Untangling Tau & Alzheimer’s
While researching the ins and outs of beta-amyloid and Alzheimer’s, we of course wanted to know what other targets pharma companies had up their sleeves. The most obvious next big target is tau, the other hallmark pathology in the brains of people with Alzheimer’s.
As we wrote, most of big pharma’s eggs are in the beta-amyloid basket, with nearly every drug in the Alzhiemer’s pipeline looking to block the production of or somehow clear the peptide. But in addition to beta-amyloid filled plaques, the brains of people with Alzheimer’s are marked by “tangles,” or clumps of an abnormal form of the protein tau. The beauty of tau as a drug candidate is that “it doesn’t rise and fall with the amyloid hypothesis,” Charles Albright, group director of neuroscience biology at Bristol-Myers Squibb, told us. In other words, because overproduction of tau hasn’t been definitively linked to overproduction of beta-amyloid (though some researchers do believe the link exists), it could still be a viable target if none of the beta-amyloid blockers in the clinic prove effective.
And studies in animal models suggest that dampening tau production could improve the outcome for Alzheimer’s patients. “Certainly some of the experimental data suggests if you’re a demented plaque and tangled mouse and your tau level is knocked down, your behavior improves,” said Sam Gandy, associate director of the Mount Sinai Alzheimer's Disease Research Center. Further, he noted that scientists have shown that at least some neurons die by a tangle-dependent process.
But when it comes to drug discovery, there are some key differences between beta-amyloid and tau. Beta-amyloid is a small peptide, whereas tau is a protein of about 50 kilodaltons. And despite clues, no one is really sure about a role for beta-amyloid outside of plaque-building, while tau is a rather ubiquitous protein that clearly binds to and stabilizes microtubules.
The bottom line for tau, is it is “very interesting, and very challenging,” Mene Pangalos said just weeks before leaving his job as Pfizer’s CSO in Neuroscience to head research at AstraZeneca.
One problem has been that the most obvious targets for tau are kinases that block the phosphorylation of tau. But it can be difficult to find selective kinase inhibitors without a lot of unpleasant side effects. “That’s where its been a struggle,” Pangalos added.
“It’s more challenging, but in a way, the target is common to more dementing processes than is amyloid, so it is important to keep hammering away at it,” Mount Sinai’s Gandy said.
Most companies involved in Alzheimer’s are indeed hammering away at it. David Michelson, vice president of clinical neuroscience and ophthalmology at Merck, believes that a range of drugs to test the tau hypothesis will be in the clinic in the next few years. “We and I’m sure others have very active programs looking at a lot of novel ways of trying to get at it, and I do believe that those will eventually bear fruit, but it probably will take a little longer.”
Bristol-Myers Squibb appears to have made some progress against the tough target. Francis Cuss, the company’s senior vice president for discovery and exploratory clinical research, recently told investors that the company would put a microtubule stabilizer targeting abnormal tau into Phase I trials later this year.
Meanwhile, Xconomy profiled the Vancouver, Canada-based Allon Therapeutics, which believes its peptide davunetide is the most advanced candidate to tackle tangles. Davunetide is in Phase IIa trials in Alzheimer’s, and early data has shown the therapy improved cognition in a small group of patients. Promising, to be sure, though other exciting early-stage results have taught the Alzheimer’s community to be cautious about expectations. The Haystack is curious whether Allon also measured tau in the cerebrospinal fluid, before and after dosing with its drug to show that it is having an effect on the protein.
Our own Sophie Rovner will take a more in depth look at the challenge and promise of tau in an upcoming issue. We’ll make sure to highlight the story when it comes out. Stay tuned!