One month after the long-awaited approval of its first Alzheimer’s drug, Eli Lilly said that another experimental medicine aimed at slowing dementia failed in a Phase 2 study of 330 people.
The drug, known as an OGA inhibitor, was designed to prevent a protein called tau from clumping in the brain. Tau often builds up after amyloid plaques — the target of Lilly’s recently approved Kisunla — have formed. Tau proteins are believed to play a bigger role in the death of brain cells.
Dan SkovronskyIn the company’s earnings call with investors on Thursday morning, chief scientific officer Dan Skovronsky said that both low and high doses of the drug “failed to meet the primary endpoint” on Lilly’s own scale measuring cognitive decline. Lilly plans to present detailed results at the Clinical Trials on Alzheimer’s Disease conference, which begins in late October.
But Skovronksy emphasized that Lilly isn’t giving up on developing new tau-targeting drugs altogether. “While this negative outcome was disappointing, we remain committed to tau as a high conviction target in Alzheimer’s disease and plan to continue studying tau biology,” he said.
The failure is bad news for other companies working on their own OGA inhibitors. Biogen is testing its own pill in a Phase 1 study. And the Swiss biotech Asceneuron last month raised $100 million to test an OGA inhibitor in a Phase 2 study.
In the run-up to the approval of Kisunla, the Indianapolis drugmaker has increasingly discussed a future where amyloid-busting and tau-lowering drugs are paired together for greater effect. Its OGA inhibitor was especially exciting, because as a pill, it could be a more accessible alternative to Kisunla, which requires monthly infusions and repeated brain scans to monitor for side effects.
The pill inhibits an enzyme called O-GlcNAcase, or OGA, that chemically alters tau proteins and makes them more prone to form toxic tangles that kill brain cells. In an interview with Endpoints News last month, Mark Mintun, Lilly’s VP of neuroscience research and development, downplayed the molecule’s chances of success.
Mark Mintun“The OGA inhibitor does a really remarkable job in the animals. But it does it in a very indirect way,” he said. “If we designed something that attacked the tau itself or attacked the tau tangles themselves, we might feel really confident that this is going to work in humans.”
“We joke that we’ve cured Alzheimer’s in mice a lot of times,” Mintun added. “A lot of things just don’t translate to the human Alzheimer’s condition. And we will not be surprised if this is one of those things that doesn’t translate. We feel like we have to try it.”
Lilly has previously tried targeting tau directly with an antibody drug, which failed. Mintun said the company is working on another small molecule that targets tau directly inside brain cells, and a genetic medicine that uses an siRNA to prevent brain cells from making tau in the first place.
In an interview with Endpoints last August, Skovronksy compared tau drugs to the decades-long efforts to attack amyloid in many different ways. “It’s a bit like amyloid,” he said. “We have such conviction on the target, we’re willing to attack it from different mechanisms until we find the mechanism that can actually affect the target. I know that feels stubborn, but to us it just feels logical.”
Kyle LaHucik contributed to reporting.