Anti-VEGF and Beyond: Expanding Therapeutic Options for Wet AMD

After 20 years of therapy with anti-VEGF agents, the landscape for wet AMD management is now transforming from anti-VEGF monotherapy to a diverse pipeline of novel disease targets and innovative delivery technologies. In this article, we summarize the spectrum of emerging therapies for wet AMD (Table), including biosimilars, gene therapy, tyrosine kinase inhibitors (TKIs), and other novel drug targets.

Click to view larger

GENE THERAPIES

Current investigational gene therapies for wet AMD employ a one-time administration (intravitreal, subretinal, or suprachoroidal) of an adeno-associated viral (AAV) vector carrying non-integrating transgenes encoding anti-VEGF proteins or multitarget constructs. By enabling continuous intraocular production of these therapeutics, gene therapy may greatly reduce or eliminate anti-VEGF injection burden in patients with wet AMD.

4D-150 (4D Molecular Therapeutics) is an intravitreally delivered AAV R100 vector containing an aflibercept/anti-VEGF-C miRNA transgene. In the phase 1/2 PRISM trial (NCT05197270) 4D-150 reduced the injection burden by 83% and eliminated injections entirely in 57% of patients, compared with aflibercept (Eylea, Regeneron) every 8 weeks.¹ The phase 3 4FRONT-1 (NCT06864988) and 4FRONT-2 (NCT07064759) trials are enrolling.²

ABBV-RGX-314 (sura-vec, Regenxbio/Abbvie) contains a ranibizumab-like protein transgene delivered subretinally or suprachoroidally via an AAV8 vector (Figure). The phase 2b/3 ATMOSPHERE (NCT04704921) and phase 3 ASCENT (NCT05407636) trials are assessing noninferiority of subretinal ABBV-RGX-314 to monthly ranibizumab (Lucentis, Genentech/Roche) and bimonthly aflibercept, respectively. In the phase 2 AAVIATE trial (NCT04514653), suprachoroidal delivery of ABBV-RGX-314 led to a reduction or elimination of supplemental anti-VEGF injections in 80% and 50% of patients, respectively, over 6 months compared with monthly ranibizumab.³

Click to view larger

Figure. Intraoperative OCT can help clinicians ensure proper subretinal bleb formation during treatment with gene therapy. Image courtesy of Lejla Vajzovic, MD.

ADVM-022 (ixo-vec, Adverum) contains an aflibercept transgene delivered intravitreally using the AAV2.7m8 vector. In the phase 2 LUNA trial (NCT05536973), ADVM-022 led to an 80% reduction in supplemental anti-VEGF injections over 52 weeks compared with patients’ prior injection burden. Additionally, 50% of patients remained injection free.⁴ The phase 3 ARTEMIS trial (NCT06856577) is enrolling.

FT-003 (Frontera Therapeutics) is an intravitreally delivered AAV2.7m8 vector containing an aflibercept transgene. Interim data from a phase 1/2 trial (NCT06492863) demonstrated an 80% reduction in the need for supplemental aflibercept injections, along with improvements in BCVA and retinal structure.⁵

Several gene therapies are in phase 1 trials, including EXG102-031 (Exegenesis Bio; NCT05903794), HG202 (HuidaGene Therapeutics; NCT06031727 and NCT06623279), KH631 (Chengdu Origen/Vanotech; NCT05657301), and KH658 (Chengdu Origen/Vanotech; NCT06825858 and NCT06458595).

BISPECIFIC AND TRISPECIFIC DRUGS

Anti-VEGF therapy coupled with alternative pathway targeting is a promising strategy to improve efficacy of wet AMD therapies; this approach was recently validated with the approval of faricimab (Vabysmo, Genentech/Roche), a bispecific VEGF-A/angiopoietin-2 antibody. Others are under investigation, including the following:

KSI-301 (tarcocimab tedromer, Kodiak Sciences) is an intravitreally delivered anti-VEGF-A antibody, which did not meet its primary endpoint of noninferiority to 8-week dosing of aflibercept based on BCVA in the phase 2b/3 DAZZLE trial (NCT04049266).⁶ The phase 3 DAYBREAK trial (NCT06556368) is assessing adjusted dosing and trial design with a primary endpoint of noninferiority to aflibercept based on BCVA.

KSI-501 (tabirafusp tedromer, Kodiak Sciences) is also under investigation as part of the DAYBREAK trial. This therapy is an intravitreal bispecific VEGF trap/anti-interleukin-6 fusion protein.

IBI302 (efdamrofusp alfa, Innovent Biologics) is an intravitreal recombinant fusion protein containing decoy VEGFR and a complement receptor 1 domain to reduce VEGF and C3b/C4b activation. In a phase 2 trial (NCT05403749), IBI302 showed noninferiority to every-8-week aflibercept based on BCVA.⁷ The phase 3 STAR trial (NCT05972473) is ongoing.

RC28-E (RemeGen) is an intravitreally delivered decoy receptor trap fusion protein that binds soluble VEGF and fibroblast growth factor 2. An open-label phase 1 clinical trial showed evidence of improvements in BCVA and retinal anatomic parameters.⁸ A phase 3 trial (NCT05727397) is assessing noninferiority of RC28-E with aflibercept based on BCVA.

AXT107 (AsclepiX Therapeutics) is a suprachoroidally injected, integrin-regulating peptide that inhibits VEGF-A/C and activates Tie2 signaling and has completed recruitment in phase 1/2 testing in the DISCOVER trial (NCT05859776).

AM712 (AffaMed) is a recombinant humanized monoclonal antibody targeting VEGF and angiopoietin-2 that showed improvements in BCVA, central subfield thickness (CST), and anti-VEGF dosing frequency in the phase 1 CONQUER trial (NCT05345769).⁹

TYROSINE KINASE INHIBITORS

TKIs block receptor-mediated (ie, VEGFR) signaling by decreasing receptor phosphorylation. These drugs may have the potential to augment or replace existing anti-VEGF or multitarget therapies.

EYP-1901 (Duravyu, EyePoint Pharmaceuticals) is a semiannually administered intravitreal implant containing the TKI vorolanib. In the phase 2 DAVIO2 trial, EYP-1901 demonstrated noninferiority to aflibercept and reduced supplemental anti-VEGF injection burden by approximately 80%.¹⁰ The phase 3 LUCIA (NCT06683742) and LUGANO (NCT06668064) trials are fully enrolled.

OTX-TKI (Axpaxli, Ocular Therapeutix) is an intravitreal hydrogel implant containing axitinib. In a phase 1 trial (NCT04989699), treatment with OTX-TKI showed noninferiority to aflibercept and led to an 89% reduction in anti-VEGF injection burden.¹¹ The phase 3 SOL-1 (NCT06223958) and SOL-R (NCT06495918) trials are ongoing.

ANTI-VEGF BIOSIMILARS

Two ranibizumab (Lucentis, Genentech/Roche) and six aflibercept (Eylea, Regeneron) biosimilars are FDA approved in the United States and several others have been approved in the European Union (Table). The bevacizumab (Avastin, Genentech/Roche) biosimilar Lytenava (ONS-5010, Outlook Therapeutics) is approved for intravitreal use by the European Medicines Agency, and the company was recently issued a complete response letter by the FDA in August 2025.

Click to view larger

CLS-AX (axitinib, Clearside Biomedical) is a suprachoroidally delivered TKI. In the phase 2b ODYSSEY trial (NCT05891548), treatment with CLS-AX was noninferior to aflibercept every 8 weeks based on BCVA and led to an 84% reduction in anti-VEGF injections.¹²

D-4517.2 (migaldendranib, Ashvattha Therapeutics) is a subcutaneously administered TKI that bioaccumulates within choroidal neovascularization. In a phase 2 trial (NCT05387837), treatment with D-4517.2 led to a 69% reduction in supplemental aflibercept injections compared with patients' injection history, with stable BCVA and CST.¹³

TO-O-1002 (MG-O-1002, Theratocular Biotek) is a TKI delivered as a topical eye drop three times a day. In a phase 2a study (NCT05390840), TO-O-1002 was shown to reduce the need for supplemental anti-VEGF injections by 86% compared with a placebo drop.¹⁴

KHK4951 (tivozanib, Kyowa Kirin Group) is another topical TKI in a phase 2 trial (NCT06116890) evaluating high, middle, and low doses. The primary outcome is the reduction of 15 or more letters in BCVA at week 44; secondary outcomes include the need for intravitreal aflibercept and OCT and fluorescein angiography changes.

Other TKIs in early-phase investigations include AR-14034 (axitinib, Alcon; NCT05769153), PAN-90806 (PanOptica/Zhaoke; NCT03479372), and lenvatinib (AIV-007, AiViva BioPharma; NCT05698329).

NOVEL DRUG TARGETS AND DELIVERY MODALITIES

Innovation continues for novel drug targets, offering the opportunity to expand the therapeutic repertoire outside of mainstay anti-VEGF therapy.

ISTH0036 (Isarna) is an intravitreally administered antisense oligonucleotide that reduces expression of TGF-Β2 to reduce profibrotic signaling. In a recent phase 2a trial (EudraCT 2021-001213-36), ISTH0036 led to a 70% decrease in subretinal hyperreflective material, stable or improved BCVA, and decreased CST relative to baseline.¹⁵

RBM-007 (umedaptanib pegol, Ribomic) is an intravitreally delivered pegylated anti-FGF-2 RNA aptamer with antifibrotic activity. In the phase 2 TOFU (NCT04200248) and RAMEN (NCT04640272) trials, RBM-007 did not show a benefit over aflibercept alone. The TEMPURA open-label extension study (NCT04895293) showed BCVA and CST stabilization or improvements compared with baseline in anti-VEGF-naïve patients.¹⁶

SYL1801 (Sylentis) is a daily eye drop containing an anti-NRARP siRNA that modulates notch-Wnt crosstalk to reduce angiogenesis; the phase 2a trial (NCT05637255) showed stabilization or improvements in BCVA compared with baseline.¹⁷

MK-3000 (Restoret, EyeBio/Merck) is an intravitreal anti-FZD4/ LRP5/TSPAN12 antibody that activates canonical Wnt signaling. In the phase 1/2 AMARONE trial (NCT05919693), MK-3000 in combination with monthly aflibercept resulted in improved BCVA and decreased CST.¹⁸

OLX10212 (OliX Pharmaceuticals) is an intravitreally delivered siRNA targeting an undisclosed target involved in inflammation, which is currently undergoing phase 1 testing (NCT05643118).

CG-P5 (Caregen) is a once-daily eye drop containing a VEGFR2-inhibiting peptide. A phase 1 study (NCT06132035) is assessing the safety of CG-P5 compared with a placebo drop or monthly aflibercept.

Episcleral brachytherapy (Salutaris Medical Devices) involves the delivery of transscleral radiation to reduce actively proliferating, pathological cells within areas of choroidal neovascularization. In the phase 1 NEAMES trial (NCT02988895), this focal radiation treatment reduced anti-VEGF injection burden compared with patient history.¹⁹

LOOKING AHEAD

The wet AMD treatment landscape is rapidly shifting toward highly durable, targeted, and potentially curative approaches. As we enter 2026, key phase 3 readouts and potential regulatory approvals could mark the beginning of a new era, one in which anti-VEGF monotherapy is augmented by an armamentarium of complementary therapies that can be tailored to the needs of an individual patient.

1. 4D Molecular Therapeutics. 4DMT presents positive 52-week results from Phase 2b cohort of PRISM Wet AMD study and long-term durability data supporting 4D-150 4FRONT global registration program [press release]. February 2, 2025. Accessed October 27, 2025. tinyurl.com/rfpek677

2. 4D Molecular Therapeutics. 4DMT announces first patients enrolled in 4FRONT-1 Phase 3 clinical trial evaluating 4D-150 in wet AMD [press release]. March 10, 2025. Accessed October 27, 2025. tinyurl.com/y9fz888f

3. Pitcher JD. Suprachoroidal delivery of investigational ABBV-RGX-314 for neovascular AMD: results from the phase II AAVIATE study. Presented at Hawaiian Eye and Retina 2024 Meeting; Grand Wailea, Hawaii; January 16, 2024. tinyurl.com/2wyu3y9h

4. Adverum Biotechnologies. Adverum Biotechnologies announces positive 52-week LUNA and 4-year OPTIC results, and provides key pivotal program design elements [press release]. Published November 18, 2024. Accessed October 27, 2025. tinyurl.com/44j6vu4d

5. Frontera Therapeutics. Frontera Therapeutics receives FDA clearance for phase 2 clinical trial of FT-003 for diabetic macular edema (DME) [press release]. Published December 30, 2024. Accessed October 27, 2025. tinyurl.com/b9vu9hp9

6. Kodiak Sciences. Kodiak Sciences announces top-line results from its initial Phase 2b/3 study of KSI-301 in patients with neovascular (wet) age-related macular degeneration [press release]. Published February 23, 2022. Accessed October 27, 2025. tinyurl.com/3v86fcw6

7. Sun J, Song Y, Gong Y, et al. Efficacy and safety of efdamrofusp alfa versus aflibercept in participants with neovascular age-related macular degeneration: a randomized, double-masked, active-controlled, noninferiority, phase II trial. Ophthalmol Retina. 2025;9(2):156-165.

8. Lu Y, Yu X, Chen Y, et al. Safety and efficacy of multiple escalating doses of RC28-E for neovascular age-related macular degeneration: a phase 1b trial. Ophthalmol Ther. 2024;13(9):2405-2415.

9. Hershberger V, Lally DR, Schneider EW, et al. Safety, tolerability and efficacy of intravitreal AM712 for neovascular age-related macular degeneration (CONQUER). Invest Ophthalmol Vis Sci. 2025;66(8):693.

10. EyePoint Pharmaceuticals. Phase 2 DAVIO 2 positive results in wet AMD [press release]. Accessed October 27, 2025. tinyurl.com/kma2bfd4

11. Ocular Therapeutix. Ocular Therapeutix announces interim 10-month data from the ongoing U.S. Phase 1 clinical trial evaluating OTX-TKI for the treatment of wet AMD. Published February 11, 2023. Accessed 2025. tinyurl.com/y4jr7wyr

12. Clearside Biomedical. Clearside Biomedical announces additional data from the CLS-AX ODYSSEY phase 2b trial presented at the Angiogenesis, Exudation, and Degeneration 2025 meeting [press release]. Published February 10, 2025. Accessed October 27, 2025. tinyurl.com/59cz76r8

13. Ashvattha Therapeutics. Ashvattha presents positive phase 2 data for subcutaneous migaldendranib at Angiogenesis 2025 conference [press release]. Published February 10, 2025. Accessed October 27, 2025. tinyurl.com/3nh3dm6j

14. Lin CW, Sanguansak T, Rojanaporn D, Luangsawang K, Taweebanjongsin W. A Phase IIa study of a novel non-invasive treatment, TO-O-1002, in nAMD patients. Invest Ophthalmol Vis Sci. 2024;65(7):1935.

15. Isarna Therapeutics. Isarna Therapeutics presents positive phase 2 BETTER trial final results at ARVO 2025 [press release]. Published March 7, 2025. Accessed October 27, 2025. tinyurl.com/mwkx9r5b

16. Pereira DS, Maturi RK, Akita K, et al. Clinical proof of concept for anti-FGF2 therapy in exudative age-related macular degeneration (nAMD): phase 2 trials in treatment-naïve and anti-VEGF pretreated patients. Eye (Lond). 2024;38(6):1140-1148.

17. PharmaMar. Sylentis, a PharmaMar Group company, announces the positive results of the Phase IIa dose-ranging study for SYL1801 in patients with age-related macular degeneration (AMD) [press release]. Published May 5, 2025. Accessed October 27, 2025. tinyurl.com/yc2kpba5

18. Eyebiotech. EyeBio announces positive visual, anatomic and safety data from first-in-human Ph1b/2a AMARONE trial of Restoret at Macula Society Annual Meeting [press release]. Published February 13, 2024. Accessed October 27, 2025. tinyurl.com/4pkjre4k

19. Chhablani J, Jager R, Ong J, et al. Two-year outcomes of episcleral brachytherapy adjunct to anti-VEGF therapy for treatment-resistant nAMD. Graefes Arch Clin Exp Ophthalmol. 2022;260(12):3791-3798.