Eylea breezes through adcom and looks ahead to approval

Eylea cleared its first major regulatory hurdle with ease. The unanimous support of FDA expert panellists, a vote largely anticipated following strong clinical data and benign staff briefing documents, builds expectation that the Regeneron Pharmaceuticals eye drug will be approved for macular degeneration in August and bid for the crown of market leader Lucentis.

Although shares in Regeneron slid 5% post-vote on Friday and a further 2% in early trade today, this is most likely due to shareholders cashing in on impressive profits, the stock having gained 75% in the last six months to $57.82 before the advisory committee meeting. The commercial battle against Lucentis and off-label use of Avastin will be an intriguing one in what is now a rapidly evolving and growing market.

Well-known class

Known generically as aflibercept and formerly referred to as VEGF Trap-Eye, Eylea is a vascular endothelial growth factor (VEGF) inhibitor that, like Roche’s Lucentis and similar cancer drug Avastin, blocks blood vessel growth. In the case of wet age-related macular degeneration (AMD) Eylea blocks the abnormal growth of blood vessels which bleed and leak, causing scarring to photoreceptors. In a cancer setting, a VEGF inhibitor prevents the development of blood vessels that feed tumour cells, which is the mode of action of Avastin and Regeneron’s cancer version of aflibercept, Zaltrap (Regeneron, Sanofi finally get an aflibercept cancer win, April 27, 2011).

In pivotal trials, Eylea has shown itself the equal of Lucentis on efficacy and safety, but comes with an advantage: injections every two months. This dosing schedule, half as often as Lucentis, reduces the risk of adverse events, according to adcom members (Event - Regeneron's eye drug looks good for positive vote, June 9, 2011).

Given that VEGF inhibitors have been in use for five years in AMD, with Lucentis an approved drug and titrated Avastin used off-label, only a safety worry would have derailed the Regeneron drug. As it was, the adcom noted the need to monitor for increases in intraocular pressure, which the proposed label already warns of.

High hopes

Regeneron retains full rights in the US and has partnered ex-US rights with Bayer. Forecast US sales of the drug are $663m in 2016, giving it a net present value of $2.32m, roughly half of Regeneron’s market capitalisation, according to EvaluatePharma data. With the company's only marketed drug, Arcalyst in gout, accounting for another 4% of the company’s market value, it is clear that investors have high hopes for Eylea.

Part of that is hoped to come from expansions to Eylea’s label. AMD accounts for 79% of the forecast sales in 2016. Another 6% is forecast to come from central retinal vein occlusion (CRVO), in which it reported positive pivotal data in April, and 15% in diabetic macular oedema, in which has just begun two phase III trials that are expected to report in 2013 and 2014. Regulatory filing in CRVO is expected later this year.

What questions there are about Eylea have much to do with commercial uncertainty. The US National Institutes of Health’s Catt study, which has already reported one-year comparative data of Lucentis and Avastin, is testing both on an “as needed” basis, a treatment protocol that has resulted in four to five fewer injections per year with only a slight efficacy loss (Catt is out of bag but Lucentis-Avastin debate far from over, May 4, 2011).

The second year of Regeneron’s pivotal View studies also are testing Lucentis against Eylea on an as-needed basis, so much will be learned about the effectiveness of various dosing protocols in the next 12 months. In the meantime, there are aspirants in the wings with the hope of cutting the dosing schedule even further, such as Molecular Partners’ candidate, recently partnered with Allergan, which hopes to reduce the schedule to even once every three or four months (Allergan sees dosing potential in Molecular Partners' AMD candidate, May 5, 2011).

Predicting FDA decisions is often a fool’s game, but Eylea is about as sure a bet for approval as there can be, and a rejection would be a very big surprise. Proven non-inferiority to an incumbent product, with no apparent safety worries raised by FDA staff and a reduction of treatment burden - both for patients and the specialists with growing patient rolls - seems to queue up an almost-certain approval by its PDUFA target date of August 20. There is then good reason to hope for a successful launch.