Event - Regeneron hoping to show clear advantages for VEGF Trap-Eye

Despite developing drug discovery platforms that generate hundreds of millions of dollars in partnering revenue each year and achieving a healthy market value of almost $2bn, a long-standing niggle with Regeneron Pharmaceuticals is that after 21 years at it, the company has yet to bring a significant product to market.

Pivotal data due before the end of the year from two trials of its macular degeneration drug, VEGF Trap-Eye, could spell an end to the drought. The project has long been regarded as the company’s most promising and valuable clinical candidate so these data are awaited with much anticipation (Regeneron's eye drug holds most value, August 20, 2008). Viewed as a potential challenger to Lucentis, which generated $2.34bn in global sales last year, hopes are high for a strong readout, and promising mid-stage data has meant analysts are already pencilling in a blockbuster future for the drug.

Targeting vessels

VEGF Trap-Eye is a low dose formulation of the kinase inhibitor aflibercept. Partnered with Sanofi-Aventis in oncology indications, where much higher doses are used, Bayer bought ex-US rights in eye indications in 2006 for $75m upfront. The deal sees development costs shared equally whilst Regeneron will pocket half of the profits that its partner makes in overseas markets.

Like Roche’s megablockbuster Avastin, aflibercept targets vascular endothelium growth factor (VEGF), a protein released by cells into surrounding tissue, which signals for the formation of new blood vessels. This mechanism, called angiogenesis, is used by tumours to grow and spread.

Both Avastin and aflibercept attach themselves to VEGF but through different mechanisms, the former using an antibody receptor and the latter a kinase receptor. This prevents VEGF from binding to receptors on cells' walls, blocking the signalling pathway.

Indeed, aflibercept has been described as a “me-too” Avastin and in this way VEGF Trap-Eye can broadly be considered a “me-too” Lucentis, an antibody that is very similar to Avastin and also targets VEGF.

By binding to more targets than Avastin, many hoped aflibercept would prove to be more potent; however in the cancer indications this appears to have also translated into an increase in side effects. Still, the molecule binds also with much greater affinity to VEGF than Avastin, and although recent research has not been particularly encouraging there are still hopes a future will be found for the drug in oncology.

Different situation

The situation is very different in age-related macular degeneration (AMD), where much lower doses of aflibercept are used, significantly muting side effect concerns.

In AMD, overenthusiastic blood vessel growth causes the retina to thicken, eventually damaging eye sight. VEGF is highly implicated in this process, hence the success of Lucentis, and Avastin off-label, to treat the disorder.

Regeneron is gearing up to report results from two identical pivotal trials, View 1 and 2, which each recruited 1,200 patients. Both will track four different patients groups: those receiving a low dose, 0.5mg, of VEGF Trap-Eye every four weeks, those receiving a higher dose, 2mg, administered either every four weeks or every eight weeks, and those receiving Lucentis, which is administered every four weeks, at a dose of 0.5mg.

The primary endpoint is the proportion of patients who maintain vision at 52 weeks and the studies are designed to demonstrate non-inferiority to Lucentis.

A little bit more

However, the trials are designed to show a little bit more. Firstly, success in the higher dose group could show improved efficacy over Lucentis. And secondly, the eight-week dosing schedule could suggest similar or greater efficacy but with fewer treatments.

Phase II studies of VEGF Trap-Eye have already raised hopes that this is the case. Most past research with Lucentis has pointed to the need for monthly dosing to avoid vision deteriorating again.

Considering the huge cost of Lucentis, the potential for an equally efficacious but lower cost therapy to take market share is clear. This could become even more important if several ongoing trials pitting the much lower cost Avastin against Lucentis in AMD fall in favour of the former. With Avastin costing $50 an injection compared with closer to $2,000 for Lucentis, the days could already be numbered for the latter (Head-to-head trials could threaten Lucentis franchise, May 27, 2010).

However, whilst the ability to compete on cost will clearly be important many analysts believe that a dosing advantage for VEGF Trap-Eye would be the biggest win over Lucentis, or Avastin. The fewer injections into the eye the better.

As such, whilst the company will be hoping to provide convincing evidence that its drug is as good as Lucentis, it will also be hoping to show a bit more.