New Alzheimer’s drug too good to be true?

Details of a clinical trial for a potential new Alzheimer’s drug, Lecanemab, have been released to widespread acclaim. The medicine is the first to alter the progression of the disease, rather than just alleviate the symptoms.

The trial results were published in the New England Journal of Medicine, and confirm that treatment with Lecanemab reduces decline in cognitive ability by 27% over 18 months compared to the placebo group. The study was made up of just under 1,800 people, and involved participants being given infusions of either Lecanemab or a placebo every 2 weeks.

What is Alzheimer’s Disease?

Alzheimer’s disease is neurodegenerative, meaning neuron structure and/or function is slowly lost. This manifests itself as a loss of brain function, including short-term memory loss, apathy, and worsening of communication skills. The severity of symptoms increases as the disease progresses, with late-stage Alzheimer’s rendering the patient completely dependent on a caregiver.

The exact causes of Alzheimer’s disease aren’t fully known. A relatively small proportion of Alzheimer’s cases appear in people under 65, known as early onset Alzheimer’s, and these are thought to be caused by genetic factors. The majority of cases are seen in people over the age of 65 and are influenced by a myriad of factors – such as head injuries, lifestyle choices, and high blood pressure.

In the UK alone, 944,000 people are estimated to be living with dementia, of which around 65% may be caused or worsened by Alzheimer’s. The impacts on a patient’s personality, family life, and memory make it a particularly distressing disease. Despite being in the top 10 causes of death in the UK, we currently have no treatment to prevent, cure, or slow its progression.

Lecanemab is an antibody therapy and works by helping the immune system clear a certain soluble form of the protein amyloid beta, widely thought to be responsible in part for the brain damage observed during Alzheimer’s.

The group that received Lecanemab showed an average decrease in amyloid levels of 71%, whereas the placebo group showed a slight increase. Eisai, one of the companies behind Lecanemab, believe this confirms the ‘amyloid hypothesis’. This is a popular hypothesis proposing that these amyloid build-ups are the primary cause of Alzheimer’s disease.

Limitations of lecanemab

The slowing of disease shown by Lecanemab is a landmark moment. It is the first indication we have that Alzheimer’s disease itself is treatable.

The improvement is seen, although statistically significant, is only small. The 27% reduction in brain decline corresponds to a difference of 0.45 on the 18-point CDR-SB scale. This scale is a common way of measuring clinical dementia, where higher numbers correspond to more pronounced dementia symptoms.

This small improvement will “probably not be detectable” for most patients in the clinic, writes Dr Matthew Schrag on Twitter, a Neurologist at Vanderbilt University. Some of the side effects observed in the trial have also caused concern, with one of the deaths that occurred during the trial described as “a treatment-caused illness and death” in a detailed report by Science.

A known side effect of amyloid-targeting antibody therapies are amyloid-related imaging abnormalities, or ARIA. These abnormalities are observed by MRI, and can indicate brain bleeding or swelling.

When drugs such as Lecanemab remove amyloid deposits in the brain, they can weaken and inflame blood vessels. This can in turn lead to an increased risk of swelling or bleeding in the brain. Just over 20% of the Lecanemab group experienced some kind of ARIA, compared with just under 10% for the placebo group.

A real crisis can develop if an ARIA event is experienced by a patient who is taking blood-thinning medication. Blood thinners are routinely prescribed to treat conditions such as atrial fibrillation, and are administered as treatment during strokes. Some, such as tPA given to stroke victims, are known to cause brain bleeds on their own. Together with amyloid-targeting therapies, the combination can be fatal.

In the report by Science, multiple scientists agreed that the combination of Lecanemab and blood thinners played a part in the death of one of the patients participating in the clinical trial. Despite this report, Eisai has said they see no need for restrictions on which patients might be eligible for Lecanemab, and deny that any of the deaths during the trial can be attributed to Lecanemab. Regulatory bodies will have to consider both perspectives when they decide lecanemab’s fate.

A new wave of Alzheimer’s treatments may almost be here

Even if Lecanemab isn’t approved, the study represents a promising step forward in the field of Alzheimer’s research. Showing that we have a way to influence the progression of the disease opens the door for future work, and gives hope to people living with Alzheimer’s around the world. A decision on whether or not the FDA will approve Lecanemab is expected by 6^th January 2023.