Gantenerumab 'shows sign of preventing Alzheimer's dementia'
Randall Bateman, MD, Charles F and Joanne Knight Distinguished Professor of Neurology at WashU Medicine.
A study of Roche's anti-amyloid drug gantenerumab has suggested that early treatment to remove amyloid plaques from the brain years before symptoms arise may delay the onset of Alzheimer's dementia – although some specialists have urged caution in interpreting the data.
The finding comes from an open-label extension of the phase 2/3 DIAN-TU trial of gantenerumab that looked at a group of 73 people with rare, inherited genetic mutations that cause the overproduction of amyloid in the brain that generally lead to the development of Alzheimer's in middle age.
The study found that – in a subgroup of 22 subjects with no sign of cognitive problems at the study's outset, who had received Kisunla for an average of eight years – the drug reduced the risk of developing symptoms from 100% to about 50%. The results have been published in The Lancet Neurology journal.
"Everyone in this study was destined to develop Alzheimer's disease and some of them haven't yet," said senior author Randall Bateman of Washington University School of Medicine, which ran the study.
"We don't yet know how long they will remain symptom-free – maybe a few years or maybe decades," he added. "In order to give them the best opportunity to stay cognitively normal, we have continued treatment with another anti-amyloid antibody in hopes they will never develop symptoms at all."
The positive funding comes despite DIAN-TU missing its primary readout in 2020, with neither gantenerumab nor another anti-amyloid drug – Eli Lilly's now defunct solanezumab – showing a benefit on cognition.
Roche has also abandoned the development of gantenerumab. However, since DIAN-TU's first readout, two amyloid-targeting drugs have reached the market for Alzheimer's – Eisai/Biogen's Leqembi (lecanemab) and Lilly's Kisunla (donanemab) – and, while initial take-up has been slow, their developers are still predicting blockbuster sales at peak.
The authors concede that the study is small and limited by the open-label design, saying the funding needs to be confirmed in long-term trials, but add that it helps support the amyloid hypothesis of Alzheimer's, which holds that the first step on the road to dementia is the build-up of amyloid plaques in the brain and removing them can stop symptoms emerging.
One commentator – Professor Robert Howard, an expert in old age psychiatry at UCL in the UK – warned, however, that the claims made in the press release accompanying the study are not supported by the data and could result in false hope for patients with inherited forms of Alzheimer's and their families.
"No responsible clinical trialist should claim on the basis of [this] data to have shown a 50% lowering of the risk of developing dementia symptoms," said Prof Howard. "If you look at the wording of the summary of the published paper, you will see that such a claim does not appear, as presumably the scientific peer reviewers and editorial staff would not have permitted such a misleading overstatement to be published in the journal."
Dr Richard Oakley, associate director of research and innovation at Alzheimer's Society, also said the results should be treated with caution, but "hint" that long-term anti-amyloid treatments, started before Alzheimer's symptoms appear, may potentially delay symptom onset.
"Longer-term follow-up of this group and larger studies will tell us more about the effect of these drugs in these types of Alzheimer's," he suggested.
The researchers behind DIAN-TU are continuing the study with Leqembi treatment, although, data from this stage is not yet available and the progress of the study may depend on NIH grant funding, which is still under review – and may or may not materialise given the disruption and cost-cutting at US federal agencies under President Trump.
Some funding for the study has been provided by the Alzheimer's Association, whose chief science officer and medical affairs lead - Maria Carrillo – said: "Discoveries like this convincingly illustrate why it is so important for research into Alzheimer's and all diseases that cause dementia to continue, expand, and accelerate."
