Donanemab data an “important advance” in Alzheimer’s
The full data from the TRAILBLAZER-ALZ 2 trial of Eli Lilly’s amyloid drug donanemab has confirmed the top-line results reported in May, but also new findings that reinforce its benefits in Alzheimer’s disease.
An update presented at the Alzheimer's Association International Conference (AAIC) today confirmed the earlier readout that donanemab slowed the decline in cognitive function compared to placebo by 35% using the iADRS scale and 36% using the CDR-SB scale.
New information from the study is that participants with earlier-stage Alzheimer’s had the greatest benefit – a 60% improvement with donanemab compared to the control group on the iADRS and 46% on the CDR-SB scales - and nearly half (47%) of them showed no signs of clinical progression at one year.
The new data also showed that the beneficial treatment effect continued to increase compared to placebo over the course of the trial, with the greatest difference seen at 18 months, even though treatment with donanemab was only continued until amyloid plaques in the brain were cleared.
“The delay of disease progression over the course of the trial is significant and will give people more time to do such things that are meaningful to them,” said Liana Apostolova of Indiana University School of Medicine, one of the TRAILBLAZER-ALZ 2 investigators.
7.5 months gained
On average, the slowdown in cognitive decline meant that patients had an extra seven and a half months before they reached the same level of decline as the control group.
There were also better results in patients aged under 75, and the effects of the drug were similar regardless of whether they carried an ApoE4 gene mutation, which is a risk factor for Alzheimer’s disease. However, donanemab had little effect in people with high levels of tau protein, who are likely to be in more advanced stages of Alzheimer’s.
“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 Alzheimer’s,” commented Maria Carrillo, chief scientific officer at the Alzheimer’s Association.
Treatment with donanemab reduced amyloid plaque burden on average by 84% at 18 months, compared with a 1% decrease for participants on placebo. Around half of the patients taking the antibody were able to stop treatment at 12 months, rising to around 70% at 18 months, pointing to the potential for intermittent treatment with off-drug ‘holidays’ that could limit side effects and potentially reduce costs.
On that score, the level and severity of potentially life-threatening amyloid-related imaging abnormalities (ARIA) – a recognised risk with amyloid drugs – were consistent with the earlier readout, according to the investigators. The side effects could, however, be managed with monitoring and removal from treatment if necessary.
Crucially, the data is consistent with and reinforces the positive results seen with Eisai and Biogen’s amyloid-targeting drug Leqembi (lecanemab) in the CLARITY-AD study, which led to the drug becoming the first drug in the class to secure full FDA approval.
With pivotal trials now showing clinical benefits on cognition, as well as functional scores, there is now greater confidence that targeting amyloid can have a true, disease-modifying effect.
The data ties in with the long-held assumption that early treatment will be key to unlocking the greatest benefit of these drugs, but also that there is potential to slow disease progression even when treatment is started later on.
FDA filing completed
Lilly said that its marketing application for donanemab with the FDA is now complete, and it is hoping to hear the regulator’s verdict before the end of the year. Filings in other regions are also underway, said the drugmaker.
“If approved, we believe donanemab can provide clinically meaningful benefits for people with this disease and the possibility of completing their course of treatment as early as 6 months once their amyloid plaque is cleared,” said Anne White, head of Lilly’s neuroscience unit.
The presentation of the data at the AAIC was accompanied by simultaneous publication in the Journal of the American Medical Association (JAMA).
Prof Gill Livingston, professor of psychiatry of older people at University College London (UCL) in the UK, said the trial was “well conducted” and shows that “in the short term, these drugs help a little in the populations tested,” but notably excluded people with other concurrent illnesses and those aged over 85.
“We do not know if the treatment will continue to make more difference over a longer period,” she added. “Thus, it is a beginning and important, but with a small change in a relatively physically well population and significant side effects, there is still a lot of work to do to know what it means for most people with Alzheimer’s dementia.”