Amyloid Hypothesis Takes a Hit As Lilly’s Alzheimer’s Drug Fails Again

Xconomy Indiana — 

Weeks earlier than expected, Eli Lilly delivered news this morning that will affect not just millions of patients with Alzheimer’s disease but also will rekindle fierce debate about the underlying cause of the memory-robbing disorder.

Eli Lilly (NYSE: LLY) said that solanezumab, an experimental Alzheimer’s drug, failed a long-anticipated, high-stakes Phase 3 trial known as “Expedition 3.” The drug failed to slow the cognitive decline of patients with mild dementia due to Alzheimer’s disease, adding to the long list of major clinical failures over the past decade, even as the financial and social impact of the disease looms ever larger.

More than five million Americans have Alzheimer’s disease, most of them over 65. As the population ages, the Alzheimer’s burden will grow. The Alzheimer’s Association estimates nearly 14 million Americans will have the disease in 2050. But no treatments other than a pair of old cognition-boosting drugs have been approved to treat Alzheimer’s, in 1996 and 2003.

Lilly didn’t provide more specifics on the solanezumab data; they’ll be presented at the Clinical Trials on Alzheimer’s Disease meeting on Dec. 8. The company only said that while the data by various measures “directionally favored solanezumab,” they weren’t good enough to show a meaningful impact on the disease. Lilly won’t seek regulatory approval of solanezumab, which was the closest possible experimental Alzheimer’s treatment to market. It hasn’t decided what the next steps for the drug are. Shares of Eli Lilly fell more than 13 percent in pre-market trading on Wednesday, immediately wiping out billions of dollars in market value.

The news puts a dent in the amyloid hypothesis. The hypothesis holds that Alzheimer’s is the result of clumps of amyloid protein, called plaques, and that clearing them from the brain with a drug might slow or even halt the decline of patients’ memory loss. Many drugs, including solanezumab in an earlier set of trials, have failed to show that clearing out plaques can help patients’ memory. Those failed trials led researchers not to abandon anti-amyloid drugs but to revamp their clinical attack: Perhaps the drugs weren’t being tested in the right patients, or perhaps patients’ disease was too far along for these drugs to have an impact.

The Expedition 3 trial was the first major test of those revamped theories. As Lilly reported in 2012, solanezumab failed to improve the condition of people with mild to moderate Alzheimer’s disease in studies called Expedition 1 and 2. But Lilly pooled the data, analyzed subgroups of patients, and saw rays of hope among the mild patients—those earlier in the course of their disease.

Executives, led by CEO John Lechleiter, saw enough positive signs to green-light more millions upon millions of dollars on a new trial, Expedition 3, for that mild population. (The company said this morning it would write off $150 million in the fourth quarter alone.)

Expedition 3 even failed after Lilly boosted its chances earlier this year. It said in mid-trial that it would turn one of the primary goals, the improvement of function in daily activities such as getting dressed, into a secondary goal. That left improvement in cognition as the only primary goal, theoretically lowering the bar for success and improving its odds.

At the time, Leerink’s Seamus Fernandez gave the trial a 30 percent chance of success. Another biotech analyst, Barclays analyst Geoff Meacham, wrote in a recent report, for instance, that the most likely outcome of the study was for solanezumab to slow cognitive decline, while posting mixed results on secondary measures.

The solanezumab failure also blunts the momentum of hard-charging Biogen (NASDAQ: BIIB), which jumped its anti-amyloid Alzheimer’s drug aducanumab from a large Phase 1 trial into Phase 3 trials last year. The Phase 1 data showed, for the first time, that an Alzheimer’s drug could have an impact on patients’ memory and cognition. There are caveats to that data, however, and Biogen now faces the huge hurdle that so many others, including solanezumab, have failed to overcome. There are differences between aducanumab and solanezumab, but investors sent the Cambridge, MA, company’s shares down more than 10 percent in pre-market trading.

“Other competitors’ programs based on [the amyloid hypothesis] will probably continue, but this will likely have negative read-through on these results in the short term,” wrote Leerink’s Fernandez in a note to investors on Wednesday.

Alex Lash contributed to this report.