Is Alzheimer’s drug donanemab really a 'turning point' for treatment?

The full clinical trial results for an Alzheimer’s therapy called donanemab were released on Monday. While the experimental drug has been hailed as a turning point in treating the condition, questions remain about its effectiveness, safety and practicality.

What is donanemab and how does it work?

Donanemab is an antibody that binds to a protein in the brain called amyloid, which is thought to play a role in Alzheimer’s disease.

Results from a large trial of more than 1700 people found that after 18 months, those who received the treatment had less progression of their dementia symptoms, such as memory loss and confusion, than those who got a placebo. The symptom scores for those who got the treatment were about 30 per cent lower than the people in the placebo group, overall.

What does this mean for people with Alzheimer’s?

The result might sound like good news, but some doctors are urging caution, including in an opinion piece in the journal JAMA that accompanied the results. Concerns mainly centre on the relatively small benefit from the drugs, potentially fatal side effects and practical difficulties in health systems’ capacity to give brain scans – which are necessary before the treatment can begin – to everyone who might benefit.

Is any improvement welcome when it comes to Alzheimer’s?

People who got the drug didn’t improve, they deteriorated at a slightly slower rate than those who had a placebo. Doctors have also questioned whether the degree of slowed deterioration would be noticed by people with Alzheimer’s or their families.

An analysis published in 2019 in collaboration with donanemab’s manufacturer, Eli Lilly, concluded that, for a noticeable effect, a treatment would need to produce at least a 1-point difference on a symptom rating scale. In the latest trial, the 30 per cent figure came from a 0.7-point difference between the donanemab and placebo groups. Eli Lilly, however, has previously said that the 2019 analysis concerned differences between individuals, not the averaged effects on groups of people.

Did any groups in the trial see a greater benefit?

For people in the earliest stages of this sort of dementia – classed as having mild cognitive impairment, not Alzheimer’s itself – there was about a 60 per cent difference between the treatment and placebo groups on another of the rating scales used. However, this figure comes from an analysis of the results presented at the Alzheimer’s Association International Conference in the Netherlands on Monday and hasn’t yet been published in a peer-reviewed paper, so is hard to interpret.

If it stands up, it suggests that, in this group of people, the benefit could nudge into a worthwhile level. However, if the people eligible for treatment have only mild cognitive impairment, not actual Alzheimer’s, that makes it even harder to imagine health systems coping with demand.

Why is health system capacity such an issue?

Before treatment can start, people need a type of brain scan called a PET scan, which can reveal amyloid levels in the brain. The therapy is then given by infusion, which means recipients would need to be taken to a clinic to receive it once a month. They would also need regular brain scans to check for dangerous side effects.

What kind of side effects does donanemab have?

As well as being present within brain tissue, amyloid can be found in the walls of the brain’s blood vessels. When antibodies bind to amyloid here, it can lead to leakage of fluid from the blood, resulting in brain swelling, bleeding and, in a few cases, deaths. In this trial, such brain swelling was seen in 24 per cent of people who got the treatment and in 2 per cent of those who got a placebo.

Is donenemab similar to other amyloid antibodies?

The reported difference in symptom scores for donanemab is similar to the 27 per cent seen with another antibody that was approved in the US this year, called lecanemab. Strictly speaking, the effects of two drugs can only be directly compared by carrying out one trial that includes both treatments.

One clear difference, however, is that Eli Lilly chose a different treatment strategy in this trial of donanemab, by ceasing infusions after PET scans show all amyloid has been cleared from the brain. This happened for about half of participants after one year’s treatment. Such a strategy could potentially reduce treatment costs.

When will donanemab be available?

It depends where you live. In the US, a decision by the Food and Drug Administration is expected by the end of this year, but it is unclear what will happen in countries with more cost-conscious health systems.

In the UK, for instance, once drugs get regulatory approval deeming them safe and effective, they still need to be judged as cost-effective by bodies such as the National Institute for Clinical and Healthcare Effectiveness before they can be used within national health services.

Given that donanemab’s benefits are relatively small and the costs are likely to be high – not only for the drug itself, but also the cost of providing brain scans and infusions – outcomes are uncertain.