- First, in the human food-drug interaction study we found that healthy subjects who took inosine (1.0 gram) by mouth had a significant increase in their blood levels of urate. The extent and timing of the blood urate increase after taking inosine (e.g., with a peak occurring approximately 4-6 hours later) was no different when the inosine was taken with a standard meal compared to on an empty stomach, indicating the effects and safety of inosine would not be appreciably altered by food.
- Second, in the test tube study of urate’s effects on drug-metabolizing enzymes, urate was found to produce no effects that would be expected to significantly alter the safety of a wide range other medications.
Funding from The Parkinson Alliance helped to finance the following Parkinson’s research. Grantees were selected by scientific review committees of participating organizations. Updates will be posted, when available.
Project Title: Interdisciplinary Home Visits to Improve Outcomes for Advanced Parkinson’s Disease Patients
Principal Investigator: Jori Fleisher, MD, Amy C. Lemen, LCSW, Meghan Sweeney, LMSW, Alessandro Di Rocco, MD, NYU Langone Medical Center, NYU School of Medicine, NYU Langone Parkinson’s, and Movement Disorders Center
Objective/Rationale: Our Center has a proven track record of pushing back the clinic walls in an effort to develop new models of care for our patients and the Parkinson’s community. Our unique medical-community partnership with the JCC Manhattan – The Edmond J. Safra Parkinson’s Wellness Program–NYC – is a demonstrated model of success that is currently being adapted to locations across the country through the Edmond J. Safra National Parkinson’s Wellness Initiative. The Interdisciplinary Home Visit Program (IHVP) is the next step in our effort to develop new models of care that push past the clinic walls to help improve outcomes and quality of life (QoL) for all patients, including our most vulnerable.
While patients with PD may be able to access comprehensive, multidisciplinary care during the early and middle phases of PD, advancing PD often causes motor fluctuations, falls, and severe non-motor symptoms that make accessing necessary, specialized care difficult or impossible. As symptoms progress, QoL for the patient and caregiver deteriorates and patients can lose their critical connections to neurologists, allied health professionals, ancillary services and community resources. IHVP extends the reach of our Center into the home by providing quarterly, comprehensive home visits with a social worker, nurse, and PD specialist neurologist for our homebound patients.
Project Description/Methods/Design: Patients with advanced PD who are homebound, live within the 5 boroughs of NYC, and are followed at the NYU PMDC are eligible to participate in the IVHP. Patients are visited approximately every three months by our IHVP team, consisting of a Parkinson’s specialized social worker and nurse. A movement disorders neurologist either accompanies the team in person, or joins via live video conferencing. Each visit entails a detailed history, home safety and medication evaluations, physical and cognitive examinations using validated scales for PD, and a full needs assessment of both the patient and caregiver(s). Referrals to necessary services are provided, including in-home physical, occupational, and speech therapies, supportive counseling, assistive technologies, meal services, organizing services and other medical and community resources. A unified note summarizing all aspects of each visit is created, shared with the supervising neurologist for collaborative planning as needed. The program has become a valuable learning opportunity for our clinical Fellows training to become movement disorders specialists.
Relevance to Treatment of Parkinson’s Disease: While advances have been made in the management of PD in early and middle stages, optimal treatments for late PD are not as well-studied. Many patients become homebound, missing both clinical care and the opportunity to participate in research that would shed light on this stage of disease. Thus, best practices for the treatment of late PD are understudied. Extending medical, social work, and nursing services into the home allows us to learn more about advanced PD in general, anticipate and comprehensively manage progressive motor and non-motor symptoms, address goals of care, prevent institutionalization and hospitalization, and provide palliative services as needed.
Expected Outcome: The IVHP will demonstrate that interdisciplinary home visits are a feasible, sustainable model for improving access to care for patients with advanced PD. We anticipate stabilization in the patient’s QoL, decrease in caregiver burden, and satisfaction with the IHVP, as measured by the NeuroQOL, Multidimensional Caregiver Strain Index, and Client Satisfaction Inventory, respectively. Compared to matched patients in the National Parkinson Foundation’s Parkinson’s Outcome Project, IHVP patients will have fewer hospitalizations and lower caregiver burden. In addition, additional resources and the incorporation of telemedicine systems will help broaden patients’ access to care, including patients in the PMDC Parkinson’s and Movement Disorders Clinic at Bellevue Medical Center, the largest public hospital in the country.
August 2016 Project Update:
Since receiving the grant from The Parkinson Alliance, we have worked closely with NYU Langone Medical Center’s Information Technology Department, receiving strong support from the Chief Medical Information Officer, in developing and implementing a telemedicine platform that is sensitive to the needs of our patients. As the pioneer effort in telemedicine at NYU Langone, the IVHVP spurred the creation of the NYU Virtual Health Steering Committee in November 2015. The Committee is the oversight body for virtual health initiatives across the medical center.
After piloting several models, we went live with telemedicine on home visits in February 2016. The Parkinson’s specialized social worker and nurse visit patients in their homes, bringing with them an iPad with built-in WiFi connection. After entering the home, the social worker and nurse contact the movement disorders specialist, who has remained in the office, and joins the visit via HIPAA-secure live video teleconferencing. This enables real-time documentation of the visit in the electronic medical record, expedites prescription orders and referrals, and improves communication between the IVHVP team and the patients’ other health care providers, while laying the foundation for increased capacity.
In a pilot study of a small subset of IHVP patients (n=27), we have found that we are indeed reaching an older and more disabled PD population than has ever been recorded. Despite an average age of 81 and total Unified Parkinson’s Disease Rating Scale (UPDRS) score of 65 at home visit 1, and despite expected progression of their disease (average change of UPDRS of 12 points over year), QoL as measured by 9 domains of the NeuroQOL instrument, stabilized or improved. On average, IHVP patients and care partners rated their satisfaction with the program as 98 on a scale of 0-100. Additionally, feasibility is supported by all eligible patients by indicating their desire to continue receiving home visits.
The IHVP continues to grow, and in August 2016 we launched a new study of the effect of the program on people with advanced PD. We have expanded our study of this vulnerable population to include those with with cognitive impairment and atypical parkinsonism. Additionally, we are studying the healthcare utilization and unmet needs of this population – both patients and their caregivers – in an effort to prevent unnecessary and often dangerous hospitalizations and nursing home placement.
Project Title: Optimization and Pharmacokinetics of Molecular Tweezers
Investigator/Author: Gal Bitan, PhD, UCLA
Objective: We are developing a novel drug candidate, a “molecular tweezer” that blocks the pathologic aggregation of proteins into toxic “clumps.” In Parkinson’s disease, the protein alpha-synuclein self-associates into toxic clumps that kill the dopaminergic neurons in the brain. CLR01 can stop alpha-synuclein clumping and thereby protect the brain from the harmful action of the clumps. CLR01 was found to protect animal models of Parkinson’s disease from toxic alpha-synuclein clumps without apparent side effects, and therefore it is a promising candidate for development towards human clinical trials. To achieve the goal of initiating clinical trials, the pharmacology of CLR01, including its oral bioavailability and blood–brain barrier penetration, need to be fully characterized and potentially optimized, which are the goals of the current project.
Background: We hypothesize that compounds preventing the self-association of alpha-synuclein into toxic clumps will provide disease-modifying therapy for Parkinson’s disease. Our data in animal models so far support this hypothesis. We will now take the necessary steps to allow future examination of this hypothesis in patients with Parkinson’s disease.
Methods/Design: In the current project, we will prepare novel formulations and pro-drug derivatives of CLR01, test them to select the ones showing the best performance, and then carry out a full pharmacokinetic characterization of the top 1-2 candidates. The initial step will include testing each formulation or derivative at one time-point, which was determined in previous studies to be the most informative. Subsequently, the candidates that show the highest oral bioavailability and/or blood–brain barrier penetration, will be assessed using a full-fledged pharmacokinetic and toxicokinetic analyses in animals, which will be used as guidelines for future human clinical trials.
Relevance to Diagnosis/Treatment of Parkinson’s Disease: We expect that the project will lead to selection and full characterization of a clinical candidate, which will lead to a first-in-class disease modifying therapy for Parkinson’s disease.
Next Steps for Development: Following completion of the study, the chosen candidate(s) will be subjected to formal Investigational New Drug (IND)-enabling studies, as required by the Food and Drugs Administration (FDA). Once the FDA approves IND status, clinical trials will be initiated.
September 2016 Project Update:
We have made progress on all three of our goals. Towards determination of full brain pharmacokinetics of CLR01, we have established a new and improved bioanalytical method. The method has been optimized and validated for detection of CLR01 in the brain. We are currently in the process of performing brain pharmacokinetic analysis, testing route of administration, blood-brain barrier penetration, brain clearance, and steady-state brain concentration.
Using a bioanalytical method in which CLR01 is radioactively labeled, we tested a number of new formulations for their ability to increase blood-brain barrier penetration and oral bioavailability. Our latest data show that both blood-brain barrier and oral bioavailability can be increased by at least 2.5 fold by the initial formulations. We plan to switch to testing formations now using the new bioanalytical method and to test additional ones best on the results from the initial experiments.
September 2017 Project Update:
We have made significant progress toward improving the pharmacokinetics of molecular tweezers. We screened a series of pro-drugs and new derivatives and discovered two derivatives and two pro-drugs with improved blood–brain barrier penetration, plasma half-life, oral bioavailability, or a combination of all three. We are now moving on to fully characterize these four candidates and expect to select the best one in the beginning of 2018, which will be an important step toward clinical trials.
We have also initiated a new project aimed at developing highly sensitive and specific biomarkers for Parkinson’s disease. This will allow not only to improve the diagnosis of PD at early stages, but also to stratify the correct patient population into appropriate clinical trials and to monitor the effect of treatments using a simple blood test. Our initial results show that this new methodology has high specificity and sensitivity to distinguish PD not only from healthy people, but also from the closely related disease multiple system atrophy. We expect to publish the data in the next few months and are applying for additional funding for further improvement and expansion of this new methodology.
New Publications Supported by Team Parkinson/The Parkinson Alliance:
F Richter, I Magen, P Lee, S Subramaniam, J Hayes, A Attar, C Zhu, N Franich, N Bove, K De La Rosa, J Kwong, F-G Klärner, T Schrader, M- F Chesselet, and G Bitan (2017) A molecular tweezer ameliorates motor deficits in mice overexpressing α-synuclein. Neurotherapeutics, in press. E-pub ahead of print, DOI: 10.1007/s13311-017-0544-9.
Project Title: Pivotal Drug Studies in Developing Inosine for Parkinson’s Disease
Investigator/Author: Michael Alan Schwarzschild, MD, PhD
Objective: To determine if oral inosine is subject to interactions with food or drugs in a way that warrants additional safety precautions for human administration in a phase 3 clinical trial.
Background: Inosine is a natural urate precursor and can be taken by mouth to raise urate levels in the body, whereas taking urate itself does not (apparently because it is broken down in the intestines). Positive safety and proof-of-concept results of a recent phase 2 trial of inosine for Parkinson’s warrant further development. However before embarking on the next phase of testing, specific studies for potential inosine interactions (with food and with other drugs) must be conducted to ensure that patient safety standards and regulatory requirements of the US Food & Drug Administration (FDA) are met.
Urate has been identified as a potential target in the search for treatments to slow the progression of Parkinson’s disease. Urate a natural end product of human metabolism possesses antioxidant properties. Because oxidative damage is thought to contribute to brain cell degeneration in Parkinson’s disease, scientists have hypothesized that higher levels of urate may be neuroprotective in this disease.
This hypothesis has gained strong support from human observational (epidemiological) studies showing that higher blood urate levels are linked to a lower risk of getting Parkinson’s, and to a slower rate of worsening among people who have the disease. In animal studies raising urate levels protects brain cells from the kind of degeneration that occurs in people Parkinson’s disease. The convergence of these human and laboratory findings have encouraged research by the Parkinson Study Group (PSG) to determine whether raising urate levels in people with Parkinson’s could slow the progressive decline that they endure.
However, while raising urate might protect the brain in Parkinson’s disease, it is known to increase the risk of certain kidney stones and of gout, and may produce other side effects. Accordingly the development of urate-elevating therapy is being carefully pursued as reflected in this key safety project, which is required to advance to a full scale effectiveness (phase 3) testing of urate elevation as a candidate disease-modifying therapy.
Methods/Design: The study will determine whether a) eating a meal just before an oral dose of inosine affects the increased blood urate level produced by inosine, and b) increased urate levels alters the cellular machinery known to metabolize or transport other commonly used drugs. The inosine-food interaction study will be conducted with healthy individuals who after giving informed consent will receive a dose of inosine alone or with a standard meal before blood samples are collected for urate measurements. The inosine-drug interaction study will be conducted by measuring the effect of urate on cells in a dish.
Relevance to Diagnosis/Treatment of Parkinson’s Disease: The results may alter the way the inosine is administered to patients (e.g., only on an empty stomach versus without restriction on food intake), and thereby will help ensure the safety of Parkinson’s disease patients who volunteer for a trial of urate-elevating inosine treatment intended to slow the worsening of the disease.
Next Steps for Development: The results (along with any changes to the planned phase 3 clinical trial protocol that the results may warrant) will be promptly submitted to the FDA for its determination of whether the trial may proceed.
September 2016 Project Update:
With the support of The Parkinson Alliance and its Parkinson’s Unity Walk (PUW) program’s proceeds – leveraging funding from the Michael J. Fox Foundation (MJFF) – we have achieved our project’s original objective in support of the SURE-PD3 trial of inosine in people with early Parkinson’s disease (PD). We successfully conducted the two key safety studies of 1) whether food affects the ability inosine capsules to raise blood levels of urate in healthy subjects, and 2) whether urate alters the activity of enzymes known to metabolize other drugs that PD patients may be taking.
Together these findings supported moving ahead as planned with the SURE-PD3 trial, a major phase 3 clinical trial of urate-elevating treatment with inosine in PD patients to determine whether it can slow disease progression. Based on the results of this MJFF-/PUW- supported project subjects enrolling in SURE-PD3 may take the study medication without restrictions on how it is taken (with or without food) or with other medications. The results of these safety studies were submitted to the FDA and ClinicalTrials.gov, and subject enrollment for the trial began in August 2016. Recruitment for the trial is expected to continue through 2017 at 60 sites of the Parkinson Study Group across the Unites States. The study is seeking people with people at an early stage of typical PD not yet requiring PD medications (except that rasagiline and selegiline are permitted) and meeting additional criteria. More information about the trial and where it is being conducted can be found at ClinicalTrials.gov.
Results: This project has been concluded. It is going to publication on ClinicalTrials.gov and has been submitted the FDA as noted above. It has supported the start of the SURE-PD3 trial, now under way.
ClinicalTrials.gov has now posted the final inosine FDI study entry update, along with resluts. The Parkinson Alliance were collaborators and funders along with the Michael J. Fox Foundation.
September 2017 Project Update:
The safety study results were submitted to the FDA, which has indicated its concurrence, and are now publicly posted on ClinicalTrials.gov (https://clinicaltrials.gov/show/NCT02614469). Based on these results the phase 3 clinical trial protocol was finalized and subject enrollment began in August 2016 at 60 sites of the Parkinson Study Group (http://www.parkinson-study-group.org/) across the Unites States. Enrollment was 80% complete as of July 2017 and is expected to close by the end of the year. In 2017 two sub-studies were added to introduce additional PD progression measurements using a smartphone app called Smart4SURE and serial dopamine transporter brain scans.
Project Title: Deep Brain Stimulation for Parkinson’s Disease: Key Opinions from the Mid Atlantic Region
Principal Investigator(s)/Author(s): Zachary Levine, M.D., Matthew Boyce, MD, et al.
Objective: To develop guidelines that help patients understand deep brain stimulation and its benefits and limitations, and to help physicians and surgeons improve their practice.
Background: The Parkinson Alliance hosted a meeting in the Richmond Virginia on February 20th – 21st 2015 to obtain “key opinions” about Deep Brain Stimulation (DBS) for Parkinson’s Disease from experienced physicians and neurophysiologists in the respective region of the United States. The focus of this discussion was to develop guidelines for best practice of deep brain stimulation for PD. The document does not represent all of the opinions in the field regarding the treatment of Parkinson’s disease (PD) with deep brain stimulation, but rather was a result an exchange among experienced physicians and surgeons.
Methods/Design: Experienced physicians and neurophysiologists familiar with DBS for PD from the mid-Atlantic region of the United States were invited to participate in a “key opinions” meeting pertaining to DBS procedures. In attendance were neurologists, neurosurgeons, neurophysiologists, industry and the Chief Executive Officer of The Parkinson Alliance who hosted the event. Although many of the topics discussed were verified in the literature, some of the discussion points were based on the experience of those in attendance. Topics were introduced at the meeting, followed by group discussion. A report will be generated consisting of the Key Opinions from the attendees pertaining to current guidelines for DBS procedures.
Relevance to Diagnosis/Treatment of Parkinson’s Disease: As the evolution of DBS therapy occurs for individuals with PD, it is important for professionals to convene as a group to ensure a best practice approach to this respective intervention. Common challenges of DBS for PD were highlighted in this meeting and include: Determining optimal candidates for surgery, identifying what techniques and targets are best, maximizing benefit and mitigating risk as well as side effects from stimulation, and making the surgical procedure better.
June 2016 Project Update:
A white paper titled Key Opinion Leaders in Deep Brain Stimulation (Mid Atlantic region) A Consensus Meeting Hosted by The Parkinson Alliance is now available.