FDA Issues Complete Response Letter to Aflibercept 8 mg for Extended Dosing
The FDA identified no issues with the safety or efficacy of aflibercept 8 mg in any of its already approved dosing regimens or indications.
Image Credit: US Food and Drug Administration
The US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to the supplemental Biologic License Application (sBLA) for an extended 24-week dosing duration for aflibercept 8 mg (EYLEA HD) in the treatment of wet age-related macular degeneration (AMD), diabetic macular edema (DME), and diabetic retinopathy (DR).1
Announced by Regeneron on April 18, 2025, the CRL did not identify issues with aflibercept 8 mg in its already approved dosing regimens or its indications for wet AMD, DME, or DR. However, the FDA disagreed with the company's proposal to add extended dosing intervals greater than 16 weeks, the current maximum according to the label.1
Aflibercept 8 mg is a longstanding treatment for various ophthalmic diseases, including wet AMD and DME. It was initially approved for the treatment of both diseases in August 2023, based on the data from the PULSAR and PHOTON trials.2
The dosing extension plan was first announced during Regeneron’s presentation at the J.P. Morgan Healthcare Conference in January 2025. At the time of presentation, the FDA was already reviewing the application.3
The sBLA submission was based on positive results from the PULSAR (wet AMD) and PHOTON (DME) trials, which indicated durable vision gains at extended dosing intervals. The PULSAR and PHOTON trials were double-masked, active-controlled trials evaluating the non-inferiority of aflibercept 8 mg dosing regimens to an 8-week aflibercept 2 mg treatment regimen for treating wet AMD and DME, respectively. Participants receiving aflibercept 8 mg received 3 initial monthly doses in both trials, while those receiving aflibercept 2 mg received 3 initial monthly doses in PULSAR and 5 in PHOTON.4
In both studies, most aflibercept 8 mg recipients sustained visual gains and anatomic improvements achieved by the end of the second year, while also achieving longer treatment intervals. Those who switched from aflibercept 2 mg to aflibercept 8 mg at the beginning of the third year also exhibited and maintained anatomic and vision improvements with longer dosing intervals and fewer injections.4
During the first year, patients could have their dosing intervals shortened to an every 2-month interval if specific criteria were observed; intervals could not be extended until the second year. Both trials were followed up with an optional extension study beginning at week 96, which saw participating patients initially randomized to aflibercept 2 mg switched to 8 mg at the start of the extension and assigned a 3-month dosing interval.4
The safety profile for aflibercept 8 mg in both trials was similar to aflibercept 2 mg and remained consistent throughout the three years. The endpoints of both trials were reached, and on February 8, 2025, Regeneron announced the positive results.4
"Regeneron is evaluating the FDA's decision and will determine a path forward in due course," the company wrote in its April 18 announcement.1
References
Regeneron. "Regeneron Provides Update on EYLEA HD® (aflibercept) Injection 8 mg Supplemental Biologics License Application". Regeneron. April 18, 2025. Accessed April 18, 2025. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-eylea-hdr-aflibercept-injection-8-mg1. Campbell
P. Aflibercept 8 mg (eylea HD) approved by FDA for wet AMD, DME, and Diabetic retinopathy. HCP Live. August 23, 2023. Accessed April 18, 2025. https://www.hcplive.com/view/aflibercept-8mg-eylea-hd-approved-by-fda-for-wamd-dme-and-diabetic-retinopathy.
Regeneron provides business updates and highlights from Broad Clinical Pipeline at the 43rd Annual J.P. Morgan Healthcare Conference. Regeneron Pharmaceuticals Inc. January 13, 2025. Accessed April 18, 2025. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-business-updates-and-highlights-broad.
Regeneron. Three-Year Results for EYLEA HD (aflibercept) Injection 8 mg in Patients with Wet Age-Related-Macular Degeneration Demonstrate Continued Durable Vision Gains and Anatomic Improvements with Extended Dosing Intervals. Regeneron. February 8, 2025. Accessed April 16, 2025. https://investor.regeneron.com/news-releases/newsA-release-details/three-year-results-eylea-hdr-aflibercept-injection-8-mg-patients
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