Related Experiment Video
Updated: Dec 12, 2025
The Multiple Sclerosis Performance Test MSPT: An iPad-Based Disability Assessment Tool
Published on: June 30, 2014
Idebenone does not inhibit disability progression in primary progressive MS
Peter Kosa1, Tianxia Wu2, Jonathan Phillips1
1Neuroimmunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Background:
Multiple sclerosis (MS) is a chronic, immune-mediated neurodegenerative disorder of the central nervous system (CNS). While current MS therapies target the inflammatory processes, no treatment explicitly targets mitochondrial dysfunction and resulting axonal loss. Therefore, the aim of this study was to determine whether idebenone inhibits mitochondrial dysfunction and accumulation of disability in primary progressive MS (PPMS) and to enhance understanding of pathogenic mechanisms of PPMS progression using cerebrospinal fluid (CSF) biomarkers.
Methods:
The double-blind, placebo-controlled Phase I/II clinical trial of Idebenone in patients with Primary Progressive MS (IPPoMS; NCT00950248) was an adaptively designed, baseline-versus-treatment, placebo-controlled, CSF-biomarker-supported trial. Based on interim analysis of the 1-year pre-treatment data, change in the area under the curve of Combinatorial Weight-Adjusted Disability Score (CombiWISE) became the primary outcome, with >80% power to detect ≥40% efficacy with 28 patients/arm treated for 2 years in baseline versus treatment paradigm. Changes in traditional disability scales and in brain ventricular volume were secondary outcomes. Exploratory outcomes included CSF biomarkers of mitochondrial dysfunction (Growth/differentiation factor 15 [GDF15] and lactate), axonal damage (neurofilament light chain [NFL]), innate immunity (sCD14), blood brain barrier leakage (albumin quotient) and retinal nerve fiber layer thinning.
Results:
Idebenone was well tolerated but did not inhibit disability progression or CNS tissue destruction. Concentrations of GDF15, secreted predominantly by astrocytes and choroid plexus epithelium in vitro, increased after exposure to mitochondrial toxin rotenone, validating the ability of this biomarker to measure intrathecal mitochondrial damage. CSF GDF15 levels correlated strongly with age and MS patients had CSF levels of GDF15 significantly above age-adjusted healthy volunteers, with highest levels measured in PPMS. Idebenone did not change CSF GDF15 levels.
Conclusion:
Mitochondrial dysfunction exceeding normal aging reflected by age-adjusted CSF GDF15 is present in the majority of PPMS patients, but it is not inhibited by idebenone.
Insights
Idebenone did not slow disability progression in primary progressive multiple sclerosis (PPMS). Mitochondrial dysfunction is common in PPMS, indicated by cerebrospinal fluid biomarkers, but idebenone did not improve these markers.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Multiple sclerosis (MS) is a chronic, immune-mediated neurodegenerative disorder affecting the central nervous system (CNS).
- Current MS therapies focus on inflammation, not mitochondrial dysfunction or axonal loss.
- Primary progressive MS (PPMS) presents unique challenges in understanding and treating neurodegeneration.
Purpose of the Study:
- To evaluate if idebenone can inhibit mitochondrial dysfunction and reduce disability accumulation in PPMS.
- To explore cerebrospinal fluid (CSF) biomarkers for insights into PPMS pathogenesis.
- To assess idebenone's impact on specific CSF biomarkers related to mitochondrial damage and axonal loss.
Main Methods:
- A double-blind, placebo-controlled Phase I/II clinical trial (IPPoMS) was conducted.
- The study utilized an adaptive design with a baseline-versus-treatment paradigm.
- Primary outcome was change in the Combinatorial Weight-Adjusted Disability Score (CombiWISE); secondary outcomes included traditional scales and brain volume; exploratory outcomes involved CSF biomarkers (GDF15, lactate, NFL, etc.).
Main Results:
- Idebenone was well-tolerated but did not significantly inhibit disability progression or CNS tissue destruction.
- CSF GDF15 levels, a biomarker for mitochondrial damage, were elevated in PPMS patients compared to age-adjusted healthy volunteers.
- Idebenone treatment did not alter CSF GDF15 levels, indicating no inhibition of intrathecal mitochondrial damage.
Conclusions:
- Mitochondrial dysfunction, exceeding normal aging, is prevalent in most PPMS patients.
- This dysfunction, as measured by age-adjusted CSF GDF15, is not ameliorated by idebenone treatment.
- The study highlights the presence of mitochondrial dysfunction in PPMS but identifies idebenone as ineffective in targeting it.
More Related Videos
Related Concept Videos
01:24Parkinson's Disease: Treatment
Parkinson's Disease is primarily a result of the loss of dopaminergic neurons in the substantia nigra pars compacta. The cornerstone of...
01:22Alzheimer's Disease: Treatment
01:15Parkinson's Disease: Overview
01:20Myasthenia Gravis: Overview and Treatment
These antibodies interfere with the function of the nicotinic receptors in three ways: by binding to the receptor and disrupting acetylcholine binding; by causing cross-linking of receptors which...
01:20Antiepileptic Drugs: Potassium Channel Activators
Ezogabine has gained approval as an adjunctive treatment...
01:18Antiepileptic Drugs: GABAergic Pathway Potentiators
The key GABA pathway potentiators used in epilepsy management are as follows.
Benzodiazepines are a well-known class of drugs used for...