Regeneron said results from two phase 2 studies that added the angiopoietin2 (Ang2) antibody nesvacumab to the anti-VEGF Eylea (aflibercept; Regeneron) injection did not provide sufficient differentiation to warrant phase 3 development. The RUBY study evaluated patients with DME and the ONYX study evaluated patients with wet AMD. Eylea results were consistent with findings in previous clinical studies. There were no new safety signals in these studies.
"We knew from the start that it would be difficult to improve on the already high bar set by Eylea, which is the market-leading branded therapy in its approved indications, providing significant improvements in vision and strong long-term outcomes in patients with wet AMD and DME," said George D. Yancopoulos, MD, PhD, President and Chief Scientific Officer, Regeneron. "We expect to report results in the first half of 2018 from our Eylea Phase 3 study in diabetic retinopathy, which represents a growing patient population with significant need. We also continue to invest in additional R&D approaches in ophthalmology with the goal of providing new innovations to patients with serious vision-threatening diseases."
RUBY and ONYX were two randomized, double-masked, active-controlled phase 2 studies designed to investigate if a combination of aflibercept and nesvacumab offered additional benefit over aflibercept monotherapy. The studies evaluated two different doses of nesvacumab in combination with aflibercept, both administered as a single coformulated intravitreal injection, as well as aflibercept monotherapy. The primary endpoint for both trials was change in BCVA between week 12 and 36 as measured by the Early Treatment Diabetic Retinopathy Study letter score.
Results from RUBY and ONYX will be further analyzed and will be submitted for presentation at a future medical congress.
Genentech and Aerpio are also conducting clinical trials that include an Ang2 component but Pravin Dugel, MD, of Retinal Consultants of Arizona, cautioned that no conclusions should be drawn on the Genentech and Aerpio studies based on the disappointing Regeneron data.
“The other two drugs have different MOAs (mechanisms of action),” said Dr. Dugel.
The failure of Regeneron's ONYX and RUBY trials is a disappointment to all retina specialists hoping to expand on the efficacy of anti-VEGF therapeutics, said Paul A. Yates, MD, PhD, associate professor of ophthalmology and bioengineering and director of retina services at the University of Virginia.
"Dual targeting of Ang2 and VEGF is a rational approach, based on preclinical studies, to potentially improve treatments for DME and wet AMD. It will be interesting to examine the raw data from this trial to gain insight into the specifics of this particular failure and whether benefit is perhaps suggests for any subgroups of patients," said Dr. Yates. Although without seeing the specific data it is difficult to reach any conclusion, he said, the generally high bar set by anti-VEGF agents is an obvious culprit. "One also cannot rule out that the specific formulation of Ang2 and VEGF inhibition might matter, given the favorable phase I results reported for Roche's Ang2/VEGF bispecific antibody. Notably, in that study patients with wet AMD specifically refractory to anti-VEGF were enrolled, with evidence of BCVA and anatomic improvement," he added.