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J&J-Pfizer's Alzheimer's Drug Crashes, Burns in Phase III

By Cormac Sheridan
Staff Writer

DUBLIN, Ireland – The headline on a note from Jefferies & Co. research analyst Corey Davis said it all: "At least it's not ambiguous: Bapi's Dead." Following a second Phase III miss within a couple of weeks, Pfizer Inc. and Johnson & Johnson decided to terminate development of bapineuzumab, the anti-amyloid beta antibody originally discovered and developed by Elan Corp. plc, which retained an approximate 25 percent stake in the asset.

The writing was on the wall in late July, when bapineuzumab failed to meet the co-primary cognitive and functional performance endpoints in the so-called 302 study, in around 1,100 patients, who are carriers of the ApoE4 (apolipoprotein E epsilon 4) allele, a risk factor for Alzheimer's.

Topline data from the 301 study in about 1,300 non-ApoE4 carriers, released after the markets closed Monday, indicated the drug failed to have an effect in that study population as well. Two further studies, both led by Pfizer, Study 3000 and Study 3001, are now being halted, as are all follow-on extension studies.

Data from 301 and 302 will be presented at the European Federation of Neurological Societies meeting in Stockholm, Sweden, which runs Sept. 8-11. But the fact that the companies are halting the program at this point is a strong indication that the product also failed to demonstrate efficacy on secondary endpoints or in any patient subgroups.

"That's what makes it disappointing," Jack Gorman, analyst at Davy Stockbrokers in Dublin, told BioWorld International.

While the present failure may not represent the final nail in the coffin for the beta amyloid hypothesis in Alzheimer's, it does offer the most complete argument to date that blocking the formation of beta amyloid plaques simply doesn't work in patients who are already exhibiting mild-to-moderate symptoms of the disease. Given previous failures in other programs based on the same presumed mechanism, hopes for progress had been modest in any case.

"The expectations for this were relatively low across the board," Gorman said.

Market responses were, accordingly, muted. Shares in Dublin-based Elan (NYSE:ELN) were off by more than 5 percent by noon EST Tuesday. Shares in New Brunswick, N.J.-based J&J (NYSE:JNJ) and in New York-based Pfizer (NYSE:PFE), which controlled about 50 percent of the asset, were down by 0.6 percent and 2 percent, respectively. Shares in Indianapolis-based Eli Lilly & Co. (NYSE:LLY) edged down 2.5 percent, as hopes for its anti-beta-amyloid antibody solaneuzumab also faded.

The Janssen Alzheimer's Immunotherapy alliance also contains two other assets, a therapeutic vaccine, ACC-001 , and a subcutaneous version of bapineuzumab, both of which are undergoing Phase II trials.

Pfizer gained a 50 percent stake in Elan's Alzheimer's immunotherapy program through its $68 billion acquisition of Wyeth in 2009. J&J subsidiary Janssen bought into Elan's stake in the program around the same time, in a $1 .5 billion deal, which also involved the sale of 18.4 percent of Elan's equity. In hindsight, that now looks to have been a very savvy move by Elan CEO Kelly Martin. "He was clever enough to give away some of the potential reward to fix their balance sheet," Gorman said. (See BioWorld International, July 8, 2009.)

Elan's balance sheet is now in the black, with $800 million of cash and investments, vs. $625 million in debt. The company now plans to focus on maximizing sales of its multiple sclerosis drug Tysabri (natalizumab), which it markets in partnership with Cambridge, Mass.-based Biogen Idec Inc. The companies aim to double revenues over the next five years, which would give Elan alone a $2 billion business.

Their alliance is subject to a change-of-control clause, which would probably rule out any third bids for Elan, as a change of ownership would give Biogen Idec an option to acquire Tysabri outright.

"They hold a lot of the cards in this particular situation," Gorman said.

Biogen (BIIB) is unlikely to make any move in the near future, however, given the likely approval of its oral MS drug BG-12 early next year.

"We reiterate our previous view that BIIB may wait at least until [the second half of 2013] before seriously considering an M&A transaction with ELN so as to provide an opportunity to evaluate how BG-12 might affect the Tysabri growth curve and associated 2013 revenues," Leerink Swan analyst Marko Kozul wrote in a research note.

In the Alzheimer's community, meanwhile, all eyes will now shift to the Phase II prevention trial in Colombia of crenezumab, which is being administered to members of a large extended family who share a genetic mutation associated with early onset Alzheimer's. The hope is that early administration of the drug might prevent the deposition of amyloid plaques before clinical symptoms become apparent. (See BioWorld Today, May 17, 2012.)