Which disease-modifying Alzheimer’s drugs are the most promising?

This week England’s health spending watchdog rejected a new Alzheimer’s drug – the second such drug it has turned down this year.

Both donanemab and lecanemab were approved by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA), yet the National Institute for Health and Care Excellence (Nice) said their benefits were too small to justify their costs, while there have also been concerns over potential side effects – such as brain swelling and bleeding.

For some, including Prof Rob Howard of University College London, the decision underscores the need to focus on ensuring people with Alzheimer’s have access to diagnoses, therapy, social care and existing drugs that can help with symptoms of the disease.

But while others agree such support is crucial, they are optimistic that disease-modifying drugs could play a role. According to Alzheimer’s Research UK, about 130 drugs are under development, three-quarters of which aim to delay, slow or reverse the disease.

“There are many promising treatments coming through the pipeline,” said Tara Spires-Jones, professor of neurodegeneration at the University of Edinburgh. Here are some of those treatments:

Amyloid-beta targeting drugs
Clumps of a sticky protein known as amyloid beta are a hallmark of Alzheimer’s disease, causing disruption in cell communication, inflammation and cell death. Lecanemab and donanemab, both monoclonal antibodies, prevent these clumps from building up.

Some believe the decisions by Nice are far from the end of the road for these drugs. Prof Andrew Doig, of the University of Manchester, said: “Donanemab has not been ruled out forever and this decision could change. We will continue to track how well it works over longer time periods. Costs may also come down.”

Other therapies are also on the way and could work even better than donanemab, Doig added.

Dr Rich Oakley, the associate director of research and innovation at Alzheimer’s Society, said one such drug is the monoclonal antibody remternetug. “It targets the same type of amyloid as donanemab but is hoped to be more effective, more practical and reduce the adverse effects seen with the other immunotherapy drugs,” he said.

Another drug causing interest is buntanetap – a small molecule that helps decrease production of the precursor to toxic amyloid. “A recent trial has shown significant improvements in memory and thinking scores in people with early-stage Alzheimer’s disease after 12 weeks of buntanetap treatment,” said Oakley. “Importantly, buntanetap treatment did not lead to any serious side effects.”

There is also valiltramiprosate, an oral drug that is being looked at for people with a gene that raises the risk of developing Alzheimer’s.

Prof Charles Marshall of Queen Mary University of London, said another approach is to change the stage at which amyloid-lowering treatments are given, or the way they are administered, to make them more effective.

He said: “For example, trontinemab is a new version of a previously trialled amyloid-lowering molecule that has been adapted to make it enter the brain more easily. This means it can have much greater effect on amyloid protein in the brain despite being given at a lower dose that may have less side effects.”

Tau-lowering drugs
Buntanetap not only lowers levels of beta-amyloid but, as Oakley points out, it has also been found to reduce levels of tau in the blood. And it is not the only drug that affects this protein.

Marshall also said BIIB080, or MAPTRx, is causing enthusiasm. This works by “switching off” the gene that gives rise to the tau protein. While still early days, experts are now hoping to explore whether the drug can slow the progression of physical symptoms of Alzheimer’s.

Inflammation
Among the drugs causing a stir in this area are liraglutide and semaglutide – perhaps better known for their use in weight-loss jabs.

There are several possible ways these drugs might help slow Alzheimer’s, including by reducing levels of inflammation in the brain. Early data is promising, with liraglutide found to reduce shrinkage in parts of the brain and slow cognitive decline.

There are now several phase 3 clinical trials under way to explore whether semaglutide has benefits for individuals with Alzheimer’s disease. Yet with many drugs in development, and focusing on different targets, experts say the long-term goal is unlikely to involve a single type of treatment.

Marshall said: “It is also possible that for amyloid-lowering treatments to be more effective, we need to give them alongside treatments that target other components of Alzheimer’s disease such as tau protein or brain inflammation.”