Alzheimer's disease has been steadily on the rise in our ageing population and, alarmingly, those living with it have gone 20 years without new medicines (Gregory, 2023). However, recent advances in medicine have led to the first generation of possible treatments. Donanemab and lecanemab are two of the most recent medications showing good efficacy in trials. This article will explore these further.
Donanemab
Eli Lilly (2023) created donanemab, noting last year that 47% of participants taking the medication had no clinical progression at one year of the disease. However, the placebo group also had no progression at one year in 29% of participants. The Phase 3 trial for donanemab also met the primary endpoint and all secondary endpoints that measured cognitive and functional decline, finding that the treatment slowed clinical decline by 35%, and causing 40% less decline in the functional ability to carry out every day activities of daily living.
The TRAILBLAZER-ALZ 2 trial, a randomised, double-blind, placebocontrolled study, examined whether donanemab is safe and efficacious (Sims et al, 2023). The drug itself is an investigational amyloid plaque targeting therapy. The participants receiving the drug were people with early symptoms of Alzheimer's disease, defined as mild cognitive impairment (MCI), which is known as the mild dementia stage of the disease, with diagnostic investigations having confirmed the presence of Alzheimer's neuropathology. The participants completed the course of donanemab once they had reached a prespecified level of amyloid plaque clearance.
Sims et al (2023) identified participants by their level of tau – a protein found in the brain that is a predictive biomarker for Alzheimer's disease progression. They examined 1182 people who were part of the primary analysis. This population had an intermediate level of tau and clinical symptoms of Alzheimer's disease. For this group, the primary endpoint was shown to slow decline of clinical function by 35%.
The welcome news of the drug's success, although not replicated throughout the entire sample, was still significant to some, as participants taking the drug showed a 40% lower rate of decline in ability to perform activities of daily living at 18 months. This was measured using the Alzheimer's Disease Cooperative Study – instrumental Activities of Daily Living Inventory (ADCS-iADL). Participants taking donanemab experienced a 39% lower risk of going on to the next stage of the disease in comparison to the placebo. According to Daniel Skovronsky, Lilly's chief scientific and medical officer, and president of Lilly Research Laboratories, ‘This is the first Phase 3 trial of any investigational medicine for Alzheimer's disease to deliver 35% slowing of clinical and functional decline.’
“The team found that infusion-related reactions also happened to 8.7% of participants but most cases were found to be mild to moderate in severity”
In addition to these findings, the research also had a smaller trial of those with high levels of tau at baseline (552 participants). This showed a later stage of disease progression. However, these people were predicted to be less responsive to the therapy owing to the later stage of disease progression, so the focus was on those with intermediate level of tau. However, a combined primary analysis of both intermediate and high-level tau populations (n=1736) showed ‘meaningful positive results’ across all clinical endpoints (p<0.001), with CDR-SB and iADRS showing 29% and 22% slowing of decline, respectively.
Side effects
The incidence of amyloid-related imaging abnormalities (ARIA) was observed to be consistent with the TRAILBLAZER-ALZ Phase 2 study. The team from Eli Lilly (2023) discussed that ARIA is usually observed with the amyloid plaque clearing antibody class of therapies and is most often observed as temporary swelling in an area or areas of the brain (ARIA-E) or as microhaemorrhages or superficial siderosis (ARIA-H), in either case detected by MRI. This type of abnormality is, therefore, of some significant concern to study populations taking this type of therapy, despite therapeutic good efficacy in some of the population in slowing disease progression. ARIA-E was observed in 24% of treated participants taking donanemab, with 6.1% experiencing symptomatic ARIA-E. ARIA-H was also observed, in 31.4% of cases in the donanemab group and 13.6% in the placebo group. The majority of these ARIA cases were noted to be mild or moderate in nature and were able to be resolved or stabilised (Eli Lilly, 2023).
The team explained that cases of ARIA are usually without any symptoms. However, there can occasionally be serious or life-threatening events associated with cases of ARIA. Unfortunately, this did occur in the donanemab study, with 1.6% of the study population suffering from serious incidents, two participant deaths being attributed to ARIA directly and a third person dying following a serious incident of ARIA. The team found that infusion-related reactions also happened to 8.7% of participants but most cases were found to be mild to moderate in severity.
Mark Mintun, group vice president Neuroscience Research and Development at Lilly, and president of Avid Radiopharmaceuticals, commented last year: ‘We are encouraged by the potential clinical benefits that donanemab may provide, although like many effective treatments for debilitating and fatal diseases, there are associated risks that may be serious and life-threatening. We note that these results suggest that people in the early pathological stage of disease could be the most responsive to therapeutics targeting amyloid.’
Therefore, it seems that the price to pay for efficacious treatment in some of the populations is serious adverse events in a minute part of that population. Without treatment, the disease progression would worsen and no one would be better off; yet with a treatment, despite the risk, everyone has a chance of positive results to slow the progression of such a debilitating disease. Many drugs are approved on this basis, with a small risk of adverse events accepted. There were also significant reductions in brain amyloid plaque after 6 months of treatment, as observed on positron emission tomography (PET) brain scans, with many patients reaching amyloid levels considered negative for pathology (34% of participants in the intermediate tau population achieved amyloid clearance at 6 months and 71% achieved clearance at 12 months). These results were highly promising for the new treatment, given than amyloid plaque is a significant defining feature of Alzheimer's disease.
Lecanemab
Lecanemab was approved in January 2023 by the US Food and Drug Administration (FDA), having shown to reduce Alzheimer's disease progression by 27% in clinical trials towards the end of 2022, and has just now been approved in China (Biogen, 2024). However, it has not yet been approved in the UK and it is not known whether it will be (Alzheimer's Society, 2023).
Lecanemab, a humanised IgG1 monoclonal antibody, is able to bind with high affinity to Aβ soluble protofibrils, which are part of the responsible neuropathology for Alzheimer's disease progression (van Dyck et al, 2023). The 18-month Phase 3 trial involved people between the ages of 50 and 90 with early Alzheimer's disease showing, similar to the aforementioned study, mild cognitive impairment or mild dementia due to Alzheimer's disease pathology, confirmed on PET scans or by cerebrospinal fluid testing.
Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kg of body weight every 2 weeks) or placebo. The primary end point was identified as the change from baseline at 18 months in the score on the Clinical Dementia Rating–Sum of Boxes (CDR-SB; range 0–18, with higher scores indicating greater impairment). The team defined secondary end points as the change in amyloid burden on the PET scan, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range 0–90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range 0–1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range 0–53; lower scores indicate greater impairment).
A total of 1795 participants were enrolled and 898 received lecanemab. The rest received the placebo and the results were compared, finding that the lecanemab patients showed a reduction in markers of amyloid in early stages of Alzheimer's disease, and this cohort also showed moderately less decline when it came to analysis of their cognition and function, compared with the placebo at 18 months. However, the lecanemab was linked with adverse events and therefore longer trials are needed in order to determine the efficacy and significantly in this case, the safety of using lecanemab for the indication of early Alzheimer's disease (van Dyck et al, 2023).
Conclusion
Reardon (2023) discussed the safety concerns around this new generation of possible Alzheimer's treatments in her analysis published in Nature. She noted that bleeding and seizures are a risk of ARIA, and that through attacking amyloid plaques, the new drugs are also causing antibodies to weaken the blood vessels in the brain. This was especially noted in people who were taking anticoagulants and these new drugs were seen to have a higher chance of ARIA complications.
Reardon (2023) discussed the slowing of cognitive decline being relative to markers that people's families may not recognise – the difference was only partial when compared with those on the placebo. It is difficult to say whether the cognitive decline slowing would be noticeable and therefore worth risking by taking a drug that could cause bleeding or seziures, without much efficacy for the disease itself. This is something that will require a longer series of trials to analyse safety and efficacy.
“Lecanemab was approved in January 2023 by the US Food and Drug Administration (FDA), having shown to reduce Alzheimer's disease progression by 27% in clinical trials towards the end of 2022”
Alzheimer's Research UK has been pushing for regulators to act promptly to approve donanemab and lecanemab to cut short the long wait of those living with Alzheimer's disease for clinically effective treatments (Gregory, 2023). The National Institute for Health and Care Excellence (NICE) is also working on its appraisal of donanemab (Walsh and Roberts, 2023).
There will be a boom in research into amyloid-attacking drugs of this generation; as such, the cost to the country's economy will be high when some are eventually approved. However, effective treatments will reduce the cost to the economy in the long term due to reduced health and social care costs if the condition becomes less debilitating. Ultimately, with each new drug produced we are edging closer to finding a cure for Alzheimer's disease.