FDA Delivers CRL for Longer Dosage Intervals in Aflibercept for DME, Wet AMD

High-dosage aflibercept (Eylea HD; Regeneron) can not be taken every 24 weeks for diabetic macular edema (DME) or wet age-related macular degeneration (AMD) after the FDA delivered a complete response letter (CRL) to Regeneron on April 18.¹ High-dosage aflibercept was first approved by the FDA for use in DME and AMD in August 2023.²

High-dose aflibercept can be used in DME, wet AMD, and diabetic retinopathy in an 8-mg dose, which is 6 mg more than the original dose. The treatment can be taken at 8 mg every 4 weeks for 3 months and then 8 mg every 8 to 16 weeks for wet AMD or DME. The treatment offered fewer injections than the regular dose and was the first and only treatment to offer up to 16 weeks between injections. This biologics license application sought to build on that approval to offer up to 24 weeks between injections with noninferior results.

This application was based on a phase 3 PULSAR trial (NCT04423718) whose results were presented in February 2025.³ The trial evaluated the efficacy of high-dose aflibercept injection of 8 mg in patients with wet AMD. The trial found that visual gains and anatomic improvements lasted through 2 years although the patients had longer intervals between injections. These results were also found in patients who switched from 2 mg to 8 mg at the beginning of the third year, although vision and anatomic improvements lasting with fewer injections and longer intervals between doses.

There were 375 patients who completed 2 years of treatment and participated in the extension study that was conducted for 60 weeks, totaling 3 years. All patients were randomly assigned to either 3 or 4 months between doses after taking their first 3 doses monthly. All patients could change their dosing interval based on criteria. The study found that 88% of the patients were able to have at least 3 months between doses, 60% kept an interval of at least 4 months, 40% extended to at least 5 months, and 24% extended to 6 months. All of their visual gains and anatomical improvements achieved through 2 years lasted through the extension study.

Patients who switched from a regular 2-mg dose of aflibercept of taken every 2 months to a high dose of aflibercept were included in the study after 2 years. The 186 patients saw all improvements maintained through the last year of treatment, with 79% of patients having a dosing interval of at least 3 months and 43% having a dosing interval of at least 4 months. Adverse events related to treatment occurred in at least 4% of the participants, with reduction of visual acuity, vitreous floaters, retinal hemorrhage, cataracts, and an increase in ocular pressure all recorded.

The PHOTON trial (NCT04429503) was also the basis of this application,⁴ with this trial focusing on DME. The trial was conducted similarly to the PULSAR trial, with 658 patients randomized to 12-week and 16-week dosing intervals with 8 mg of aflibercept. Dosing intervals could be extended or shortened based on certain criteria. The trial was conducted over 2 years and found that 89% of the patients maintained a dosing interval of at least 12 weeks, 83% maintained an interval of at least 16 weeks, 16% extended to 20 weeks, and 27% extended to 24 weeks without loss of vision gains. Adverse events related to treatment were reported in at least 5% of the patients, with conjunctival hemorrhage, cataracts, and vitreous floaters all reported.

Regeneron is looking to evaluate the decision made by the FDA in order to address any issues that the FDA had with the application in order to move forward, as the CRL did not specify any issues with aflibercept in its current dosing intervals. High-dosage aflibercept will continue to be available to patients with AMD and DME in its current form.

References

1. Regeneron provides update on Eylea HD (aflibercept) injection 8 mg supplemental biologics license application. News release. Regeneron; April 18, 2025. Accessed April 21, 2025. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-eylea-hdr-aflibercept-injection-8-mg
2. Jeremias S. FDA approves higher-dose version of aflibercept. AJMC^®. August 31, 2023. Accessed April 18, 2025. https://www.ajmc.com/view/fda-approves-higher-dose-version-of-aflibercept
3. 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. News release. Regeneron; February 8, 2025. Accessed April 18, 2025. https://investor.regeneron.com/news-releases/news-release-details/three-year-results-eylea-hdr-aflibercept-injection-8-mg-patients
4. Two-year results for aflibercept 8 mg from pivotal PHOTON trial demonstrate durable vision gains at extended dosing intervals in diabetic macular edema. News release. Regeneron; June 27, 2023. Accessed April 18, 2025. https://investor.regeneron.com/news-releases/news-release-details/two-year-results-aflibercept-8-mg-pivotal-photon-trial