular degeneration presented at AAO. News release. September 30, 2022. https://investor.regeneron.com/news-releases/news-release-details/aflibercept-8-mg-positive-pivotal-results-diabetic-macular-edema . Accessed June 7, 2023.
15. Levin AM, Chaya CJ, Kahook MY, Wirostko BM. Intraocular pressure elevation following intravitreal anti-VEGF injections: short- and long-term considerations. J Glaucoma. 2021;30(12):1019-1026.
16. Gillies MC et al (2020) Macular atrophy in neovascular age-related macular degeneration: a randomized clinical trial comparing ranibizumab and aflibercept (RIVAL Study). Ophthalmology. 127:198–210
17. Sadda SR et al (2018) Macular atrophy development in the HARBOR study for neovascular age-related macular degeneration. Ophthalmology 125:878–886
18. Eshtiaghi A et al. Geographic atrophy incidence and progression following intravitreal anti-vascular endothelial growth factor agents for age-related macular degeneration: a meta-analysis. Retina. 2021;41:2424-2435.
19. A Depot Formulation of Sunitinib Malate (GB-102) Compared to Aflibercept in Subjects With Wet AMD (ALTISSIMO). ClinicalTrials.gov . https://clinicaltrials.gov/ct2/show/results/NCT03953079 . Accessed June 7, 2023.
20. Ocular Therapeuti Announces Interim 10-Month Data From The Ongoing U.S. Phase 1 Clinical Trial Evaluating OTX-TKI For The Treatment Of Wet AMD. https://ocutx.gcs-web.com/news-releases/news-release-details/ocular-therapeutixtm-announces-interim-10-month-data-ongoing-us . Accessed June 7, 2023.
21. Clearside Biomedical Announces Positive 6-Month Results from OASIS Extension Study with Suprachoroidal CLS-AX (axitinib injectable suspension) in Wet AMD. Clearside Biomedical. https://ir.clearsidebio.com/news-releases/news-release-details/clearside-biomedical-announces-positive-6-month-results-oasis . Accessed June 7, 2023.
22. Dugel PU, Boyer DS, Antoszyk AN, et al. Phase 1 Study of OPT-302 inhibition of vascular endothelial growth factors C and D for neovascular age-related macular degeneration. Ophthalmol Retina. 2020;4(3):250-263.

Narine Viruni, MD, is an assistant professor of ophthalmology and co-assistant chief of service at the Wilmer Eye Institute in Baltimore. She is fellowship trained in vitreoretinal surgery, and her research interests include clinical trials and surgical outcomes in vitreoretinal surgery.

Kapil Mishra, MD, is an assistant professor of ophthalmology and co-assistant chief of service at the Wilmer Eye Institute in Baltimore. He is fellowship trained in vitreoretinal surgery, and his research is focused on surgical education, vitreoretinal surgery pathology, global health ophthalmology initiatives and big data in ophthalmology. The authors report no relevant financial disclosures.