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Drug Targeting Toxic Alpha-Synuclein Is Found Safe in Early Clinical Trial

In an early, small clinical trial an experimental drug designed to clear away a toxic protein associated with Parkinson’s disease (PD) was found to be safe in people. This result is a step toward evaluating whether therapies that target the alpha-synuclein protein can slow PD progression.  The research appears in the February edition of Movement Disorders.

Scientists agree that alpha-synuclein plays a role in causing PD.  Changes in its shape cause it to clump together and form Lewy-bodies, the hallmark of PD inside brain cells.  From genetics, researchers have also learned that mutations in alpha-synuclein can cause PD.  Recent studies point to a possible mechanism:  abnormal alpha-synuclein may travel from cell to cell like an infection, damaging the normal forms of the protein along the way.

So the search is on for potential therapies that would target and remove alpha-synuclein molecules and clumps, and block its spread through the nervous system.  The new study tested an antibody called PRX002.

Building on earlier research in mice, scientists led by the late Dale B. Schenk, Ph.D., of Prothena Biosciences, Inc., in San Francisco, tested 5 different doses of PRX002 in 40 healthy volunteers.  Study participants received one intravenous infusion of the drug, or a placebo.  For the next 12 weeks, the researchers monitored volunteers’ blood levels of both alpha-synuclein and the drug, and watched for side effects.

Results

  • The experimental drug PRX002 was safe and had no serious side effects at all doses tested 
  • Within one hour of receiving the drug PRX002, participants’ blood levels of alpha-synuclein dropped.  The higher the dose participants received, the lower their level of alpha-synuclein.
  • The drug PRX002 stayed in the body, with half of it eliminated by about 18 days after infusion. 

What Does It Mean?

The presence of alpha-synuclein in brain of people with PD is the hallmark of brain pathology in PD. Whether clearing alpha-synuclein from the brain by manipulation of the immune system can help treat the disease remains unknown. Similar strategy has been previously tested in Alzheimer’s disease (targeting different proteins) without success to date. 

The current study of the antibody PRX002 tell us that method is safe and paves the way for future research. But it doesn’t tell us yet whether the drug can effectively treat PD.   An early step in this direction is a study, already under way, that is assessing PRX002’s safety in people with PD and includes measurements of alpha-synuclein levels in cerebrospinal fluid.

In a commentary accompanying the research article, C. Warren Olanow, M.D., and Jeffrey H. Kordower, Ph.D. write:  “It is too soon to say if PRX002 or any other anti-synuclein agent will ultimately prove effective, but the science suggesting that α-synuclein should be targeted in PD is compelling, and establishing safety and tolerability is the first step.”

References

Schenk DB, Koller M, Ness DK, et al. (2017). First-in-Human Assessment of PRX002, an Anti–a-Synuclein Monoclonal Antibody, in Healthy Volunteers. Movement Disorders DOI: 10.1002/mds.26878

Olanow CW, Kordower JH (2017). Targeting α-Synuclein  as a Therapy for Parkinson’s Disease: The Battle Begins. Movement Disorders DOI: 10.1002/mds.26935

Friday, June 16, 2017
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