Alzheimer's disease - Emerging treatments

Aducanumab

The US Food and Drug Administration (FDA) has granted aducanumab, an intravenously administered monoclonal antibody against amyloid beta, accelerated approval for the treatment of AD. Aducanumab is the first treatment directed at the underlying pathophysiology of AD. In double-blind randomised controlled phase 3 trials, patients with mild AD receiving aducanumab showed a significant dose- and time-dependent reduction of amyloid beta plaque in the brain. Patients in the control arm showed no reduction.[195][196] While a reduction of amyloid beta plaque in the brain, a surrogate endpoint, is reasonably likely to predict a reduction in cognitive decline, the FDA notes that there are residual uncertainties regarding the clinical benefit of aducanumab. The accelerated approval necessitates that post-approval studies are conducted; continued approval is contingent upon verification of clinical benefit in these trials. Treatment with aducanumab should be initiated only in patients with mild cognitive impairment or mild dementia stage of disease, to reflect the population in the clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of Alzheimer's disease. An American Academy of Neurology (AAN) report has reviewed the evidence for the efficacy and safety of aducanumab for treating AD, presented clinical considerations regarding its use, and made suggestions for future research.[197] An AAN position statement recommends discussion of potential benefits and risks/burdens of aducanumab with patients and families to facilitate informed consent.[198] Aducanumab has not been approved in Europe.

Lecanemab

Lecanemab is a humanised IgG1 monoclonal antibody that binds with high affinity to amyloid-beta soluble protofibrils. In a multicentre, double-blind, phase 3 trial involving people aged 50 to 90 years with early AD (defined as mild cognitive impairment or mild dementia due to AD), intravenous lecanemab was associated with moderately less decline in cognition and function, as well as reduced brain amyloid burden, at 18 months, compared with placebo. Adverse effects of lecanemab included infusion-related reactions (26.4% of participants) and amyloid-related imaging abnormalities with oedema or effusions (12.6%).[199] Three deaths due to brain haemorrhages have been reported among patients taking lecanemab.[200] Lecanemab is approved for the treatment of Alzheimer's disease by the US FDA. Applications for marketing authorisations in Japan and Europe are expected to be considered in 2023. Further studies of lecanemab are ongoing, including a phase 1 study investigating subcutaneous dosing.[201]

Donanemab

In a phase 2 trial that included patients with early symptomatic AD who had tau and amyloid deposition on positron emission tomography, patients who received donanemab (an antibody that targets a modified form of deposited amyloid beta) had a better composite score for cognition and the ability to perform activities of daily living at 76 weeks than those receiving placebo. Patients in the donanemab group also had greater reductions in amyloid plaque levels, but overall results for secondary outcomes were mixed.[202]