Results from the latest amyloid-busting dementia drug trial may spur efforts at earlier diagnosis.
Patients with early Alzheimer’s disease could get an extra seven months of independence using a new drug, but researchers are calling for a cautious approach.
The full, peer-reviewed paper covering the Phase 3 trial of donanemab (Eli Lilly) has confirmed initial efficacy results for the drug announced in a May preprint.
According to the study, published earlier today in JAMA and presented at the Alzheimer’s Association International Conference in the Netherlands, the drug slowed clinical decline across all patients by 22% compared to placebo.
The 76-week trial followed more than 1700 patients, half of whom received a placebo.
Its primary endpoint was change in integrated Alzheimer Disease Rating Scale score, and researchers also measured amyloid plaque burden.
Patients with a moderate or low tau pathology at baseline reaped the most benefit from the drug, with a 35% slowing down of disease progression.
This makes it slightly more effective than competitor Eisai’s drug lecanemab (Leqembi), which slowed decline by 27% in a similar study, according to results published earlier this year.
“With dementia the second leading cause of death of Australians, and the leading cause of death of Australian women, we welcome any steps taken towards improving the lives of people living with dementia, their families and carers,” Dementia Australia CEO Maree McCabe said.
“This research also highlights the importance of early diagnosis so people can access treatment and support as soon as possible.
“We need to raise awareness and understanding of dementia to reduce discrimination and stigma so we can ensure people with concerns about their cognition are seeking information and support as early as possible.”
Earlier this month, the US Food and Drug Administration granted traditional approval to lecanemab for use in Alzheimer’s.
It’s the first monoclonal antibody targeting dementia to do so; its predecessor, aducanumab (Aduhelm, Biogen), was given accelerated approval in late 2021.
It was a controversial move that saw a number of independent FDA advisors quit in protest.
In early June this year, Australia’s drug regulator ultimately elected to reject Biogen’s application for aducanumab to be made available in Australia.
Implications for general practice
An Eli Lilly spokesman confirmed with The Medical Republic that a regulatory submission to the TGA was imminent and plans for a PBS listing were under way.
The pharmaceutical company did not comment on how the drug would be priced but emphasised that it would be seeking a listing on the PBS as soon as possible.
Geriatric psychiatrist Associate Professor Steve Macfarlane, who ran a clinical trial site in Melbourne as part of the donanemab study, estimated that the drug would cost around $39,000 per year without subsidy.
“The PBS is going to be the stumbling block,” he told TMR.
In the meantime, given that both lecanemab and donanemab were most effective in patients near the beginning of the disease course, he said that GPs could look out for patients showing early signs of cognitive decline.
“It’s my perception, in private practice, that GPs are reluctant to refer because the perception is there’s nothing that can be done anyway,” Professor Macfarlane said.
“We know from Dementia Australia data that there’s about a three-year delay between symptoms being noticed by the person and the diagnosis being given. Two years of that delay [tends to be] before they actually see the GP to raise their concerns.”
If the drugs get a PBS listing, he added, the eligible population is most likely to resemble the low- and moderate-tau cohort that responded better in the trial.
“Perhaps … GPs can change their clinical practice by referring people on for early evaluation, with the hope that they will be suitable to get one of these drugs,” said Professor Macfarlane.
“But … until it’s on the PBS, it won’t be widely available.”
On the other hand, Professor Macfarlane also noted that treatment with donanemab would not necessarily be long term for most patients; the amyloid levels in about half of patients had reduced below the Alzheimer’s diagnosis threshold within 12 months, and in three-quarters of patients at 18 months.
“It’s not necessarily going to be an indefinite cost burden for the next 10 years once you go on,” he said. “There’s a good chance that you can stop treatment once the amyloid has been cleared from your brain, which might be 18 months in the majority of cases.”
False hope and other adverse events
Other researchers cautioned against moving too fast.
“The full published version [of this trial] is slightly different from the rather breathless press release put out by Eli Lilly,” University of Adelaide molecular pharmacologist Dr Ian Musgrave told TMR.
While he acknowledged the results were positive and robust, Dr Musgrave said he was curious to see how it performed in an undifferentiated population.
The progression of patients on donanemab, he noted, falls off after about 36 weeks and the average hippocampal volume continued to decrease across patients.
“If we’re going to do wide screening [for early Alzheimer’s], you’re going to have to be sure that screening will result in meaningful change,” Dr Musgrave said. “[At its worst,] screening causes people to be extremely stressed and will have no benefit.”
There’s also the potential for serious adverse events, which affected about 17% of the donanemab cohort and 16% of the placebo group.
Like lecanemab and aducanumab before it, donanemab is associated with amyloid-related imaging abnormalities (ARIA).
Three people in the treatment arm of the trial died following serious ARIA-related incidents.
“Further evaluation of the risks associated with serious and life-threatening amyloid-related imaging abnormalities will be important to identify the best approaches for managing risks and maximising benefit, in addition to earlier treatment of the disease when less amyloid pathology is present and, theoretically, when amyloid-related imaging abnormalities risk is lower,” the researchers wrote in JAMA.
Alzheimer’s researcher Associate Professor Lyndsey Collins-Praino, from the University of Adelaide, was also cautious about celebrating too soon.
“The safety profile – there are still questions around that, particularly when used on a larger scale than in this trial,” she told TMR.
“There’s questions around long-term benefit, because they do stop treatment once the amyloid plaques have been removed, but we know from the research literature that cognitive decline isn’t really tied to amyloid plaque burden, it’s more tied to tau tangles.”
While the results were clearly positive, Professor Collins-Praino said, it will be important to remember that they still amount to just four or seven months of slowed deterioration.
“When we’re dealing with people with dementia and their caregivers, yes, we want to offer hope,” she said. “But we don’t want to offer false hope.”
