Research News

FDA Approves Extended Release Levodopa-Carbidopa

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Today MJFF-awardee Impax Pharmaceuticals announced that the U.S. Food and Drug Administration approved RYTARY, an extended-release oral capsule formulation of levodopa-carbidopa, for the treatment of Parkinson’s disease.

“The FDA approval of RYTARY (pronounced rye-TAR-ee) is an important new development for the treatment of Parkinson’s disease,” said Fred Wilkinson, president and CEO, Impax Laboratories. “RYTARY is designed to address one of the most significant unmet needs for patients living with Parkinson’s disease, which is to reduce the amount of time during the day when their symptoms are not adequately controlled.”

Participants in a Phase III clinical trial experienced nearly an hour and a half less “off time” per day when taking the drug, as compared with carbidopa-levodopa plus entacapone, another drug to lengthen efficacy of levodopa.

The Michael J. Fox Foundation for Parkinson’s Research

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A recently published study funded by The Michael J. Fox Foundation and using MJFF research tools showed two avenues through which inhibiting the function of the protein LRRK2 may help treat Parkinson’s. The paper from the laboratory led by Andrew West, PhD, from the University of Alabama at Birmingham, appears in the Proceedings of the National Academy of Sciences.

Mutations in the LRRK2 gene are the greatest known genetic cause of PD, accounting for one to two percent of all cases of PD and more in certain ethnic populations. Mutations appear to heighten activity of the LRRK2 protein. Therefore, development of LRRK2 inhibitors is a priority of the Foundation.

“LRRK2 is one of our most promising areas of research toward a therapy to stop or slow the progression of Parkinson’s, and MJFF has established a roadmap to learn more about this target and build the infrastructure to accelerate discovery and drug development,” said Marco Baptista, PhD, MJFF associate director of research programs.

Part of the Foundation’s LRRK2 roadmap is the creation of research tools such as pre-clinical models and antibodies important to hasten the development of future therapeutics. The LRRK2 knockout pre-clinical model is bred without the LRRK2 gene, which can mimic the effects of a LRRK2 inhibitor drug.

Dr. West and his team studied both the LRRK2 knockout model and a wild-type model (typical form) when they introduced an excess of the protein alpha-synuclein. Parkinson’s is marked by clumps of alpha-synuclein in brain cells, which leads to cell death. The scientists compared the effects of too much alpha-synuclein in a LRRK2 knockout and a control model.

They found cell loss from the excess alpha-synuclein in the wild-type model but not in the LRRK2 knockout, meaning inhibiting LRRK2 could protect from neurodegeneration.

Using new antibodies developed by MJFF, Dr. West also found that LRRK2 was highly expressed in cells that responded to injury, leading to another hypothesis that inhibiting LRRK2 may help alleviate a specific type of inflammation. To test this hypothesis, they also introduced an inflammatory agent into both models and found, again, that the wild-type model experienced cell loss while the LRRK2 knockout did not.

Often tests of LRRK2 inhibitors use models with LRRK2 gene mutations. Since this study compared only knockout and wild-type models, its findings suggest LRRK2 inhibition may also benefit people who have PD but no LRRK2 mutations (the majority of PD patients).

“This broadens the window of those who might be helped by this therapeutic approach beyond only those with a LRRK2 mutation,” said Dr. West. “Seeing protection in this study gave us the green light to attempt and copy the symptomatic results pharmacologically, to help find a drug that we can bring to clinical trial.”

He is working on testing LRRK2 inhibitors, through separate projects with the Alabama Drug Discovery Alliance and with Pfizer. MJFF is funding the collaborative project with Pfizer.

 

Levodopa better than any drug.

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Whether to begin Parkinson’s treatment with the gold-standard levodopa or other therapy (e.g., dopamine agonist, MAO-B inhibitor) is a question debated among neurologists and patients.

A paper published today in The Lancet reports that early treatment of levodopa provides better mobility and quality of life after seven years over early treatment with dopamine agonists or MAO-B inhibitors. In the largest-ever Parkinson’s disease trial — called PD MED — a group of researchers from 80 sites throughout the United Kingdom and led by Dr. Richard Gray of the University of Oxford compared the three therapies in a total of 1,620 newly diagnosed patients, including those with young onset PD.

In a comment also published by The Lancet, Drs. Anthony Lang and Connie Marras (both from the University of Toronto) wrote, “The results of this study will help to persuade physicians and reassure patients that the fears that have served as the groundwork in establishing levodopa phobia — that often results in patients experiencing unnecessary and easily managed disability and reduction in quality of life in the early years of their disease — are unfounded.”

Some physicians are reluctant to begin patients on levodopa due to the earlier onset of levodopa-induced dyskinesia — a side effect of the medication that presents with jerky, fractured movements — and motor fluctuations or “off” episodes.

The PD MED study asked patients to complete a questionnaire on their quality of life relative to their mobility. After three years, patients on levodopa averaged 1.8 points better than patients on dopamine agonists or MAO-B inhibitors, and that beneficial difference remained seven years into the trial.

Dr. Gray was quoted saying, “Although the differences in favor of levodopa are small, when you consider the short- and long-term benefits, side-effects, quality of life for patients, and costs, the old drug levodopa is still the best initial treatment strategy for most patients.”

Scientists Discover Potential Pathway of LRRK2 Dysfunction.

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Researchers from Johns Hopkins University have reported on a potential route through which mutations in the LRRK2 gene — the greatest known genetic contributor to Parkinson’s disease (PD) — lead to cell death. This finding comes as much of the PD research field, including many initiatives from The Michael J. Fox Foundation, is tuned to discover more about the biology of theLRRK2 gene and its corresponding protein, a potential target of disease-modifying therapies.

Husband and wife Ted Dawson, MD, and Valina Dawson, PhD, led the study, partially funded by the National Institutes of Health, and recently published in Cell. MJFF did not fund this study, but has supported the work of both before.

They found that mutations in the LRRK2 gene may increase the rate at which the LRRK2 protein modifies ribosomal proteins, which are key components of protein-making machinery inside cells. This could cause the machinery to manufacture too many proteins, leading to cell death.

Experiments suggested that mutations in LRRK2 increase the rate at which it modifies two ribosomal proteins, called s11 and s15. Further tests showed that increased s15 activation was associated with cell death and abnormally high levels of all proteins. This action caused by the LRRK2 mutation may cause ribosomes (the cell’s protein-making factories) to make too much protein.

“Our results support the idea that changes in the way cells make proteins might be a common cause of Parkinson’s disease and possibly other neurodegenerative disorders,” said Dr. Ted Dawson.

He and his colleagues think that blocking excess activation of s15 ribosomal could lead to future therapies and measuring s15 could also act as a biomarker of LRRK2 activity in treatment trials.

MJFF has a LRRK2 Consortium of world-class investigators working to identify substrates of LRRK2 — the proteins that it modifies — to reveal new drug targets and biomarkers. More so toward those goals, the Foundation is gathering data and biosamples from people with and without PD with a LRRK2 mutation through the LRRK2 Cohort Consortium and the Parkinson’s Progression Markers Initiative, two large-scale clinical studies.

 

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More Alpha-Synuclein in Spinal Fluid Linked to Faster Cognitive Decline

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Alpha-synuclein — the protein that clumps in the cells of Parkinson’s patients — is currently the major focus of Parkinson’s biomarker studies. Researchers are analyzing biosamples (spinal fluid, blood, tissue) to make a connection between alpha-synuclein and risk, onset or progression of Parkinson’s disease (PD). The latest findings, published in The American Journal of Pathology, report that patients with higher levels in spinal fluid experienced faster cognitive decline.

In a project funded by The Michael J. Fox Foundation (MJFF), Jing Zhang, MD, PhD, and his team at the University of Washington in Seattle examined samples and data from PD patients obtained in the DATATOP study. Led by the Parkinson’s Study Group in the late 1980s, the deprenyl and tocopherol antioxidative therapy of parkinsonism (DATATOP) study collected samples and clinical data from PD subjects for up to eight years.

In this latest analysis, researchers compared alpha-synuclein levels to scores from tests of cognition, such as verbal learning and memory, visuospatial memory and processing speed, among 304 PD patients. They found that patients with higher levels of alpha-synuclein in spinal fluid had faster cognitive decline.

“This is a surprising conclusion,” says Mark Frasier, PhD, MJFF vice president of research programs. “One would think that people with more cognitive problems would have less alpha-synuclein in spinal fluid because more would be caught up in the brain causing those problems.”

Zhang’s group also reported that while alpha-synuclein levels decreased significantly over two years, that decline could not predict motor symptoms. These findings join a list of observations about how alpha-synuclein in spinal fluid relates to PD. Initial analysis from the MJFF-sponsored Parkinson’s Progression Markers Initiative (PPMI) reported last year that PD patients had lower alpha-synuclein levels in spinal fluid compared to controls. They also found that patients with posture/gait disturbance averaged lower alpha-synuclein than patients with tremor-dominant PD.

Further investigation into alpha-synuclein continues in PPMI and other studies. Zhang and his coauthors cited PPMI as a potential source for validation of their cognition findings. Since PPMI includes healthy controls, researchers could test whether those results are PD-specific or seen in healthy aging adults with cognitive decline, too.

To accelerate research around PD biomarkers, MJFF spearheaded an effort to make data and samples from varied Parkinson’s studies available to investigators. The Foundation also offers funding to use the data and samples, such as to Zhang for the DATATOP analysis.