Back to the future with Parkinson’s research

Michael J. Fox Foundation partners with leading CROs to develop biomarker candidates for Parkinson’s disease

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NEW YORK—The Michael J. Fox Foundation for Parkinson's Research (MJFF) is working with contract research organizations (CROs) Covance Inc., Parexel International and Epitomics Inc. to develop biomarker candidates, with the foundation earmarking nearly $1.1 million for projects aimed at advancing the development of leading biomarker candidates for Parkinson's disease (PD).

According to Mark Frasier, associate director and team leader of research programs at MJFF, the foundation is "committed to developing research tools that are critical for advancing therapeutic targets toward the clinic, but which no single drug discovery/development stakeholder has a financial incentive to invest in."

"In this case, MJFF is working to generate high-quality, consistently performing and reproducible antibodies and assays for measuring the proteins alpha-synuclein and DJ-1, which appear to change in people with Parkinson's disease," he notes. "The foundation is also funding the collection and storage of body fluids from healthy volunteers to use as a resource for testing and optimizing biochemical biomarkers."

For alpha-synuclein biomarkers, MJFF is coordinating a series of projects to optimize assays around this protein. The projects are being led by Frasier in partnership with the three companies. For DJ-1 biomarkers, MJFF is working with Dr. Un Kang of the University of Chicago Medical Center and Covance to develop DJ-1 assays.

According to Larry Ereshefsky, chief scientific officer, vice president and principal consultant at Parexel, Parkinson's has a progressive deteriorating course, and it shares many end-stage similarities with other neurodegenerative disorders.

"Recent work performed at Parexel's Early Phase Unit in Los Angeles has included pioneering the application of continuous cerebral spinal fluid (CSF) sampling for up to 48 hours," he says. "The utility of this technique has been demonstrated as a tool for the evaluation of Alzheimer's disease diagnosis and progression as well as proof of drug action. The application of this approach to other degenerative disorders is a next step as part of a more sophisticated approach to drug development to address the unmet needs of patients."

Ereshefsky points out that the development of biomarkers that can be used as a surrogate for disease modification and progression effects for novel drug therapies is a key to expedited development of new therapies where the course of illness is measured in years, rather than in weeks or days.

According to Dr. Tom Turi, vice president of biomarker services at Covance, the current lack of validated PD biomarkers particularly impacts the development of disease-modifying treatments. He also notes that other candidate biomarkers may emerge for use in future clinical studies.

Since 2007, MJFF has been a pioneer in partnering with CROs whose specialized expertise allows for efficient and cost-effective execution of specific research goals, and that made Covance, Epitomics and Parexel attractive partners for the effort, Frasier says.

"Recognizing the number of bottlenecks that keep research from moving out of academic labs and toward the clinic and patients, MJFF has always been willing to put our money wherever it can most effectively speed the drug development process," he says.
Biomarkers are often used to stratify patients for treatment or detect the effectiveness of a test drug in clinical trials.

"Several biochemical biomarkers have been identified in previous studies, but the sensitivity must be improved if they ever will be used in a routine laboratory setting," Frasier says. "Our studies will help develop sensitive, rigorous and consistent methodologies for biomarker detection that will be available to researchers around the world. This will allow investigators to compare the results of studies to each other more effectively. We also anticipate that the banked biospecimens will be a valuable resource for researchers who have identified a novel biochemical biomarker and would like to test its variability in the same individual over a 24-hour period."

Turi explains that MJFF has supported the generation of an immunoassay for detection of alpha-synuclein in human samples.

"Covance has been conducting laboratory studies to evaluate and optimize the performance of this assay to support future clinical research," he says. "In particular, we've helped demonstrate the utility of the assay on CSF samples, and optimized the assay to meet sensitivity criteria required in this setting."

Turi also points out that the DJ-1 protein is one of a number of molecules that have been the focus of intense study in the PD research community.

"The field has not yet established whether the link between DJ-1 protein and PD that has been identified to-date is translatable to clinical association with PD," he notes.

The research teams involved in the endeavor still can face plenty of potential challenges.

"In the evaluation of 'established' biomarkers, like alpha-synuclein and DJ-1, a major challenge faced by researchers in this effort is the availability of robust assays that allow detection of the biomarker of interest with the required specificity and sensitivity," Turi notes. "For the study of 'novel' markers, researchers face the challenge of developing the appropriate reagents and methods that will serve as the building blocks for new assays."
Turi points out that Covance can help to address those challenges by applying its expertise and a high standard of scientific rigor to the assay development process. To set up for improved biomarker assays for future clinical studies, Turi says this includes "assessing the influence of biological matrix on assay readout, performing assay validation, and anticipating the need for stable long-term reagent supply."

Moreover, these diagnostic biomarkers can be used to more accurately evaluate or classify patients and assess disease progression.

"Biomarkers can provide early evidence of the effects of novel candidate drugs either through measuring the direct biologic interaction between the drug candidate and its target or through measuring a biologic process that is closely associated with the target of interest, e.g., a change in downstream products," Turi says. "Incorporating biomarkers at all stages of drug discovery and development enable better and more informed decisions when deciding to advance clinical candidates."

The foundation is expecting a final report on the outcomes of these studies before summer's end, according to Frasier.

"Analysis of the results will lead to next steps, including chaperoning the work to the next logical phase of development and providing follow-on funding where suitable, to further refine these critically needed research tools and determine feasible methods of distribution," he concludes.

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