Dementia, defined as a loss of cognitive abilities primarily related to memory, affects over 55 one million people worldwide. Age is the most common risk factor, and as the world's population ages, falls are expected tripled until 2050.
The most common form of dementia is Alzheimer's disease (AD) – a neurodegenerative disease characterized by the loss of function and eventual death of brain cells that control memory and cognition. The disease is progressive, meaning symptoms worsen over time, leading to shortened lifespan, heavy emotional burden for patients and their loved ones, and a significant increase in healthcare costs.
Unlike most cells in our bodies, neurons rarely regenerate once they have been damaged. This means that neurodegenerative diseases and brain and spinal cord injuries are extremely challenging to treat, not to mention difficult to cure. In fact, there are very few therapeutic treatments for Alzheimer's disease, and those that do exist only temporarily relieve some of the worst symptoms and do not address the disease directly.
Targeting beta-amyloid
One of the most important hallmarks of AD pathology is the accumulation of beta-amyloid (Aß) protein in the brain during the early stages of the disease. Aß forms clumps of plaques that starve these nerve cells of the energy they need to function properly.
Drug developers have been investing in immunotherapy targeting Aß for decades to prevent its accumulation in the brain. In the late 2010s, there were rumors of a potential breakthrough with this technology when Biogen and Eisais Aß antibody aducanumab showed promising results in the first two phases of clinical development. However, hopes were dashed in the spring of 2019 when the pharmaceutical giants announced poor Phase III results.
A controversial first FDA approval
Development of aducanumab resumed later that year when Biogen announced that a larger data set evaluating a higher dose showed reduced clinical deterioration in patients with early Alzheimer's disease. This data was sufficient to FDA would grant the candidate priority review.
Despite the myriad of warning flags raised during the final data analysis by an external expert panel, final approval for aducanumab came in June 2021, making it the first drug targeting Alzheimer's disease to reach the market. Aducanumab is now sold under the name aduhelm in the USA, but not in Europe then EMA has chosen not to approve the drug due to lack of efficacy standards.
Despite the controversy surrounding its approval, Aduhelm is considered in many ways a breakthrough in the treatment of Alzheimer's disease, if nothing else, it is certainly a springboard for more breakthroughs to come.
New treatments on the horizon
This year has actually brought more good news on the Alzheimer's front. Two drugs under development, both Aß antibodies, have shown promising results in clinical trials.
The first, lecanemab, is another Biogen/Eisai co-developed drug, originally discovered by the Swedish biotechnology company BioArcticResults from the phase III study in 1795 patients show that the candidate reduced clinical deterioration by 27 percent compared to placebo.
The other, donanemab, owned by Eli Lilly, has demonstrated superior Aß reduction compared to Aduhelm in a phase III study. Data showed that after six months, 37,9 percent of study participants treated with donanemab experienced elimination of Aß in the brain compared to 1,6 percent of Aduhelm-treated patients.
Challenges remain
After the initial euphoria that followed the announcement of positive Phase III results with lecanemab, alarm bells have started to ring as two deaths have been reported to be associated with the drug. Both deaths were linked to bleeding in the brain, which is one of the potential side effects of Aß-eliminating drugs, and something that was also seen in the studies with Aduhelm.
Despite the recent negative news regarding the safety of lecanemab, the Alzheimer's Association on the study results with enthusiasm and said in a statement that the drug "can meaningfully change the course of the disease for people in the earliest stages of Alzheimer's disease."
Both anticipation and anxiety in the air for 2023
Eisai hopes to receive full market approval for lecanemab in the US, Japan and Europe in 2023, while a decision regarding Eli Lilly's donanemab is expected to come later.
However, expectations surrounding both decisions are tempered by what happened with Aduhelm – was that approval rushed? Did it set a precedent for new controversial Alzheimer’s approvals in the future? Despite donanemab showing better Aß clearance compared to Aduhelm, one of the biggest controversies surrounding Aduhelm was the fact that Aß clearance was not accompanied by a strong clinical effect. Will donanemab follow the same pattern?
Eisai and Biogen are more optimistic, as they see clear cognitive benefits with their drug, which they believe gives lecanemab an edge in the fight to make a mark in the Alzheimer's field. Time will tell if we will see another breakthrough in AD treatment in 2023.