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

This week, Britain’s health spending watchdog rejected a new Alzheimer’s drug – the second to be rejected this year.

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

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

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

“There are many promising treatments in the pipeline,” says Prof. Tara Spires-Jones, a neurodegeneration expert at the University of Edinburgh.

Here we look at some of those treatments:

Amyloid beta-targeted drugs

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

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

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

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

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

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

Professor Charles Marshall from 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: “Trontinemab, for example, is a new version of a previously tested amyloid-lowering molecule that has been modified to make it easier to enter the brain. This means it can have a much greater effect on amyloid protein in the brain, despite being given at a lower dose and potentially having fewer side effects.”

Tau-lowering drugs

Buntanetap not only reduces the amount of beta-amyloid, but, as Oakley notes, it has also been found to reduce the amount of tau in the blood. And it’s not the only drug that affects this protein.

Marshall also said BIIB080or MAPTRx, creates enthusiasm. This works by ‘switching off’ the gene that gives rise to the tau protein. Although still in its early stages, experts now hope to investigate whether the drug can slow the progression of physical symptoms of Alzheimer’s disease.

Inflammation

Among the drugs making waves in this area are liraglutide and semaglutide – perhaps better known for their use in weight loss.

There are several possible ways these drugs could help slow Alzheimer’s disease, including by reducing levels of inflammation in the brain. The first data are promising: liraglutide appears to reduce shrinkage in parts of the brain and slow cognitive decline.

Several Phase 3 clinical trials are underway to investigate whether semaglutide has benefits for people with Alzheimer’s disease. But because there are many drugs in development and they target different targets, experts say it’s unlikely the long-term goal will include a single type of treatment.

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