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Alzheimer's Biomarkers and the therapy targets

According to experts, biomarker-based diagnostic criteria for dementia will increasingly become part of the diagnostic routine, whereas clinical symptoms will play a secondary role. Why this?


More and more research is currently being carried out into disease-modifying therapy approaches targeting specific biomarkers.


Among these causal approaches, anti-amyloid therapy leads the way.


Aducanumab


The FDA approval in 2021 was based on the results of the phase III studies EMERGE and ENGAGE with almost 3,000 patients who received either the β-amyloid antibody intravenously in different doses or a placebo. However, Aducanumab is not the Holy Grail of dementia therapy.

Retrospectively, the data shows a small clinical effect at a high dose. However, the results are sometimes contradictory. Although the antibody is specifically directed against amyloid, there was a drastic reduction in tau protein in patients.


Many American neurologists are very cautious about prescribing the drug till further studies are completed.




At the CTAD Congress in December 2022, two more antibodies were presented: gantenerumab and lecanemab.


Gantenerumab

In the placebo-controlled gantenerumab phase III study, almost 1,000 patients with prodromal to mild Alzheimer's received the monoclonal antibody in each study arm. It was applied subcutaneously every two weeks. The primary endpoint was Clinical Dementia Rating-Sum of Boxes (CDR-SB) at week 116. The study results showed only a very low effect on amyloid clearance.


Lecanemab


In the Clarity Study, Lecanemab was administered intravenously every 14 days to around 1,800 mildly affected patients over 18 months. A slightly reduced deterioration in CDR-SB compared to placebo was evident as early as six months (p<0.01) and continued through 18 months (p<0.0001). According to the study's authors, the drug "resulted in moderately less decline on measures of cognition and function," particularly in patients in the early stages of the disease with mild cognitive symptoms.

The study also showed that some patients experienced brain swelling, observed in other experimental drugs targeting amyloid beta.

As with aducanumab, brain amyloid decreased drastically. Lecanemab is now approved in the USA.


DRUG SPECIFIC SIDE-EFFECTS


Another downer: As mentioned above, during treatment with the monoclonal antibodies, edema-brain swelling (amyloid-related imaging abnormalities ARIA-E) and bleeding (ARIA-H) in the brain occurred.


Antibodies against tau protein (another dementia biomarker): Negative results


In addition to β-amyloid antibodies, tau antibodies are also being tested, for example, in a current phase IIb study with patients with prodromal or mild Alzheimer's and proven β-amyloid and tau pathology. The monoclonal tau antibody Semorinemab caused a reduction in tau, but to a lesser extent than expected. In addition, the data showed no difference in cognition compared to the placebo.


To sum up, Alzheimer's cure is not available yet. Therefore, effective and sustainable approaches to dementia prevention and risk reduction are urgently needed.


More information at www.mindr.us

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