High-Dose, Extended Duration Aflibercept Injections Benefit Patients With DME, nAMD

A higher dose of aflibercept (Eylea) with longer time between injections sustains improvements in visual acuity with no safety signals, according to results from 2 pivotal trials presented at the annual meeting of the American Academy of Ophthalmology (AAO).

PHOTON and PULSAR evaluated the use of 8-mg aflibercept every 12 or 16 weeks compared with the traditional dosing of 2 mg every 8 weeks. Researchers presented the 48-week results that showed both PHOTON, with patients who have diabetic macular edema (DME), and PULSAR, with patients who have neovascular age-related macular degeneration (nAMD), met their primary end points.

Aflibercept is a vascular endothelial growth factor (VEGF) inhibitor delivered via intravitreal injection and is currently approved in the 2 mg formulation.

“…our current VEGF drugs, while great and revolutionary, often require monthly or near monthly dosing to control diabetic macular edema,” David M. Brown MD, a retina surgeon with the Retina Consultants of Texas, explained during his presentation on the results of PHOTON.

The trial was an international study with 650 patients randomized 1:2:1 to 2 mg of aflibercept every 8 weeks after 5 initial monthly injections (n = 167) or 8 mg of aflibercept given either every 12 weeks (n = 328) or every 16 weeks (n = 163) after 3 initial monthly injections.

The primary end point was a mean change in Best Corrected Visual Acuity (BCVA) score.

Patients in the 8-mg groups with a 10-letter loss and a 50-micron increase in centralized retina thickness from week 12 had their dose shortened to either 12 or 8 weeks.

At baseline, 43.8% of all patients had prior treatment for DME, mostly anti-VEGF therapy. Based on the Diabetic Retinopathy Severity Score, 62.2% of patients had mild severity and 32.4% were severe.

At the end of the trial, the researchers found all 3 groups had a robust increase in visual acuity:

• Increase of 9.2 letters for the 2-mg groups
• Increase of 8.8 letters for the 8-mg-every-12-weeks group
• Increase of 7.9 letters for the 8-mg-every-16-weeks group

According to Brown, a big, but pleasant surprise, was most patients maintained their dosing intervals. In the 8-mg-every-12-weeks group, 91% of patients maintained their interval, and 89% maintained the 16-week interval. Combined, 93% of patients remained on dosing intervals 12 or more weeks, he said.

There were no significant safety signals, with 31.0% of patients receiving an 8-mg dose experience 1 or more adverse events (AEs) compared with 27.5% of patients receiving the 2-mg dose. The most common AE across all groups was conjunctival hemorrhage (4.1% for the 8-mg groups vs 3.6% for the 2-mg group).

Only 15.1% of patients, overall, had nonocular serious AEs through week 48, although Brown noted that there was no increase in hypertension with the increased 8-mg anti-VEGF dose.

Ultimately, the PHOTON trial showed the noninferiority of the 8-mg dose given either 12 or 16 weeks despite greatly increased dosing intervals.

“We hope to get this benefit out to our patients in the coming future,” Brown concluded.

PULSAR was a multicenter, randomized, double-masked study with patients randomized 1:1:1 to receive 2 mg every 8 weeks (n = 336), 8 mg every 12 weeks (n = 335), or 8 mg every 16 weeks (n = 338). All of the groups received 3 initial monthly injections, explained presenter Paolo Lanzetta, MD, Department of Medicine – Ophthalmology, University of Udine, and Instituto Europeo di Microchirurgia Oculare.

PULSAR followed the same dosing modification as PHOTON. The 2 primary end points were mean change in BCVA at week 48 and the proportion of patients without fluid in the center subfield at week 16.

Similar to PHOTON, there was an increase in visual acuity for patients in PULSAR:

• Increase of 7.6 letters for the 2-mg group
• Increase of 6.7 letters for the 8-mg-every-12-weeks group
• Increase of 6.2 letters for the 8-mg-every-16-weeks group

A higher proportion of patients receiving the 8 mg doses had no fluid in the center subfield at week 16: 83% for both 8-mg groups vs 52% for the 2 mg-group (P = .0002).

The PULSAR study found the proportion of patients maintaining the dosing interval remained high, although not as high as the PHOTON study. In PULSAR, 83% of patients maintained a dosing interval of 12 weeks or greater.

There were also no safety signals in the PULSAR study, with 38.0% of all patients on 8 mg and 38.7% of patients on 2 mg experiencing 1 or more AEs. The most common AE was visual acuity reduction (4.5% for 8-mg groups vs 6.0% for 2 mg).

Overall, the results of PULSAR were very encouraging for an extended duration, high-dose regimen of aflibercept, Lanzetta said.

"Our presentations at AAO demonstrate that aflibercept 8-mg 12- and 16-week dosing regimens have achieved a high bar, sustaining improvements in visual acuity and anatomic measures of retinal fluid across 48 weeks in patients with diabetic macular edema and wet age-related macular degeneration," George D. Yancopoulos, MD, PhD, president and chief scientific officer at Regeneron, and a principal inventor of aflibercept, said in a statement. "These results were all achieved in patients who were rapidly initiated on extended dosing intervals with the vast majority not requiring regimen modification. Altogether, the pivotal data support aflibercept 8 mg as providing a longer duration of action while maintaining a safety profile similar to Eylea."