This week England’s health spending watchdog a new Alzheimer’s drug rejected – the second such drug he has turned down this year.
Both donanemab and lecanemab were approved by the UK’s 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 were also concerns about possible side-effects 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 that 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 that such support is crucial, they are optimistic that disease-modifying drugs can play a role. According to Alzheimer’s Research UKaround 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 Prof Tara Spires-Jones, a neurodegeneration expert at the University of Edinburgh.
Here we look at some of those treatments:
Amyloid-beta-targeting agents
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 clots from building up.
Some believe the decisions by Nice 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 may change. We will continue to track how well it works over longer periods of time. Costs can also come down.”
Other therapies are also on the way and may 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 it is hoped to be more effective, more practical and reduce the adverse effects seen with the other immunotherapy drugs,” he said.
Another drug that is causing interest is buntanetap – a small molecule that helps reduce the production of the precursor to toxic amyloid. “A recent trial showed significant improvements in memory and thinking scores in people with early-stage Alzheimer’s disease after 12 weeks of buntanetap treatment,” Oakley said. “Importantly, buntanetap treatment did not lead to serious side effects.”
There is also valyltramiprosate, an oral drug being looked at 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 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 tried amyloid-lowering molecule that has been modified to allow it to enter the brain more easily. This means it can have a much greater effect on amyloid protein in the brain despite being given at a lower dose which may have fewer side effects.
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Tau-lowering agents
Buntanetap not only lowers levels of beta-amyloid, but, as Oakley points out, it has also been found to lower levels of tau in the blood. And this is not the only drug that affects this protein.
Marshall also said BIIB080or MAPTRx, cause enthusiasm. It works by “switching off” the gene that gives rise to the tau protein. While it’s still early days, experts now hope to investigate 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 injections.
There are several possible ways these drugs can help slow Alzheimer’s disease, including by reducing levels of inflammation in the brain. Early data is promisingwith liraglutide found 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 individuals with Alzheimer’s disease. But 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 together with treatments that target other components of Alzheimer’s disease such as tau protein or brain inflammation.”
