A landmark drug donanemab, is being hailed as a turning point in the fight against Alzheimer's after a global trial confirms it curbs cognitive decline. Although not a cure, Donanemab is a disease-modifying treatment. It relieves symptoms, slowing down memory and intellectual decline in people living with early-stage Alzheimer’s disease, but also tackles one of its root causes.
Donanemab reduces Alzheimer’s progression
Donanemab is a monoclonal antibody treatment which consists of a humanised version of a mouse antibody. It works by modifying the disease rather than just relieving symptoms. Donanemab was developed to recognise, target and remove toxic beta-amyloid proteins that build up in the brains of people with Alzheimer's disease, much like Lecanemab, another drug used to treat Alzheimer’s that recently made the headlines.
Donanemab and lecanemab are immunotherapies. Immunotherapy drugs are already used to treat different diseases, including cancers. They tell the body’s immune system to attack and get rid of specific problematic cells or proteins. In the case of donanemab and lecanemab, it teaches the immune cells to recognise and remove a protein called amyloid, which builds up in patients with Alzheimer’s disease. Amyloid protein build-up is thought to be toxic to brain cells, and the cause of many symptoms that patient’s experience.
Although both drugs target amyloid proteins, they do so at different stages. Lecanemab neutralises amyloid as it begins to form fibres, whereas donanemab binds to amyloid once these fibres have clumped together to become a larger build-up or plaque in the brain. This may be partly why we see a difference in how effective both drugs are at slowing down the disease.
The latest trial regarding Donanemab showed that the drug appears to have slowed the disease pace by about a third, allowing people to retain more of their day-to-day lives and tasks. This equated to a delay in the progression of Alzheimer’s by 4.5-7.5 months over the 18 months of the trial. People taking donanemab also had a 40% reduction in the decline of their ability to carry out daily activities, such as managing finance, driving and carrying out hobbies.
After a year, around half of the patients experienced no progression in their disease. Three-quarters of the patients taking donanemab had amyloid successfully cleared from their brains by the end of the trial. The evidence from the trial suggests that the earlier in the disease the treatment was given, the greater the benefit.
These are exciting results, but research is still ongoing. We still don’t fully know the effects of taking the drug in the long term as the trial only lasted 18 months. Moreover, 91.5% of the participants in the trial were from a white background, as such diversity needs to be factored in.
Animal research behind Donanemab
For a long time now, animal studies have suggested that amyloid β-proteins are responsible for the pathogenesis of Alzheimer’s disease. Beta amyloid molecules tend to aggregate, forming oligomers, protofibrils, mature fibrils and then plaques in the brains of patients. However, most clinical trials designed to reduce the production of this molecule and plaque burden have been unsuccessful. As it turns out, not all beta amyloid forms are pathogenic. Recent studies using synthetic beta amyloid peptides, cell culture models, Arctic transgenic mice, and human samples of Alzheimer’s disease brain tissues have suggested that the pre-fibrillar forms of beta amyloid, particularly soluble beta amyloid protofibrils, may be more toxic, compared with extracellular fibrillar forms.
When it came to immunotherapies, and finding antibodies that could target these amyloid peptides, investigators have long focused therapeutic endeavours on N-terminal antibodies, which can bind either soluble or insoluble forms of Amyloid beta. Prior studies have shown that both active and passive immunotherapy are effective in reducing amyloid deposition in transgenic APP mice when performed as a preventative measure; however, when these approaches are performed in aged transgenic mice with pre-existing deposits that model later stages of the disease, they showed diminished or no efficacy.
To counter this problem, Donanemab was developed to selectively target and remove, through microglial-mediated clearance, existing deposited amyloid plaques in the brain, more specifically the Abp3-42 peptide which is plaque specific and has aggressive aggregation properties. Scientists generated and engineered high-affinity murine (mouse) monoclonal antibodies specific to Abp3-x which led to a significant reduction of deposited amyloid beta in an ex vivo phagocytosis assay. Where other N-terminal antibodies which bind both soluble and insoluble amyloid beta lacked efficiency in mice, anti-Abp3-42 antibodies showed significant plaque-lowering in extremely aged PDAPP mice (23 to 26 months of age). The Abp3-42 antibodies crossed the blood-brain barrier and bound to the deposited amyloid beta, which wasn’t the case for all N-terminal antibodies.
This murine surrogate of donanemab was able to lower plaques in dose-dependent manner in aged amyloid precursor protein transgenic mice. These studies had profound implications for the development of the human trials.
The next steps for Donanemab
Following these positive results in animal followed by human trials, the pharmaceutical company Eli Lilly which makes donanemab are likely to apply to the Medicines and Healthcare Products Regulatory Agency (MHRA) for the approval of donanemab in the UK. If approved, it will then be reviewed by the National Institute for Health and Care Excellence (NICE).
In the time being, several other trials are being conducted with donanemab. A trial called TRAILBLAZER-ALZ 3 is exploring whether donanemab treatment can delay or prevent the development of Alzheimer’s disease. Another trial called TRAILBLAZER-ALZ4 has compared donanemab treatment to that of another anti-amyloid drug called aducanumab, which is currently only approved for the treatment of Alzheimer’s disease in the United States.
With this third new Alzheimer’s drug expected to be approved by the Food and Drug Administration (FDA), the field is beginning to show progress in the fight to slow the disease. This is likely “just the opening chapter in a new era of molecular therapies for Alzheimer’s disease and related neurodegenerative disorders,” according to Gil Rabinovici, director of the University of California San Francisco Alzheimer Disease Research Center.
The next steps for lecanemab
With the positive results of this phase 3 clinical trial, the pharmaceutical companies are now applying for regulatory approval for the drug to be given in the US, Europe and Japan.
However, research is still ongoing to improve the therapeutic strategy. Now that the monoclonal antibiody has proven to be successful, researchers are hoping to increase efficacy by using bi-specific antibodies. Hexavalent antibodies based on lecanemab are also being developed, with the goal of enhancing binding strength selectively to beta amyloid protofibrils.
Research is also hoping to reduce the incidence of adverse events which was 21.3% for those who received lecanemab and 9.3% for those who received a placebo.
Read more on recent breakthroughs in Alzheimer's research.
Last edited: 16 October 2023 15:05
