Understanding Leqembi: A conversation with NeuRA’s Dr Bill Brooks 

In a significant step forward in the battle against Alzheimer’s disease, the US Food and Drug Administration (FDA) has given the green light to a drug, Leqembi, which has been shown in clinical trials to slow the progression of Alzheimer’s in individuals during the early stages of the disease. Although yet to be approved in Australia, this medication stands on the cusp of transforming Alzheimer’s treatment, offering hope to the estimated 55 million people living with Alzheimer’s around the world and their loved ones.

To help us understand the implications of this major development, we sat down with Dr Bill Brooks, Senior Research Fellow (Honorary) at NeuRA. Dr Brooks has been studying families with the inherited forms of Alzheimer’s disease for over three decades. Since 2009, this work has been carried out as part of the  DIAN study (Dominantly Inherited Alzheimer Network), an international study of familial Alzheimer’s disease funded by the US National Institute on Ageing and led by a team at Washington University in St Louis.

Can you provide more insight into how Leqembi works in relation to Alzheimer’s disease? 

Leqembi, whose generic name is Lecanemab, works by removing the amyloid protein from the brain in Alzheimer’s disease. It is one of a group of drugs called monoclonal antibodies, which have been developed to bind specifically to a section of each amyloid protein molecule, thus marking it so that the body’s clearance mechanisms can dispose of it. The amyloid peptide is the key component of the plaques which form in the brain of people with Alzheimer’s disease. 

Who would be the ideal candidate for Leqembi?

The ideal candidate at our present state of knowledge would be someone with very mild symptoms of memory and thinking problems, who has been able to have an amyloid PET scan which has demonstrated amyloid deposits in the brain. However, it is important to note that currently Lecanemab is not available in Australia other than in clinical trials, and that amyloid PET scans are also not widely available and are not subsidised by Medicare. 

What makes Leqembi different to other treatments available for Alzheimer’s?

There are now four monoclonal antibodies which have been shown to reduce brain amyloid and remove plaques in Alzheimer’s disease. Although we believe that amyloid deposits in the brain play a major part in the disease process, it has been difficult to show that removing amyloid has an effect on symptoms of memory loss and thinking problems, which is of course what we want to do. Of the four monoclonals, Lecanemab is the first for which there is statistical evidence of an effect on memory and thinking, although it was a slowing of the decline rather than an actual improvement. 

While the results from the larger 1,800-patient study showed that the drug slowed memory and thinking decline, how significant is this effect in practical terms? i.e. is a five-month delay substantial enough to make a noticeable difference in patients’ lives?

The trials so far have involved people who already have memory symptoms. Slowing the decline by five months could be enough for a person to enjoy getting to know a newborn grandchild or to attend and enjoy a family wedding, graduation, sporting or artistic achievement for example, so it could make an important difference to some people.
Preventing or delaying the onset of symptoms by several months, if this turns out to be possible, might be enough to allow someone to do the administration necessary to hand over their job, to go on a holiday, or to do other things on their ​“bucket list”.

The difficulty with prevention trials is knowing who is likely to benefit. At the moment we can tell whether someone has amyloid in the brain by doing a scan called a PET scan, but amyloid PET scans are not widely available and are very expensive. If we had a relatively cheap blood test to tell whether someone was developing amyloid build-up in the brain, this might be more feasible, and scientists are working on this, but they need further refinement and testing before they can be used generally. 

Can you elaborate on the potential side effects of Leqembi, such as brain swelling and bleeding? 

When the drugs (antibodies) bind to the amyloid and it is then removed, this causes a certain amount of inflammation. Also, some of the amyloid is deposited in the walls of blood vessels in the brain, and when it is removed, the blood vessels can become a bit ​“leaky” until this all settles down. These changes can also occur in people with Alzheimer’s disease who are not taking drugs, but they are more frequent in people who are taking the drugs, and we believe they are part and parcel of the way the drugs work. There are two types of changes, microhaemorrhages (or microbleeds), which are normally asymptomatic, i.e. the person doesn’t notice any symptoms, and they are only found on MRI scans, which are done regularly during treatment trials for safety reasons. The other type of change is oedema, or localised brain swelling, which is also detected by MRI scan, but can sometimes cause symptoms such as headache, ​“brain fog”, or other neurological problems such as disturbance of vision or in severe cases epileptic seizures. These changes usually settle down if the drug is stopped for a few weeks. Sometimes the dose needs to be reduced. If micro-oedema causes symptoms, a short course of steroid drugs is sometimes used to settle these down. 

With Lecanemab, there have been a small number of cases where major brain haemorrhage has occurred, including several deaths. This seems to be a problem when people have also been on blood thinners such as warfarin, or in one case where a stroke was treated with ​“clot-busting” agents. It also seems to be a problem when there is a lot of amyloid deposited in the blood vessel walls, a condition known as amyloid congophilic angiopathy, which can occur in Alzheimer’s disease. Lecanemab is not yet approved for use in Australia, but the prescribers and people thinking about taking the drug would need to consider the potential risks of using warfarin or clot-busting drugs while they are taking  Lecanemab.