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The National Institute on Aging recently announced plans to provide the Banner Alzheimer's Institute with $33 million to fund a clinical trial examining Alzheimer's disease in a specific subset of predisposed patients. The study will track disease onset in healthy subjects ages 60-75 with two copies of the gene for ApoE4, a protein that increases the risk of late-onset Alzheimer's by 10-fold. The longitudinal approach hopes to be the first to identify a significant preventative effect in the highest risk patients.
But here's the kicker: The drug to be examined hasn't been selected yet! We know that the treatment will be targeted at amyloid beta, a protein that aggregates in the brain to form the plaques thought to underlie the disease (though many argue against this hypothesis). So, with that in mind, which sprinter in the race for an Alzheimer's blockbuster will be the recipient of some nice federal aid? And how is this trial going to be any different than the disappointing trials so far?
A new kind of trial
Patients, scientists, and investors have been foiled time and time again by this debilitating neurological disease. The dearth of impressive clinical data could be the result of many factors. One factor -- and the one that this project addresses -- is the timing of treatment relative to the disease onset. Most trials have been designed to examine the slowing or reversal of cognitive decline in symptomatic patients. In those cases, much of the underlying neurological damage has already occurred. This trial will be a longitudinal study of preventative treatment in high-risk individuals, to correct the pathology of Alzheimer's before neurological damage and cognitive decline.
There are several Alzheimer's treatments floating around in clinical trials or in the wastebaskets of R&D directors. The most advanced of these drugs is Eli Lilly's (NYSE: LLY ) solanezumab -- but advanced doesn't necessarily mean successful. Solanezumab is a monoclonal antibody that binds to amyloid beta, with the intent of clearing the protein before it can form debilitating plaques. Solanezumab failed two of its phase 3 clinical trials, but did show some slowing of cognitive decline in patients with mild Alzheimer's. Lilly is currently gearing up another phase 3 trial in early stage patients and could really use some good results after a string of disappointments recently.
Lilly isn't the only company with an underwhelming amyloid beta immunotherapy. Baxter International (NYSE: BAX ) saw its Gammagard miss primary endpoints in phase 3 trial data reported in May. Like solanezumab, though, data mining revealed some effect in a specific subset of patients with moderate disease. Gammagard is approved for inflammatory diseases, so it hasn't been completely shelved yet. Pfizer (NYSE: PFE ) and Johnson & Johnson (NYSE: JNJ ) did shelve their bapineuzumab, which failed multiple phase 3 trials both in patients with and without the ApoE4 gene.
In addition to the monoclonal antibody approach, several clinical programs are investigating the utility of blocking the enzyme involved in the processing of amyloid beta, BACE. By blocking BACE, a competing enzyme called alpha-secretase chops up the precursor protein and prevents amyloid beta production.
Lilly's BACE inhibitor LY2886721 was another of its recent failures. Phase 2 trials were halted after routine blood tests suggested that the drug was causing liver damage. This leaves the door wide open for Merck's (NYSE: MRK ) MK-8931 to take the lead. MK-8931 wrapped up a Phase 1b trial this summer, and it showed a dose-dependent reduction in cerebro-spinal amyloid beta in patients with mild to moderate Alzheimer's. I wouldn't put too much hope in Merck's drug yet, though -- the trial didn't examine clinically relevant cognitive outcomes. While phase 2/3 studies will examine these clinical outcomes, I'd bet on it suffering the same fate as bapineuzumab and solanezumab.
Another way to go
I have been critical of the industry in the past for its single-minded approach to Alzheimer's. With so many failed amyloid beta-directed immunotherapies, I think the NIA could have chosen to allocate this money to treatments off the beaten path. Eli Lilly is one company leading the way toward a new approach with its recent focus on tau tangles, another protein aggregate thought to underlie the Alzheimer's pathology. Lilly recently purchased two tau tangle imaging markers to facilitate R&D and reserves the right to commercialize them for some R&D revenues.
The bottom line
The $33 million grant is pennies in the deep pocketbooks of the big pharma contenders, but the federal aid represents more than financial support; it represents a final push to settle the amyloid beta debate. If this trial fails to find a preventative effect in highest-risk patients, you can expect the field to shift in new directions. If it uncovers a clinically relevant effect, it will be a golden opportunity for patients and shareholders.
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