The fourth attempt to prove Eli Lilly's experimental Alzheimer's disease drug solanezumab ended Monday the same way the first three did, with the company announcing a closely watched study missed its goal.
Results from the trial, called DIAN-TU, showed again that solanezumab doesn't work to slow cognitive decline from the neurodegenerative disease. Learning from the first three study failures, researchers had designed DIAN-TU to test treatment at a very early stage of the disorder, enrolling patients who, due to faulty genes, are almost certain to get sick at a young age and progress rapidly.
In announcing the results of the eight-year trial, researchers from Washington University in St. Louis said data from DIAN-TU will help them set up better Alzheimer's studies in the future. Yet an innovative study design didn't yield new support for the case that reducing levels of a toxic protein called amyloid beta can slow disease progression.
The finding represents yet another blow to the dominant hypothesis in Alzheimer's research, which argues that accumulation of amyloid beta in the brain is the cause of cognitive decline. Along with solanezumab, DIAN-TU also studied Roche's gantenerumab, which also failed to show a benefit, as have numerous other amyloid-blocking drugs in recent years.
DIAN-TU's readout could give reviewers at the Food and Drug Administration more reason to question an application for approval of Biogen's aducanumab, which is controversially supported by mixed data from the biotech's Phase 3 trials in patients with non-genetic Alzheimer's.
While aducanumab binds to and removes amyloid beta from the brain, solanezumab works on a soluble variety of the protein. The fact that the experimental Biogen drug failed to slow patients' cognitive decline in one Phase 3 trial should cast some doubt over whether that makes a difference, and the DIAN-TU results won't help.
Lilly executives had sought to lower expectations ahead of Monday's readout, pointing to the small number of patients studied as well as a change in dosing that happened mid-trial — only 50 patients received solanezumab, and of those, only 36 were on for four years or more. Just 25% of doses were at the higher level, which was four times that used in earlier, failed trials.
"These results reflect the difficult nature of treating Alzheimer's disease and the great need for continued research," Lilly's chief science officer Dan Skovronsky said Monday in a statement. "If we have learned one thing after more than 30 years of Alzheimer's research, it is that even negative results propel the science forward."
Following the announcement, shares in Lilly fell 2% to about $143 apiece in late morning trading.
If solanezumab or gantenerumab had worked, Lilly or Roche would have had a case to make for FDA approval. The patients studied had rare mutations that can be identified through familial relationships and genetic testing, which would have qualified the drugs for orphan disease status.
Despite the failure, researchers still aren't giving up on amyloid-blocking drugs in the early, preventive setting. Two major trials are still underway, one of which also tests solanezumab. Called A4 and run by the University of Southern California, that study is in asymptomatic patients with evidence of amyloid beta accumulation.
A4's enrollment of 1,140 patients, early intervention and greater exposure at the high dose of solanezumab may give it a better chance at success, wrote Cantor Fitzgerald analyst Louise Chen in a Feb. 10 note to investors. A4 is not expected to deliver results until 2022.
The other trial is called API-ADAD and studies 252 patients in a Colombian family group with a mutation that was included in DIAN-TU. That study is testing another Roche amyloid-beta blocker called crenezumab.