FDA Issues Complete Response Letter to Regeneron for EYLEA HD sBLA on Extended Dosing Intervals

Regeneron Pharmaceuticals has announced that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding its supplemental Biologics License Application (sBLA) for EYLEA HD (aflibercept 8 mg). The application sought approval to expand dosing intervals up to every 24 weeks for all approved indications.

FDA Declines Extended Dosing Beyond 16 Weeks

According to Regeneron, the CRL did not cite any safety or efficacy concerns related to aflibercept 8 mg. However, the FDA did not agree with the proposal to extend dosing intervals beyond every 16 weeks, which is the currently approved maximum for EYLEA HD.

At present, EYLEA HD is approved with dosing intervals of 8 to 16 weeks for wet age-related macular degeneration (wAMD) and diabetic macular edema (DME).

For diabetic retinopathy (DR), dosing intervals range from 8 to 12 weeks, following three initial monthly injections.

Supporting Data and Clinical Background

The sBLA was supported by one-year data from Regeneron’s PULSAR and PHOTON phase 3 trials, which were published in The Lancet in March 2024. These studies demonstrated that aflibercept 8 mg administered every 12 or 16 weeks produced noninferior visual acuity gains compared with standard dosing schedules, following initial monthly loading doses.

       • PULSAR studied 3 initial monthly doses

       • PHOTON studied 5 initial monthly doses

Despite these positive findings, the FDA declined to include 24-week dosing intervals in the updated product label.

Regeneron stated it is currently evaluating the FDA’s feedback and will determine the next steps “in due course.”

Ongoing Regulatory Applications for EYLEA HD

In parallel, Regeneron has filed an additional sBLA seeking:

       • Approval for aflibercept 8 mg in the treatment of macular edema following retinal vein occlusion (RVO)

       • Authorization to include monthly (every-4-week) dosing intervals across all approved uses

The FDA’s target action date for this application is set for August 19, 2025. A similar regulatory submission for RVO indication expansion has also been filed with the European Medicines Agency.

Approved Indications and Safety Overview

EYLEA HD (Aflibercept 8 mg)

Approved for:

       • Wet AMD

       • Diabetic macular edema (DME)

       • Diabetic retinopathy (DR)

EYLEA (Aflibercept 2 mg)

Approved for:

      • Wet AMD

      • Macular edema following RVO

      • DME

      • DR

      • Retinopathy of prematurity (ROP)

Common Side Effects

Aflibercept 8 mg:

       • Cataract

       • Eye redness

       • Elevated intraocular pressure

       • Eye discomfort, pain, or irritation

       • Blurred vision

       • Vitreous floaters or detachment

       • Retinal injury or bleeding

Aflibercept 2 mg:

       • Similar ocular effects as 8 mg

       • Floaters, increased eye pressure

       • In preterm infants with ROP: retinal detachment, eye redness, and elevated pressure

Serious Risks (Both 2 mg and 8 mg):

       • Infection

       • Retinal detachment

       • Vasculitis with or without vascular occlusion

       • Temporary spike in intraocular pressure

       • Risk of thromboembolic events such as stroke or heart attack (rare)

Infants treated for ROP with aflibercept require long-term follow-up due to potential risks.