As the societal burden of Alzheimer’s disease continues to grow, drug development in the field has struggled to keep up the pace. A huge void in Alzheimer’s therapy remains, however hopes spiked during the fall when Japanese pharma company Eisai presented positive phase III results with anti-Amyloid Beta immunotherapy candidate lecanemab. Since then, however, safety concerns around the drug have emerged after two study participants died from adverse events.
Dementia, defined as a loss of cognitive abilities mainly related to memory, affects over 55 million people worldwide. Age is the most common risk factor, and as the world population ages, cases are expected to triple by 2050.
The most common form of dementia is Alzheimer’s disease (AD) – a neurodegenerative disorder characterised by the loss of function, and eventual death of brain cells that control memory and cognition. The disease is progressive, meaning that symptoms get worse over time, leading to a shortened life expectancy, enormous emotional pain to the patients and their loved ones, and to a huge rise in healthcare costs.
Unlike most of the cells in our body, neurons seldom regenerate once injured. This makes neurodegenerative diseases or brain and spinal cord injuries extremely challenging to treat, much less cure. In fact, very few therapeutic treatments for AD exist, and those that do, only temporarily alleviate some of the worst symptoms and do not tackle the disease head-on.
Targeting Amyloid Beta
One of the key hallmark of AD pathology is the accumulation of Amyloid Beta (Aß) protein in the brain during the early stages of the disease. The proteins clumps up into placques that starve these nerve cells of the energy they need to function properly.
For decades, drug developers have been betting on immunotherapy targeting Aß to prevent its accumulation in the brain. In the late 2010’s, whispers of a potential breakthrough with this technique were swirling as Biogen’s and Eisai’s Aß antibody aducanemab showed promising results in the first two phases of clinical development. However, hopes came crashing down in the spring of 2019 when the pharma giants announced poor phase III results.
A controversial first FDA approval
Development of aducanumab was reignited later that year when Biogen announced that a larger data set evaluating a higher dose showed reduced clinical decline in patients with early AD – the evidence was enough for the FDA to grant the candidate priority review.
Then, in June 2021, despite a myriad of red flags raised during the final data analysis by an outside panel of experts, final approval came for aducanumab, becoming the first AD targeted drug to reach the market. Now, aducanumab is sold under the name Aduhelm in the US, but it is not being sold in Europe as the EMA has rejected the drug, citing lack of efficacy standards.
In many ways, despite the controversy surrounding its approval, Aduhelm is considered a breakthrough in the AD therapeutics field – if anything else, certainly a stepping stone for more breakthroughs to come.
New therapies on the horizon
Indeed, this year we have seen more good news on the AD front. Two drugs in development, both AB antibodies, have shown promising results in the clinic.
The first, lecanemab, is another Biogen/Eisai co-developed drug, originally discovered by Swedish biotech BioArctic. Results from the phase III trial in 1795 patients show that the candidate reduced clinical deterioration by 27 per cent compared to placebo.
The other, donanemab, held by Eli Lilly, has shown superior Aß reduction compared to Aduhelm in a phase III study. The data showed that 37.9 per cenet of donanemab-treated participants experienced brain Aß clearance compared with 1.6 per cent of Aduhelm-treated patients at six months.
Since the initial euphoria from the announcement of positive phase III results with lecanemab, alarm bells have been going off as two deaths have been reported as being associated with the drug. Both deaths were linked to bleeding inside the brain, which is one of the potential adverse events from Aß-clearing drugs, and something that was seen in the Aduhelm trials as well.
Despite the recent negative safety news regarding lecanemab, the Alzheimer’s Association reacted to the trial results with enthusiasm, saying in a statement that the drug “can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease.”
Excitement and apprehension in the air for 2023
Eisai hopes to receive full market approval for lecanemab in the US, Japan and Europe during 2023, while a decision for Eli Lilly’s donanemab is expected later on.
The excitement surrounding both decisions is hampered by what happened with Aduhelm – was that approval rushed? And did it set a precedent for new controversial AD approvals in the future? Despite the better Aß clearing ability of donanemab compared to Aduhelm, one of the main controversies surround Aduhelm was the fact that Aß clearance was not followed by a strong clinical effect. Will this be the story for donanemab?
Eisai and Biogen are more optimistic, as they see clear cognitive benefits with their drug, giving lecanemab the overall edge in this race to make an impact in the AD field. Only time will tell whether we will see a new breakthrough in AD therapy in 2023.