Eli Lilly’s investigational antibody donanemab met all of its primary and secondary endpoints in the Phase III TRAILBLAZER-ALZ 4 study, the company announced Wednesday.
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Eli Lilly’s investigational antibody donanemab met all of its primary and secondary endpoints in the Phase III TRAILBLAZER-ALZ 4 study, the company announced Wednesday.
The data, presented at the 15th Clinical Trials on Alzheimer’s Disease (CTAD) conference, showed 37.9% of donanemab-treated patients achieved brain amyloid plaque clearance at 6 months, defined as plaque levels lower than 24.1 Centiloids. Meanwhile, only 1.6% of comparators treated with Biogen and Eisai’s Aduhelm (aducanumab) met this efficacy mark.
Donanemab also outperformed Aduhelm in the second co-primary endpoint, which was brain amyloid clearance at 6 months in the subpopulation of patients with intermediate tau levels.
With nearly 150 patients enrolled and randomized to receive one of two anti-amyloid antibodies, TRAILBLAZER-ALZ 4 is the first study to present active-comparator data regarding the clearance of plaques in patients with early-stage and symptomatic disease. At 6, 12 and 18 months, patients underwent positron emission tomography scanning to assess donanemab’s efficacy vs Aduhelm.
Analysis of a key secondary endpoint also revealed that at 6 months, 65.2% of donanemab-treated patients saw a drop in brain amyloid levels relative to baseline, while Aduhelm was able to achieve this benchmark in only 17% of its treated participants. Plasma P-tau217 levels were also significantly lowered after donanemab treatment after 6 months, but not after Aduhelm administration.
In terms of safety, amyloid-related imaging abnormalities (ARIA) occurred in comparable rates between the trial interventions: 25.4% in donanemab and 26.1% in Aduhelm. Symptomatic ARIA was documented in 2.8% and 4.3% of the respective arms.
Lilly announced in August that the FDA accepted donanemab’s regulatory application under the accelerated approval pathway. Meanwhile, TRAILBLAZER-ALZ 4 is ongoing, with 12-month and 18-month data expected in the future.
As part of the accelerated approval pathway, Lilly is also running TRAILBLAZER-ALZ 2, the confirmatory study for donanemab, Dawn Brooks, Ph.D, global development leader of donanemab and remternetug at Lilly, told BioSpace. Results are expected mid-next year.
In the Shadow of Lecanemab
While Lilly’s donanemab posted impressive results at CTAD, lecanemab, also from Eisai and Biogen, commanded most of the attention, with four back-to-back presentations at the conference.
In September, Eisai and Biogen first announced that lecanemab, also an investigational antibody, was able to slow the progression of Alzheimer’s disease by 27% compared with placebo. Like Aduhelm and donanemab, lecanemab targets amyloid beta protofibrils.
Lecanemab’s success reinvigorated the industry’s interest in the amyloid approach to Alzheimer’s disease, which at the time had been suffering from Aduhelm’s disappointing market performance and a slew of controversies of doctored data.
“The positive Phase III results on lecanemab delivered good news for people with Alzheimer’s disease,” Brooks said, adding that Lilly’s findings also support an important implication of lecanemab’s data: “that removal of amyloid plaque is linked to slowing of cognitive decline” in early Alzheimer’s.
Data from the TRAILBLAZER-ALZ study, Brooks continued, suggest that donanemab may differentiate itself from lecanemab by offering “the possibility to stop treatment with donanemab once plaque is considered cleared.”
Still, lecanemab has encountered its fair share of issues. In October, a study investigator who chose to remain anonymous linked a patient death to the investigational antibody. A second death was similarly connected with lecanemab, according to an assessment by an outside expert. Both deaths were due to bleeding in the brain.
