World Alzheimer’s Month: Learning from lecanemab and donanemab to develop better, safer treatments

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In the past year, we have seen unprecedented progress in Alzheimer’s research, as two new drugs, lecanemab and donanemab, showed for the first time that the disease can be slowed. Hailed as a ‘chink in the armour’ and ‘the beginning of the end’ by scientists, news of the drugs was met with great excitement by many. Proving it is possible to alter the course of the disease, the new drugs are a beacon of hope for the millions affected by Alzheimer’s.

The treatments work by reducing the amount of harmful amyloid protein, which builds up in clumps known as ‘plaques’ in the brains of people who have Alzheimer’s disease. Removing the protein reduced damage to the brain and slowed cognitive decline over the course of the trial, a period of 18 months, compared to a placebo.

However, many challenges and questions remain around the drugs: relating to side effects, how the drugs work, who should be able to access them, and more. In this article, Prof Sir John Hardy and Prof Bart De Strooper, who each played a pivotal role in uncovering the role of amyloid in Alzheimer’s, take a closer look at some of these issues – asking what we can learn from lecanemab and donanemab to take forward and develop safer, more effective treatments.

“What these trials do is teach us what we need to do in future. If you’ve got another drug, people will test it against this model, and it should speed up the drug discovery process, because we know what we need to do now.” Prof Sir John Hardy, Group Leader at the UK DRI at UCL

Uncovering the mechanism is key

Tests clearly show that the drugs reduce amyloid build-up in the brain and this leads to a reduced rate of the hallmark decline in memory in people who have Alzheimer’s, but we don’t yet know exactly how this happens. Understanding this will be critical in building on these drugs to develop even better treatments in future.

Another question experts have been grappling with, is why trial participants continued to decline, albeit more slowly, once all the amyloid had been removed from their brain.

Prof Sir John Hardy, Group Leader at the UK DRI at UCL, predicts that the answer lies with tau, the other hallmark protein implicated in Alzheimer’s. Misfolded tau accumulates in the brain in ‘tangles’, but its role in the disease is not yet well understood.

“Understanding why there is residual decline is crucial,” Prof Hardy explains. “Why doesn’t the disease stop when we remove the amyloid? My guess would be that tau pathology becomes self-sustaining, and so we would need to have an anti-tau drug as well, and treat people with a combination of drugs at the same time.”

Several anti-tau drugs are currently undergoing clinical trials, with two currently in phase 3 trials.

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Ensuring safer future drugs

Researchers also believe that elucidating the mechanisms of the drugs will help ensure safer future treatments. Most drugs have side effects, and lecanemab and donanemab are no exception. Some people who were given the drugs during clinical trials were found to have swelling or microbleeds in the brain in response to treatment – known as Amyloid Related Imaging Abnormalities (ARIA). The majority of people who experienced ARIA had no symptoms, but in rare cases, more severe symptoms and complications occurred.

Prof Bart De Strooper, Group Leader at the UK DRI at UCL, explains:

“We still don’t understand how these antibodies actually clear amyloid. Unlocking this will help us understand exactly why side effects occur, and we may then be able to mitigate them.”

Detecting the disease earlier

If there is one thing scientists agree on, it is that early diagnosis is essential to ensure people who would benefit from treatment can start being treated before Alzheimer’s begins to cause extensive, irreversible damage to the brain.

“By diagnosing earlier, you might be able to treat people before amyloid starts to build up in their blood vessels, and avoid ARIA,” Prof Hardy explains. “So early diagnosis might also help reduce side effects.”

However in reality, if lecanemab and donanemab were approved for use in the UK, people with dementia would face a significant wait to access them. Most people receive a dementia diagnosis from a psychiatrist in a memory clinic. According to Alzheimer’s Research UK, only 6% of these services fully meet the clinical guidance for diagnostic testing.

At the UK DRI, work is ongoing to develop new diagnostic tools. In the UK DRI Biomarker Factory, work led by Prof Henrik Zetterberg and Dr Amanda Heslegrave seeks to develop blood biomarkers – markers of disease that can be detected via a blood test. Prof Valentina Escott Price (UK DRI Group Leader) is leading work on polygenic risk scores – genetic tests that provide information about an individual’s risk of developing a disease. Together, these new tools could help deliver accurate, earlier diagnosis of Alzheimer’s in the general population.

Easier ways to administer treatment

The drugs are currently administered by intravenous (IV) infusion, which needs to be given every two weeks in a specialist clinic. Trials are ongoing to develop easier ways to deliver the drug – for instance, subcutaneously, meaning an injection into the layer of tissue below the skin. This, Prof De Strooper explains, could make the process simpler and more scalable.

“I think we need to be practical and pragmatic,” he says. “We need to ensure we get the maximum benefit out of these expensive drugs, and one way to do that is to try and get easier ways to deliver them.”

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Whether benefits outweigh risks

In clinical trials, lecanemab and donanemab were found to slow cognitive decline by 27% and 35% respectively. But it is difficult to define what this actually looks like for people affected by dementia, and some have questioned whether the effect is significant enough to warrant the risks of the treatment. Others believe it comes down to what people find meaningful to their own experience of their disease.

“If you have someone in front of you and you can tell them they’re going to take 5 months longer to get to a particular stage, they might find that clinically meaningful,” Dr Cath Mummery, Head of Novel Therapeutics at the Dementia Research Centre, UCL, said in the UK DRI’s virtual roundtable on lecanemab, held in November 2022.

“They might still be able to say hello or goodbye to their [loved one], or recognise their daughter for 5 months longer. That’s potentially small, but it’s meaningful,” Dr Mummery added.

A hopeful future

All things considered, the outlook is optimistic.

“We’ve made a major breakthrough,” says Prof De Strooper. “We’ve shown it is possible to change the course of the disease, and that’s really something, it’s a big first step.”

Prof Hardy agrees:

“What these trials do is teach us what we need to do in future,” he says. “If you’ve got another drug, people will test it against this model, and it should speed up the drug discovery process, because we know what we need to do now.”

Lecanemab and donanemab have generated excitement amongst the research and dementia community, and rightfully so. These drugs are not perfect, but they are the first effective treatments for this devastating disease. Much like in other fields of medicine such as HIV/AIDS and cancer, researchers hope this major development will be the first of many, and will kickstart progress in dementia research and drug discovery. With further fundamental research and sustained efforts to improve earlier diagnosis, we can keep this momentum going and develop better, safer treatments to improve the lives of people affected by dementia.

This World Alzheimer’s Month, the UK DRI is highlighting how its research is filling the dementia knowledge gap and bringing us closer to effective treatments for all. We’re also bringing attention to where progress still needs to be made. To learn more and join in the conversation, follow our campaign on social media using the hashtag #FillingTheGaps.

Article published: 21 September 2023
Banner image: Shutterstock/Monkey Business Images