Aflibercept Injection Reduced Risk of Developing Vision-Threatening Events by 75% After Two Years in Patients with Diabetic Retinopathy

Regeneron Pharmaceuticals, Inc announced positive two-year results from the Phase 3 PANORAMA trial evaluating EYLEA (aflibercept) Injection 2 mg (0.05 mL) in patients with moderately severe to severe non-proliferative diabetic retinopathy (NPDR). The data were presented today for the first time at the Angiogenesis, Exudation, and Degeneration 2020 meeting in Miami, Florida.

The two-year pre-specified exploratory data demonstrate that untreated moderately severe and severe NPDR can lead to vision-threatening events, which includes vision-threatening complications (VTCs; proliferative diabetic retinopathy or anterior segment neovascularization) and center-involved diabetic macular edema (CI-DME). Based on a Kaplan-Meier analysis, more than half (58%) of patients in the untreated sham arm developed a VTC or CI-DME within two years of entering the trial, while EYLEA treatment was shown to reduce the likelihood of these vision-threatening events by at least 75% (nominal p<0.0001).

“These data reinforce that regular EYLEA treatment can be highly effective at reducing the risk of new vision-threatening events among patients with moderately severe to severe non-proliferative diabetic retinopathy,” said Charles C. Wykoff, M.D., Ph.D., PANORAMA investigator, retina surgeon and ophthalmologist with Retina Consultants of Houston. “The PANORAMA trial shows that more than half of all untreated patients developed vision-threatening events over two years, underscoring the value of treating patients proactively and regularly.”

The two-year results also showed a greater benefit for EYLEA patients treated at regular intervals compared to patients who received EYLEA treatment less frequently. Per the protocol, the group of trial patients who received EYLEA every 8 weeks in the first year were switched to receive it when their doctor determined they needed it (called pro re nata, or PRN) in the second year (i.e., the 8-week/PRN group). The proportion of these patients with a >2-step improvement from baseline in Diabetic Retinopathy Severity Scale (DRSS) scores decreased in the second year (80% improvement at 52 weeks and 50% at 100 weeks).* By comparison, in patients who continued to receive EYLEA every 16 weeks (i.e., the 16-week group), the >2-step DRSS scores remained consistent (65% at 52 weeks vs. 62% at 100 weeks).* In the second year, patients received an average of 1.8 injections in the 8-week/PRN group (out of a possible 6); a review of data from the independent reading center of investigator PRN decisions suggests that some of these patients may have been under-dosed based on the protocol rules of the trial. Patients in the 16-week group received 2.6 injections (out of a possible 3) in the second year.

During the 2-year PANORAMA trial, adverse events were consistent with the known profile of EYLEA. Serious ocular adverse events in the study eye occurred in 2% and 0% of the EYLEA 8-week/PRN and 16-week groups, respectively, and 2% of patients in the sham group. Ocular inflammation occurred in 2% and 1% of patients in the EYLEA treatment groups, respectively, and 1% of patients in the sham group. Anti-platelet trialists’ collaboration (APTC)-defined arterial thromboembolic treatment emergent events occurred in 3% and 6% of patients in the EYLEA treatment groups, respectively, and 5% of patients in the sham group.

*p<0.0001 at 52 weeks; nominal p<0.0001 at 100 weeks, as all prespecified endpoints at 100 weeks are considered exploratory.

High-Dose Aflibercept Update 
Also presented today was the rationale for high-dose (8 mg) aflibercept clinical trials. A Phase 2 trial (CANDELA) evaluating high-dose aflibercept in wet age-related macular degeneration (wet AMD) is currently enrolling. Phase 3 trials planned to start in 2020 in wet AMD (PULSAR, sponsored by Bayer) and DME (PHOTON, sponsored by Regeneron) will evaluate dosing intervals of 12 weeks and longer.

“Through millions of injections and eight pivotal Phase 3 trials, EYLEA has built a substantial body of evidence and safety profile. High-dose aflibercept will hopefully build on this standard-of-care therapy and represents our ongoing commitment to ophthalmologic research and development,” said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer at Regeneron. “We are eager to explore the potential of high-dose aflibercept to deliver sustained vision gains and extended duration of action in patients with wet AMD and DME.”

The potential use of high-dose aflibercept is currently under clinical development and the safety and efficacy for this use have not been fully evaluated by any regulatory authority.

About the PANORAMA trial
The U.S. Food and Drug Administration (FDA) approval of EYLEA to treat diabetic retinopathy was based on six-month and one-year results from PANORAMA, a randomized, multi-center, controlled Phase 3 trial that enrolled 402 patients and was designed to investigate EYLEA for the improvement of moderately severe to severe NPDR without DME, compared to sham injection. PANORAMA is the first prospective trial to study whether vascular endothelial growth factor (VEGF) inhibition can also help prevent worsening disease in patients with NPDR without DME.

Details on trial design included:

• Three treatment arms – an observational sham injection group and two EYLEA treatment groups. EYLEA was dosed every eight weeks (following five initial monthly doses) or every 16 weeks (following three initial monthly doses and one 8-week interval). At week 52, the 8-week interval group switched to as needed (PRN) dosing determined by the investigator. All patients were followed to week 100.
• Primary endpoint – the primary endpoint was the proportion of patients who experienced a 2-step or greater improvement in the DRSS score from baseline for the combined EYLEA treatment groups at week 24, and for each EYLEA treatment group separately (every 8-week group and every 16-week group) at week 52. The DRSS is a systematic grading scale to assess diabetic retinopathy severity based on photographs of the retina.
• Secondary endpoints – the secondary endpoints included assessment of whether EYLEA reduced the risk of worsening disease – specifically progression to PDR (including anterior segment neovascularization [ASNV]) or the development of CI-DME – as well as change in visual acuity, through week 52.
• Exploratory endpoints – all prespecified endpoints at week 100 (year two) are considered exploratory.

One-year results from PANORAMA were previously reported in October 2018 and February 2019. A separate ongoing trial sponsored by the Diabetic Retinopathy Clinical Research Network known as Protocol W is also evaluating EYLEA for the treatment of NPDR in patients without DME.