Drug Repurposing Yields Hope for Reversing Effects of Parkinson’s

By Valerie Lauer
Tuesday, March 1, 2016

Preliminary findings from a small-scale study by Georgetown University Medical Center (GUMC) researchers indicate that a medication approved to treat leukemia may halt or reverse the progression of Parkinson’s disease and Lewy body dementia.

The study, which examined the efficacy of the chemotherapy medication nilotinib, was the work of the Director of Georgetown’s Laboratory of Dementia and Parkinsonism, Charbel Moussa, MD, PhD, and Fernando Pagan, MD, Director of the Movement Disorders Program at MedStar Georgetown University Hospital.

“Treating people with neurodegenerative diseases and limited access to drugs or treatments made me feel the need to pursue more translational and lab work — to basically identify new drugs or new compounds that would potentially halt or reverse the neurodegenerative nature of Parkinson’s and Alzheimer’s and other neurodegenerative diseases,” Dr. Moussa said in an interview for GUMC’s news outlet. “Our work has been focused on repositioning this already-FDA-approved drug, that we now have a good safety profile to use, for the treatment of neurodegenerative diseases — to stop or halt cell death in the brain and reverse the progression of the disease.”

Small but Promising

During preliminary experiments, Dr. Moussa and his team found that exposing brain cells in a petri dish to nilotinib effectively cleared cellular accumulations of Lewy bodies — protein deposits thought to be responsible for the disruption of normal cell function and dopamine production, and thus for the declining function of those with Parkinson’s disease.

Two years after this discovery, the phase 1 GUMC study began. The study enrolled 12 participants, 11 of whom completed the trial. Each received either 150mg or 300mg of nilotinib daily, significantly lower doses than those prescribed for the treatment of leukemia — up to 800mg.

The results were astonishing. All 11 subjects experienced improvement in motor skills and cognitive function. One participant who had previously been confined to a wheelchair was able to walk again, and three others regained the ability to speak.

Researchers observed that nilotinib penetrated the blood-brain barrier better than other medications designed to treat the decline in dopamine production that occurs in patients with Lewy body complications. Some patients were able to reduce or completely stop the use of dopamine-sparing medications. Participants with earlier stages of the disease responded best to treatment.

“To my knowledge, this study represents the first time a therapy appears to reverse — to a greater or lesser degree depending on stage of disease — cognitive and motor decline in patients with these neurodegenerative disorders,” Dr. Pagan said in a GUMC news release. “But it is critical to conduct larger and more comprehensive studies before determining the drug’s true impact.”

Understanding the Limitations

Although the initial findings are exciting, questions remain about the long-term safety and efficacy of using nilotinib to treat Parkinson’s disease. Study limitations included a small patient pool and no control group.

“There is controversy about what the mechanism is of this medication,” says James Beck, PhD, Vice President of Scientific Affairs for the Parkinson’s Disease Foundation. “Another issue is regarding the dose. The Georgetown group used 25 percent of the dose used for leukemia. That’s because the drug can cause sudden death. There are other inhibitors of alpha-synuclein [the protein that makes up Lewy bodies] that may be safer.”

Determining the safety of nilotinib to treat patients with Parkinson’s disease was the primary goal of the GUMC group’s initial trial. The researchers noted that the regimen was well-tolerated by participants, even though the medication in its use to treat leukemia is linked to a wide variety of complications, several of which affect more than 10 percent of patients treated for leukemia using this medication.

Beck points to the promising field of immunotherapy as a potentially safer approach to halting the progression of Lewy body development. While Parkinson’s disease is not infectious, the abnormal cell development responsible for the disease can spread from cell to cell, affecting additional portions of the brain and speeding the progress of the disease. Immunotherapy seeks to combat that process using antibodies. A vaccine and passive therapies are currently being researched.

In the wake of the GUMC research, the Parkinson’s Disease Foundation released a statement recommending against the use of nilotinib in a clinical setting at this time while endorsing additional research into the drug’s safety and benefits.

What’s Ahead

Participants in the GUMC study regressed when they stopped taking nilotinib. Once the initial trial closed, patients were able to continue the use of the medication as part of an expanded access trial. A larger clinical trial is slated to begin in 2016. Researchers are optimistic about the drug’s potential to help the 7 million to 10 million people living with Parkinson’s disease worldwide.

“A lot of institutions talk about expediting the translation of research from the lab to the bedside, but it doesn’t happen quickly very often,” Dr. Moussa says. “This is a solid example of how that is possible and why it is so important.”