Objective/Rationale:
HE3286 is an anti-inflammatory drug in phase II clinical trials for other diseases that is being evaluated for treatment of Parkinson’s disease (PD). HE3286 taken orally rapidly enters the brain and targets a molecular pathway that causes the loss of muscle coordination in PD and the loss of muscle control caused by long-term levodopa therapy. Extensive safety testing suggests that HE3286 is safe, and because the drug does not alter normal brain functions, no side effects are anticipated.
Project Description:
Non-human primates with chemically induced PD will be treated for several weeks with placebo, HE3286 or reference drug (amantadine) alone and in combination with levodopa. The subject’s symptoms of PD, such as loss of muscle coordination and reduced mobility, will be monitored using video recordings to aid in the assessment of the drug’s activity.
After several weeks of treatment, high doses of levodopa will be administered to induce a loss of muscle control (levodopa-induced dyskinesia or LID) that almost always besets Parkinson’s patients after lengthy levodopa treatment. The primates will be treated with placebo, HE3286, or amantadine for several weeks and observed for anti-LID efficacy. After anti-LID testing, the brains will be analyzed to determine drug effects on molecular signals that cause PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
HE3286 as a stand-alone PD therapy may improve motor coordination and/or decrease LID, or it may enhance the efficacy of levodopa. HE3286 could be an alternative to levodopa for patients who have developed LID or desire or need to postpone initiation of levodopa therapy. Because HE3286 is a disease-modifying agent with low potential for drug-to-drug interactions, it has the potential to be combined with other disease-modifying agents to build new treatment paradigms.
Anticipated Outcome:
We expect to learn if HE3286 can decrease the development of motor coordination problems and LID in a model of Parkinson’s disease that very closely resembles the disease in humans, and to see how the activity of HE3286 compares to a drug already in use (amantadine). We will also learn if HE3286 and levodopa therapies have increased benefit when used together. Although greatly unexpected, the experiments may also expose unanticipated side effects of HE3286 treatment.
Progress Report
In this study HE3286 improved the ability to move and decreased signs of disease in an advanced pre-clinical model of Parkinson’s disease. Models that were treated with HE3286 had almost twice as many surviving brain cells in the part of the brain that controls body movement, compared to models that received placebo. When HE3286 was given with the most common Parkinson’s medication, levodopa, mobility improved and apathy decreased more than when levodopa was given with placebo. We also found that HE3286 decreased levodopa-induced dyskinesia better than placebo and better than amanatidine, an FDA-approved drug to reduce the dyskinesia side effect. No safety or side effect problems were expected from HE3286, and none were observed in the study. The study results suggest that HE3286 should be investigated in human clinical trials for Parkinson’s disease.
Presentations & Publications
Ingrid Philippens, Guus Baarends, Fred Batenburg and Clarence Ahlem. Anti-Parkinson and anti-L-Dopa induced dyskinesia efficacy of HE3286 in a MPTP non-human primate model. Poster presented on November 9, 2013, at the Society for Neuroscience meeting in San Diego, CA.
June 2014