High-Dose Aflibercept in Wet AMD and DME Provides Therapeutic Benefits, No New Safety Signals

An increased dose of 8 mg aflibercept, up from 2 mg, can provide greater therapeutic benefit for patients with diabetic macular edema (DME) and wet age-related macular degeneration (AMD) and an extended injection interval without any new safety signals, according to 2 presentations at the Angiogenesis, Exudation, and Degeneration 2023 meeting, held virtually February 10-11, 2023.

Aflibercept is a vascular endothelial growth factor (VEGF) inhibitor that is currently approved in the United States as a 2-mg dose for patients with wet age-related macular degeneration (AMD), macular edema following retinal vein occlusion, DME, and diabetic retinopathy.

David M. Brown, MD, a retina surgeon with Retina Consultants of Texas, presented the results of the PULSAR study (NCT04423718), an ongoing, double-masked, 96-week, phase 3 trial in patients with wet AMD. The global study had 223 sites in 26 countries. The purpose was to evaluate a novel intravitreal formulation delivery of 8 mg of aflibercept in a slightly higher volume.

The higher dose “should give us 2 extra half-lives and a longer effective vitreous concentration and enable more sustained effect on VEGF signaling,” Brown explained.

Patients 50 years or older with wet AMD were randomly assigned to receive either 8 mg aflibercept every 12 weeks (8q12; n = 335), 8 mg aflibercept every 16 weeks (8q16; n = 338), or 2 mg aflibercept every 8 weeks (2q8; n = 336).

The primary end point at week 48 was mean change in Best Corrected Visual Acuity (BCVA) and a secondary end point at week 16 was the proportion of patients without intraretinal fluid and subretinal fluid in the center subfield.

The study had dose regimen modification criteria for shortening the dosing interval: greater than 5-letter loss and greater than 25-μm increase in central retina thickness (CRT) or new-onset foveal neovascularization or foveal hemorrhage. Patients who met this criteria would have the dosing interval shortened from 16 weeks to 12 weeks or from 12 weeks to 8 weeks.

“It was a one-way subway,” Brown said. “In other words, once you went down a dose then you never got escalated back up.”

The mean number of injections for the 8q16 arm was 5.2, the mean for 8q12 was 6.1 injections, and the mean for 2q8 was 6.9 injections. BCVA change from baseline was similar among the arms at +7.6 letters for the 2q8 arm, +6.7 letters for the 8q12 arm, and +6.2 letters for the 8q16 arm.

The average patient had a fluid-free center subfield by the first dose, and by the third dose, approximately 80% of patients were fluid free.

Overall, 83% of all patients on the 8-mg dose maintained dosing intervals at 12 weeks or greater:

• 79% of patients in the 8q12 arm maintained dosing
• 77% of patients in the 8q16 arm maintained dosing
• 11% of patients in the 8q16 arm moved down to 8q12 and maintained dosing

There were no new safety signals, and the safety of the 8-mg doses was consistent with the 2-mg dose. Despite the increased volume of the formulation, there was no increase in pressure problems and despite the higher protein levels, there was little difference in intraocular inflammation: 0.6% for the 2-mg dose vs 0.7% for all 8-mg doses.

David Boyer, MD, senior partner at Retina Vitreous Associates Medical Center, presented the results of the PHOTON study (NCT04429503), which had a similar design to PULSAR: it is an ongoing 96-week, double-masked, noninferiority trial. The global study involved 138 sites in 7 countries.

Patients were randomized to receive aflibercept 8q12 (n = 328), 8q16 (n = 163), or 2q8 (n = 167). Patients in the 8q12 and 8q16 arms would scale down dosing intervals if they met the dose regimen modification criteria: greater than 10-letter loss in BCVA and greater than 50-micron increase in CRT. As in PULSAR, patients only had their dosing intervals shortened and not lengthened.

The primary end point at week 48 was the mean change from baseline in BCVA, while thethe key secondary endpoint at week 48 was the proportion of patients with at least a 2-step improvement in Diabetic Retinopathy Severity Scale (DRSS) score.

At week 48 the mean BCVA change from baseline was +9.2 letters for 2q8, +8.8 letters for 8q12, and +7.9 letters for 8q16. At the same time period, 27% in the 2q8, 29% in the 2q12, and 20% in the 2q16 had at least a 2-step improvement from baseline in DRSS score.

Similar to PULSAR, a high proportion of patients maintained their dosing by week 48. Overall, 93% of the patients maintained 8 mg at a dosing interval of at least 12 weeks. In the 8q12 group, 91% maintained their original dosing interval and in the 2q16 group, 89% maintained their original dosing interval.

Boyer did note that this improvement “was much less than what we would have expected” based on previous studies. However, the study had a large group (>60%) of patients who “had very small levels of DRSS that usually don’t progress.” When looking at the patients with a DRSS score of 47 or worse, the 2-step improvement echoed other studies with 63% to 77% of patients gaining 2 lines of the DRSS level.

PULSAR was sponsored by Bayer and cofunded by Regeneron, and PHOTON were sponsored by Regeneron. Aflibercept is jointly developed by Regeneron and Bayer. Brown serves as a scientific advisor for both Regeneron and Bayer. Boyer has served as a consultant for both Bayer and Regeneron.