Alpha-Synuclein-Binding Anti-Parkinson Antibodies Fail in Clinical Trials | Health City Berlin

Sunday August 14, 2022 – Author:

In Parkinson’s disease, alpha-synuclein proteins are deposited in the brain. The hope of stopping the progression of the disease with alpha-synuclein-binding antibodies has been dashed for the time being. Two clinical studies show disappointing results.

Two alpha-synuclein-binding antibodies disappoint in clinical studies: both the antibody cinpanemab and prasinezumab had Parkinson’s disease patients in the early stages no significant effects. Neither was it possible to show a breakdown of the protein deposits in the imaging, nor could the progression of the disease be delayed. The results of the two randomized, placebo-controlled phase 2 studies were published last week in The New England Journal of Medicine/NEJM.

A study terminated prematurely

The study of cinpanemab involved 357 patients who received two different doses of the antibody (1,250 mg or 3,500 mg) or a placebo. Since no differences could be determined after 72 weeks, the study was terminated prematurely.

Treatment with the α-synuclein-binding antibody prasinezumab did not perform any better. The drug was also administered in two different dosages and compared with a placebo. Here, too, there were no improvements in clinical outcome and imaging in the treatment arms.

α-synuclein deposits probably not the cause

The two antibodies were developed on the assumption that α-synuclein deposits were the cause of the degenerative process. Because the Parkinson-typical Lewy bodies, round inclusions in the cytoplasm of nerve cells, consist of this special protein. Therefore, there was great hope that a causal therapy against Parkinson’s disease could be found with α-synuclein-binding antibodies.

However, α-synuclein may not be the cause of Parkinson’s at all, but merely a biomarker, Prof. Lars Timmermann suspects, which is why “a targeted therapy against α-synuclein is in vain”, according to the deputy president of the German Neurological Society. “With a cause-and-effect chain between α-synuclein and Parkinson’s progression, the results should have been positive, at least in terms of trend.”

There are different subtypes of Parkinson’s disease

However, neurologist Timmermann is not entirely pessimistic about the situation: “Currently, research is also being carried out into so-called “small molecules” and RNA-based therapeutic approaches in order to prevent the supposedly pathogenic protein aggregations. It remains to be seen whether these substances may have a greater effect.”

Timmermann emphasizes that although people are talking about “the” Parkinson’s disease, many different clinical pictures with different courses are hidden behind it. One goal must therefore be to classify the subtypes better and to test therapy options for the individual types of disease. “A study on a cancer drug that is effective for one tumor type would probably also be negative if cancer patients with different tumor diseases were included.”

Nerve cells die off in the substantia nigra

In Parkinson’s disease, nerve cells in the substantia nigra – a dark-colored brain region in which movement is controlled – perish. As a result, there is a lack of the neurotransmitter dopamine in the brain, which is needed to transmit nerve stimuli. When there is a lack of dopamine, commands from the brain to the muscles are delayed, incomplete or not received at all. This is how the motor symptoms typical of Parkinson’s develop: reduced mobility, stiff muscles and tremors at rest. What exactly causes nerve cells in the substantia nigra to die off has not yet been clarified. The theory that α-synuclein deposits cause the degenerative process seems less plausible after these two studies.

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