"Alzheimer's is the black hole of R&D," says Wolters Kluwer's Ben Weintraub. "It's the only big disease left that is basically untreatable." Since 2003, more than 10 much-hyped compounds have bitten the dust. Almost all targeted the protein amyloid-beta, the hallmark plaque long thought to cause the disease's devastation of brain matter. But experimental agents that slow or stop the amyloid buildup have stubbornly shown no cognitive or memory benefit in patients. Last summer, the amyloid hypothesis hit a crisis point when a Phase III Lilly drug was shown to do a great job removing the plaque—only to result in a negative clinical effect. Two top Harvard Alzheimer's experts published a paper promoting the inevitable, if heretical, hypothesis: Does amyloid protect rather then destroy neurons?
Ben Weintraub, Director of Research, Wolters Kluwer Pharma Solutions
There is a growing consensus that by the time amyloid buildup is detectable, the disease has likely progressed too far to be modified. Effective treatment must begin much earlier, but so far no biomarker has been discovered to identify vulnerable patients. And with the association between surrogate markers and clinical benefits increasingly in doubt, the FDA is currently at a loss when it comes to evaluating the efficacy of new drugs. Drugmakers are understandably discouraged at the prospect of progressing yet another risky molecule, given the fact that Phase III Alzheimer's trials are among the longest, hardest, and most expensive in pharma R&D. "Companies are forced to do proof-of-concept in Phase III because Phase II trials are too small and there are no acceptable animal models," says Alan Carr.
Bapineuzumab (bapi), a monoclonal antibody developed by Elan and Wyeth (now J&J and Pfizer), may win FDA approval by sheer dint of its drugmakers' refusal to shelve it. A passive immunotherapy that triggers amyloid antibodies, bapi reduced plaques by 25 percent but flunked midstage efficacy tests—except in a subset of patients who lacked a specific mutation. The determined J&J/Pfizer group has launched 14 Phase III trials with a total of 10,000 patients. Recently, researchers made the intriguing finding that bapi may show some clinical benefits because of an indirect downstream effect: it appears to lower the amount of tau, Alzheimer's No. 2 surrogate marker, in spinal fluid.
Despite its recent setback, Lilly is full steam ahead with its Alzheimer's program, one of the industry's largest. Its new lead product is a second amyloid-targeting Phase III compound, solanezumab, a monoclonal antibody that sucks up amyloid before it can form plaque deposits.
EnVivo Pharmaceuticals is testing EVP-6124, a partial a7 nicotinic receptor agonist that appears to stimulate neurons, increasing the alertness effect of the neurotransmitter acetylcholine. If this effect pans out, EVP-6124 may be given in tandem with current cholinesterase inhibitors, which increases levels of acetylcholine, potentially allowing for lower doses and fewer side effects.
The outlier in the late-stage pipeline is Baxter's Gammagard, an IV immunoglobulin containing amyloid-beta antibodies, which emerged as an Alzheimer's contender after a retrospective analysis revealed that people previously treated with the passive immune therapy had 42 percent less risk of developing the disease. A Phase II study showed significant benefits in three measures—cognitive, functional, and neuroimaging—a first for any Alzheimer's trial. Two Phase III trials are ongoing.
Meantime, the need for new drugs intensifies as more and more Baby Boomers live into advanced old age. The global market is estimated to be worth $20 billion by the end of the decade. "This is a time of major soul-searching in the field," says Dr. Murali Doraiswamy, an Alzheimer's researcher at Duke University.