Donanemab (Eli Lilly), an investigational anti-amyloid therapy, significantly slowed decline in a composite measure of cognition and daily function in patients with early symptomatic Alzheimer's disease (AD) in the phase 2 TRAILBLAZER-ALZ study, the company has announced.
Donanemab met the primary endpoint of change from baseline to 76 weeks in the Integrated AD Rating Scale (iADRS), slowing decline by 32% relative to placebo.
The iADRS combines the 13-item AD Assessment Scale–Cognitive and AD Cooperative Study–Activities of Daily Living Inventory.
Donanemab also led to consistent improvements in all prespecified secondary endpoints regarding cognition and function compared to placebo, although nominal statistical significance was not reached on every secondary endpoint, the company said.
"We are extremely pleased about these positive findings for donanemab as a potential therapy for people living with Alzheimer's disease," Mark Mintun, MD, vice president of pain and neurodegeneration at Lilly, said in the news release announcing the topline results.
"In addition, we are committed to reproducing and extending these important findings in our second ongoing pivotal donanemab trial, TRAILBLAZER-ALZ 2," said Mintun.
Donanemab targets a modified form of beta amyloid called N3pG. Amyloid imaging has shown that the drug rapidly leads to "high levels of amyloid plaque clearance," the company said.
The TRAILBLAZER-ALZ study is a randomized, placebo-controlled, double-blind, multicenter phase 2 study testing the safety, tolerability, and efficacy of donanemab in 272 patients with early symptomatic AD. Patients were selected for the trial on the basis of cognitive assessments in conjunction with amyloid plaque imaging and tau imaging.
According to the company, donanemab-treated patients, on average, showed an 84 centiloid reduction of amyloid plaque at 76 weeks compared to a baseline of 108 centiloids.
Less than 25 centiloids is typical of a negative amyloid scan. Patients in the study stopped receiving donanemab and were switched to placebo once their plaque level fell below 25 centiloids on two consecutive measures or below 11 centiloids on any one measure.
"This unique mechanism and antibody for clearing plaques, discovered at Lilly, has the potential to provide high levels of durable amyloid plaque clearance after limited duration dosing," Daniel Skovronsky, MD, PhD, chief scientific officer at Lilly and president of Lilly Research Laboratories, said in the release.
The positive results in TRAILBLAZER-ALZ "give us confidence in donanemab and support its rapid and deep plaque clearance for the potential treatment of Alzheimer's disease," said Skovronsky.
The safety profile of donanemab was consistent with observations from phase 1 data, with observed amyloid-related imaging abnormalities (ARIA) consistent with amyloid plaque clearing antibodies.
In the donanemab treatment group, ARIA related to edema (ARIA-E) occurred in 27% of treated participants. The overall incidence of symptomatic ARIA-E was 6%.
Lilly plans to present full results of the TRAILBLAZER-ALZ study at a future medical congress and to submit the results for publication in a peer-reviewed clinical journal, the announcement notes.
Encouraging Preliminary Data
In a statement, Maria Carrillo, PhD, chief science officer for the Alzheimer's Association, said, "On behalf of the more than 5 million Americans living with Alzheimer's, the Alzheimer's Association is encouraged by these preliminary data. We look forward to seeing the results of a second, larger phase 2 trial, which is currently recruiting.
"There are several innovative aspects of this trial, which may indicate how Alzheimer's clinical trials will be conducted ― and even accelerated ― in the future," Carrillo said.
Rebecca Edelmayer, PhD, director of scientific engagement for the Alzheimer's Association, elaborated on this point in an interview with Medscape Medical News.
"What we've learned from past trials is that we need to look not only at changes in an individual's cognition and their activities of daily living but truly understand the biological changes that are occurring with treatment to understand whether or not these drugs are going to be effective," Edelmayer said.
An interesting aspect to this trial, she said, is that patients stopped taking donanemab and were switched to placebo once their amyloid plaque level was considered normal.
"There are many questions that we still have around this particular therapeutic. How long do you have to take the drug, and at what frequency? With the way they designed the trial, some of those questions may be answered by this trial and the larger phase 2 trial still underway," she said.
Regarding the big picture, Edelmayer said, "There is still a lot of conversation about what is the right target. This is a complex disease, and we know that there's likely not going to be one silver bullet to treat Alzheimer's and many other dementias. But as we learn more about the biology of the disease, we will understand how to target it.
"I think amyloid in some way will certainly play a role in treatment, but we're likely looking at essentially combination therapies as a way to treat Alzheimer's and also with risk reduction strategies that can help individuals to stave off the disease and also potentially slow down a trajectory," she said.
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Cite this: Positive Topline Data for Lilly's Donanemab in Early Alzheimer's - Medscape - Jan 11, 2021.
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