Duravyu misses noninferiority end point in phase 3 LUCIA wet AMD trial

LUCIA, the second of 2 pivotal phase 3 trials in neovascular (wet) age-related macular degeneration (AMD), missed its primary endpoint evaluating vorolanib intravitreal insert (Duravyu; EyePoint).¹ The result follows LUGANO, the program's first phase 3 trial, which also missed its primary end point in the full dataset.

The vorolanib intravitreal insert (Duravyu; EyePoint), a sustained-release tyrosine kinase inhibitor (TKI) dosed every 6 months, did not achieve noninferiority to on-label aflibercept 2 mg for best-corrected visual acuity (BCVA) in LUCIA.¹

In LUCIA, insert-treated eyes gained a least squares mean of 2.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline at blended weeks 52 and 56, compared with 6.1 letters in the aflibercept arm, a difference of −3.7 letters. The confidence interval extended beyond the prespecified −4.5-letter noninferiority margin, according to an investor presentation filed with the US Securities and Exchange Commission.² The same day, EyePoint announced it would reduce its workforce by approximately 53%, conclude both wet AMD trials early, and focus on diabetic macular edema (DME).³

Trial design

LUCIA (NCT06683742) is a randomized, double-masked, aflibercept-controlled noninferiority trial that enrolled 475 patients aged 50 years or older with active wet AMD, including treatment-naive and previously treated eyes.^1,4 Following 3 monthly aflibercept loading doses, patients received either the vorolanib insert 2.7 mg every 24 weeks or aflibercept 2 mg every 8 weeks. Both arms could receive supplemental aflibercept for a loss of more than 5 letters with at least 75 µm of new fluid or for new sight-threatening hemorrhage.² Each insert dose consists of 2 inserts delivered in a single injection.²

At baseline, approximately 76% of patients in each arm were treatment naive. Mean BCVA was 65.0 and 64.5 letters in the insert and aflibercept arms, respectively, and mean age was approximately 77 years.²

Secondary end points and safety

Through week 56, insert-treated eyes received a mean of 3.3 injections after loading, including the 2 scheduled insert doses, compared with 5.3 in the aflibercept arm. That is a 38% reduction in treatment burden, against a maximum possible reduction of 60% under the protocol (nominal P < .001).^1,2 Seventy percent of insert-treated eyes were supplement-free through week 32 and 52% through week 56. Seventy-one percent received 0 or 1 supplemental injection through week 56.²

Central subfield thickness (CST) decreased by 66 µm with the insert and 82 µm with aflibercept. The 16-µm difference favored aflibercept (nominal P = .002).²

There were no reported cases of insert migration into the anterior chamber, anterior chamber opacities, free-floating particles, or retinal vasculitis. Severe intraocular inflammation and endophthalmitis each occurred in fewer than 1% of patients in both arms. Discontinuation through week 56 was approximately 8% in each arm, and none was attributed to the insert.²

Several ocular adverse events were more frequent in the insert arm:

• conjunctival hemorrhage: 9.1% vs 3.7%
• vitreous floaters: 8.2% vs 2.1%
• retinal hemorrhage: 4.7% vs 1.2%
• vitreous hemorrhage: 3.0% vs 0%
• increased intraocular pressure: 4.3% vs 2.5%

Cataract rates were similar (4.7% vs 5.3%).² All data are described as preliminary, pending final analysis.²

LUGANO and the regulatory path

LUGANO (NCT06668064), an identical trial of 432 patients, reported topline data in August 2026.^5,6 It did not meet noninferiority in the full dataset. Noninferiority was shown only in an ad hoc analysis that excluded 9 of 211 insert-treated patients whose loss of 15 or more letters the company attributed to causes other than wet AMD (nominal P = .0096).⁵ LUGANO reported a 42% reduction in treatment burden.⁵ In pooled data from both trials, burden fell by 40%, and the CST difference was 10 µm favoring aflibercept.²

After LUGANO, EyePoint had said it planned a possible new drug application in the first half of 2027.⁵ The October announcements do not repeat that timeline. Instead, the company said it will complete further analyses of LUCIA and the pooled datasets to assess next steps in wet AMD.¹ Under the restructuring, both wet AMD trials will end before completing their second year. The company projects annualized savings of about $30 million and reported approximately $118 million in cash and investments as of September 30, 2026.³

Clinical context

AMD was projected to affect 196 million people worldwide in 2020, rising to 288 million by 2040, although those estimates cover all forms of the disease rather than neovascular AMD alone.⁷ Intravitreal anti–vascular endothelial growth factor (VEGF) therapy remains the standard of care. Aflibercept dosed every 8 weeks after 3 monthly loading doses showed efficacy similar to monthly ranibizumab in the VIEW 1 and VIEW 2 trials (n = 2419).⁸ The FDA approved aflibercept for neovascular AMD in November 2011.⁹ Because treatment is chronic, injection frequency remains a central challenge, and it has driven development of longer-acting approaches.

Drug background

Vorolanib is a small-molecule TKI. EyePoint describes it as inhibiting VEGF receptors and platelet-derived growth factor receptors intracellularly and as suppressing interleukin 6/JAK1 signaling.¹ It is formulated in a bioerodible Durasert E insert designed to release drug for at least 6 months.¹

The phase 1 DAVIO trial, an open-label dose-escalation study in 17 previously treated patients, was published in 2024.¹⁰ In the phase 2 DAVIO 2 trial (NCT05381948), a single insert dose was compared with aflibercept every 8 weeks in previously treated eyes. Investigators reported at ARVO 2025 that the trial met its noninferiority primary end point at averaged months 7 and 8.^11,12 The phase 3 trials differed in several ways: they enrolled mostly treatment-naive eyes, used repeat dosing, and assessed the primary end point at 1 year.

Interpretation

In 2 consecutive pivotal trials, the vorolanib insert produced numerically smaller BCVA gains than fixed-interval aflibercept, with the deficit pointing in the same direction both times. Because the primary end point was not met, the secondary results are reported with nominal P values. They should be read as descriptive rather than confirmatory.

The treatment-burden comparison was made against protocol-mandated dosing every 8 weeks. It did not compare against treat-and-extend regimens or newer extended-interval agents used in practice. The supplement-free rates are single-arm measures with no comparator.

"We are disappointed that the LUCIA trial did not meet the primary endpoint," said Jay S. Duker, MD, EyePoint's president and CEO.¹

Limitations and next steps

The topline data are preliminary. The confidence interval for the primary end point was not disclosed, and outcomes by treatment-naive vs previously treated status have not been reported. With both trials ending early, full 2-year data will not be collected.³

The company's focus now shifts to DME. COMO and CAPRI, 2-phase 3 noninferiority trials with 551 patients in total, are expected to report topline data in the fourth quarter of 2027.³ These trials follow the phase 2 VERONA trial (NCT06099184). In VERONA, the company reported a 7.1-letter BCVA gain and a 76-µm CST reduction at week 24 with the 2.7-mg dose. Seventy-three percent of patients in that arm were supplement-free, compared with 50% in the control arm.^1,13

References

1. EyePoint announces topline results from LUCIA, the second pivotal phase 3 clinical trial of Duravyu in wet AMD. News release. EyePoint, Inc. October 19, 2026. https://investors.eyepoint.bio/news-releases/news-release-details/eyepoint-announces-topline-results-lucia-second-pivotal-phase-3

2. EyePoint, Inc. LUCIA phase 3 clinical trial: Duravyu in wet AMD topline results. Investor presentation (Form 8-K, exhibit 99.2). US Securities and Exchange Commission. October 19, 2026. https://www.sec.gov/Archives/edgar/data/1314102/000119312526424644/eypt-ex99_2.htm

3. EyePoint announces strategic prioritization. News release. EyePoint, Inc. October 19, 2026. https://www.globenewswire.com/news-release/2026/10/19/3383318/0/en/eyepoint-announces-strategic-prioritization.html

4. A 2-year study of EYP-1901 in subjects with wet age related macular degeneration (wAMD) (LUCIA). ClinicalTrials.gov identifier: NCT06683742. https://clinicaltrials.gov/study/NCT06683742

5. EyePoint announces topline data from LUGANO, the first of two pivotal phase 3 clinical trials for Duravyu 2.7mg in wet AMD. News release. EyePoint, Inc. August 17, 2026. https://investors.eyepoint.bio/news-releases/news-release-details/eyepoint-announces-topline-data-lugano-first-two-pivotal-phase-3

6. A 2-year study of EYP-1901 in subjects with wet age related macular degeneration (wAMD) (LUGANO). ClinicalTrials.gov identifier: NCT06668064. https://clinicaltrials.gov/study/NCT06668064

7. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-e116. https://pubmed.ncbi.nlm.nih.gov/25104651/

8. Heier JS, Brown DM, Chong V, et al; VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537-2548. doi:10.1016/j.ophtha.2012.09.006 https://pubmed.ncbi.nlm.nih.gov/23084240/

9. Aflibercept in wet age-related macular degeneration: a perspective review. 2012;3(4):153-161. doi:10.1177/2040622312446007 https://pmc.ncbi.nlm.nih.gov/articles/PMC3539286

10. Patel S, Storey PP, Barakat MR, et al. Phase I DAVIO trial: EYP-1901 bioerodible, sustained-delivery vorolanib insert in patients with wet age-related macular degeneration. Ophthalmol Sci. 2024;4(5):100527. doi:10.1016/j.xops.2024.100527

11. DAVIO 2 (EYP-1901 vs aflibercept in previously treated wet AMD). ClinicalTrials.gov identifier: NCT05381948. https://clinicaltrials.gov/study/NCT05381948

12. A review of the DAVIO 2 phase 2 trial results. Ophthalmology Times. July 9, 2025. https://www.ophthalmologytimes.com/view/a-review-of-the-davio-2-phase-2-trial-results

13. VERONA: study of EYP-1901 in patients with diabetic macular edema (DME). ClinicalTrials.gov identifier: NCT06099184. https://clinicaltrials.gov/study/NCT06099184