What’s Next for Eli Lilly Alzheimer’s Drug Donanemab? Trial Enrollment Continues

This weekend, Eli Lilly and Company presented detailed results of its phase 2 TRAILBLAZER-ALZ trial, showing that its investigational drug donanemab — monoclonal antibody for treatment of early symptomatic Alzheimer’s disease — met its primary endpoint, slowing cognitive decline in symptomatic early-stage Alzheimer’s patients nearly a third more than those in the placebo group.

Being Patient checked in with Dr. Pierre Tariot for his thoughts on this weekend’s news. Director of the Banner Alzheimer’s Institute since its founding in 2006, Tariot has worked extensively as supporter or a consultant in research efforts related to the development of Alzheimer’s treatments with major drug developers across the pharmaceutical industry; his expertise focuses especially on the design and implementation of Alzheimer’s-related clinical trials.

With more than 100 investigational Alzheimer’s drugs currently in the pipeline, and a 99-percent failure rate in human trials so far, Alzheimer’s researchers have seen their share of disappointments. But Tariot said the newest data from Eli Lilly offers cause for optimism: “I confess that I did not expect to see a win on the primary clinical outcome,” he told Being Patient.

“This was, in a sense, a scientifically aggressive design,” Tariot said of Eli Lilly’s TRAILBLAZER-ALZ trial. “I personally am quite encouraged that this led to a positive outcome on the primary outcome in a relatively small (but nonetheless adequately powered) Phase 2 clinical trial.” 

How does Alzheimer’s drug donanemab work, and what does it do?

In the brains of people with Alzheimer’s disease, a protein called beta-amyloid clumps together forming plaques. While it’s still unclear whether this protein plaque is the cause of Alzheimer’s, or just a symptom, its presence is closely linked to the disease’s symptoms. Donanemab was developed to clear these beta-amyloid plaques, by targeting a specific plaque-associated type of beta-amyloid called N3pG. 

According to Lilly, six months after starting treatment, donanemab was indeed achieving what it set out to do: The drug “has been shown to rapidly result in high levels of amyloid plaque clearance, as measured by amyloid imaging,” the company said in a January press release, and that outcome held up in the new batch of data. Trial results show that 40 percent of study participants who had been administered the drug had achieved “amyloid negativity,” and after 18 months of treatment, the proportion of participants with amyloid negativity had increased to 68 percent. 

Data from secondary analyses showed that absence of amyloid mirrored the slowing of cognitive decline, with ranges between 20 to 40 percent in all secondary endpoints. Beyond the thwarting of cognitive decline, participants also underwent four other tests of their memory and functional abilities, all of which demonstrated positive trends, although the significance was statistically nominal compared to the placebo. 

“I confess that I did not expect to see a
win on the primary clinical outcome.”

Donanemab also appeared to slow the development of another key Alzheimer’s biomarker: the accumulation of tau tangles in the brain. While the drug slowed down the appearance of these tangles, it didn’t reduce them in number. The researchers to believe that tau may take longer to change than amyloid, and they need more than the 18-month follow-up period in this study to note significant differences. 

According to Tariot, this degree of reduction in cognitive decline — 32 percent better than participants on a placebo — is considered a ‘clinically meaningful’ difference, although he said this interpretation “will require further scrutiny.” 

“The details are unknown,” he said, “but this sounds encouraging. The amount of brain amyloid reduction is impressive.” 

Is donanemab safe?

While it appears donanemab’s safety and tolerability are viable so far, Tariot said there is still more to be learned. Anti-amyloid monoclonal antibody drugs like this one are sometimes accompanied by a side effect called amyloid-related imaging abnormality-edema, or ARIA-E. According to Tariot, ARIA-E probably represents a form of fluid leakage into brain tissue.

Lilly reported that 27 percent of patients in the TRAILBLAZER-ALZ trial experienced some degree of ARIA, and 6 percent experienced ARIA-related symptoms like headache, nausea and vision problems.

Tariot said that so far, this looks like a relatively low extent of ARIA-E relative to the amount of amyloid lowering.

However, he added, it is yet to be learned how many patients will ultimately have had to drop out of the trial because of ARIA: “We do not know how many people were taken off treatment, nor do we know how they fared subsequently,” he said. “We need to see the details, and need to learn whether it is possible to ‘power through’ the ARIA, as is the case for some other therapies.” 

This will shed light on the drug’s tolerability, which will be key to its success as a treatment.

What are the next steps for Eli Lilly and donanemab now?

Eli Lilly’s TRAILBLAZER-ALZ study set out to address both cognition and daily function, using PET imaging to look at both amyloid and tau burdens in order to select participants at a super-precise stage in the disease’s development. Once their amyloid levels lowered to below the threshold required for trial participation, they were dropped from the trial. This precision was innovative, and researchers believe it has contributed to donanemab apparent success so far.

“All in all, especially taken in the context of progress with other monoclonal antibodies targeting amyloid, the results certainly justify further development of the drug — and provide support for the notion that the right form of anti-amyloid therapy, in the right patients at the right stage of disease, might prove effective,” Tariot said. 

But further research is needed: “We need to learn what happened to people after their brains were ‘rinsed,’ so to speak, of amyloid, and how many people this represented,” he added. “We need to learn what other clinical outcomes looked like and whether any baseline characteristics, like degree of tau burden, predicted good or poor clinical response.”

He added that researchers are curious to learn to what extent the biomarker changes — slower tau accumulation and reduced beta-amyloid — correlated to actual clinical changes. “And,” he said, “we need to learn more about ARIA and perhaps other safety issues.”

All of this is done through further trials, four out of five of which lag due to difficulty in finding participants.

Eli Lilly will issue an update on the TRAILBLAZER trial program via webcast Monday morning March 15 at 10:30 AM EDT, including further information on the ongoing TRAILBLAZER-ALZ 2 trial which continues to seek new participants.