Editor

Lucentis (ranibizumab, Genentech Inc./Roche AG) may be the well-entrenched market leader in wet age-related macular degeneration (AMD), and it may have decimated all previous competitors, but that's no reason to think there's not room in the field for anyone else.

At least, that's the opinion of Regeneron Pharmaceuticals Inc. and LPath Inc., both of which recently made big strides in their wet AMD programs. Regeneron and partner Bayer AG reported that VEGF Trap-Eye (aflibercept) met its endpoints in two Phase III wet AMD trials, while LPath inked a potential $511.5 million option deal with Pfizer Inc. for Phase II wet AMD drug iSONEP. (See BioWorld Today, Nov. 23, 2010, and Dec. 21, 2010.)

Lucentis, approved in mid-2006, was touted as a long-awaited advance in the wet AMD field because of its ability not only to maintain but to improve vision. The vascular endothelial growth factor (VEGF) inhibitor quickly decimated competing products like Visudyne (verteporfin, QLT Inc. and Novartis AG) and Macugen (pegaptanib sodium, OSI Pharmaceuticals Inc.). (See BioWorld Today, July 5, 2006.)

Other biotechs with late-stage VEGF inhibitors in development for wet AMD found Lucentis a formidable opponent as well. Genaera Corp. dropped its anti-VEGF drug Evizon (squalamine) because it couldn't enroll patients in its Phase III trial once Lucentis was approved. The company later went belly-up. Meanwhile Opko Health Inc. and Allergan Inc.'s siRNA approaches to targeting VEGF for wet AMD each fizzled. (See BioWorld Today, Jan. 5, 2007, and March 9, 2009.)

All the while, Lucentis reigned supreme. In fact, its only real competition to date has come from Roche's own sister VEGF inhibitor Avastin (bevacizumab), a cancer drug with cheaper pricing that has stolen an estimated 60 percent of the U.S. market from Lucentis. Even so, Roche reported U.S. Lucentis sales of $1.12 billion in the first nine months of 2010.

Challenging the Leader

Some analysts are concerned that Avastin's encroachment on Lucentis' territory might be about to get worse. The NIH is currently running a head-to-head trial comparing the two drugs, and the data "could further substantiate these drugs' interchangeability, casting doubt on the value-proposition of more expensive agents in this field," according to a research note from Robert W. Baird & Co. analyst Christopher Raymond.

For that reason, Raymond is cautious about the prospects for Regeneron's VEGF Trap-Eye and other wet AMD up-and-comers.

Like Lucentis, VEGF Trap-Eye inhibits blood vessel leakage in the eye by targeting VEGF. But while Lucentis is a monoclonal antibody, Regeneron's drug is a VEGF receptor fusion protein, which the biotech has long claimed allows more potent binding and the potential for less-frequent dosing. In the recent Phase III trials, VEGF Trap-Eye dosed every two months was noninferior to Lucentis dosed monthly.

Dosing convenience isn't always an easy sell to payers and physicians, but in this case, "the convenience factor is very important," Regeneron spokesman Peter Dworkin told BioWorld Insight. Aside from the fact that these drugs are given via injection into the eye – something patients likely will be happy to minimize – Dworkin said physicians don't make a lot of money on the office visits required to administer the injections, and Regeneron's market research indicates they see a significant advantage in less frequent dosing.

Regeneron is not alone in its quest to develop a better VEGF inhibitor for wet AMD. Molecular Partners AG is in Phase I with VEGF-A antagonist MP0112, and Genaera's VEGF inhibitor Evizon has been picked up by Ohr Pharmaceutical Inc. (See BioWorld Today, Nov. 25, 2009.)

"It's gonna be a dogfight," LPath President and CEO Scott Pancoast predicted of the competition between anti-VEGF drugs for wet AMD.

Thus LPath – and a number of other biotechs – are working on other mechanisms of action that could be complimentary to whatever VEGF inhibitor emerges as the market leader.

LPath's iSONEP is a humanized antibody targeting the bioactive lipid sphingosine-1-phosphate (S1P). Pancoast said targeting the S1P pathway provides some overlapping benefit with the anti-VEGF drugs, in that both stop leaky vessels. But iSONEP also addresses other dimensions of wet AMD, including the inflammatory and fibrotic components. Thus Pancoast views iSONEP as potentially complementary to the VEGF inhibitors.

Also taking the complementary approach is Ophthotech Corp., in Phase II with platelet-derived growth factor (PDGF) inhibitor E10030. In a Phase I trial, combining the drug with Lucentis led to visual improvement and 100 percent neovascular regression.

But perhaps the hottest emerging area of AMD research is inhibition of complement factors, members of a protein family involved in inflammation and innate immunity. Several big pharmas are looking at complement inhibition for AMD, as are Ophthotech, Potentia Pharmaceuticals Inc., Taligen Therapeutics Inc., Optherion Inc., ReVision Therapeutics Inc. and others.

Enough to Go Around

Is the wet AMD market sufficient to support so many competitors, especially given pressure from Avastin?

Dworkin sees plenty of opportunity for a Lucentis competitor like VEGF Trap-Eye. Even if Avastin and Lucentis are proven in the ongoing NIH study to be comparable products, he thinks VEGF Trap-Eye's less frequent dosing will still resonate with doctors and patients. Additionally, there are "a number of reasons to think Avastin may not show comparability" to Lucentis, Dworkin said – and that could result in the 60 percent of wet AMD patients on Avastin switching over to Lucentis or VEGF Trap-Eye.

Pancoast believes the market opportunity for drugs seeking to complement VEGF inhibitors in wet AMD is even larger – perhaps worth $4 billion to $5 billion annually. That's a lot more than Lucentis' current sales, but Pancoast noted that a complementary drug could be paired with Lucentis, Avastin or VEGF Trap-Eye. He also added that aging baby boomers are soon expected to double the wet AMD patient population.

And for both the VEGF inhibitors and the other drugs, wet AMD is likely just the tip of the iceberg. Lucentis recently picked up an FDA approval for macular edema following retinal vein occlusion, a smaller market but one that could still be worth $500 million to $1 billion annually, by some estimates.

Meanwhile, VEGF Trap-Eye recently met its endpoints in a Phase III trial for macular edema due to central retinal vein occlusion, and it has shown solid Phase II data for diabetic macular edema, a market worth some $2 billion to $4 billion.

LPath's iSONEP, meanwhile, has shown promise in resolving pigment epithelial detachment, a complication of wet AMD that anti-VEGF drugs haven't been successful in treating.

And many of the complement inhibitors are also targeting dry AMD, which accounts for 90 percent of the overall AMD market and is currently untreatable. Although the anti-VEGF products aren't designed to address dry AMD, drugs that can shouldn't need much market penetration to make the endeavor worth their while.