Catt is out of bag but Lucentis-Avastin debate far from over

The US government’s publication of head-to-head data on Lucentis and its less-expensive cousin Avastin in the treatment of wet age-related macular degeneration (AMD) answers a clinical question: after one year, the two drugs are equally good at improving eyesight (Event - Trial expected to let Catt out of the bag on Lucentis and Avastin, January 20, 2011). What the Catt trial failed to answer is whether they are equally safe.

With a slew of additional comparative studies with hundreds of enrolees due to report in coming months and years, the relative profiles of the two drugs will likely crystallise further, providing further clarity on the cardiovascular safety concerns of Avastin, when used off-label in eye care. With practice patterns already well-established, further erosion of Lucentis sales are not necessarily anticipated based on these efficacy findings. However some observers reckon that Lucentis’ bigger risk comes not from Avastin but in Regeneron's phase III candidate VEGF Trap-Eye, which is dosed half as often.

“Catt really does not bring enough definitive data to tilt prescribing in one direction or another. The status quo will prevail,” says Andrew Weiss, an analyst with Vontobel in Switzerland. “In the Catt trial we’re basically getting a first flavour of efficacy that will be confirmed from trial to trial. Whether or not adverse events are going to be beneficial or detrimental to Avastin remains to be seen.”

Head to head

A high-profile example of comparative effectiveness, the US National Eye Institute’s Catt trial sought to answer a question dogging the two Roche products: was there any difference between Avastin, a monoclonal antibody titrated by opthalmologists for treating AMD, and Lucentis, an antigen binding fragment derived from the same humanised mouse antibody.

Both are vascular endothelial growth factor inhibitors with the same mechanism of action, blocking blood vessel growth. However whereas Lucentis was designed for the eye, Avastin was destined to attack large solid tumours.

In AMD, Lucentis is expected to have global sales of $2.46bn in 2011, with Roche booking just over $1bn in North America and global partner Novartis taking the rest, according to EvaluatePharmadata. That total is expected to shrink to $1.3bn in 2016, with the partners taking roughly equal shares.

As it is an off-label use, very few sales forecasts exist for Avastin in AMD, although Mr Weiss estimates about half of prescribing physicians use Avastin and half Lucentis.

The one-year data from the 1,100 patient Catt trial unveiled at the Association for Research in Vision and Opthalmology (Arvo) meeting showed the two antibodies to have roughly equal efficacy. Patients taking Lucentis monthly improved their mean visual acuity scores by 8.5 letters and those taking Avastin improved by 8 letters, a finding of non-inferiority. Given as needed, Lucentis patients improved 6.8 letters and Avastin patients 5.9 letters, also non-inferior.

Investigators also found that monthly versus as-needed Lucentis was non-inferior. The per-patient cost for Lucentis was much higher – given monthly it was $23,400 per patient to Avastin’s $595, and given as needed the cost was $13,800 to Avastin’s $385.


There were not enough patients to judge the two on safety, the question on which Roche has hung its hat for Lucentis. However, data from a Roche backed retrospective analysis of Medicare claims also unveiled at the Arvo meeting showed a 57% greater risk of cerebrovascular events in patients taking Avastin.

As a retrospective study, the data have caveats. However, the ongoing trials in Europe, along with follow-up two year data from Catt, will likely explore this further. In Europe alone, head-to-head trials comprising more than 2,000 patients have been announced, with the next expected completion the 320-enrolee Austrian Manta trial in December 2011.

Even if these are also insufficiently designed to provide a safety view, the growing body of research will help physicians feel their way.

New kid on the block

But the data may come too late to matter from a commercial standpoint, should VEGF Trap-Eye continue to live up to hopes (Dosing the jewel in VEGF Trap-Eye’s crown, November 22, 2010). It has already been judged non-inferior to Lucentis in two phase III trials on efficacy, and with a similar safety profile and less frequent dosing, it stands a chance to be best in class.

Analysts now forecast it to launch in 2012, and by 2016 have AMD sales of $703m for Bayer and Regeneron, nearly matching Lucentis.

Thus, the Lucentis-Avastin debate will likely rage on, but within a few short years the protagonists could be generals fighting the last war.

Trial ID NCT00593450

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