Eli Lilly will expand an ongoing mid-stage study of its experimental Alzheimer's disease drug donanemab with the aim of obtaining enough data to seek approval from the Food and Drug Administration.
The announcement Monday of the drugmaker's regulatory plan follows results from a Phase 2 trial which were published in the New England Journal of Medicine Saturday. The study's topline success — noteworthy in a field with a long history of drug failures — had raised long-shot hopes from some investors and analysts that Lilly might be able to ask for an accelerated OK sooner.
Lilly shares fell 9% on Monday, erasing nearly $20 billion of the company's market value.
The upsized trial, called TRAILBLAZER-ALZ 2, is meant to replicate the findings of the 257-patient TRAILBLAZER-ALZ, which found donanemab slowed Alzheimer's progression by a third when measured using a disease rating scale that assesses cognition and function.
"In my world, for years we have said a 25% difference in decline would be clinically significant," said Pierre Tariot, director of the Banner Alzheimer's Institute in Arizona. "That's admittedly arbitrary but it's a standard that's been espoused for at least a decade. This average difference suggests that there are some individuals who show very little decline and that would be great."
Tariot pointed to the drug's effects on the toxic amyloid plaques that accumulate in the brains of Alzheimer's patients, and the trial's main finding of slowed decline as factors experts will be watching closely.
But while the trial's principal outcome gave some like Tariot reason for optimism, inconsistent data on other measures weakened the study's findings.
In particular, donanemab did not prove statistically superior over placebo on a rating scale known as CDR-SB, which is commonly used in other Alzheimer's drug trials and was originally the main goal of TRAILBLAZER-ALZ 2.
Aiming to improve the chance of success for its second study, Lilly executives said Monday they will enroll 1,000 more volunteers into the trial than they had initial planned, as well as change the goal to the composite measure that was met in the now-completed TRAILBLAZER-ALZ 1 trial.
The additional Alzheimer's patients Lilly plans to recruit will be similar to those who appeared to respond to treatment in the first study, specifically people with intermediate levels in their brains of a protein called tau.
Tau is associated with Alzheimer's disease decline; those with high levels are thought to be too far along to benefit from drugs like donanemab, while those with too little aren't likely to worsen over the course of an 18-month study. Donemab binds to and removes amyloid plaques, which are also characteristic of Alzheimer's and have been the central hypothesis for treating the disease.
So far, Lilly has enrolled patients into TRAILBLAZER-ALZ 2 who have both high and intermediate levels of tau accumulation. Participants with high levels will now be excluded from the primary analysis of the trial, although Lilly said it will continue to study them.
Enrollment of additional volunteers is expected to complete later this year. Lilly executives said they anticipate the trial will deliver data in early 2023.
"Our base case expectation remains that TRAILBLAZER 1 and TRAILBLAZER 2, together as two positive trials, will be required for approval," Lilly chief scientific officer Dan Skovronsky said in a call with analysts on Monday.
Regulatory developments — particularly the possibility that the FDA could approve a similar drug from Biogen despite mixed data that includes one major trial failure — could still alter Lilly's regulatory strategy, however. The agency is expected to make a decision on Biogen's drug, called aducanumab, by June 7.
Asked by analysts, Skovronsky emphasized the need to show a clear-cut benefit for his company's drug. "[Donanemab] should not be launched in the face of controversial data," he said.
While some analysts had earlier predicted Lilly could submit donanemab for approval on the basis of TRAILBLAZER-ALZ 1 data alone, the detailed results disclosed Saturday appeared to close the door on that possibility.
"The data increases the likelihood of the need for additional studies to obtain FDA approval," wrote Cantor Fitzgerald's Louise Chen, one of those who had suggested a clear data set from TRAILBLAZER-ALZ 1 could support a regulatory submission.
Others were more critical, noting study data showing that, while two-thirds of patients receiving donanemab became "amyloid negative," that effect didn't seem to translate to a large clinical difference.
"The chance of a meaningful clinical effect size from removing plaque is off the table," Brian Skorney, an analyst at Baird, wrote in a March 15 note to clients.
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