More than 50 million people around the world live with Alzheimer’s disease (AD). According to the UN, if no scientific breakthroughs are made, rates could exceed 150 million people by 2050. Guus Scheefhals, Biotech CEO working on Alzheimer’s and Parkinson’s disease for more than a decade, looks into the first ever AD drugs that have come on the market or are close to regulatory approval.
What is the underlying mechanism in Alzheimer’s disease (AD)?
“The brains of AD patients bear two cellular hallmarks: clumps of amyloid-β proteins, known as plaques, that form outside the cells, and strings of a protein called tau, known as tangles, inside cells. Most AD drugs currently in development, are based on eliminating the clumps of amyloid-β. The general consensus is that deposition of amyloid plaque precedes tau tangles formation and is believed to destroy neurons in the brain, eventually leading to cognitive decline. Critics of this amyloid cascade hypothesis, however, claim that solely targeting amyloid plaques is like putting out a match while the whole forest is already on fire.
Earlier this year, scientific discoveries made by Sylvain Lesné were disputed, work that was providing strong support for the molecular model of AD and the role of β-amyloid for the disease. What does this mean for the AD field?
A lot of people were already skeptical about the amyloid cascade hypothesis, so when the Lesné case came to light, they said “here we go! The data were fabricated and that shows that the whole β-amyloid hypothesis is invalidated!”. This, of course, is not the case, since there is a great body of work besides Lesné’s publications supporting the amyloid cascade hypothesis. Hence, amyloid still poses a logical therapeutic target for Alzheimer’s, but the tricky part is whether we are targeting it at the right time.
Given that historically approaches that target amyloid have not yielded the desired results in the clinic, could it be that a combinatory approach, targeting both amyloid and tau, might make a difference for AD patients?
Definitely! I think that is where the field is heading. What I think is also important to keep in mind, is that a lot of these past failed approaches were developed in the absence of proper biomarkers. Nowadays, clinicians can make use of reliable diagnostic methods to stratify patients and better define AD populations for inclusion in clinical studies and in the future matching them with the most efficacious treatment option.
Have these advances in the field led to the development of more successful AD therapeutics?
There are two recent, promising compounds on the market and close to regulatory approval. The first one is Aducanumab, which has had a rather unorthodox development trajectory, that raised several doubts in the field, but could still hold promise for AD patients. I am certainly still awaiting the long-term clinical effects, but it seems to be very effective in plaque removal and this could translate to cognitive benefits at longer treatment duration. This year, another antibody therapeutic, Lecanemab, has successfully concluded phase 3 clinical trials, slowing down cognitive decline as well as showing plaque removal.
Indeed, Lecanemab has been one of the most anticipated drug releases of 2022. Could it be the answer for AD patients?
Lecanemab has shown impressive results in the trials and the effect on cognitive performance might seem modest in the eyes of critics. Of course, we need to wait for the regulatory approval of Lecanemab, but it feels like we are pulling the edge of something that could turn out to be either a handkerchief or perhaps a blanket. It will be revolutionary for the field to come up with an truly effective treatment, also because it allows us to better judge the validity of the preclinical and diagnostic models that we are using Key steps towards the development of more and more effective treatments, identifying the disease in early stages and the best care for AD patients.
