Although neovascular age-related macular degeneration (nAMD) develops in 10% of AMD patients, it accounts for most of the severe vision loss in AMD. The development of choroidal neovascular membranes is mediated primarily by homodimeric ligands in the vascular endothelial growth factor (VEGF) family, and current treatments primarily target VEGF-A. Although these drugs are highly effective in stabilizing or improving vision in most patients, ongoing challenges include treatment burden and recalcitrant fluid.
In response to these limitations, multiple trials of molecules targeting the larger anti-VEGF family and other pathways have been initiated (Table 1). These molecules may translate into a future of durable and efficacious therapies.
Tyrosine Kinase Inhibitors
Tyrosine kinase inhibitors (TKI) are capable of inhibiting all VEGF-1, VEGF-2, and VEGF-3 receptors (pan-VEGFR blockade), platelet-derived growth factor (PDGF) signaling, and fibroblast growth factor (FGF).1 Two TKI molecules have progressed to phase 3 trials: EYP-1901 (Duravyu; EyePoint Pharmaceuticals) and OTX-TKI (Axpaxli; Ocular Therapeutix).
EYP-1901 combines a sustained-release implant (Durasert E) with vorolanib, which has pan-VEGFR and PDGF inhibitory effect. The implant is expected to last 9 months. The phase 2 DAVIO 2 trial showed promising results. In 160 previously treated wet AMD patients, EYP-1901 met its noninferiority endpoint compared to aflibercept (Eylea; Regeneron) every 8 weeks at 6 months. Rescue aflibercept was allowed in both the 3 mg and 2 mg implant groups. Only 56% and 64%, respectively, required rescue injection for an 85% to 89% reduction in treatment burden. These promising results are rolling into a pair of phase 3 clinical trials, LUCIA and LUGANO. The global, randomized, double-masked, aflibercept controlled, noninferiority phase 3 trials will enroll both previously treated and treatment-naïve patients. They will be randomized to a 2.7 mg dose of EYP-1901 every 6 months or 2 mg aflibercept every 8 weeks after both groups are loaded with aflibercept. Rescue with aflibercept is permitted. The primary endpoint is change in best-corrected visual acuity (BCVA) at weeks 52 and 56 vs baseline. Secondary endpoints include safety, reduction in treatment burden, need for supplemental aflibercept injections, and anatomic results as measured by optical coherence tomography (OCT).2,3
Similarly, OTX-TKI uses axitinib, a selective inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3 with an investigational hydrogel bioresorbable implant (Elutyx). In a phase 1b trial, 15 patients receiving 0.6 mg OTX-TKI were compared to 5 patients receiving 2 mg aflibercept every 8 weeks. At 1 year, an 89% reduction in treatment burden was observed with comparable BCVA and central subfield thickness (CST). Thirty-three percent of patients maintained this without supplemental aflibercept injection at 1 year.4 These promising results led to SOL-1 and SOL-R. Both are multicenter, double-masked, parallel-group, phase 3 pivotal trials. SOL-1 is a superiority study whose primary endpoint is the proportion of patients who maintain visual acuity, defined as the loss of <15 ETDRS letters of BCVA at week 36. Patients will be randomized 1:1 to a single dose of OTX-TKI or a single dose of aflibercept 2 mg, with the patient able to receive rescue aflibercept. SOL-R is designed as noninferiority study in the change in mean BCVA change from baseline at 1 year.5 SOL-R with be randomized 2:2:1, with the first arm receiving an OTX-TKI dose at day 1 and week 24, the second arm receiving aflibercept 2 mg at 8 week intervals, and the third aim receiving aflibercept 2 mg at day 1 and week 24. The patient again can receive rescue aflibercept.
Axitinib has also been introduced to the eye other than as an intravitreal implant. It can be formulated into a suprachoroidal suspension (CLS-AX; Clearside Biomedical). In the phase 2b ODYSSEY trial, 60 patients were enrolled for a 36-week study and randomized 2:1 to either CLS-AX 1 mg with mandatory redosing at 24 weeks or aflibercept 2 mg with a 2:1 randomization schedule. Top-line results suggested an 84% reduction in treatment burden for a stable BCVA and CST.6 Alcon is working on an sustained-release axitinib implant, AR-14034, formulated in a unique bioerodible polymer blend using PRINT technology. The phase 1/2 NOVA-1 trial, a 2-stage dose escalation and randomized parallel-group study to evaluate the safety and preliminary treatment effects of AR-14034, is currently enrolling.
Other TKIs in the pipeline are delivered in varying modalities. KHL4951 (Tivozanib; Kyowa Kirin Co), a selective inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3, is delivered in a topical nanocrystalized drop, with an active phase 2 clinical trial.7 Likewise, PAN-90806 (PanOptica/Zhaoke Ophthalmology) is delivered topically to achieve a pan-VEGF blockade.8 Subcutaneous delivery of D-4517.2 (Ashvattha Therapeutics) is being investigated in the phase 2 TEJAS trial.9 D-4517.2 acts by selective inhibition of VEGF receptor tyrosine kinases in activated microglia and macrophages and hypertrophic retinal pigment epithelial (RPE) cells. Finally, combined intravitreal and periocular delivery of AIV007 (AiVvia Biopharma), a broad-spectrum TKI, is being studied in phase 1 trials for nAMD and diabetic macular edema (DME).10,11
Table 1: Trials Targeting Alternate Pathways
|
Mechanism/Target |
Phase |
NCT (Name) |
Status |
|
|---|---|---|---|---|
|
EYP-1901 (EyePoint Pharmaceuticals) |
Implant with pan-VEGFR and PDGF inhibition |
3 |
LUCIA (NCT06683742) |
Recruiting |
|
LUGANO (NCT06668064) |
Recruiting |
|||
|
OTX-TKI (Ocular Therapeutix) |
Selective inhibitor of VEGFR-1,VEGFR-2, and VEGFR-3 |
3 |
SOL-R (NCT06495918) |
Recruiting |
|
SOL-1 (NCT06223958) |
Active, not recruiting |
|||
|
ABBV-RGX-314 (Regenxbio) |
AAV8 vector expressing anti-VEGF-A antigen-binding fragment |
3 |
ASCENT (NCT05407636) |
Recruiting |
|
ATMOSPHERE (NCT04704921) |
Recruiting |
|||
|
OPT-302 (Opthea) |
Fc-fusion protein inhibiting VEGF-C and VEGF-D |
3 |
ShORe (NCT04757610) |
Active, not recruiting |
|
COAST (NCT04757636) |
Active, not recruiting |
|||
|
IBI302 (Innovent Biologics) |
Recombinant human anti-VEGF and anticomplement (C3b and C4b) bispecific fusion protein |
3 |
STAR (NCT05972473) |
Recruiting |
|
ADVM-022 (Adverum Biotechnologies) |
Proprietary AAV7m8 vector produces aflibercept |
2 |
LUNA (NCT05536973) |
Active, not recruiting |
|
AXT107 (Asclepix Therapeutics) |
Inhibition of VEGF and promotion of Tie2 signaling |
2 |
DISCOVER (NCT05859776) |
Active, not recruiting |
|
D-4517.2 (Ashvattha Therapeutics) |
Inhibition of microglia, macrophages, and RPE |
2 |
TEJAS (NCT05387837) |
Active, not recruiting |
|
KHL4951 (Tivozanib, Kyowa Kirin Co) |
Selective inhibitor of VEGFR-1,VEGFR-2, and VEGFR-3 |
2 |
NCT06116890 |
Recruiting |
|
CLS-AX (Clearside Biomedical) |
Selective inhibitor of VEGFR-1,VEGFR-2, and VEGFR-3 |
2 |
ODYSSEY (NCT05891548) |
Completed |
|
MK-3000 (Merck and EyeBio) |
Wnt pathway agonist |
2 |
AMARONE (NCT05919693) |
Completed |
|
RBM-007 (Ribomic) |
Anti-fibroblast growth factor 2 aptamer |
1 |
STAR (NCT05972473) |
Recruiting |
|
OLX10212 (Olix Pharmaceuticals, Inc) |
Cp-asiRNA targeting inflammatory pathways |
1 |
NCT05643118 |
Recruiting |
|
OCU-10-C-110 (Ocugenix Corporation) |
CXCR3 activation |
1 |
NCT05904691 |
Recruiting |
|
EXG102-031 (Exegenesis Bio) |
AAV-based vector expressing a fusion protein that binds subtypes of VEGF and Ang-2 |
1 |
Everest (NCT05903794) |
Recruiting |
|
4D-150 (4D Molecular Therapeutics) |
AAV vector (R100) expressing aflibercept and VEGF-C inhibitory RNAi |
1 |
PRISM (NCT05197270) |
Recruiting |
|
RC28-E (RemeGen) |
Dual decoy receptor fusion protein targeting VEGF and FGF |
1 |
NCT05727397 |
Recruiting |
|
AM712 (AffaMed) |
Fusion protein targeting VEGF and Ang-2 |
1 |
NCT05345769 |
Completed |
|
AIV007 (Aivvia BioPharma) |
Broad-spectrum TKI |
1 |
NCT05698329 |
Active, not recruiting |
|
PAN-90806 (PanOptica) |
Pan-VEGF blockade |
1 |
NCT03479372 |
Completed |
|
AR-14034 (Alcon) |
Selective inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3 |
1 |
NOVA-1 (NCT05769153) |
Recruiting |
Dual Targets
By inhibiting more than 1 angiogenic signal, more rapid and durable visual acuity recovery may be possible compared to the single target of VEGF-A. All molecules in development are delivered intravitreally.
Sozinibercept (OPT-302; Opthea) is an Fc-fusion protein designed to inhibit VEGF-C and VEGF-D after intravitreal injection. VEGF-C and VEGF-D are the only known ligands for VEGFR-3, which is also an important driver of angiogenesis and lymphangiogenesis.12 In contrast to VEGF-A, VEGF-C and VEGF-D can bind and activate VEGFR-2. VEGF-C and VEGF-D have been shown to rise in response to VEGF-A inhibition, suggesting these factors contribute to a poor response to agents like bevacizumab.13 In the phase 2b trial, mean visual acuity gain in the 2 mg OPT-302 group was significantly superior to sham (+14.2±11.61 ETDRS letters vs +10.8±11.52 letters; P=.01).14 This led to phase 3 trials COAST and ShORe, evaluating the efficacy and safety of sozinibercept in combination with 2 mg aflibercept or ranibizumab (Lucentis; Genentech), respectively.15,16 On March 24, Opthea reported top-line data from the COAST trial, which found that sozinibercept did not meet its primary endpoint of change in BCVA at week 52. A week later, Opthea reported that the ShORe trial had also failed to meet its primary endpoint, and the company announced that it would suspend both trials.
Similar agents in this family typically combine VEGF inhibition with other pathways that may have a role in wet AMD development. RC28-E (RemeGen) is a dual decoy receptor fusion protein targeting VEGF and fibroblast growth factor. Phase 1 results showed a favorable profile leading to progression to a phase 2 trial comparing RC28-E every 12 weeks vs aflibercept 2 mg every 8 weeks (both after 3 loading doses).17
IBI302 (efdamrofusp alfa; Innovent Biologics) is an anti-VEGF and anticomplement (C3b and C4b) bispecific fusion protein. The company has announced the start of the phase 3 STAR trial, comparing intravitreal injections of 8 mg efdamrofusp alfa to 2 mg aflibercept.18,19
AXT107 (Asclepix Therapeutics) blocks VEGF and promotes Tie2 signaling using a suprachoroidal injected suspension that self-assembles into a gel inside the eye. The phase 1/2 trial has completed enrollment of 12 patients, with results expected this year.20
Like faricimab-svoa, AM712 (AffaMed) is a fusion protein targeting VEGF and Ang-2 that has completed a phase 1 clinical trial.21 Boehringer Ingelheim use a nanobody designed to strongly bind to and inhibit the activity of VEGF-A and Ang-2. The nanobody contains albumin to increase the half-life of the medication. The phase 1/2a trial has recently posted favorable results.22
Other Novel Targets
Modulating the Wnt pathway may inhibit retinal degeneration and improve structure and function.23 MK-3000 (Restoret; Merck/EyeBio) is a trispecific antibody that acts as an agonist of the Wnt pathway. Data from the phase 1/2 AMARONE trial provided evidence of MK-3000’s efficacy in DME and nAMD.24
Small aptamer RBM-007 (Ribomic) targets anti-fibroblast growth factor 2 to inhibit angiogenesis and scar formation. Although the TEMPURA trial showed notable improvement in visual acuity and CST in 5 patients, no further studies appear to be planned.25
Similar small molecule–based therapies include OLX10212 (Olix Pharmaceuticals, Inc), a cell-penetrating asymmetric small interference RNA (cp-asiRNA) that targets inflammatory pathways. A phase 1 trial is actively enrolling.26 Likewise OCU-10-C-110 (Ocugenix) activates CXCR3 to promote an angiostatic effect and is actively enrolling a phase 1 trial.27
Less invasive oral and topical routes are also under investigation. A trial evaluating 50 mg doxycycline daily to achieve MMP-9 inhibition in recalcitrant wet AMD is under way at the University of Iowa.28
Gene Therapy
Finally, advances in gene therapy are under way. Although these do not provide any new innovations in terms of the active agent, the delivery is different. Rather than injections, a 1-time subretinal delivery forms an “anti-VEGF factory,” obviating the need for further therapy.
ABBV-RGX-314 (Regenxbio) is an adeno-associated virus (AAV) serotype 8 vector used to transduce RPE cells so that they express a ranibizumab-like anti-VEGF-A antigen-binding fragment. After promising phase 1/2a results, there are a pair of phase 3 trials investigating the subretinal therapy.29 ASCENT and ATMOSPHERE compare ABBV-RGX-314 to intravitreal aflibercept and ranibizumab, respectively.30,31 Another trial, AAVIATE, is a phase 2 study of a 1-time suprachoroidal dose of ABBV-RGX-314.32
EXG102-031 (Exegenesis Bio) is also delivered subretinally. This AAV-based vector expresses a fusion protein that can bind all subtypes of VEGF and ANG-2. The phase 1 Everest trial is actively recruiting.33
Other AAV therapies can be delivered intravitreally, such as ADVM-022 (ixoberogene soroparvovec; Adverum Biotechnologies), which uses a AAV7m8 vector to produce aflibercept. After favorable safety results in the phase 1 OPTIC trial, the phase 2 LUNA trial is under way.34,35 The interim 26-week results demonstrated 76% of patients were injection free with comparable BCVA and CST, compared to standard of care.34 4D-150 (4D Molecular Therapeutics) also uses a proprietary AAV vector (R100) that crosses the internal limiting membrane to carry a dual anti-VEGF transgene that expresses aflibercept and VEGF-C inhibitory RNAi. The phase 1/2a PRISM trial showed a favorable safety profile, and an interim analysis indicated that 70% of patients may be injection free.36,37 Plans are underway for a phase 3 trial.37
Conclusions
This varied landscape of new therapies reaches beyond targeting VEGF-A to address treatment burden in neovascular AMD. As we strive to be ever better in the practice of retina, it is difficult to predict how this landscape will change. We can be confident that we will have more tools in our toolbox to treat patients. RP
References
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30. Pivotal 2 study of RGX-314 gene therapy in participants with nAMD (ASCENT). Clinicaltrials.gov Identifier: NCT05407636. Updated October 16, 2024. Accessed March 16, 2025.
31. Pivotal 1 study of ABBV-RGX-314 (also known as RGX-314) gene therapy administered via subretinal delivery 1 time in participants with nAMD (ATMOSPHERE). Clinicaltrials.gov Identifier: NCT04704921. Updated January 29, 2025. Accessed March 16, 2025.
32. RGX-314 gene therapy administered in the suprachoroidal space for participants with neovascular age-related macular degeneration (AAVIATE). Clinicaltrials.gov Identifier: NCT04514653. Updated June 27, 2024. Accessed March 16, 2025.
33. A study of EXG102-031 in patients with wAMD (Everest). Clinicaltrials.gov Identifier: NCT05903794. Updated September 19, 2024. Accessed March 16, 2025.
34. Safety and efficacy of ADVM-022 in treatment-experienced patients with neovascular age-related macular degeneration (LUNA). Clinicaltrials.gov Identifier: NCT05536973. Updated March 3, 2025. Accessed March 16, 2025.
35. Khanani AM, Boyer DS, Wykoff CC, et al. Safety and efficacy of ixoberogene soroparvovec in neovascular age-related macular degeneration in the United States (OPTIC): a prospective, two-year, multicentre phase 1 study. eClinicalMedicine. 2024;67. doi:10.1016/j.eclinm.2023.102394
36. 4D-150 in patients with neovascular (wet) age-related macular degeneration. Clinicaltrials.gov Identifier: NCT05197270. Updated November 5, 2024. Accessed March 16, 2025.
37. 4D Molecular Therapeutics. 4DMT highlights robust and durable clinical activity for 4D-150 and design of 4FRONT phase 3 program at 4D-150 wet AMD development day. News release. September 18, 2024. Accessed March 16, 2025. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-highlights-robust-and-durable-clinical-activity-4d-150-and/