DUBLIN Novartis AG gained FDA approval for its VEGF-A inhibitor Beovu (brolucizumab) in wet age-related macular degeneration (AMD) a week ahead of its presumed PDUFA date.

The Basel, Switzerland-based pharma used a priority review voucher to speed up the review process, which kicked off on April 15. The stage is now set for what could be an eye-catching – pun intended – contest between Beovu, a single-chain antibody fragment that binds all VEGF-A isoforms, and Eylea (aflibercept), the VEGF trap that has developed into a multibillion-dollar behemoth straddling several ophthalmic indications since its original approval for treating wet AMD in November 2011.

Novartis is slightly undercutting Tarrytown, N.Y.-based Regeneron Pharmaceuticals Inc.'s current list price for Eylea on a per-vial basis, although its competitive positioning is not solely based on price. "Beovu is differentiated clinically from other anti-VEGFs indicated for the treatment of wet AMD in the U.S. but will still be priced competitively. List price is $1,850 per vial," Novartis spokesman Eric Althoff told BioWorld by email.

Eylea costs $1,941 per vial. It has a recommended introductory dosing regimen of one intravitreal injection every four weeks for three months, followed by injections every eight weeks thereafter. For patients with bilateral wet AMD – affecting both eyes – initial costs can run to about $31,000 over the course of a year, based on the recommended introductory regimen of injections every four weeks for the first three months, followed by injections every eight weeks thereafter. The Beovu label offers patients either eight-week or 12-week regimens, after a similar three-month induction period involving monthly doses, but it does not stipulate which course patients should follow.

The two drugs work by the same essential mechanism, blocking the formation of new blood vessels during the neovascular or advanced stage of wet AMD, which can lead to rapid loss of central vision. Beovu gained FDA approval on the basis of two phase III trials, Hawk and Harrier, in which it attained the primary endpoint of noninferiority vs. Eylea in mean change in best corrected visual acuity from baseline at week 48 of each study. In each study, more than half of the patients on Beovu (56% in Hawk and 51% in Harrier) were maintained on a three-month dosing interval.

The biggest issue for analysts was a previously undisclosed imbalance in the rates of intraocular inflammation (IOI) between those treated with Beovu during the Novartis pivotal phase III program and those in the control arm, who received Eylea. "Although the [adverse event] rate for Beovu was known, the 4x incidence of IOI in the label (4% vs. 1% for Eylea) could be a key differentiator between the two treatments," Cory Kasimov, analyst at J.P. Morgan, wrote in an investor note.

SVB Leerink's Geoffrey C. Porges concurred: "This is likely to be the main defense used by Regeneron to retain share for Eylea in this indication," he wrote in an investor note. "Intraocular inflammation is a major concern for retinal specialists and a key factor in the treatment selection. Physicians are more likely to continue to use the two approved drugs Eylea and Lucentis until Novartis can provide additional data or evidence to address this issue."

The adverse event profile of the drugs does not otherwise differ greatly, although in Beovu's favor, it appeared to cause less occurrence of cataracts than did Eylea (7% vs. 11%). Beovu elicits immunogenicity concerns as well, however: "Beovu also appears to be associated with an increased rate of anti-drug antibodies, which has uncertain significance," Porges noted. That may have arisen from the rabbit origin of the drug's complementarity determining region, even though it has undergone humanization. Beovu's roots lie in Esbatech, a Swiss antibody developer, which Alcon Inc. acquired a decade ago for just $150 million up front plus up to $439 million more in R&D milestones. That was just before Novartis became the outright owner of Alcon, and it retained the latter organization's pharmaceuticals business when it spun out the medical device maker as an independent entity this year. The present approval does not entail any residual payment to former Esbatech shareholders, Althoff confirmed.

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