The amyloid plaque targeting therapy met primary endpoint and all secondary endpoints, which Lilly will use in its submission to the FDA this quarter.
Pictured: Red and white Lilly sign on building/MichaelVi/Adobe Stock
Data from the Phase III TRAILBLAZER-ALZ 2 study showed Eli Lilly’s investigational amyloid plaque targeting therapy donanemab met its primary efficacy endpoint, significantly slowing down cognitive and functional decline in patients with early symptomatic Alzheimer’s disease (AD), the company announced Wednesday.
Using these data, Lilly will engage the regulatory bodies “as quickly as possible,” according to the company’s press release. The expectation is for the company to make a submission to the FDA this quarter.
In TRAILBLAZER-ALZ 2’s main target population, AD patients with intermediate levels of the tau protein, donanemab treatment slowed cognitive and functional deterioration by 35% relative to placebo, as measured by the integrated Alzheimer’s Disease Rating Scale (iADRS). In the study’s overall population, the investigational therapy slowed decline by 22%.
Originally developed by Lilly, the iADRS combines two widely accepted measures in the AD space: the Alzheimer’s Disease Cooperative Study–instrumental Activities of Daily Living (ADCS-iADL) and the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog).
The iADRS assesses patients using their scores in an extensive cognitive battery based on how well they can perform key daily tasks, such as driving, holding conversations and managing finances.
Aside from iADRS, TRAILBLAZER-ALZ 2 also employed another, more commonly used tool to measure cognitive decline, the Clinical Dementia Rating-Sum of Boxes (CDR-SB). On this scale, donanemab slowed deterioration by 37% in the intermediate-tau group and by 29% in the overall study sample, as compared with placebo.
Donanemab also was significantly better than placebo when assessed using the two-component scales of iADRS: ADAS-Cog and ADCS-iADL.
Alongside its cognitive and functional effects, donanemab also significantly lowered amyloid plaque levels in the brain as early as six months after treatment initiation.
As for safety, Lilly documented several cases of amyloid-related imaging abnormalities (ARIA) in donanemab-treated patients, though most were mild to moderate in severity and were resolved following treatment. ARIA is a common side effect of medicines that clear amyloid plaques, according to the company.
ARIA manifesting as temporary brain swelling was reported in 24% of donanemab recipients, with 6.1% showing symptoms. Meanwhile, ARIA with microhemorrhages arose in 31.4% of patients treated with the investigational therapy and in 13.6% of placebo counterparts.
Two patient deaths were conclusively attributed to ARIA, while a third fatality occurred after a serious ARIA episode, though was not explicitly linked to it.
These data set Lilly up for an Alzheimer’s showdown with Biogen and Eisai, whose Leqembi (lecanemab) won accelerated FDA approval in January. In September 2022, the partners surprised the biopharma industry and revived the anti-amyloid theory in AD when their therapeutic antibody significantly slowed disease progression in the late-stage CLARITY AD trial.
The FDA is set to decide on whether to grant Leqembi full approval in July. A Peripheral and Central Nervous System Drugs Advisory Committee is scheduled for June 9.
Lilly had also previously tried for the FDA’s accelerated pathway but was rejected in January 2023. In its Complete Response Letter, the regulator flagged the low number of patients that had been on donanemab for at least 12 months. At the time, the FDA also indicated it would need additional unblinded controlled safety data from a Phase III study.
Tristan Manalac is an independent science writer based in metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.
