An Alzheimer’s Win: How Lilly Designed Donanemab Trial To Succeed
Phase II Results May Support Accelerated Approval
Executive Summary
Lilly took a different path to positive results in Alzheimer’s with a smaller, biomarker-driven study to test the hypothesis that rapid, robust clearance of amyloid could slow disease progression, CEO David Ricks explains at J.P. Morgan.
Eli Lilly and Company has learned a lot about what it takes to fail in Alzheimer’s disease drug development and applied those lessons to its next-generation anti-amyloid antibody donanemab, CEO David Ricks said on the second day of the J.P. Morgan Healthcare Conference. Ricks described how the company used what it learned to design the Phase II TRAILBLAZER clinical trials of donanemab for success, as seen in positive top-line results from the first study, which were reported on the first day of the virtual meeting.
It remains to be seen whether the US Food and Drug Administration and other regulators will be receptive to Lilly’s approach, but Ricks said on 12 January that the company will submit data from the first pivotal Phase II trial to the FDA while continuing to enroll patients in the second pivotal Phase II trial. The company will raise the question of whether accelerated approval based on the completed TRAILBLAZER-ALZ study may be possible with the condition that the Phase II TRAILBLAZER-ALZ 2 trial or a larger Phase III study confirm the prior results.
Donanemab, which targets a modified form of beta-amyloid called N3pG, slowed Alzheimer’s disease progression by 32% relative to placebo, as measured by a composite primary endpoint measuring cognition and function in the 272-patient TRAILBLAZER-ALZ. Results from the roughly 500-patient TRAILBLAZER-ALZ 2 study are not expected until 2023.
The studies are much smaller than the Phase III EXPEDITION clinical trials that tested Lilly’s failed anti-amyloid antibody solanezumab, including the placebo-controlled EXPEDITION 3 trial, which enrolled 2,129 patients. (Also see "Lilly’s Solanezumab Fails, But The Surprise Would Have Been Success" - Scrip, 23 Nov, 2016.)
“We've been involved in running Alzheimer's studies for some time, as you know, and [it has been a] kind of rather dissatisfying exercise to this point,” Ricks said. “I think probably no entity has more experience in looking at failed Alzheimer's trials and trying to improve the framework by which we try to ascertain a benefit for these patients. Then, on the other side, you also have the drug itself.”
The Lilly CEO opted for a fireside chat-style J.P. Morgan presentation rather than the typical slideshow presentation followed by a question-and-answer session, since the company delivered its 2021 guidance to investors on 15 December. (Also see "Lilly’s 2021 Double-Digit Growth Comes From COVID-19 Drugs, New Products" - Scrip, 15 Dec, 2020.)
Finding The Right Trial Design, Population, Drug
“The instruments we use to measure this disease are noisy; they have a lot of rater variation,” Ricks said. “I think we used to believe that the way to run studies was to overcome those things by scale. So one of the criticisms, I think, of the [TRAILBLAZER-ALZ] study is it's small. Actually, I think that's a strength – to show a benefit in a small study is remarkable, because the path in the past was to power up based on getting 800 patients in an arm or whatever to overcome that variability.”
In large trials, like the EXPEDITION studies, there might be a signal of efficacy, but that signal still could be fairly small. Powering up studies by enrolling more patients at more locations also introduced more variability because each site may have carried out the trial with slight differences. Ricks said Lilly moved away from those issues by conducting smaller studies for donanemab that were designed to detect a higher threshold of effect.
The company also enrolled patients more carefully, looking beyond a clinical diagnosis of Alzheimer’s dementia. PET screening was used to identify patients with both amyloid and tau in their brains. They excluded patients with no tau, because there are people who have amyloid with no tau and never develop Alzheimer’s symptoms. Patients with high levels of tau were excluded, because of the likelihood that their disease would progress rapidly.
Ricks said the patient population tested in the TRAILBLAZER studies actually is quite large, since about 70% of Alzheimer’s patients have amyloid plaques, but the trials will help the company determine whether low, medium or high levels of tau in the brain narrows the population that can be effectively treated with donanemab. He estimated that the market would be about half of the overall Alzheimer’s population.
In a same-day note, Mizuho Securities analyst Vamil Divan put the US Alzheimer’s patient population at nearly 6 million, “while globally the number is estimated to be at least 30m-35m, with both numbers expected to continue to grow as the population continues to age.”
Beyond determining the right study design and the right patient population to test the amyloid hypothesis, Ricks explained that the third hurdle was testing the right drug – one that could rapidly and robustly clear amyloid plaques.
In TRAILBLAZER-ALZ, it appears that donanemab fit the bill, because “more than half the people at the end of the study had no measurable plaque” and “actually at the first measurable time point, a significant portion of patients had no measurable plaque,” he said. The more than 80% reduction in amyloid plaque on average for donanemab-treated patients is “better than any other drug we've seen,” he added.
Early Approval Potential Unknown
Risks noted that “the FDA wants to see this data, and we want to show it to them. They have policy levers to rapidly approve drugs. I hope they would look at that here. Of course, that's mostly not been applied in neuroscience; that's been applied in other disease settings, but that's possible. That's their judgment to make, not ours.”
That's why Lilly made a commitment to continue and complete TRAILBLAZER-ALZ 2.
“We think, first of all, these results are strong and reproducible, and we plan to reproduce them,” Ricks said, noting that the second Phase II study may be “tweaked” in some way, such as adding patients in order to collect more safety data or converting the study to a Phase III trial.
In the interim, Lilly will present detailed TRAILBLAZER-ALZ results at the International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD), which is scheduled for 9-14 March. Ricks said the data will be publication simultaneously in a major journal.
As for the timing of data from TRAILBLAZER-ALZ 2, he said that depends entirely on the pace of patient enrollment, which is expected to speed up now that the TRAILBLAZER-ALZ top-line results have generated greater interest in donanemab.
Increasing the second Phase II study’s enrollment is not expected to push results out past 2023, but Ricks said Lilly will talk to regulators about whether they want more or less than 18 months’ worth of data, which is what TRAILBLAZER-ALZ 2 currently is designed to deliver.