Which disease-modifying Alzheimer's drugs hold the most promise? | Alzheimer

This week England's health spending watchdog rejected a new Alzheimer's drug – the second drug of its kind it has rejected this year.

Both donanemab and lecanemab were 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 and there were also concerns regarding the potential side effects – such as brain swelling and bleeding.

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

While others believe such support is crucial, they are optimistic that disease-modifying drugs could play a role. According to Alzheimer's Research UK, there are around 130 drugs in development, three quarters of which aim to delay, slow or reverse the disease.

“There are many promising treatments in the pipeline,” said Tara Spiers-Jones, a professor of neurodegeneration at the University of Edinburgh. Here are some of these treatments:

Medication against amyloid beta
Clumps of a sticky protein called amyloid beta are a hallmark of Alzheimer's disease and cause disruptions in cell communication, inflammation and cell death. Lecanemab and donanemab, both monoclonal antibodies, prevent these clumps from forming.

Some believe the Nice decisions are far from the end of the road for these drugs. Prof 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 performs over longer periods of time. Costs can also go down.”

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

Dr. Rich Oakley, associate 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 is intended to be more effective, more practical and reduce the side effects of the other immunotherapy drugs,” he said.

Another interesting drug is Buntanetap – a small molecule that helps reduce the production of the precursor to toxic amyloid. “A recent study showed significant improvement in memory and thinking scores in people with early Alzheimer's disease after 12 weeks of treatment with Buntanetap,” said Oakley. “It is important that treatment with Buntanetap did not result in any serious side effects.”

There's also valiltramiprosate, an oral medication being studied for people with a gene that increases the risk of developing Alzheimer's.

Prof Charles Marshall, of Queen Mary University of London, said another approach was 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 tested amyloid-lowering molecule that has been adapted to reach the brain more easily.” This means it can have a much greater effect on the amyloid protein in the brain, even though it is in given at a lower dose that may have fewer side effects.”

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

Marshall also said BIIB080, or MAPTRx, is generating excitement. This works by “turning off” the gene that is responsible for the creation of the tau protein. Although it's still early days, experts now hope to find out whether the drug can slow the progression of the physical symptoms of Alzheimer's.

inflammation
Drugs making waves in this area include liraglutide and semaglutide — perhaps better known for their use in weight-loss vaccinations.

There are several ways these drugs could help slow Alzheimer's disease, including by reducing inflammation in the brain. Initial data is promising: liraglutide reduces shrinkage of parts of the brain and slows cognitive decline.

Several phase 3 clinical trials are currently underway to examine whether semaglutide has benefits for people with Alzheimer's disease. But with many drugs in development and focused on different targets, experts say it is unlikely that the long-term goal will involve a single type of treatment.

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