Duravyu's Lugano Failure: Ad Hoc Rescue Clause Cannot Substitute for Primary Endpoint Success

EyePoint's Duravyu Misses Primary Endpoint in Phase 3 wAMD Trial

EyePoint’s investigational tyrosine kinase inhibitor (TKI) duravyu failed its Phase 3 Lugano trial for wet age-related macular degeneration (wAMD). The trial, involving about 400 patients, aimed to improve average change in vision (BCVA) after two years compared to standard-of-care aflibercept. The primary endpoint was not met, causing EyePoint’s stock to crash 70%. An ad hoc analysis, which excluded nine patients with vision loss unrelated to wAMD, suggested duravyu was non-inferior to aflibercept, a finding that has raised questions among analysts. Despite this, positive secondary endpoints, including a 42% reduction in treatment burden, were reported. The company now awaits topline data from its twin trial, Lucia, expected in October, which is crucial for its planned New Drug Application filing in the first half of next year.

• EyePoint's investigational TKI, duravyu, failed to meet its primary endpoint in the Phase 3 Lugano trial for wet age-related macular degeneration. The trial aimed to demonstrate superiority in improving vision (BCVA) compared to standard-of-care aflibercept. This clinical miss resulted in a significant 70% drop in EyePoint's stock price, falling to $4.28 per share, reflecting investor concern over the drug's future.
• Despite the primary endpoint miss, EyePoint presented an ad hoc analysis suggesting duravyu was non-inferior to aflibercept after excluding nine patients who experienced vision loss unrelated to wAMD. This post-hoc adjustment, which was not applied to the control arm, has been met with skepticism by analysts, who noted the unusually clean performance of the aflibercept arm and questioned the cause of vision loss in the excluded duravyu patients.
• While the primary endpoint was missed, duravyu showed positive results in several secondary endpoints, including a 42% reduction in treatment burden, which was superior to Eylea and equated to almost two fewer injections through week 56. The drug also demonstrated a clean safety profile and high supplement-free rates. The company and analysts are now looking to the upcoming topline data from the identically designed twin trial, Lucia, expected in October, to potentially de-risk the ad hoc narrative and support a New Drug Application filing.

Duravyu's Mixed Phase 3 Results in Wet AMD

Recent Phase 3 and real-world studies in wet AMD have evaluated a range of anti-VEGF and bispecific agents across treatment-naïve and switch populations, yielding important insights into both efficacy and tolerability. The following trials represent key data points shaping current clinical and strategic thinking in this space.

• HAWK and HARRIER Trials (Brolucizumab): These pivotal studies demonstrated robust visual acuity gains and superior fluid resolution compared to aflibercept, with the potential for extended treatment intervals. However, a notable safety signal emerged: intraocular inflammation (IOI) was observed in 4.6% of patients (definite or probable), with retinal vasculitis in 3.3% and retinal vascular occlusion in 2.1%, raising meaningful clinical concerns around the benefit-risk profile.

• FAR WEST Study (Faricimab — switch population): In patients transitioned from prior anti-VEGF therapy to faricimab, the recurrence-free injection interval extended significantly from 5.7 weeks to 8.6 weeks at 12 months (+2.9 weeks). The proportion of patients with active exudation decreased from 68% to 42%, and among 238 refractory cases at baseline, 35% achieved a dry macula by 12 months. Annual injection burden declined from 8.7 to 6.1, while BCVA remained stable (0.33 to 0.35 logMAR). The intraocular inflammation rate was low at 1.6% (n=14).

• Treatment-Naïve Faricimab Study (three monthly loading injections): Following three initial monthly doses, BCVA improved from 0.64 ± 0.41 to 0.47 ± 0.39 logMAR, and central retinal thickness decreased substantially from 424.1 ± 155.5 μm to 266.3 ± 71.7 μm. Fluid resolution was pronounced across all compartments: subretinal fluid prevalence fell from 79.7% to 15.9%, intraretinal fluid from 56.5% to 8.7%, and serous pigment epithelial detachment from 82.6% to 14.5%. Type 2 (88.2%) and type 3 (94.7%) macular neovascularization demonstrated particularly high rates of complete fluid resolution. Formal safety data were not reported in the available study context.

• HARBOR Study (Ranibizumab — 0.5 mg and 2.0 mg; monthly and PRN regimens): This study characterized the differential resolution kinetics of fluid compartments, with intraretinal fluid resolving most rapidly and completely, followed by subretinal fluid and pigment epithelial detachment. Loading dose regimens achieved fluid levels approaching the lowest attainable thresholds, and both dosage and treatment regimen correlated directly with resulting fluid volumes. Fluid-function analyses confirmed a volume-dependent negative impact of intraretinal fluid on visual acuity, alongside a weak positive prognostic association with subretinal fluid. Formal safety outcomes were not reported in the available study context.

Unpacking the Lugano Trial Design and Primary Endpoint Miss

The landscape of wet AMD clinical trials encompasses a diverse range of study designs, patient populations, and endpoint structures. The TREX-AMD study was a Phase IIIb, multicenter, randomized controlled trial enrolling 60 treatment-naïve neovascular AMD patients (1:2 randomization to monthly or treat-and-extend cohorts), with intravitreal ranibizumab 0.5 mg administered no less frequently than every 12 weeks in the TREX arm. Its primary endpoint was mean ETDRS best-corrected visual acuity (BCVA) change from baseline over 24 months, with eligibility defined by a Snellen-equivalent BCVA range of 20/32 to 20/500. The HAWK and HARRIER trials evaluated brolucizumab in neovascular AMD as randomized controlled trials, with an external safety review committee subsequently identifying rates of 4.6% for definite or probable intraocular inflammation, 3.3% for retinal vasculitis, and 2.1% for retinal vascular occlusion as key safety findings shaping the agent's post-approval profile.

Surgical intervention trials have introduced additional complexity to the endpoint landscape. The MERLOT trial was a Phase 3 randomized controlled trial enrolling 363 patients already receiving intravitreal ranibizumab, comparing pars plana vitrectomy with 24-gray epimacular brachytherapy plus PRN ranibizumab (n=224) against PRN ranibizumab monotherapy (n=119). Its co-primary endpoints at 12 months were the number of PRN ranibizumab injections required and ETDRS BCVA, supplemented by secondary endpoints including proportion of participants losing fewer than 15 ETDRS letters, angiographic total lesion size, choroidal neovascularization size, and OCT foveal thickness. The TIGER trial adopted a pan-European, two-group, active-control, observer-masked, superiority design enrolling 210 participants with large fovea-involving submacular haemorrhage of no more than 15 days' duration, randomized 1:1 to pars plana vitrectomy with subretinal tissue plasminogen activator (up to 25 μg), intravitreal sulfahexafluoride gas, and aflibercept versus aflibercept monotherapy. Its primary efficacy outcome was the proportion of participants achieving a BCVA gain of ≥10 ETDRS letters at month 12, with secondary outcomes spanning reading speed, quality-of-life instruments, scotoma size, and presence of subfoveal fibrosis or atrophy.

Earlier-phase and post hoc work has further informed the field's methodological standards. The VEGF Trap-Eye Phase I dose-escalation study enrolled 21 patients with neovascular AMD lesions ≤12 disc areas and BCVA ≤20/40, administering a single intraocular injection across six dose cohorts ranging from 0.05 mg to 4 mg, with a primary endpoint of safety assessments at six weeks and bioactivity measures — including BCVA, OCT, and fluorescein angiography changes — evaluated through 12 weeks. Complementing these interventional designs, the OSPREY post hoc analysis introduced fluid volatility as a novel metric, quantifying standard deviation across weeks 12 to 56 for six OCT parameters: central subfield thickness, total fluid volume, subretinal fluid volume, intraretinal fluid volume, macular total retinal fluid index, and central macular total retinal fluid index — reflecting an evolving emphasis on dynamic fluid behavior rather than static cross-sectional measurements as a marker of disease control.