Alzheimer’s disease has long been seen as a tale of two proteins: beta amyloid, which forms sticky plaques in the brain, and tau, which in its diseased state creates tangles inside neurons. Antibodies that clear beta amyloid have been approved to treat Alzheimer’s, but it was tau that made headlines this week, as researchers presented key new details about a drug that reduced production of the protein and slowed cognitive decline in a recent clinical trial.
At the Alzheimer’s Association International Conference, neurologist Catherine Mummery of University College London presented results from a phase 2 trial testing diranersen, a drug developed by Biogen to lower the body’s production of tau, in more than 400 patients with early-stage Alzheimer’s. On the study’s main measure of cognition, participants getting diranersen saw as much as a 26% slowing of decline—about on par with the effect seen in earlier trials of approved antiamyloid drugs. (Biogen had announced in May the drug slowed cognitive decline but did not say by how much.)
Although the presentation sparked enthusiasm from Alzheimer’s researchers, it also drew attention to puzzling aspects of the trial results. A potentially worrisome side effect emerged at high doses, and contrary to expectations, patients taking the lowest of three possible doses saw the greatest benefit. For these reasons, the findings represent “a double, not a home run,” says neurologist Adam Boxer of the University of California San Francisco, who this month launched a clinical trials platform to try different antitau therapies in Alzheimer’s.
Diranersen belongs to a class of drugs known as antisense oligonucleotides, strands of RNA that dampen activity of specific genes. It interrupts production of tau by binding to the messenger RNA that encodes instructions for producing the protein, and must be injected directly into the cerebrospinal fluid to reach the brain. After 18 months, participants in all three dose groups had between one-third and one-half as much tau in their cerebrospinal fluid as when they started the trial, whereas levels increased slightly among people receiving placebo. Imaging done on a subgroup of participants showed the drug also reduced tau tangles in the brain.
Glenn Harris, who directs research partnerships for the Rainwater Charitable Foundation, a group that supports research on brain diseases involving tau, says many in the field had higher expectations for the drug’s cognitive benefit. But the findings create momentum for tau therapies at a time when several other candidates—mostly antibodies targeting abnormal tau—have failed in Alzheimer’s trials. “I think the enthusiasm is highest with this one because [it works by] shutting off the faucet of [tau] production or at least slowing it,” he says, apparently allowing the brain to clean out tangles.
At the meeting Mummery addressed the finding of decreasing cognitive benefits at higher doses, which caused the trial to fall short of the dose-dependent effect the investigators had chosen as its primary endpoint. The low dose appears to be “showing the most consistent positive clinical effect” across neuropsychological tests, Mummery said. Biogen is moving forward with a larger clinical trial, but has not revealed which doses it will investigate.
About one-quarter of people in the higher dose groups experienced a “confusional state” after diranersen was administered, a side effect that lasted up to 1 week. This was unexpected, Boxer says, and might be an off-target effect of the antisense molecules. “But a troubling possibility,” he says, is that it is related to tau reduction. “Maybe we can’t knock down tau without some effects.”
The cognitive benefit seen with diranersen is not enough to argue it should replace the approved antiamyloid antibodies, says Washington University in St. Louis neurologist Eric McDade, who co-directs a research group that tests Alzheimer’s drugs in families with inherited forms of the disease. Combination treatment with both drug types appears to be “the strongest way forward,” he suggests. “Maybe there is a synergistic effect—but that needs to be tested now.”
A few trials are testing antitau and antiamyloid drugs in combination, though none involve diranersen. One, by McDade’s group, uses an antitau antibody, and Boxer’s group is working with a vaccine that prompts the immune system to attack abnormal tau.
The modest cognitive effects in the trial may speak to the complexity of the disease process, Boxer says. “There’s been a long-standing hypothesis among Alzheimer’s researchers that amyloid lights the fire of the disease, but that it’s tau [fueling neurodegeneration],” Boxer says. These data “provide pretty clear support for that.” But Boxer thinks other abnormal proteins seen frequently in Alzheimer’s brains—among them alpha synuclein and TDP-43—might be stoking the flames, too, possibly lessening the beneficial effects of tau lowering.
And the disease involves a lot more than proteins, researchers have increasingly come to acknowledge. “We know that there’s a huge vascular component [in Alzheimer’s],” Harris says. “There’s a huge neuroinflammation component and neuroimmune component and synaptic health component.” Fortunately, he says, “There are pipelines for those therapies as well.”