Regeneron said today it has halted codevelopment with Bayer of a therapy combining the companies’ marketed treatment Eylea® (aflibercept) and Regeneron’s nesvacumab—an up-to-$130 million-plus collaboration launched last year—following the combination’s failure in a pair of Phase II trials in eye disorders.
The combination “did not provide sufficient differentiation to warrant Phase III development” compared with Eylea alone in the two trials, Regeneron stated. The Eylea–nesvacumab combination was assessed in the RUBY trial (NCT02712008), which evaluated patients with diabetic macular edema (DME), as well as the ONYX study (NCT02713204), which evaluated the combo in patients with wet age-related macular degeneration (wet AMD).
Eylea results were consistent with findings in previous clinical studies, according to Regeneron, which added that results from RUBY and ONYX will be further analyzed and submitted for presentation at an unspecified future medical congress.
RUBY enrolled 304 patients and ONYX enrolled 265. The studies evaluated two different doses of nesvacumab in combination with Eylea, both administered as a single coformulated intravitreal injection, as well as aflibercept monotherapy. The primary endpoint for both trials was change in best-corrected visual acuity (BCVA) between weeks 12 and 36 as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score.
“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,” Regeneron president and CSO George D. Yancopoulos, M.D., Ph.D., said in a company statement.
Eylea is a vascular endothelial growth factor (VEGF) trap that Regeneron and Bayer have partnered to develop and commercialize globally under the name Eylea. The drug is approved for wet AMD, DME, diabetic retinopathy in patients with DME, and macular edema following retinal vein occlusion.
Since its launch as a wet AMD treatment on November 21, 2011, Eylea has grown into a blockbuster for Regeneron and Bayer, generating just over $5 billion in combined sales for both companies last year—ranking No. 12 on GEN’s list of the Top 15 Best-Selling Drugs of 2016—and $4.368 billion in combined sales in the first nine months of 2017, up 12.5% from a year ago.
Regeneron and Bayer agreed in March 2016 to develop the Eylea–nesvacumab combination as well as other combination therapies for eye diseases, citing preclinical data that showed angiopoietins act together with the VEGF family to promote the formation and maturation of blood and lymphatic vessels in the eye. Angiopoietins are a family of vascular growth factors discovered by Regeneron.
“Inhibiting the angiopoietin 2 pathway is a promising new approach for a combination therapy, and we are looking forward to working on it together with Regeneron,” Jörg Möller, M.D., member of the executive committee of Bayer's Pharmaceuticals Division and head of development, said in a statement announcing the collaboration.
Bayer agreed to pay Regeneron $50 million upfront while the companies agreed to share global development costs, with Regeneron also eligible for up to $80 million in payments tied to achieving development and regulatory milestones.
The failure of the Eylea–nesvacumab combination marks Regeneron’s latest setback in 14 months tied to candidates designed to improve on Eylea. In September 2016, the company acknowledged that a combination of Eylea and the anti-platelet-derived growth factor receptor beta antibody rinucumab did not improve on the efficacy of aflibercept alone in a Phase II study.
And twice this year, Novartis announced positive results for its eye treatment candidate RTH258 (brolucizumab) in the HAWK and HARRIER Phase III trials. On June 20, Novartis first reported that RTH258 met its primary and key secondary efficacy endpoints in a pair of Phase III studies—noninferiority of RTH258 to Eylea in mean change in BCVA from baseline to week 48, and average mean change over the period of weeks 36 to 48.
On November 10, Novartis added that RTH258 also showed superiority in key retinal health outcomes, including intraretinal fluid (IRF) and/or subretinal fluid (SRF) and central subfield thickness—as well as a long-lasting effect in patients with neovascular age-related macular degeneration (nAMD).
In today’s statement, Dr. Yancopoulos added that Regeneron expects to report results in the first half of 2018 from a Phase III study of Eylea in diabetic retinopathy, “which represents a growing patient population with significant need.”