An update on anti-amyloid therapies

My wife and I have just returned from a wonderful visit to Norway. I was quite taken by the legend of the trolls, the mischievous beasts that wreak havoc in the lives of country people. I encountered this troll in a café in the Kjenndal Valley at the end of Loen Lake. It occurred to me that the beta-amyloid plaques and neurofibrillary tangles of Alzheimer’s disease are a bit like little trolls in my brain. 

So far, all trials of medications directed at removing the tau-containing neurofibrillary tangles from the brain have failed. Many trials of anti-amyloid monoclonal antibodies have also failed, but researchers have learned from the failures and have focused on attacking different portions of the amyloid molecule with some success. One of these, lecanemab has already been approved in the US, Japan and China. European approval could come by the end of June. A second, donanemab, is scheduled for FDA review on June 10. The first anti-amyloid monoclonal antibody approved, aducanumab, has been withdrawn from the US market as it appears to be inferior to lecanemab and donanemab. 

An interesting article in Alzforum this week discusses the clinical rollout of lecanemab in the US and expectations for the future use of these medications. Lecanemab is given every two weeks by IV infusion, and this has placed a burden on IV infusion centers.  Also, the need for PET scans and surveillance MRI scans has created other bottlenecks.  These issues are being addressed, and Alzheimer’s centers are reporting significant growth in use.  There has been some uncertainty about how long treatment should be continued. Although PET scan evidence of amyloid plaques usually disappears with treatment, plasma biomarker evidence of ongoing beta-amyloid production persists suggesting a need for maintenance treatment. This could produce an unsustainable burden on infusion centers with time.  Eisai, the maker of lecanemab, is discussing with the FDA the possibility of switching from biweekly IV infusions to monthly subcutaneous injections done at home for maintenance dosing once amyloid PET scans have cleared.  Not only would this decrease the burden on infusion centers, it should markedly reduce the cost of ongoing treatment. Finally, Lilly has a new antibody in the works, remternetug, with a mode of action similar to donanemab, but it does not appear to cause the anti-drug antibodies and infusion reactions that have plagued donanemab.  Remternetug is given as a subcutaneous injection making it easier and probably less expensive to take. A phase 3 trial is underway with results expected in 2025.It is worth remembering that none of these medications constitute a cure for Alzheimer’s disease. At best they slow the rate of cognitive decline by 25 – 35%, but none of them reverse or even halt cognitive decline. However, there are hints that these drugs are most effective in the earliest stages of Alzheimer’s. Perhaps we may first succeed in preventing Alzheimer’s dementia in those with presymptomatic disease. Such trials are underway.