Researchers : Treatment Study Should Go On

Contact: Allison Elliott

 

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In the wake of Amgen’s latest denial, researchers and patients are seeking a third-party sponsor to provide the drug to the patients who already have undergone surgery for GDNF delivery to the brain and want to continue treatment. The Kentucky research team asks Amgen not to block progress on treating Parkinson’s disease.

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LEXINGTON, Ky. (Feb. 17, 2005) -- In a recently published study, University of Kentucky researchers say a promising experimental drug actually appears to slow the progress of Parkinson’s disease, unlike current treatments that only treat the debilitating disease’s symptoms.

The progress shown in an early clinical trial of glial cell line-derived neurotrophic factor (GDNF) is why the decision by the drug’s maker – Amgen – to halt testing is so disappointing, UK researchers and patients who have been taking the drug contended in a news conference today.

“We are very disappointed by Amgen’s decision,” said Don Gash, the UK Alumni Chair in Anatomy and Neurobiology, professor in the Department of Anatomy and Neurobiology, and director of the M. Margrite Davis-Ralph E. Mills Magnetic Resonance Imaging and Spectroscopy Center at UK. “Parkinson’s is a debilitating disease, and the patients and families who have staked their hopes and lives on the testing of this treatment deserve better.”

However, Amgen’s decision to deny compassionate use, announced Feb. 11, 2005, leaves patients cut off from the drug they say they need. In its decision, the pharmaceutical company cited safety and efficacy concerns, but their data are based upon tests utilizing animal models and dosing procedures that differ from the successful UK study, contend Gash and fellow researcher Greg Gerhardt. Gerhardt is a professor in the Department of Anatomy and Neurobiology and Department of Neurology, director of the UK Morris K. Udall Parkinson’s Disease Research Center of Excellence, and director of the Center for Sensor Technology.

In the Journal of Neurosurgery, UK researchers report that their open label study of direct brain delivery of GDNF, a natural brain protein, demonstrates the safety and potential efficacy of the procedure.

According to Gash, the best hope for the Kentucky patients to resume receiving GDNF lies in the possibility of sponsorship of Phase 2 clinical trials by a third party. UK was one of several international sites testing GDNF.

Researchers who oversaw the various successful human trials of the drug first joined together in a request for compassionate use of the drug by those patients whose lives had already been improved by GDNF. Though the FDA supported their case, Amgen did not.

In the wake of Amgen’s latest denial, researchers and patients are seeking a third-party sponsor to provide the drug to the patients who already have undergone surgery for GDNF delivery to the brain and want to continue treatment. The Kentucky research team asks Amgen not to block progress on treating Parkinson’s disease.

“For science to advance, it is very important to continue studying the patients who chose to resume GDNF treatment,” said Gash.

The University of Kentucky study expands upon an initial report on GDNF authored by neurosurgeon Dr. Steven Gill and colleagues at the Frenchay Hospital in Bristol, United Kingdom. The six-month Kentucky study was an FDA-approved, Phase 1 trial of 10 patients with advanced Parkinson’s disease. The Kentucky patients were the first in the United States to receive direct brain delivery of GDNF.

The drug was delivered directly to patients’ brains via implanted pumps. Patients received a fixed daily dose, increased at successive eight-week intervals, followed by a five-week “washout” period during which GDNF was not administered.

The results were positive. Patients who were unable to complete simple tasks before receiving GDNF experienced substantial improvements in motor skills and physical function during treatment. Twenty-four weeks after beginning GDNF administration, patients’ scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) – the standard clinical measure of Parkinson’s – improved 34 percent in the “off” and 29 percent in the “on” state, compared to a baseline measured before GDNF treatment.

Although patients received GDNF to only one side of their brains, measures using standard neurological tests showed improvements of 40 to 50 percent in fine motor control and speed on both sides of their bodies, along with improvements in posture stability and gait. All improvements of motor function continued through washout. The only side effect, reported by two of the patients, was a mild tingling sensation known as transient Lhermitte’s sign.

“GDNF appears to slow the loss of dopamine cells in the brain – a key factor in stemming the progression of Parkinson’s disease,” said Dr. John Slevin, professor in the UK Department of Neurology and Department of Pharmacology and director of the Movement Disorders Clinic at UK. Slevin said, “Amgen contends current treatments are therapeutically equivalent to GDNF, but the drugs now available lose efficacy as the disease progresses, and do little to slow the loss of dopamine cells.”

One reason cited by Amgen for the withdrawal of GDNF was the observation of cerebellar lesions when large doses of GDNF were used in an animal model.

“None of the patients have shown evidence of cerebellar injury; it has only been seen in animals. To understand what has happened, we are increasing our testing of potential adverse effects of GDNF,” Gerhardt said. “These toxicity results should be taken very seriously. However, we need to push forward and examine whether the negative results are specific to animals. Further testing is warranted.”

On Aug. 31, 2004, at the conclusion of the successful Phase 1 trial at UK, patients decided to continue receiving GDNF as part of a Phase 2 clinical trial sponsored by Amgen. The next day the drug manufacturer announced they would discontinue all testing. The patients, who met each other for the first time when they agreed to join the Phase 2 trial, have joined with patients from other test sites in asking for continued use of the drug they say improved their lives.


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