Unique Trial Design Expected to be Focus of Upcoming Donanemab Adcomm

Eli Lilly San Diego/iStock, JHVE Photo

Pictured: Eli Lilly's San Diego location/iStock, JHVE Photo

It has been a long road for Eli Lilly’s donanemab—and last Friday, that road got a little bit longer. Lilly had expected a decision from the FDA on its investigational Alzheimer’s drug by the end of 2023. Then, by the end of this quarter. But now, the regulator wants to discuss the drug’s safety and efficacy at a yet–to–be–scheduled advisory committee meeting, leaving open the question of when a final verdict may be rendered.

When a date is set, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee will be looking to glean further insight into donanemab’s safety profile and the potential efficacy implications of Lilly’s “unique” Phase III trial design, according to the company.

Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation, told BioSpace that the FDA’s decision to convene an advisory committee is not wholly unexpected, but the timing of it is. “What was a little surprising is that they’re doing it kind of late in the due diligence process,” he said, speculating that this development could push a decision on donanemab into the summer.

“I actually think it’s a positive thing overall,” Alvaro Pascual-Leone, professor in neurology at Harvard Medical School and medical director at the Wolk Center for Memory Health, Hebrew SeniorLife, said of the upcoming adcomm. “I think that it is a good thing . . .  that the FDA takes these things seriously. I don’t think it means in any shape or form that there are concerns about this medication.”  

In response to BioSpace’s request for comment, an FDA representative said it is the agency’s policy not to discuss pending applications outside the formal advisory committee setting.

The Safety Conversation

In terms of safety, Fillit said the FDA wants to determine whether donanemab’s safety profile is similar to that of Biogen and Eisai’s anti-amyloid antibodies Leqembi and Aduhelm “or if there’s a real problem.”

The biggest strike against this class of Alzheimer’s therapies is the risk of amyloid-related imaging abnormalities (ARIA), or brain swelling. In donanemab’s Phase III TRAILBLAZER-ALZ 2 trial, the incidence of symptomatic ARIA-E was 6.1% with donanemab versus 0.1% in the placebo arm. In Leqembi’s Phase III Clarity AD trial, 2.8% of patients who received Leqembi had symptomatic ARIA-E, while none on the placebo did. However, the trials consisted of different patient populations, so the comparison is not apples to apples.

In another study presented at last week’s AD/PD 2024 conference comparing donanemab and Aduhelm, the incidence of ARIA was lower in patients treated with Lilly’s drug. Occurrence of ARIA (both E and H) was 29% for patients treated with donanemab and 40.6% for those treated with Aduhelm. The rate of symptomatic ARIA-E was also lower in donanemab-treated patients at 2.8% versus 7.2% for people taking Aduhelm.

Fillit said he does not see much difference in the safety profiles of these drugs.

Novel Trial Design

Eli Lilly’s trial design consists of two novel aspects. First, the company enrolled patients based partly on levels of tau in the brain; second, patients were allowed to stop treatment once amyloid was determined to be successfully removed. This feature may have tripped up the company’s bid for accelerated approval of the drug, as fewer than 100 patients were on donanemab for 12 continuous months in Lilly’s Phase II trial, a factor the FDA cited in its Complete Response Letter in January 2023.

The Phase III TRAILBLAZER-ALZ 2 enrolled participants with early symptomatic disease based on cognitive assessments along with amyloid plaque imaging and a relatively new measure called tau staging.

Tau staging had not been used in any previous Alzheimer’s trials, Fillit noted. “I think [FDA] wanted to know whether this kind of technology should be included in the label,” he said. This would have implications for payors and patients, he said, “because tau imaging costs money.”

Fillit said donanemab’s limited dosing regimen is very important. “It demonstrates that patients can be monitored and that efficacy can be demonstrated in terms of removal of amyloid from the brain.” This regimen can potentially reduce side effects and lessen the burden on the patient, he said. At the adcomm, Fillit would like to see a discussion around the role of follow up PET scans to determine if amyloid has indeed been removed.

These two aspects of the trial’s design enable a “really individualized, personalized intervention,” Pascual-Leone said. However, as many patients reached the predefined stopping threshold early, this led to a shorter duration of follow-up, which may have limited insights on longer-term safety and duration of benefits. “It is not the traditional way of assessing efficacy and it does mean that the FDA needs to look at it in different ways,” he said.

In an email to BioSpace, Dawn Brooks, global development leader of donanemab at Eli Lilly, expressed confidence in the design. “The efficacy benefit among those who stopped their treatment at either 6 or 12 months continued to separate from placebo over the course of the trial, suggesting that once amyloid is considered cleared that the efficacy benefit continues,” she said.

Pascual-Leone said he would like to learn how to translate the clinical trial data into individual recommendations for patients. “Does this mean we need to determine amyloid status and tau level? Does it mean that therefore a spinal tap is going to be necessary . . . or would two PET [scans] be needed? It is not straightforward; it is challenging, and it is important to discuss.”

Brooks noted that Eli Lilly included tau assessment as a clinical trial design feature to better inform the stage of disease. Based on the results of TRAILBLAZER-ALZ 2, she said, “[w]e have every reason to believe that people with no or very low tau at baseline may see even better outcomes.”

“It’s exciting times,” Pascual-Leone said, “but I think we need to make sure that we don’t miss the learning opportunity.”

Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

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