Earlier this year, Eli Lilly and Company announced positive results from a Phase 3 clinical trial of their new Alzheimer’s drug, donanemab. The statement was compelling, detailing how almost half of the trial participants had not seen their disease worsen in the year since beginning the treatment. However, experts called for caution until the complete trial data were published. Today, those data were released in a peer-reviewed study.
The trial originally recruited 1,736 people who were experiencing the early symptoms of Alzheimer’s disease. Half of the group received monthly infusions of the drug for a total period of 72 weeks, while the other half received a placebo. Clinical follow-up at 76 weeks showed that the treatment led to significantly slowed disease progression.
The impact was felt most in patients with lower levels of the pathological protein tau, known to be a hallmark of Alzheimer’s disease that builds up over time. When this subset of patients was combined in a wider group with those with higher levels of tau, the overall result remained statistically significant. This is not surprising, as it's always been thought that these types of drugs are likely to work best if given as early as possible in the disease course.
The fact that donanemab, as well as the similar drugs aducanumab and lecanemab – the latter of which received full Food and Drug Administration (FDA) approval only this month – are of limited benefit to those with advanced disease was highlighted by UCSF Alzheimer’s Disease Research Center director Gil Rabinovici and colleague Renaud La Joie, in an editorial published alongside the trial results.
They wrote that these types of therapies – a class of drugs called monoclonal antibodies – could be “just the opening chapter in a new era of molecular therapies” for Alzheimer’s, and cautioned that “development of more impactful and safer treatments is still needed.”
Indeed, even as these drugs are being brought to market, research into a wealth of other ways of preventing and treating Alzheimer’s is continuing, from gene therapy, to lifestyle modifications, to vaccines.
But while it’s unlikely any one single treatment could ever be suitable for all patients, the confirmation that donanemab does indeed appear to slow disease progression in some is still being hailed as a breakthrough.
“Today’s full results support what we heard about donanemab back in May, that the drug is able to slow down the progression of Alzheimer’s disease by more than 20%,” explained Dr Richard Oakley, Associate Director of Research at charity Alzheimer’s Society, in a statement. “This study adds to the growing evidence that treating people as early as possible may be more beneficial, with the effects of donanemab greater in people who were at an earlier stage of the disease.”
Thankfully, advances elsewhere may also mean that catching the disease promptly could be about to get easier, as new diagnostic guidance points to the use of blood biomarkers as a tool to look for evidence of Alzheimer’s in people with the earliest cognitive symptoms.
No medical treatment is without risk. In the donanemab trial, three participants who were diagnosed with a condition called amyloid-related imaging abnormalities (ARIA) – a known risk with these types of therapies – subsequently died. While death and serious adverse effects were rare occurrences, mild side effects were much more common. Since the risk of ARIA appears to be higher in patients with certain genetic mutations, Rabinovici and La Joie suggest that genetic testing could be a useful step before starting these treatments.
Another limitation of the trial is that the majority of the participants were white. Dr Oakley pointed out that it is “crucial that in future trials we see more diversity to prove that new drug treatments have similar effects for everyone living with Alzheimer’s disease.”
If donanemab goes on to receive FDA approval, something experts have suggested is likely, it will only be the third such drug made available for wider use. One of these, aducanumab, has already been rejected by the European regulator over safety and efficacy concerns. But whatever happens next, there’s no denying the publication of the results is an important moment in the fight against this disease.
As Dr Susan Kohlhaas, Executive Director of Research & Partnerships at Alzheimer’s Research UK, put it in a statement, the results are “another milestone”, one which underscores that “the outlook for dementia and its impact on people and society is finally changing.”
The study, along with associated editorials, is published in the Journal of the American Medical Association.