Phase 2 Randomized Double‑Blind Study of Aganirsen Eye Drops for Extending Intravitreal Aflibercept Injection Intervals in Wet Age‑Related Macular Degeneration

Primary objective: evaluate whether two dose levels of aganirsen eye drops can extend the dosing interval of intravitreal aflibercept 8 mg over a 9‑month period in patients with wet age-related macular degeneration, thereby potentially reducing injection frequency and treatment burden. Secondary objectives:

• compare visual acuity outcomes after 9 months between aganirsen doses and placebo;
• quantify the magnitude of interval extension achieved;
• assess changes in central macular thickness;
• determine the proportion of eyes free of intra‑ and sub‑retinal fluid;
• evaluate safety profile of the two aganirsen doses over 9 months plus 1 week.

The trial enrolled adults aged 50 to 89 years of both sexes who had a documented diagnosis of wet age‑related macular degeneration in the study eye and had received at least one intravitreal injection within 48 months of diagnosis. All participants were under a treat‑and‑extend regimen of intravitreal aflibercept 8 mg, demonstrated absence of intraretinal or subretinal fluid, and possessed a best‑corrected visual acuity of at least 1/10 in the study eye. Eligibility required the ability to self‑administer eye drops twice daily for nine months, or the availability of a caregiver to do so. The sponsor did not provide information on the total number of participants enrolled.

The SKY2 study is a Phase II multicenter wet Age-Related Macular Degeneration (wAMD) trial that employs a randomized, double‑blind, placebo‑controlled design to compare two dose levels of aganirsen eye‑drop emulsion with placebo in patients receiving intravitreal aflibercept on a treat‑and‑extend regimen. After a screening visit to verify eligibility criteria (age 50‑89, documented diagnosis, BCVA ≥ 1/10, absence of retinal fluid under the current aflibercept interval, and ability to self‑administer drops), participants are randomized and begin a 9‑month treatment phase with twice‑daily study drops while continuing aflibercept injections as clinically indicated. Follow‑up visits occur at baseline (day 0), month 1, month 3, month 6, month 9, and a final safety visit one week after the month 9 visit; each visit includes OCT imaging for fluid assessment, ETDRS visual acuity testing, intra‑ocular pressure measurement, ocular surface evaluation, safety laboratory tests, and adverse‑event monitoring. The primary endpoint is the percentage of participants who extend the aflibercept interval by at least two weeks from baseline to month 9; secondary endpoints assess changes in BCVA, injection frequency, central macular thickness, fluid status, and a range of ocular safety parameters. Participant involvement therefore spans approximately nine months plus a one‑week follow‑up. Early termination may be triggered by significant adverse events, non‑adherence to the dosing schedule, emergence of exclusion criteria, or voluntary withdrawal of consent. Recruitment is planned from August 2026 to December 2027.

The study incorporates intravitreal administration of aflibercept (Eylea 114.3 mg/ml solution for injection in a pre‑filled syringe) as background therapy. The product is supplied as a sterile solution for injection and is delivered by the intravitreal route according to the protocol‑specified 8 mg dosing schedule, with interval adjustments assessed over the 9‑month treatment period.

Two investigational doses of aganirsen are evaluated. The investigational product is provided as an ophthalmic eye‑drop emulsion. Both doses are administered topically to the study eye(s) using the ophthalmic route. The exact concentration and volume per dose are defined in the study protocol, and dosing frequency is consistent with the trial design for each dose arm.

A matching placebo eye‑drop emulsion is used as a comparator. The placebo contains no active pharmaceutical ingredient and is identical in appearance and administration schedule to the active eye‑drop formulations.

All study treatments are administered under controlled conditions. Intravitreal injections are performed by qualified ophthalmologists, while eye‑drop applications are supervised to ensure correct technique. Participant compliance with eye‑drop dosing is monitored through diary entries and periodic study visits, and any deviations are recorded for safety and efficacy assessments.

The primary endpoint is the proportion of participants who achieve an extension of the intravitreal aflibercept 8 mg treatment interval by at least two weeks between baseline and month 9. Extension is determined by comparing the interval recorded at baseline with the interval recorded at the 9‑month visit. Participants are considered successful if the interval difference meets or exceeds the two‑week threshold.

Assessment of secondary endpoints includes: change in Best Corrected Visual Acuity from baseline to month 9 measured with the Early Treatment Diabetic Retinopathy Study (ETDRS) chart; number of weeks between the last successful intravitreal aflibercept interval at month 9 and baseline; total number of intravitreal aflibercept injections administered from baseline to month 9; change in central macular thickness from baseline to month 9 evaluated by Optical Coherence Tomography (OCT); proportion of participants with absence of intraretinal and subretinal fluid at month 9 on OCT; incidence and nature of adverse events throughout the 9‑month treatment period and a 1‑week follow‑up; incidence and grading of local tolerance events using a Visual Analog Scale (VAS); changes in safety laboratory markers, conjunctival hyperemia score, corneal staining score, Intraocular Pressure, and Tear Break-Up Time from baseline to month 9. All efficacy parameters are collected at baseline and at the 9‑month visit, employing the specified validated instruments and standardized scoring systems.