Another win for donanemab in TRAILBLAZER Alzheimer’s trial

In the phase III TRAILBLAZER-ALZ 2 study, donanemab significantly slowed clinical progression in individuals with early symptomatic Alzheimer’s disease* (AD) with amyloid and tau pathologies, demonstrating an important replication of the phase II findings.

At week 76, in the low/medium-tau group, adjusted mean change in iADRS** score was –6.02 with donanemab and –9.27 with placebo. This yielded a difference of 3.25 (p<0.001) and represented a 35-percent slowing of disease progression. “[This is] the largest treatment effect to date,” reported Dr John Sims from Eli Lilly and Company, who presented the efficacy findings at AAIC 2023.

Corresponding changes in CDR-SB*** were 1.20 and 1.88 (difference, 0.67; p<0.001), representing a 36-percent slowing of disease progression with donanemab.

In the combined-tau group, there was a 22-percent slowing of decline by week 76. “This was driven more by the rapid decline in the placebo arm rather than a loss of absolute treatment difference. This is illustrated more dramatically when looking at CDR-SB [29-percent slowing],” said Sims.

Treatment effect continued to widen even after patients transitioned to placebo (difference, 3.52; p<0.001 [iADRS] and 0.75; p<0.0001 [CDR-SB]). Most of donanemab recipients were already off treatment after week 47 yet the curves continued to separate over time, he said.

Secondary outcomes

Improvements in the function (ADCS-iADL^#) and cognition (ADAS-Cog₁₃^#) iADRS subscales were seen as early as week 12 and continued until week 76 in the low/medium-tau group (difference, 1.83 and 1.52, respectively). These translated to 40- and 32-percent slowing of functional and cognitive decline, respectively.

The risk of progressing to the next disease stage (CDR – Global score) was lower by about 40 percent with donanemab vs placebo over 76 weeks in both low/medium-tau (hazard ratio [HR], 0.61; p<0.001) and combined-tau groups (HR, 0.62; p<0.0001). Of note, there is a greater progression rate in the combined-tau group given the greater pathology, yet the treatment effects were similar.

“The efficacy of donanemab extends into the broader combined population, hopefully leaving no AD patient behind,” said Sims. “Overall, these data support and hold promise for studies in the preclinical stage of AD.”

Biomarker improvements

Week 24 saw a third of donanemab recipients in the low/medium-tau group achieving amyloid clearance. By week 76, 80 percent had already achieved this outcome. None in the placebo group were able to achieve this outcome (p<0.0001 for between-group comparisons at both timepoints).

Baseline plasma P-tau217 level in the low/medium-tau group dropped with donanemab at week 76 whereas with placebo, an increase was observed (–39.3 percent vs 8.4 percent; p<0.0001).

These effects were mirrored in the combined-tau group.

Safety findings

There were similar rates of serious adverse events (AEs) between the donanemab and placebo arms (17.4 percent vs 15.8 percent). The most common AEs tied to donanemab were ARIA-E^## and ARIA-H^## (24 percent and 20 percent, respectively).

Although ARIA-E events were usually transient and asymptomatic, serious and fatal cases can occur, noted Dr Stephen Salloway from the Alpert Medical School of Brown University, Providence, Rhode Island, US, who presented the safety findings. In the study, three donanemab recipients died owing to serious ARIA.

Early treatment warranted

A total of 1,736 participants (n=1,182 [low/medium tau] and 552 [high tau]) were randomized 1:1 to IV donanemab or placebo Q4W for 72 weeks. Donanemab was initially given at a dose of 700 mg (three doses) then 1,400 mg thereafter. The higher dose was sustained until the end of the trial unless amyloid clearance was achieved prior to study end.

“With this fuller picture, there is additional, convincing scientific evidence that thoroughly removing beta amyloid from the brain is associated with significant slowing of disease progression in people living with early AD,” commented Alzheimer’s Association Chief Science Officer Dr Maria Carrillo in a press release.

Despite similar magnitudes of responses, the effects were greater in the low/medium-tau group. “[This suggests] that initiating treatment as early as possible enables the possibility of a bigger beneficial effect,” Carillo added. “These benefits are real and meaningful, giving people more time to participate in daily life, remain independent, and make future healthcare decisions.”