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Study Suggests Idebenone May Improve Neurological Function in Friedreich's Ataxia

For release: Wednesday, December 5, 2007

Results of a placebo-controlled, double-blind phase II study of the antioxidant idebenone in children with Friedreich's ataxia (FA) suggest that the treatment may lead to improvements in neurological function.  It is the first placebo-controlled study to suggest that the neurological deterioration associated with this disease can be slowed or reversed.

Several previous studies using low doses of idebenone have suggested that it may reduce the heart enlargement that frequently occurs with FA, and an open-label study of idebenone in early-stage FA patients found an improvement in neurological function that appeared related to drug levels.  However, the new study is the first controlled trial to suggest a neurological benefit or a reduction in symptoms of the disease.

FA is an inherited disease that causes progressive damage to the nervous system and other organs.  It is caused by a gene defect that results in lower-than-normal levels of a protein called frataxin.  The lack of frataxin impairs the function of mitochondria and triggers a type of chemical damage in cells that is called oxidative stress.  Symptoms of FA usually begin between the ages of 5 and 15 and range from uncoordinated movements (ataxia) to speech problems, diabetes, scoliosis (abnormal curvature of the spine), and heart disease.  Most people with FA eventually need a wheelchair.  Currently there is no proven treatment that alters the progression or neurological symptoms of the disorder.

“With hereditary neurodegenerative diseases, usually the best we hope for is to slow the progression of the disease.  Here it looks like the drug may have actually reduced the manifestations of the disease,” says Kenneth Fischbeck, M.D., of the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland, who led the new study together with Nicholas Di Prospero, M.D., Ph.D.  The report appears in the October issue of Lancet Neurology.[1]

The researchers studied idebenone in 48 children ages 9-17 who had genetically confirmed FA.  Participants were divided into four groups.  Three of the groups received fixed doses of idebenone, approximately equal to 5 mg/kg, 15 mg/kg, or 45 mg/kg, for 6 months.  The fourth group received a placebo.  The study was double-blind, meaning that neither the participants nor the researchers knew which patients were receiving the drug and which were receiving the placebo.

The researchers tested the urinary levels of a chemical called 8-hydroxy-2'-deoxyguanosine (8OH2'dG), which is a marker of DNA damage from oxidative stress.  They also used two scales to rate the severity of FA before and after treatment:  the international cooperative ataxia rating scale (ICARS) and the Friedreich's ataxia rating scale (FARS).  Parents of the children also completed surveys about the children's abilities to carry out activities of daily living (ADLs).

After 6 months of treatment, the investigators found an indication of improvement in the ICARS scores that was related to the dose of idebenone.  When participants who frequently used a wheelchair were excluded from the data analysis, the results were stronger.  Participants who received the placebo had declines of approximately 2 points on the ICARS scale, while those on low-dose idebenone showed only slight improvement.  In contrast, participants given the intermediate dose improved by about 4 points on average, and those given the high dose improved by almost 6 points.  These changes amounted to a 10-17 percent reduction in symptoms from the baseline scores.  The researchers also found dose-dependent improvements in the FARS and ADL scores, although those changes were not statistically significant.

Improvements in eye movements and speech were the most marked changes seen in the ICARS scores, but all aspects of neurological function measured by the scale showed some improvement, the researchers say. 

The patients' 8OH2'dG levels at the beginning of the study were not elevated, in contrast to the results of previous studies.  The levels also did not change significantly after idebenone treatment.  This suggests that 8OH2'dG may not be a reliable biomarker for FA, the investigators say.

The results also suggested that idebenone is well tolerated by most people, even at high doses.  The majority of side effects were mild, while a few were moderate but appeared unrelated to the drug.  One patient on the highest dose of idebenone developed a low white blood cell count that might have been related to the drug, but the problem resolved after treatment was discontinued.

"FARA and the international Friedreich's ataxia community are extremely grateful for the tremendous service performed by the excellent and dedicated team at NIH/NINDS in conducting this phase II clinical trial and the phase I trial that preceded it. In this promising clinical trial, we see confirmation that the Friedreich's ataxia community, by working hard together and collaborating broadly, has indeed entered the treatment era. We eagerly await commencement of a phase III clinical trial of idebenone and the prospects of achieving the first approved treatment for this devastating disease," says Ronald J. Bartek, President of the Friedreich's Ataxia Research Alliance (FARA) in Springfield, Virginia.

These findings may help to refine the design of other clinical trials for FA.  A number of compounds are now moving into clinical trials for this disease.  The new results can help investigators decide what subjects to include, the duration of treatment, and what outcome measures to look at, says Dr. Di Prospero.  Also, the neurological improvements seen with high-dose idebenone in this study suggest that it may be useful for other diseases that include oxidative stress and/or mitochondrial abnormalities, including Huntington's disease and Alzheimer's disease, Dr. Fischbeck adds.  Previous studies have tested idebenone for these diseases, but only at low doses.

While the results of this study are encouraging, they are not definitive, Dr. Fischbeck cautions.  Investigators need to conduct a phase III clinical trial to determine if the improvements seen in this study can be confirmed.  One phase III trial is now underway in Europe, and a U.S.-based phase III study is in the planning stages.  Researchers also need to further study idebenone in the laboratory to determine exactly how it works.  Those studies may eventually lead to development of more potent drugs.

The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system.  The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services.  It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases.  For more information about NIH and its programs, visit

-By Natalie Frazin

[1]Di Prospero N, Baker A, Jeffries N, Fischbeck KH.  "Neurological effects of high-dose idebenone in patients with Friedreich's ataxia:  a randomized, placebo-controlled trial."  Lancet Neurology, October 2007, Vol. 6, No. 10, pp. 878-886.

Last Modified December 5, 2007