Is Combination Therapy on the Horizon in Diabetic Macular Edema?

Diabetic macular edema, or DME, affects an estimated 746,000 people in the United States. DME is a form of vision loss caused by diabetic retinopathy, a complication of diabetes.

The standard of care in recent years has been anti-VEGF therapy, with Eylea (aflibercept, Regeneron) overtaking Lucentis (ranibizumab, Roche/Genentech) after 2015 based on results of the NIH-funded Protocol T study, which showed Eylea’s superiority.

However, anti-VEGF therapy only targets one pathway, known as VEGF-A; if it upregulated it may stimulate the growth of blood vessels, causing fluid accumulation that threatens vision. If patients also have elevated levels VEGF-C or VEGF-D, they may experience persistent or refractory DME.

Now, treatment for DME may go the route seen in other chronic conditions: the next step may be combination therapy, which targets more than one pathway at the same time.

Recently, the biologics drug developer Opthea reported results of a phase 2a trial for OPT-302, an experimental therapy being developed to work in tandem with existing treatments that target anti-VEGF-A. The study is a randomized, double-masked, sham-controlled clinical trial designed to show proof-of-concept; it involved 144 participants at 53 sites in the United States, Israel, Australia, and Latvia. All had persistent DME despite regular anti-VEGF treatment.

The patients were randomized 2:1 to receive a combination of OPT-302 with Eylea, or a sham dose with Eylea. Study doses were given by injection once every 4 weeks, with 3 doses given through week 12. In June, Opthea announced that the study achieved its primary end point, with 52.8% of the patients (95% CI, 41%-64%) in the group taking the combination of OPT-302 and Eylea gaining at least 5 letters of Best Corrected Visual Acuity (BCVA) at week 12. The trial protocol called for meeting a response rate of at least 38% gaining at least 5 letters BCVA in the initial dosing period.

Initial reaction was mixed, because overall, 60% of the patients in the Eylea-only control group achieved the standard of gaining at least 5 letters BCVA at week 12. However, the share of patients who gained at least 10 letters BCVA from baseline to week 12 was 26.7% in the combination group and 22.5% in the Eylea control group. Also:

• 12% of the combination group patients and 7.5% the Eylea-only patients gained at least 15 letters
• The percentage that lost 5 or more letters was 2.7% in the combination group, vs 5% in the Eylea-only group.

Additional results suggest the results are especially promising for patients who are taking Eylea and add OPT-302. Researchers looked at results for a subset of patients who had previously been treated with Eylea, vs. a different anti-VEGF therapy. The mean visual acuity gain at week 12 was 8.6 letters for those treated with the combination dose vs 5.0 letters for those who continued on Eylea only. Taking the combination helped 50% of this group gain at least 10 letters by week 12, with 16.7% gaining at least 15 letters.

The trial is ongoing, and patients have recently completed the 24-week follow-up visit. That data will be reported later in 2020. In their June statement, Opthea officials said a phase 3 trial is planned in another ocular condition, wet age-related macular degeneration (AMD).

“With limited treatment options currently available and many patients who do not adequately respond to anti-VEGF-A therapies, there remains a significant unmet need for more efficacious and durable therapies for DME,” study investigator David Boyer, MD, senior partners in the Retina Vitreous Associates Medical Group, Los Angeles, and clinical professor at the University of Southern California Roski Eye Institute, said in a statement. Adding OPT-302 to Eylea to improve vision for these hard-to-treat patients, “would be significant,” he said.