Neovascular age-related macular degeneration (nAMD) remains a leading cause of blindness among adults aged ≥50 years despite effective treatment such as anti–vascular endothelial growth factor (VEGF) therapy.1 This may be partly due to the high treatment burden associated with these therapies, which can lead to treatment nonadherence in clinical practice.2,3
Duravyu (EYP-1901; Eye Point Pharmaceuticals),* a bioerodible, sustained-delivery, intravitreal (IVT) insert that delivers the tyrosine kinase inhibitor (TKI) vorolanib, has the potential to reduce treatment burden for nAMD. Unlike current anti-VEGF therapies that inhibit angiogenesis by targeting the VEGF-A ligand, vorolanib is a potent and highly selective TKI that acts intracellularly by binding to all 3 VEGF receptors. This inhibits downstream signaling without affecting the TIE2 receptor at clinically relevant doses.4
Duravyu uses Durasert E technology to provide a daily continuous release of vorolanib into the vitreous over a period of at least 6 months. This delivery method maintains a consistent drug concentration due to zero-order kinetics, eliminating fluctuations. The Durasert E system ensures immediate treatment initiation, as the drug reaches target tissues within hours of administration; and no free-floating drug, as vorolanib is fully eluted before matrix erosion. Durasert E does not require refrigeration and can be shipped and stored at ambient temperature.
Duravyu has been evaluated for the treatment of nAMD in the phase 2 DAVIO2 trial, which compared 2 doses of Duravyu vs aflibercept 2 mg injections every 8 weeks (Q8W) in previously treated patients. DAVIO2 was the largest trial of IVT TKIs to date, and 1-year results have recently been presented. Pivotal phase 3 trials LUGANO and LUCIA are set to begin enrolling in the second half of 2024 and early 2025, respectively.
DAVIO2 Trial Design
In DAVIO2, previously treated patients with nAMD were randomized 1:1:1 to a single intravitreal injection of Duravyu 2060 µg or Duravyu 3090 µg, or aflibercept 2 mg Q8W. All patients received aflibercept loading doses at day 1, week 4, and week 8. Following the week 8 dose, patients received Duravyu or sham. Patients were followed for 12 months, with visits every 4 weeks (Figure 1).
Figure 1. The clinical trial design for the phase 2 DAVIO2 trial (NCT05381948). Figure courtesy EyePoint Pharmaceuticals.
After week 8, patients in all arms were eligible to receive supplemental aflibercept treatment at each study visit if any of the following prespecified criteria were met: (1) best-corrected visual acuity (BCVA) reduction ≥5 letters from best on-study measurement due to nAMD and central subfield thickness (CST) increase ≥75 µm from lowest on-study measurement, or (2) BCVA reduction ≥10 letters from best on-study measurement due to nAMD, or (3) CST increase ≥100 µm from lowest on-study measurement from 2 consecutive visits, or (4) vision-threatening hemorrhage, new or worsening, due to nAMD.
The primary endpoint was mean change in BCVA from baseline, averaged over weeks 28 and 32 (6 months after Duravyu injection). Key secondary endpoints included mean change in CST from baseline, reduction in treatment burden, and safety.
Results From the Phase 2 Study
DAVIO2 enrolled 161 patients across the 3 treatment arms (Duravyu 2060 µg n=53; Duravyu 3090 µg n=54; aflibercept 2 mg Q8W n=54). Baseline demographics were generally well balanced between arms. On average, patients were heavily pretreated with good baseline BCVA, receiving an average of ~10 injections (normalized) in the 12 months prior to screening.5
Duravyu-treated eyes demonstrated stable visual acuity and anatomy through week 32. The primary endpoint was met, with both doses of Duravyu statistically noninferior to aflibercept 2 mg Q8W for BCVA change from baseline. Mean change in BCVA vs aflibercept averaged over weeks 28/32 was -0.3 letters and -0.4 letters with Duravyu 2,060 µg and Duravyu 3,090 µg, respectively. For anatomic outcomes, the mean change in CST compared to aflibercept 2 mg Q8W was <10 µm in both experimental arms.
Treatment with Duravyu also demonstrated a meaningful reduction in treatment burden, with burden reduced by 89% and 85% in the Duravyu 2,060 µg and Duravyu 3,090 µg arms, respectively, compared to the 6 months before trial enrollment. Two-thirds of Duravyu-treated eyes remained supplement free at 6 months after injection, further highlighting Duravyu’s long-term continuous drug release.
One year data from DAVIO2 have recently been compiled, with results demonstrating the continued maintenance of both visual and anatomic outcomes observed in the primary analysis.6
Duravyu was well tolerated through week 32, and no Duravyu-related ocular or systemic serious adverse events (SAEs) were reported with either dose. The majority (97%) of adverse events were mild and generally expected with IVT injections. This favorable safety profile was maintained through month 12, with no Duravyu-related ocular or systemic SAEs reported in either arm.6 No cases of insert migration into the anterior chamber or retinal occlusive vasculitis were reported.
Figure 2. The clinical trial design for the phase 3 LUGANO and LUCIA trials. Figure courtesy EyePoint Pharmaceuticals.
Phase 3 Trial Design
Following the positive results from the phase 2 trial, the safety and efficacy of Duravyu for the treatment of nAMD will be further evaluated in 2 pivotal phase 3 trials: LUGANO and LUCIA. LUGANO is scheduled to commence later this year across approximately 150 sites, with LUCIA to follow. Both trials are designed to follow patients for up to 96 weeks, with the primary endpoint being assessed over weeks 52 and 56.
Similar to DAVIO2, LUGANO and LUCIA are designed to assess noninferiority of Duravyu vs aflibercept Q8W. Key differences in study design between phase 2 and phase 3 are (1) assessing a single Duravyu treatment group (Duravyu 2,686 µg); (2) redosing of Duravyu at 6-month intervals; and (3) inclusion of both treatment-naïve and previously treated nAMD patients in the phase 3 studies (Figure 2).
LUGANO and LUCIA are phase 3, prospective, randomized, double-masked, multicenter trials designed to compare Duravyu 2,686 µg with aflibercept in both treatment-naïve and previously treated patients. In each trial, approximately 400 patients will be randomized 1:1 to receive either Duravyu 2,686 µg or aflibercept 2 mg Q8W.
As in DAVIO2, patients in both arms will receive aflibercept loading doses at day 1, week 4, and week 8. After week 8, patients in the aflibercept arm will receive aflibercept 2 mg Q8W. Following the aflibercept injection at week 8, patients in the Duravyu arm will receive the Duravyu dose. Additional Duravyu doses will be administered at weeks 32, 56, and 80. Starting at week 12, all patients will be assessed for supplemental injections based on prespecified criteria.
Key inclusion criteria include documented diagnosis of nAMD in the study eye, BCVA of 35 to 78 letters, and presence of fluid. Previously treated patients must have received ≥2 anti-VEGF IVT injections in the 6 months prior to screening with a demonstrated anatomic response. Trial exclusion criteria include vitreous hemorrhage within 12 weeks before screening, or history of rhegmatogenous retinal detachment. Additional exclusion criteria include history of pars plana vitrectomy, submacular surgery, or any surgical interventions for nAMD.
The primary objective of both LUGANO and LUCIA is to demonstrate noninferiority of the Duravyu 2686 µg IVT insert to aflibercept 2 mg on the basis of BCVA letter change from baseline to weeks 52 and 56 (averaged). Key secondary endpoints include anatomical assessments, such as change in CST and retinal thickness fluctuations, treatment burden reduction, supplemental injection rates, and safety.
With daily, continuous, sustained-release dosing over a period of at least 6 months, positive phase 2 efficacy results, and a favorable safety profile, Duravyu has the potential to substantially reduce the treatment burden associated with nAMD. Further evaluation of Duravyu’s efficacy and safety will be conducted in the forthcoming phase 3 trials, LUGANO and LUCIA. RP
References
1. GBD 2019 Blindness and Vision Impairment Collaborators; Vision Loss Expert Group of the Global Burden of Disease Study. Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the Right to Sight: an analysis for the Global Burden of Disease Study. Lancet Glob Health. 2021;9(2):e144-e160. doi:10.1016/S2214-109X(20)30489-7
2. Ciulla TA, Hussain RM, Taraborelli D, Pollack JS, Williams DF. Longer-term anti-VEGF therapy outcomes in neovascular age-related macular degeneration, diabetic macular edema, and vein occlusion–related macular edema: clinical outcomes in 130 247 eyes. Ophthalmol Retina. 2022;6(9):796-806. doi:10.1016/j.oret.2022.03.021
3. Okada M, Mitchell P, Finger RP, et al. Nonadherence or nonpersistence to intravitreal injection therapy for neovascular age-related macular degeneration: a mixed-methods systematic review. Ophthalmology. 2021;128(2):234-247. doi:10.1016/j.ophtha.2020.07.060
4. Bakri SJ, Lynch J, Howard-Sparks M, Saint-Juste S, Saim S. Vorolanib, sunitinib, and axitinib: a comparative study of vascular endothelial growth factor receptor inhibitors and their anti-angiogenic effects. PLoS One. 2024;19(6):e0304782. doi:10.1371/journal.pone.0304782
5. Wykoff CC. The DAVIO2 trial: topline data from a phase 2, multicenter study of a single injection of EYP-1901 (vorolanib in the Durasert E technology) vs aflibercept for previously treated wet age-related macular degeneration. Presented at: the Angiogenesis, Exudation, and Degeneration 2024 annual meeting; virtual; February 3, 2024.
6. EyePoint Pharmaceuticals to highlight Duravyu (vorolanib intravitreal insert) clinical and regulatory progress and pipeline innovation at R&D day 2024. News Release. June 26, 2024. Accessed September 4, 2024. https://investors.eyepointpharma.com/news-releases/news-release-details/eyepoint-pharmaceuticals-highlight-duravyutm-vorolanib
*Duravyu has been conditionally accepted by the FDA as the proprietary name for EYP-1901. Duravyu is an investigational product; it has not been approved by the FDA. FDA approval and the timeline for potential approval is uncertain.
