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Idebenone for neuromuscular disorders, Friedreich’s ataxia and neuropathy

Idebenone is not a very unknown molecule. In the Wikipedia idebenone has a rather lenghty entry, saying:

Idebenone (pronounced eye-deb-eh-known) is an organic compound of the quinone family and promoted commercially as a synthetic analog of coenzyme Q10 (CoQ10). Idebenone is claimed to have properties similar to CoQ10 in its antioxidant properties. Idebenone is a synthetic analogue of coenzyme Q10 used in Europe in the treatment of vascular and degenerative diseases of the central nervous system.Research on idebenone as a potential therapy of Alzheimer's disease have been inconsistent, but there may be a trend for a slight benefit. Idebenone may benefit those with Friedreich's ataxia. 

Idebenone is used as a smart drug and in cremes for treating wrinkles. All indications are backed-up by research and developmentdata, dating back from the early eighties of last century. Idebenone can be ordered by internet as a smart drug in two strenghts: 45 mg and 150 mg. In the USA idebenone is classified by the FDA as a prescription drug. When compared with a series of structural analogues, idebenone appears to have an optimal chemical structure for the restoration of mitochondrial function. idebenone functions as an anti-oxidant, protecting membranes from damage by inhibi ing lipid peroxidation in mitochondria. There are no concerns re- garding neurotoxic or adverse cardiac reactions based on all pre-clinical and clinical studies to date. Idebenone also seems to be of use in a rare neuropathy, Leber hereditary optic neuropathy (LHON).

Idebenone: start of research. Cerebral and myocardial protectant

Idebenone (2,3 dimethoxy-5-methyl-6-(10- hydroxydecyl)-1,4,-benzoquinone) is a synthetic analogue of CoQ10. Coenzyme Q10  is quite large and hydrophobic, which hinders its penetration across cell membranes, which motivated the search for derivatives (idebenone). Idebenone is a short-chain quinone, and is characterized by lower hydrophobicity and greater antioxidant activity than coenzyme Q10.

In the early 80s Japanese scientists analysed the properties of idebenone in a variety of animal models and one of the first findings were the ameliorating effect on neurological deficits related with cerebral ischemia, as well as the positive effects on the myocardium. [1] [2][3][4][5] At that time the compound also demonstrated to have renoprotective and vascular protective properties. [6]The main target of idebenone, being the mitochondrion, was quickly identified by Japanese research [7] Literature focussed on the target indication of cerebral metabolism activator. [8] Various animal studies demonstrated cholinergic effects in brain-lesion models. [9][4] Furthermore ischemia-protective properties were detected in animal models for stoke [11][12][13]

The first phase I studies quickly followed and doses up to 300 mg were analysed, without troublesome side effects.[14] The half life time of the compound was 18 hours. Later studies refered to a plasma half-life of 2–15 hours. In phase I trials the most common adverse events were loose stool, fatigue, headache, and disturbances in attention. Idebenone was well tolerated in single oral doses up to 1050 mg and in repeated daily doses up to 2250 mg.

Various trials in dementia of the Alzheimer type also followed, but in 2003 the curtain fell on this indication due to a negative pivotal trial. [15] Idebenone in a dose-range of 120, 240, or 360 mg tid was not more active than placebo. Earlier studies showed hope in this indication. [16][17][18][16][20]

A clear and crisp dose-finding was not done in earlier trials. For instance the Italian trial assessed the efficacy of 45 mg b.i.d, finding positive effects of this low dose..The positive German trials used 30 mg t.i.d. or 90 mg t.i.d. and 360 mg/day.

The Russians in may 2009 reported positive findingsl using Noben (idebenone), using 120 mg per day in an open trial of Alzheimer patients.

Idebenone in the cell and in the mitochondium

Idebenone effect is an analog of ubiquinone, Q10, which in turn is an essential component of the mitochondrial respiratory chain functioning. Q10 acts as a mobile electron transfer shuttle between flavoprotein dehydrogenases and the cytochrome bc1 (complex III) in the inner mitochondrial membrane. Idebenone can promote a redox by-pass of complex I and as a consequence, idebenone may be expected to ameliorate the bioenergetic production of the respiratory chain in the presence of a mitochondrial complex I defects.

Idebenone in Friedreich’s ataxia 

INSERM scientists reported cardioprotective properties of idebenone in in vitro models for cardiomyopathy in Friedreich’s ataxia.[21] Early clinical studies in Friedreich’s ataxia patients administrating idebenone at a daily dose of 5 mg/kg have shown reduction in oxidative stress markers and cardiac hypertrophy.[22] [23] The first case description carried the titel: "Dramatic improvement in mitochondrial cardiomyopathy following treatment with idebenone" [24]

However, in 2001 a negative finding was published and no effects could be detected in a surrogate marker for mitochondrial impairment, using 5 mg idebenone/kg. [25]

The Spanish research group from Barcelona reported positive effects of idebenone, 5mg/kg on ataxia as a core symptom in an open long term trial in9 patients: "Significantly positive correlation was observed between idebenone values and the percentage of difference between the ICARS scores before and 12 months after the start of the therapy" [26] However, an issue raised in 2003 was the discrepancy between the positive findings on cardiac parameters and the debatable effects on the core neurological symptomes were discussed by a child neurologist:

 "Although a subset of patients also report various improvements, implying that idebenone could have a broader spectrum of action including some neurological improvements, the antioxidant did not have noticeable effects on the ataxia." [27]

An Italian study at the same time carried out a 1-year, randomized, placebo-controlled trial of idebenone in 29 patients. They found significant effects on cardiac parameters, such as interventricular septal thickness and left ventricular mass in the idebenone group vs the placebo group. However, no improvement was seen in other heart ultrasound measures or neurologic condition. [28] This issue was also raised by neurologists from the UK. [29]

Belgium doctors reported data from a 1-year prospective study on eight patients with Friedreich ataxia. Also here Idebenone did not halt the progression of ataxia. Siignificant reduction of cardiac hypertrophy in six of eight patients was documented. [30]

Doctors from Barcelona studied the plasma levels of idebenone in blood versus liquor and found a very low penetration of idebenone in the spinal fluid. [31] This might be an explanation of the profound benefit of the drug on cardiac parameters and the weak efficacy in the neurological parameters.

Many of these trials arose without optimal Phase I and dose-finding studies. However, they showed that idebenone at 5mg/kg is well tolerated and that higher dosing is possible.

The tolerability of idebenone has been found to be very good. Even high dosages could be administered without clinical concern:

"higher doses of idebenone lead to a proportional increase in plasma levels up to 55 mg/kg per day and that high-dose idebenone is well-tolerated’  [32] This is an important finding, as the conclusion of one of the more pivotal placebo controlled trials was:

Treatment with higher doses of idebenone was generally well tolerated and associated with improvement in neurological function and ADL in patients with FA. The degree of improvement correlated with the dose of idebenone, suggesting that higher doses may be necessary to have a beneficial effect on neurological function. [33] Doses used in this 6-moth trial were approximately 5 mg/kg, 15 mg/kg, and 45 mg/kg.

The problem with this study was the selection of the endpoints, the primary endpoint was a surrogate marker, which made the study unfit for a pivotal registration trail:

The primary endpoint for the study was the change from baseline to 6-month follow-up in 8-hydroxy-2´- deoxyguanosine (8OH2´dG), a marker of oxidative DNA damage.  

Secondary endpoints included safety and tolerability based on the number, type, and severity of adverse events, and absolute and percentage change from baseline in scores derived from the international cooperative ataxia rating scale (ICARS)

Furthermore, the power calculation was also defined based on the surrogate marker:

A sample size of seven patients pe
r treatment group (total 28) was calculated to have 90% power to detect a difference in concentrations of the oxidative marker 8OH2´dG between the placebo and treatment groups with a two- sided α level of 5%. 

The study did not detect any effects on the selected primary endpoint, raising doubts on the proposed mechanism of action. 

As this study did not show any efficacy in its primary end point, the Phase III US clinical trial is necessary to confirm earlier clinical findings. The DoH in Canada however, accepted the clinical efficence as sufficient, given the orphan indication, and the safety of the drug and Idebenone is on the Canadian market for Freidreich’s disease.

Further complications were noted by the Barcelona group. 

Based on a small number of patients, 10, treated for 3-5 years in an open-label study they suggested:

"Our results indicate that longer-term idebenone treatment prevented progression of cardiomyopathy in both paediatric and adult patients, whereas its stabilizing effect on neurological dysfunction was present only in the paediatric population, mainly before puberty. This suggests that the age at which idebenone treatment is initiated may be an important factor in the effectiveness of the therapy." [34] 

De Lancet studie besproken door de VSN

In Nederland werd de eerste klinische dubbelblinde studie met idebenone als volgt door de VSN besproken:

Onderzoekers in de Verenigde Staten hebben aanwijzingen gevonden voor een gunstig neurologisch effect van idebenone bij kinderen patienten met ataxie van Friedreich. Dit is de eerste keer dat een dergelijk effect is aangetoond in gerandomiseerd, gecontroleerd onderzoek. Waarschijnlijk komt het door de hogere dosering van idebenone.

48 patiënten tussen de 9 en 17 jaar hebben meegedaan gedurende een half jaar. Ze gebruikten placebo of één van drie doseringen idebenone. Onderzoekers en deelnemers hoorden pas achteraf wie welke behandeling had gekregen.Over het algemeen is de idebenone goed verdragen. Een kind dat de hoogste dosering idebenone gebruikte is ermee gestopt vanwege een verlaagd aantal witte bloedcellen.

Behalve het urineonderzoek zijn drie andere meetsystemen gebruikt. ICARS en FARS zijnmeetschalen voor de ernst van de ziekte. Daarnaast zijn ADL (algemene dagelijkse activeiten) geregistreerd. Alle behandelde groepen bij elkaar genomen hadden geen statistich significant effect van idebenone behandeling, maar het lijkt er op dat er een toenemend effect was naarmate de dosis van idebenone hoger was. Dit was vooral opvallend bij de groep patienten die nog geen rolstoel nodig hadden. Toch is het zo dat zelfs met de hoogste dosering, de vooruitgang bescheiden was. Niettemin kan dit van betekenis zijn voor de ziektelast, want het ging om een verbetering van 10 tot 17% ten opzichte van de beginscore. De verbetering lag vooral in de oogbewegingen en spraak. De conclusie is dat uitgebreider onderzoek nodig is met de hogere doseringen idebenone.

De onderzoekers hadden ook gehoopt een effect van idebenone te zien op een zogenaamde biomarker, d.w.z. een biologisch uitleessysteem. 9OH2’dG is een natuurlijk voorkomende stof die ontstaat bij celschade door zuurstof radicalen (vrije zuurstof moleculen). Het wordt uitgescheiden in de urine. Bij ataxie van Friedreich zijn er te veel zuurstof radicalen vanwege het genetisch defect aan frataxine. 9OH2d’G had een handige biomarker kunnen zijn om het effect van idebenone te volgen. Onverwacht bleek dat de patienten in deze studie geen verhoogde 9OH2’dG.spiegels hadden. Idebenone had ook geen statistisch significant effect op dit ‘uitleessysteem’. Mischien is 9OH2’dG wel een geschikte biomarker bij oudere patienten maar niet bij kinderen. 

The International Cooperative Ataxia Rating Scale (ICARS) 

Neurological outcome in Freidreich patients on idebenone versusn placebo has been evaluated using the ICARS scale. This scale seems a good outcome scale, however, French neurologists casted doubt on this scale in 2007, and especially its value for long term cases was debated:" Neurological progression was underestimated, however, by the ICARS scores, which reached a plateau in patients with long disease durations." [35] The scale is the best we have, but as there is not a gold standard in the therapy of ataxia, the validation of this scale is complex, as the sensitivity for symtoms of cerebellar disorders is unknown. 

Disappointmet, no significant effects on ICARS

Santhera Pharmaceuticals announced on May 19 2009 thatits US Phase III clinical trial evaluating idebenone for the treatmentof Friedreich’s Ataxia missed its primary endpoint as measured by theInternational Cooperative Ataxia Rating Scale (ICARS). 

A press release of the company, and we quote: 

The study alsodid not show statistical significance on the second neurological endpoint, the Friedreich’s Ataxia Rating Scale (FARS). On bothendpoints, the active treatment arms showed a consistent improvementover baseline and placebo, as seen in prior studies.

However, due to alower than expected effect size combined with the fact that patients onplacebo improved unexpectedly, statistical significance could not beachieved in this study population. The safety results were consistentwith published data suggesting that idebenone is safe and well toleratedat doses up to 2250 mg/day.

The primary endpoint in the IONIA (Idebenone effects On NeurologicalICARS Assessments) study compared the effect at six months of twotreatment arms with placebo on the baseline ICARS score. For bothtreatment arms, patients on idebenone improved on average by 2.4 pointson the ICARS scale at six months over baseline.

This is about half ofthe improvement seen in the prior US Phase II study named NICOSIA (NIHCollaboration With Santhera In Ataxia) which was used to design the phase III study.

Patients on idebenone, however, improved by only 1.2 pointsover placebo, because patients on placebo did not deteriorate to theextent expected from the previous study or as described in theliterature.

These phenomena combined to produce an effect size that didnot reach statistical significance over the six-month study period.  

Comment: neurological scales like the ICARS are in general not very sensitive to change, especially not in more severe patients. These scales have never been validated with a gold standard therapy, as no such therapy exists. Thus we are trying to capture effects blindfolded.

However, idebenone is launched in the Canadian market, and Friedreich’s patients can obtain the drug and find out what it does for them.. One of the leading neurologists of the trial discussed was quoted:

Sue Perlman, Clinical Professor of Neurology at the University ofCalifornia, Los Angeles and one of the two IONIA study investigators,comments: "I still strongly support the disease-modifying effect of idebenone in Friedreich’s Ataxia. I believe it slows the progression ofthe neurological and cardiac aspects of this condition over time, and Istrongly recommend that patients continue in the open-label extensionstudy arm of the Phase III trial to enable us to gather as muchlonger term data as possible." 

LHON and idebenone; CIAP?

Leber’s hereditary optic neuropathy (LHON), is a maternally inherited disease with acute visual loss.  Multiple sclerosis (MS)-like features associated with white matter lesions on brain magnetic resonance imaging (MRI) have been described. In a patient suffering from LHON, long term
treatment with idebenone 90 mg tid resulted in a stable disease. In this patient clinical amelioration and worsening of the paraparesis with parallel changes in brain and skeletal muscle bioenergetics followied withdrawal of idebenone. The authers suggested that high doses of idebenone at onset can be a useful treatment not only for optic neuropathy.

The cause of LHON is not clear, but LHON patients seem to have little evidence of inflammatory changes in the optic nerve and tract which were shrunken and atrophic at electron microscopy. However, one clear finding was an axoplasmic stasis, probably as a consequence of decreased axonal transport due to a reduced production of [ATP] by impaired mitochondria. This finding support the speculation that idebenone might be of use in CIAP. 

Idebenone also increased nerve growth factor in animal models: In the idebenone-treated rats, NGF protein content in the hippocampus increased to 140°70 of the level in sham or vehicle-treated rats, although the expression of NGF mRNA increased to 510° of that in the vehicle-treated rats. Administration of idebenone induced increases in NGF content in the hippocampus only in the damaged brain, and not in the intact brain. [36]

Idebenone on the market


Idebenone can be obtained via the internet and has been entered the market as a orphan drug in Canada only.

Idebenone under the brand name Noben can be found in Russia.

Idebenone (mnesis): 60 45 mg tablets for $29.00

Idebenone: 45 mg 60 caps $29.95 

Idebenone powder

300 Idebenone 100mg: $33.99

Noben (idebenone), produced by Moskhimfarmpreparaty im. N. A. Semashko. 

Versie juli 2009; Auteurs: Prof.dr. Jan M. Keppel Hesselink,en Drs. David Kopsky, artsen




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