Shortly before the 2022 American Academy of Ophthalmology annual meeting, positive 1-year data from the PULSAR and PHOTON trials read out.¹ These trials investigated the clinical efficacy and safety of 8 mg aflibercept relative to 2 mg aflibercept in both AMD and DME. The trial design was a noninferiority study with the implied “superiority” manifesting as equal efficacy at longer treatment durations. We are fortunate as a retina community to already have FDA-approved faricimab (Vabysmo; Genentech) that has demonstrated efficacy at 12-week and 16-week intervals relative to aflibercept 2 mg administered every 8 weeks. Brolucizumab (Beovu; Novartis) also falls into this category, but widespread adoption of this drug is not viable given the rare but severe side effects of irrevocable occlusive vasculitis.

To make the pool of next generation of AMD and DME drugs more interesting, Dr. Lanzetta and Dr. Brown presented spectacular 1-year results from the Phase 3 PULSAR and PHOTON studies, respectively. In this issue, we have asked these investigators to share an overview of each study’s design and their interpretation of the results.

The PULSAR Trial of 8-mg Aflibercept in Wet AMD

PAOLO LANZETTA, MD

At the recent retina subspecialty day of the American Academy of Ophthalmology, I had the opportunity on behalf of the study investigators to present the phase 3 PULSAR clinical trial, which was conducted in patients with exudative age-related macular degeneration.^2,3 The study was designed to evaluate the clinical efficacy and safety of high-dose aflibercept 8 mg administered in 12-week (8q12) and 16-week (8q16) arms and compare those groups to aflibercept 2 mg (Eylea; Regeneron) in a fixed 8-week regimen (2q8), all after 3 initial monthly doses.

Overall, 1,009 patients (8q12: n=335; 8q16: n=338; 2q8: n=336) were randomly assigned 1:1:1 to 1 of 3 dosing schedules without any preselection to reflect real-world patients. In the first year of the study, patients in the high-dose arms not suitable under initial assigned treatment interval could be shortened without possibility to return to extended intervals. Therefore, the most appropriate interval was adjusted for the individual patient.

At 48 weeks, both high-dose treatment arms had noninferior best corrected visual acuity (BCVA) gains compared to aflibercept 2 mg. Mean BCVA change from baseline was +6.2 letters in the 16-week arm, +6.7 letters in the 12-week arm, and +7.6 letters in the 2 mg 8-week arm. PULSAR also met its key secondary endpoint, demonstrating superiority of aflibercept 8 mg in improving anatomic outcomes of retinal fluid. At week 16, 62% of 8q12 patients and 65% of 8q16 patients had no retinal fluid in the center subfield, compared to 52% for 2q8 patients (P=.0002).

In the 8q12 group, 79% (n=316) of patients maintained 12-week treatment intervals, and 77% (n=312) of patients in the 8q16 group maintained 16-week treatment intervals at 48 weeks. Overall, 83% (n=628) of patients receiving aflibercept 8 mg maintained ≥12-week treatment intervals. The safety of aflibercept 8 mg was similar to the safety profile of aflibercept 2 mg.

The PULSAR trial demonstrated clinicial efficacy of 8 mg aflibercept relative to 2 mg aflibercept in the form of longer duration and improved drying. This could offer great benefits to patients as well as their families and caregivers.

The PHOTON Study of 8-mg Aflibercept in Diabetic Retinopathy

DAVID BROWN, MD

Despite the efficacy of anti-VEGF medications for diabetic retinopathy, there are still a number of patients that have so much VEGF production due to their underlying disease that even the strongest available drugs aren’t effective enough, or require very frequent injections. For that reason, we thought there was a possibility we were not at the top of the dose-response curve. I had recommended that Regeneron consider testing a higher dose of aflibercept, and that’s what the PHOTON trial did. The highest dose possible because of solubility is an 8-mg dose in 70 μL. A typical anti-VEGF injection is 50 μL, so this is a slightly larger volume going into the eye. The phase 2 trial results were promising, so we tested it in a bigger population in phase 3.

The phase 3 PHOTON trial randomized patients to either 5 doses of 2 mg aflibercept monthly followed by every 8 week injections or 1 of 2 arms receiving 8 mg of aflibercept either every 12 weeks or every 16 weeks after 3 monthly loading doses.^4,5 The 2-mg aflibercept group received 5 loading doses and the 8-mg aflibercept groups received 3 loading doses. In the experimental arms, we monitored patients’ OCT and BCVA, and if they had fluid and a loss of 1 line of visual acuity, we would switch them to more frequent injections.

The primary outcome was the difference in visual acuity among the groups, and not only were the 8-mg groups statistically noninferior, but all of the visual acuity curves were right on top of one another, showing that you could treat patients far less frequently with 8 mg and still get a great result. What really surprised us was how many patients could stay on 12-week or 16-week dosing. It turns out 90% of patients stayed at 12-week dosing, and more than 80% stayed on 16-week dosing. It’s surprising that we could treat this population with only a load of 3 doses, as opposed to 5 with the control, and get similar outcomes.

What we didn’t show in this presentation and that I think will be very helpful is that it’s possible that this agent will help to control disease in very hard-to-treat patients. I think they won’t go 12 weeks or 16 weeks, but we’re not controlling them currently with 4-week intervals. If we can get them under control, we’ll certainly get better outcomes and better long-term results.

From a safety perspective, if you give anti-VEGF drugs in large systemic doses, like for chemotherapy, they cause hypertension and an increase in heart attack and stroke. So, we were concerned that, in this microvascular diabetic population that has a propensity to heart attack and stroke, we might see increased systemic toxicity or safety concerns. However, there was no increase in hypertension, heart attack, or stroke in our 8-mg arms relative to the 2-mg arm.

In practical terms, retina specialists will likely use 8-mg aflibercept in a treat-and-extend fashion, and patients will get 2 more half-lives longer than with a 2-mg dose of aflibercept. The reason that I think that some patients need monthly therapy and others need 8-week therapy or 10-week therapy is that some patients clear drug faster. If a patient clears one drug faster, they clear them all faster. The half-life of aflibercept, on average, is about 9 or 10 days. Therefore, on average, 8-mg aflibercept is going to increase a treat-and-extend interval probably by 3 weeks. There is a portion of the population for whom the drug has a half-life of 14 or 15 days. Those patients might go a month or 6 weeks longer with 8-mg aflibercept. The population that needs an injection every month probably has a half-life of 4 or 5 days. They may only get 1 or 2 weeks more, but that’s a big difference for them. For example, if a patient has to come to my clinic 13 times a year and they or a family member have to take off work, it makes a big difference when that number is reduced to 8 or 9 times a year.

What we don’t know is how 2-mg aflibercept and 8-mg aflibercept will be used in tandem, if both are available. It has yet to be determined which dose will work best for which patients, and how often. It’s possible that some will start with 2 mg and some will start with 8 mg. Part of the decision will likely be made around pricing and insurance coverage. Regeneron and Bayer will be filing for approval likely in the next year. RP

REFERENCES

1. Regeneron. Aflibercept 8 mg positive pivotal results in diabetic macular edema and wet age-related macular degeneration presented at AAO. News release. September 30, 2022. Accessed November 29, 2022. https://investor.regeneron.com/news-releases/news-release-details/aflibercept-8-mg-positive-pivotal-results-diabetic-macular-edema
2. Study to gather information on safety and use of high dose aflibercept injection into the eye in patients with an age related eye disorder that causes blurred vision or a blind spot due to abnormal blood vessels that leak fluid into the light sensitive lining inside the eye (PULSAR). Clinicaltrials.gov identifier: NCT04423718. Updated October 14, 2022. Accessed November 29, 2022. https://clinicaltrials.gov/ct2/show/NCT04423718
3. Lanzetta P. Intravitreal aflibercept injection 8 mg for nAMD: 48-week results from the phase 3 PULSAR trial. Presented at American Academy of Ophthalmology 2022 annual meeting, September 30-October 3, 2022. Accessed November 29, 2022. https://investor.regeneron.com/static-files/e3307e7d-d495-438c-b8bb-c62cdacdb375
4. Study of a high-dose aflibercept in participants with diabetic eye disease (PHOTON). ClinicalTrials.gov Identifier: NCT04429503. Updated Novebmer 4, 2022. Accessed November 29, 2022. https://clinicaltrials.gov/ct2/show/NCT04429503
5. Brown DM. Intravitreal aflibercept injection 8 mg for DME: 48-week results from the phase 2/3 PHOTON trial. Presented at American Academy of Ophthalmology 2022 annual meeting, September 30-October 3, 2022. Accessed November 29, 2022. https://investor.regeneron.com/static-files/da20405e-b843-402e-855b-d824a15dec60