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Drug Makers Push On With Alzheimer's Research After Setback

By Peter Loftus

THE WALL STREET JOURNAL 8/8/12 -- This week's failure of an experimental drug for Alzheimer's disease underscores the limitations on scientific understanding of the brain disorder, but drug companies are plowing ahead in search of new treatments because of the high medical need and potential financial payoff.

Pfizer Inc. (PFE) and Johnson & Johnson (JNJ) announced Monday they would discontinue development of intravenously administered bapineuzumab after it failed to provide a benefit in a second late-stage clinical trial. It was the latest in a series of setbacks in the drug industry's attempt to find the first drug to halt or reverse Alzheimer's.

But drug companies continue to study potential drugs for the disease, including Eli Lilly & Co. (LLY), Baxter International Inc. (BAX), Roche Holding AG (RHHBY), Merck & Co. (MRK) and Bristol-Myers Squibb Co. (BMY).

Current treatments don't stop the progression of the underlying disease, which impairs memory and cognitive skills primarily in the elderly. About 5 million Americans are estimated to have Alzheimer's.

The bapineuzumab failure further clouds the outlook for a similar drug developed by Lilly. The company is expected to report results later this month or in September of late-stage studies of solanezumab, which will help determine whether Lilly can submit it for regulatory approval or will drop development.

Both bapineuzumab and solanezumab are antibodies designed to reduce a substance in the brain called amyloid. Scientists have hypothesized that the buildup of amyloid in the brain plays a role in Alzheimer's disease.

There are certain differences between bapineuzumab and solanezumab--as Lilly has emphasized--and in the off chance that Lilly's drug succeeds, it could generate $23 billion in annual sales by 2020, Bernstein has estimated.

But few analysts expect the Lilly drug to succeed, a view reinforced by the failure of bapineuzumab.

If the Lilly drug fails, that leaves several other disease-modifying possibilities in the drug research pipeline that target amyloid in different ways or have other mechanisms. Roche also is studying an antibody that targets amyloid, among other approaches.

Most of these, however, are likely several years away from reaching the market, assuming they are successful in clinical trials.

"We will find therapies that change the course of Alzheimer's disease in the foreseeable future," said William H. Thies, chief medical and scientific officer of the Alzheimer's Association, which supports Alzheimer's research. "What I can't tell you is whether the first drug that will do that is going to be something we find in three, five, seven or 12 years. We don't really know which drug is going to be effective."

Dr. Thies said it is too soon to make any conclusions about whether drug makers have been chasing the wrong target with the amyloid hypothesis. He said the expected presentation of full results of the trials of bapineuzumab and solanezumab later this year will shed more light on the matter.

If the antibody drugs failed to significantly reduce amyloid concentrations, then it is possible that the amyloid hypothesis remains intact and other approaches to reducing amyloid might still work, he said. However, if the drugs did reduce amyloid and still failed to show a benefit, then it's possible that reducing amyloid isn't the right approach and another target is needed for a successful drug, or that patients need to be treated earlier in the course of the disease, he said.

Other Alzheimer's efforts include:

--Baxter International expects late-stage, or Phase 3, clinical results for Gammagard in Alzheimer's patients. Gammagard is currently used to treat patients with immunodeficiency diseases, but it is thought to contain antibodies that could remove amyloid from the brain. One caveat: Even if the clinical results are positive, Baxter will have to figure out how to manufacture enough of the product because it is derived from blood plasma.

--Merck expects to begin clinical studies in Alzheimer's patients by year end for MK-8931, its so-called "BACE" inhibitor, short for B-amyloid precursor protein site cleaving enzyme. The drug is designed to essentially prevent the buildup of amyloid in the brain, rather than reduce amyloid after it has built up.

Darryle D. Schoepp, senior vice president and franchise head for neuroscience at Merck Research Laboratories, said "there's strong genetic data" suggesting that reducing production of amyloid peptides at their source in the brain may protect against Alzheimer's disease. Other companies including Lilly also are developing BACE inhibitors.

--Roche's crenezumab, an antibody targeting amyloid, is being studied in cognitively healthy people in Colombia who are likely to develop Alzheimer's due to their genetic history, to test whether it can prevent the disease. Roche's Genentech unit is collaborating with the Banner Alzheimer's Institute and the National Institutes of Health on the trial.

--Cancer drug bexarotene was shown to reverse Alzheimer's symptoms in mice. A startup company called ReXceptor Therapeutics plans to begin human testing to determine whether the mice findings translate to humans. The caveat: Positive findings in animal studies often fail to translate into human benefits.

--Another hypothesis for Alzheimer's is that so-called tau proteins in brain cells malfunction, leading to Alzheimer's symptoms. TauRx Pharmaceuticals Ltd. is running clinical trials of a drug that targets the tau proteins. Merck and other companies also are exploring compounds that target tau.

Write to Peter Loftus at peter.loftus@dowjones.com