In this edition of “The Sherer Report,” my continuing series of updates on progress from the front lines of Parkinson’s research, I’m highlighting a few Foundation-funded projects to identify new drug targets for symptomatic PD treatments and improve on today’s generation of dopamine-based therapies. I also report on our continuing pursuit of a disease-modifying treatment that could slow or stop the progression of Parkinson’s disease. Finally, I want you to know about expanded industry investment in some MJFF-driven projects, which could have implications for speeding potential treatments toward pharmacy shelves.
Patients living with Parkinson’s today have a clear unmet need for improved treatment options to manage symptoms and increase quality of life. Current dopamine-based treatments are inadequate — they address only a subset of symptoms, lose effectiveness over time, and are marked by significant side effects such as dyskinesia (uncontrollable and debilitating movement). The Foundation continues to see encouraging progress toward new treatments that bypass the dopamine system altogether, as well as new formulations of dopamine replacement therapies that could address shortcomings of current treatments.
Progress with novel targets
Several clinical trials under way are based on biology that was not linked to PD a decade ago. Two MJFF awardees are pursuing innovative approaches that come directly from our increased understanding of PD over the past 10 years:
· Anders Björklund, MD, PhD, of Lund University in Sweden has been funded by MJFF since 2006 for his work on the brain chemical serotonin. In 2010 Björklund and the U.S.-based biotech PsychoGenics launched a proof-of-concept clinical trial to test a promising drug that targets serotonin as a treatment for dyskinesia. The trial is nearing completion and results are expected this year.
· Chelsea Pharmaceuticals has been developing a treatment, droxidopa, which targets the noradrenaline system, another chemical that functions in the brain. Droxidopa is being developed as a treatment for orthostatic hypotension (a sudden drop in blood pressure upon standing), a common cardiovascular symptom of PD for which there are currently no good treatments. Chelsea has completed a series of clinical trials for droxidopa in PD and is preparing for an FDA review this year, the last step in drug development. An FDA panel has already recommended droxidopa’s approval, but a final decision hasn’t been made as this issue goes to press. Interestingly, droxidopa may also have the potential to address other, untreated symptoms of PD based on the role of noradrenaline in the nervous system — which MJFF is helping researchers to explore. In 2011, we announced the support of a study led by Peter LeWitt, MD, at Wayne State University School of Medicine, to test the effectiveness of droxidopa on cognitive function in PD patients.
Work to improve dopamine-based therapies
Today’s generation of dopamine-based therapies often wear off before it is time for the next dose, leaving patients vulnerable to symptoms such as rigidity. The “peaks and valleys” of current formulations are also thought to contribute to dyskinesia. A more consistent delivery of levodopa could help patients get more benefit from their therapy with less risk of side effects. Two MJFF awardees are making progress toward improving current levodopa therapies:
· Impax Pharmaceuticals has been developing an improved extended release capsule formulation of carbidopa-levodopa that has returned encouraging results in clinical trials: Participants in a Phase III clinical trial experienced nearly an hour and a half less “off-time” per day when taking the drug — and a corresponding increase in their “on-time” without troublesome dyskinesia. Impax has completed several clinical studies and is preparing for FDA review this year for their novel dopamine-based treatment for PD.
· Civitas Pharmaceuticals is developing an inhaled formulation of levodopa for its potential to produce more rapid and continual relief from the debilitating motor fluctuations associated with Parkinson’s. Civitas is in the initial stages of clinical assessment of their drug candidate, called CVT-301. The company recently announced promising results from a study in healthy adults and is now planning a follow-on study in PD patients.
Preparation for clinical trials of disease-modifying approaches
As always, a great deal of our work focuses on strategies to slow, halt or reverse the progression of PD — something no available treatment can do. While there are many challenges to developing disease-modifying treatments, we are breaking new ground in this area and remain optimistic this will pan out sooner rather than later. Many of our efforts involve laying the groundwork for effective clinical trials:
· MJFF has been working diligently since 2005 to clarify the pre-clinical process for testing disease-modifying treatments. We are developing numerous pre-clinical tools and sharing them with the research community to accelerate science, foster collaborations and allow for comparisons of results across different labs. To date, we have generated 17 tools that have, in total, been ordered over 1,000 times by labs worldwide.
· The MJFF-led Parkinson’s Progression Markers Initiative (PPMI) continues to pave the way in the development of PD biomarkers — necessary tools for testing disease-modifying treatments in the clinic. PPMI has reached the halfway point in subject recruitment (newly diagnosed PD patients and volunteer controls). Real-time data has already been made available to the entire research community (almost 10,000 downloads and counting since March 2011) and initial observations are being reported.
Additionally, in 2012 we are looking forward to results from two clinical trials that have been driven by MJFF for several years, with a third to follow in 2013: the SURE-PD trial, which aims to test whether elevating urate (a naturally occurring anti-oxidant) through the supplement inosine could present a viable strategy for developing a disease-modifying PD treatment; the multi-site study assessing the safety of isradipine, an FDA-approved calcium channel blocker that has demonstrated potential to modify disease progression in pre-clinical models; and Ceregene’s Phase II trial of CERE-120, its gene therapy delivery of the neurotrophic factor neurturin.
Renewed interest from pharmaceutical companies
As a final note, I wanted to highlight some recent encouraging news demonstrating expanding interest in PD from the pharmaceutical industry. As potential therapies advance to and through the stages of clinical testing, costs grow exponentially. We must work to find ways to engage and encourage investment from pharmaceutical companies and other investors who have the resources, and who are motivated to develop novel, impactful medications. I am happy to report tangible progress on this front.
· Pharmaceutical company GlaxoSmithKline (GSK) recently announced separate follow-on deals with two different MJFF awardees, Signum Biosciences and Proteotech Inc. Both companies are actively developing disease-modifying treatments targeting the protein alpha-synuclein. GSK will provide needed resources for further clinical testing.
A critical component of drug development is the involvement of PD patients and control volunteers — and you can help! MJFF rolled out Fox Trial Finder in summer 2011 to make it easier for you to learn about clinical trials and find the ones that need someone specifically like you. Completing a profile is easy and your privacy is always assured. Over 3,000 people have signed up, helping to build one of the largest groups of interested and engaged PD patients in the world. Information on more than 180 PD clinical trials is available. Visit www.foxtrialfinder.org to learn more.
The level of activity in the field of PD research continues to grow. MJFF alone supported over $57 million of new research grants in 2011. But while we have made measureable progress, many challenges remain. Nonetheless I am more optimistic than ever. With the scientific breakthroughs we’re making every day, new, transformative treatments are on the horizon. Thank you, as always, for being part of our shared mission to eradicate Parkinson’s disease.