Disease-modifying treatments for Alzheimer dementia

Three different treatments for Alzheimer dementia (dementia caused by Alzheimer disease) have recently – or may soon – hit the market: Aducanumab, Lecanemab, and Donanemab. This has led to an excited media frenzy with much talk of ‘historic moments’ and ‘breakthroughs’.

These include:

• A quote from the Daily Mail – “’Historic moment’ in race to beat Alzheimer’s: Experimental brain plaque-busting drug ‘significantly slows decline of patients battling early stages of the disease’” (28/09/2022)
• The Guardian said – “Success of experimental Alzheimer’s drug hailed as ‘historic moment’” (29/09/2022)
• Another Daily Mail article – “Experimental Alzheimer’s drug made by Elli Lily slows cognitive decline by 35% and FDA will look to approve it this summer” (03/05/2023)
• And the Daily Mail again – “Is this the ‘beginning of the end’ of Alzheimer’s suffering? Breakthrough drug signals ‘treatment era’ for memory-robbing disease… but experts warn the NHS is ‘not ready’ to dish it out” (04/05/2023)

In many ways this excitement is understandable, as dementia – of which Alzheimer disease is the most common cause – is increasingly common, yet many people have the view that little can be done about it. Being a complicated topic means details are often missed out in the media reports, but I will do my best to address these here. The accuracy of these media reports is not helped by the fact that all of the headlines above are based just on the drug companies’ own press releases; the full research data were not made public until December 2022 for Lecanemab and July 2023 for Donanemab.

There is more treatment, care, and support that can be given to someone with dementia than many people think and the NHS, social care, and dementia charities are active in doing this. However, the question raised by these headlines is are these new drugs all they have been cracked up to be?

The truth behind the new dementia drugs

Aducanumab was controversially approved very quickly in America – the clinical trials finished early since they were not looking highly successful – leading to several people resigning in protest. Nevertheless, people in the US now get Aducanumab for dementia, as well as some people in the UK receiving it as part of clinical trials.

Similar events occurred for the US approval of Lecanemab even though, again, the results were not overwhelmingly positive. Lecanemab had been shown to clear the amyloid plaques in the brain that are characteristic of Alzheimer disease – an impressive feat – but unfortunately the actual difference it made was small and there were potentially serious side effects – plus, there was less evidence that the drug worked in women*; to my knowledge, this last point has never been reported in the media. This gives me the impression that, despite the effects of the drug on the brain, it did little or nothing positive to the person.

Finally, a similar process has followed the findings about Donanemab. Major headlines preceded the presentation of the full results (see above), as has been the case for all these drugs. This drug seemed to work in both men and women, but again only made a small difference to the person and had similar serious side effects.

How the findings are presented can make them look more impressive

In addition to the media often relying on research that has not yet been evaluated for their stories, the data they present are often relative effects, meaning the findings are described ‘in comparison to’ something else. For example, one press release said “Donanemab treatment slowed clinical decline by 35% compared to placebo”†, with another stating “Lecanemab treatment met the primary endpoint and reduced clinical decline … compared with placebo at 18 months by 27%”‡ (I have bolded some text for emphasis).

However, when you look at the actual difference between the two groups the results are less impressive. In clinical trials, the people taking a high dose of Aducanumab and the people taking a placebo (basically a sugar pill) BOTH got worse over time, but those on the drug were not quite so bad (less than half a point on an 18-point scale). There was even less difference between those on a low dose and a placebo. The differences for Lecanemab and Donanemab were similarly small, meaning all three drugs are no better than our current treatments, and by some measures only about half as effective.

Importantly, none of these drugs are good enough at treating Alzheimer dementia that another person would be able to detect a change in the person over time compared to someone not taking the drug.

Negative side effects

However, in addition to being no more effective than the current treatments, these new drugs are associated with substantial risks. The main significant side effects are swelling of and bleeding in the brain, both of which occurred in a large minority of participants receiving the drugs (13-31%) and in very few people taking a placebo (<10%).

Conclusion

In the UK, Lecanemab and Donanemab will separately have to be approved before being available to people with dementia. It remains to be seen whether these drugs will be licensed and made available on the NHS, but it seems unlikely that struggling NHS services – mine included – would be able to incorporate them into their current treatment pathways. Given the drugs’ limited effectiveness, huge costs for the drug alone as well as the requirement for multiple expensive scans, and the risk of potentially serious side effects, the question every doctor will have to ask themselves is “would I recommend a relative to take this treatment?”

Helpful links:

Science Media Centre

Alzheimer Scotland (24 hour Freephone Dementia Helpline 0808 808 3000)

Alzheimer’s Society (Dementia Support Line 0333 150 3456)

Scottish Dementia Research Consortium

The following provide some additional details on the sources of information included in the post above:

* See Figure S4 panel B on page 24 of the Supplementary Appendix to van Dyck et al. (2023).

† Lilly’s Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer’s Disease. [Press Release, 03/05/2023] The full sentence reads “Donanemab treatment slowed clinical decline by 35% compared to placebo, and resulted in 40% less decline on the ability to perform activities of daily living.”

‡ LECANEMAB CONFIRMATORY PHASE 3 CLARITY AD STUDY MET PRIMARY ENDPOINT, SHOWING HIGHLY STATISTICALLY SIGNIFICANT REDUCTION OF CLINICAL DECLINE IN LARGE GLOBAL CLINICAL STUDY OF 1,795 PARTICIPANTS WITH EARLY ALZHEIMER’S DISEASE. [Press Release, 27/09/2022] The full sentence reads “Lecanemab treatment met the primary endpoint and reduced clinical decline on the global cognitive and functional scale, CDR-SB, compared with placebo at 18 months by 27%, which represents a treatment difference in the score change of -0.45 (p=0.00005) in the analysis of Intent-to-treat (ITT) population.” On this occasion, the press release does also report the absolute change (-0.45 points) but does not state the scale (0-18).