Summary: comparison with other gene therapies and long-acting anti-VEGF agents in neovascular AMD

No head-to-head trial has compared 4D-150 with another gene therapy for neovascular AMD. The three most advanced AAV programs differ in capsid, route, and dose. 4D-150 uses the synthetic R100 capsid, is given as a single intravitreal injection at 3E10 vg/eye in the Phase 3 4FRONT trials, and carries two transgenes, a codon-optimized aflibercept sequence and a microRNA targeting VEGF-C. ABBV-RGX-314 (surabgene lomparvovec) uses an AAV8 vector encoding an anti-VEGF antibody fragment and is delivered by subretinal surgery in the ATMOSPHERE (671 participants enrolled) and ASCENT (735 participants enrolled) trials, with suprachoroidal delivery in earlier-phase studies. Ixoberogene soroparvovec uses the AAV2.7m8 capsid and intravitreal delivery of aflibercept, with 6E10 vg/eye selected for the Phase 3 ARTEMIS trial (311 participants enrolled). All three Phase 3 programs use a noninferiority comparison against a bolus anti-VEGF comparator: aflibercept 2 mg every 8 weeks for 4FRONT-1, 4FRONT-2, ASCENT, and ARTEMIS, and ranibizumab 0.5 mg monthly for ATMOSPHERE. Reported intraocular inflammation differs by program and prophylaxis: 2 of 71 participants (2.8%) dosed with 4D-150 at 3E10 vg/eye had mild inflammation within 28 weeks and none thereafter, while inflammation with ixoberogene soroparvovec was managed with topical corticosteroids and drove selection of a lower dose with topical-only prophylaxis, and about 23% of participants in a suprachoroidal ABBV-RGX-314 cohort had mild inflammation. Approved long-acting comparators remain repeat-administration products: aflibercept 8 mg is dosed every 4 weeks for three doses then every 8 to 16 weeks, faricimab 6 mg is dosed every 4 weeks for four doses then at intervals up to 16 weeks, and ranibizumab delivered by the Susvimo ocular implant requires surgical implantation and refill-exchange every 24 weeks, with a boxed warning for endophthalmitis.

Sponsor view of competing late-stage gene therapy programs

“We consider our most direct competitors in late-stage development with respect to 4D-150 for the treatment of retinal vascular diseases including wet AMD and DME to be late-stage AAV-based anti-VEGF genetic medicine programs including ABBV-RGX-314 from AbbVie Inc. and REGENXBIO Inc. (subretinal delivery in Phase 3 for wet AMD; suprachoroidal delivery initiating Phase 3 for diabetic retinopathy and in Phase 2 for wet AMD) and Ixo-Vec from Adverum Biotechnologies Inc., now a subsidiary of Eli Lilly and Company (intravitreal delivery in Phase 3 for wet AMD, previously discontinued in diabetic populations).” (opens the source at this quote in a new tab)
“AAV genetic medicine approaches are being developed by several companies to treat wet AMD by delivering a copy of a transgene encoding an anti-VEGF biologic by either subretinal surgery or suprachoroidal injection with a conventional AAV vector, or intravitreal administration with a mouse-evolved vector.” (opens the source at this quote in a new tab)

Comparison with interval-extension approaches

“In addition to genetic medicine approaches, other product candidates designed for extended durability are in development, with the potential to extend dosing intervals by several weeks. We believe a backbone therapy, like 4D-150, designed to provide potentially lifelong benefit with a one-time treatment, would be paradigm-shifting and highly differentiated from interval extension approaches.” (opens the source at this quote in a new tab)

Capsid, route, and transgene of competing AAV programs

“RGX-314 is one of the most advanced candidates, employing an AAV8 vector to deliver a transgene encoding an anti-VEGF antibody fragment analogous to ranibizumab” (opens the source at this quote in a new tab)
“ADVM-022 (ixoberogene soroparvovec; Ixo-vec) employs an engineered AAV2.7m8 capsid for IVT delivery of aflibercept to suppress multiple angiogenic pathways” (opens the source at this quote in a new tab)
“Based on these findings, the 6 × 10¹⁰ vg/eye dose combined with topical-only prophylaxis was selected for the pivotal Phase III program” (opens the source at this quote in a new tab)

Inflammation reported with suprachoroidal and intravitreal competitor programs

“Early interim data from Cohorts 1 and 2 (2.5 × 10¹¹ and 5.0 × 10¹¹ vg/eye) showed no drug-related serious ocular adverse events, with mild intraocular inflammation occurring in approximately 23% of patients and resolving with topical corticosteroids.” (opens the source at this quote in a new tab)
“The most common adverse event was mild-to-moderate anterior segment inflammation, generally responsive to topical corticosteroids, underscoring the need for steroid co-administration and vector dose or formulation optimization” (opens the source at this quote in a new tab)

Registered design of the ixoberogene soroparvovec Phase 3 trial

“This is a multi-center, randomized, double-masked, active-comparator-controlled, Phase 3 study in a broad participant population (treatment-naïve and treatment-experienced) with neovascular (wet) age-related macular degeneration (nAMD). The study will evaluate a single intravitreal (IVT) injection of Ixo-vec compared to an active comparator.” (opens the source at this quote in a new tab)

Registered design of the ABBV-RGX-314 Phase 3 trials

“ABBV-RGX-314 (also known as RGX-314 and surabgene lomparvovec (sura-vec)) is being developed as a novel one-time gene therapy for the treatment of neovascular (wet) age-related macular degeneration (wet AMD).” (opens the source at this quote in a new tab)

“Ranibizumab (LUCENTIS®) 0.5 mg (0.05 mL of 10 mg/mL solution) administered by intravitreal injection approximately every 28 days” (opens the source at this quote in a new tab)

Approved long-acting anti-VEGF agents: labeled dosing

“The recommended dose for EYLEA HD is 8 mg (0.07 mL of 114.3 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days) for the first three doses, followed by 8 mg (0.07 mL of 114.3 mg/mL solution) via intravitreal injection once every 8 to 16 weeks, +/- 1 week.” (opens the source at this quote in a new tab)

“The recommended dose for VABYSMO is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 ± 7 days, monthly) for the first 4 doses, followed by optical coherence tomography and visual acuity evaluations 8 and 12 weeks later to inform whether to give a 6 mg dose via intravitreal injection on one of the following three regimens: 1) Weeks 28 and 44; 2) Weeks 24, 36 and 48; or 3) Weeks 20, 28, 36 and 44.” (opens the source at this quote in a new tab)

Port delivery system: labeled administration and boxed warning

“The recommended dose of SUSVIMO (ranibizumab injection) is 2 mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO ocular implant with refills administered every 24 weeks (approximately 6 months).” (opens the source at this quote in a new tab)
“The SUSVIMO implant has been associated with an up to 3-fold higher rate of endophthalmitis than monthly intravitreal injections of ranibizumab.” (opens the source at this quote in a new tab)

Vorolanib intravitreal insert: mechanism, delivery, and Phase 3 LUGANO and LUCIA design

“DURAVYU brings a potential new multi-mechanism of action and treatment paradigm for retinal diseases beyond existing anti-VEGF large molecule ligand blocking therapies, as vorolanib acts intracellularly to suppress angiogenesis through the inhibition of all VEGF receptors and PDGFR, while also suppressing inflammation through the inhibition of interleukin 6 (IL-6)/JAK1 signaling.” (opens the source at this quote in a new tab)
“DURAVYU is delivered via a standard intravitreal injection in the physician's office, similar to current practice with FDA approved anti-VEGF treatments.” (opens the source at this quote in a new tab)
“LUGANO and LUCIA are identical, randomized, double-masked, aflibercept controlled, non-inferiority Phase 3 trials assessing the efficacy and safety of DURAVYU in patients with active wet AMD including both treatment naïve and treatment experienced patients.” (opens the source at this quote in a new tab)
“Enrollment is complete in both trials with over 900 patients enrolled.” (opens the source at this quote in a new tab)
“At Day 1, patients are randomized 1:1 to receive either DURAVYU 2.7mg every six months or on-label aflibercept as control.” (opens the source at this quote in a new tab)
“The primary endpoint of the Phase 3 pivotal trials is non-inferiority in the average change in best corrected visual acuity (BCVA) at weeks 52 and 56 compared to baseline.” (opens the source at this quote in a new tab)

“A 2-year Phase 3, Multicenter, Prospective, Randomized, Double-Masked, Parallel-Group Study of EYP-1901, a Tyrosine Kinase Inhibitor (TKI), Compared to Aflibercept in Subjects With Wet AMD” (opens the source at this quote in a new tab)

LUGANO Phase 3 results: primary endpoint, treatment burden, safety, and LUCIA data timing

“Despite the outperformance in key secondary endpoints, the primary endpoint of change from baseline in best corrected visual acuity (BCVA) versus 2 mg aflibercept on-label control was not achieved in the full dataset, confounded by this asymmetric cohort.” (opens the source at this quote in a new tab)
“42% reduction in treatment burden, achieving superiority versus on-label aflibercept (nominal p-value<0.0001) compared to a maximum possible reduction of 60%” (opens the source at this quote in a new tab)
“This reduction translates to two fewer injections on average in DURAVYU patients versus on-label aflibercept up to Week 56” (opens the source at this quote in a new tab)
“54% of DURAVYU patients were supplement-free up to Week 56” (opens the source at this quote in a new tab)
“79% of DURAVYU patients received zero or one supplement up to Week 56” (opens the source at this quote in a new tab)
“No difference in cataracts, elevated intraocular pressure, or intraocular inflammation between study and control group” (opens the source at this quote in a new tab)
“No observed occurrences of insert migration, anterior chamber opacities, free-floating drug particles, retinal vasculitis, or severe intraocular inflammation (IOI)” (opens the source at this quote in a new tab)
“The Company remains on track to report topline data from the second wet AMD pivotal Phase 3 LUCIA trial in the fourth quarter of 2026. The Company anticipates potentially filing an NDA for DURAVYU for the potential treatment of wet AMD in the first half of 2027.” (opens the source at this quote in a new tab)

Axitinib intravitreal implant: mechanism, delivery, and Phase 3 SOL-1 and SOL-R design

“AXPAXLI™ (also known as OTX-TKI) is an investigational, bioresorbable, intravitreal hydrogel incorporating axitinib, a small molecule, multi-target, tyrosine kinase inhibitor with anti-angiogenic properties, being evaluated for the treatment of wet AMD and diabetic retinal disease.” (opens the source at this quote in a new tab)
“The registrational Phase 3 SOL-1 trial (NCT06223958) is designed to evaluate the safety and efficacy of AXPAXLI in a multi-center, double-masked, randomized (1:1), parallel group trial that involves more than 100 clinical trial sites located in the U.S. and Argentina. In December 2024, the trial completed randomization of 344 treatment-naïve subjects with a diagnosis of wet AMD in the study eye.” (opens the source at this quote in a new tab)
“The registrational Phase 3 SOL-R trial (NCT06495918) is designed to evaluate the safety and efficacy of AXPAXLI in a multi-center, double-masked, randomized (2:2:1), three-arm trial that includes sites located in the U.S., Argentina, India, and Australia in subjects who are treatment-naïve or were diagnosed with wet AMD in the study eye within about four months prior to enrollment.” (opens the source at this quote in a new tab)
“In December 2025, the trial completed the randomization of 631 subjects.” (opens the source at this quote in a new tab)
“Subjects in the first arm receive a single dose of AXPAXLI (0.45 mg) at Day 1 and are re-dosed at Weeks 24, 48, and 72.” (opens the source at this quote in a new tab)
“The primary endpoint of SOL-R is to demonstrate non-inferiority in mean BCVA change from baseline between the AXPAXLI and on-label aflibercept (2 mg) arms at Week 56.” (opens the source at this quote in a new tab)

“A Phase 3, Multicenter, Double-Masked, Randomized, Parallel-Group Study to Evaluate the Efficacy and Safety of Intravitreal OTX-TKI (Axitinib Implant) in Subjects With Neovascular Age-Related Macular Degeneration (nAMD)” (opens the source at this quote in a new tab)

SOL-1 Phase 3 results: primary endpoint, rescue-free rates, safety, and SOL-R data timing

“AXPAXLI met its primary endpoint at Week 36 with high statistical significance. The proportion of subjects with <15 ETDRS letters lost from baseline at Week 36 was 74.1% in the AXPAXLI arm compared to 55.8% in the aflibercept (2 mg) arm, with a risk difference of 17.5% and p-value of 0.0006 per the pre-specified statistical model, and with an observed difference of 18.3%.” (opens the source at this quote in a new tab)
“The proportion of subjects who maintained vision at Week 52 was 65.9% in the AXPAXLI arm compared to 44.2% in the aflibercept (2 mg) arm, with a risk difference of 21.1% and a p-value of <0.0001 per the pre-specified statistical model compared to aflibercept (2 mg) subjects, and with an observed difference of 21.7%.” (opens the source at this quote in a new tab)
“The rescue-free rates in the AXPAXLI arm were 80.6%, 74.7%, and 68.8% at Weeks 24, 36, and 52, respectively, compared to 72.1%, 56.4%, and 47.7% for the aflibercept (2 mg) arm at the same time periods.” (opens the source at this quote in a new tab)
“As of the Week 52 database lock on February 5, 2026, AXPAXLI was generally well-tolerated in SOL-1 with no observed treatment-related ocular or systemic serious adverse events (SAEs). There were no events of endophthalmitis, occlusive or non-occlusive retinal vasculitis, retinal detachment, or implant migration to the anterior chamber observed in the AXPAXLI arm.” (opens the source at this quote in a new tab)
“The complementary SOL-R Phase 3 non-inferiority trial of AXPAXLI in wet AMD will continue as planned, with topline data expected in 1Q 2027.” (opens the source at this quote in a new tab)

Procedural requirements and complications of the subretinal and intravitreal routes

“However, this method is inherently invasive, requiring pars plana vitrectomy, a surgical procedure in which the vitreous gel inside the eye is removed to access the retina, and specialized surgical expertise, and may lead to serious complications such as vitreous hemorrhage and retinal detachment when performed under nonstandard conditions” (opens the source at this quote in a new tab)

“For instance, intravitreal injections have a safer profile than subretinal injections. They can be performed in out patient clinics with topical anesthesia. Panretinal transduction with the genetic vector is also possible. The main disadvantages of an intravitreal injection include a potential immune response and incomplete vector penetration through the ILM.” (opens the source at this quote in a new tab)

Dose thresholds for expression and burden reduction in the subretinal ABBV-RGX-314 program

“In the Phase I/IIa SR dose-escalation trial, higher-dose cohorts (≥6 × 10¹⁰ vg/eye) maintained protein expression for up to 2 years, with stable best-corrected visual acuity (BCVA) and central retinal thickness (CRT), and required 59–85% fewer anti-VEGF injections compared with baseline” (opens the source at this quote in a new tab)
“Subsequent dose expansion to 1.0 × 10¹² vg/eye (dose level 3) maintained a consistent safety profile and yielded an ≈80% reduction in annualized injection frequency, with 50% of eyes remaining injection-free at 6 months” (opens the source at this quote in a new tab)

Retinal pigmentary changes after subretinal delivery of ABBV-RGX-314

“Almost 70% of patients developed retinal pigmentary changes.” (opens the source at this quote in a new tab)
“These retinal pigmentary changes typically were seen in the inferior retinal periphery.” (opens the source at this quote in a new tab)

Intraocular aflibercept concentration after AAV delivery compared with bolus injection

“The aflibercept levels in the aqueous humor 7 months after an ixo-vec injection were comparable to those found in humans one month after a bolus monthly or bimonthly 2 mg aflibercept injection” (opens the source at this quote in a new tab)

Ocular adverse events reported in the ixoberogene soroparvovec Phase 1 trial

“The most common adverse events recorded was a dose dependent intraocular inflammatory response manifested by cellularity in the anterior chamber and the vitreous cavity.” (opens the source at this quote in a new tab)
“Some eyes developed asymptomatic pigment dispersion, segmental iris atrophy and transillumination iris defects.” (opens the source at this quote in a new tab)
“There was no clinical, tomographic or angiographic evidence of retinal vasculitis, retinitis or choroiditis” (opens the source at this quote in a new tab)

Onset window for inflammation and its control in the ixoberogene soroparvovec Phase 2 trial

“Both doses were well tolerated, and inflammation was effectively controlled with topical corticosteroids, with no new onset beyond week 30.” (opens the source at this quote in a new tab)