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Idebenone

January 20, 2023

Idebenone (pronounced eye-deb-eh-known, trade names Catena, Raxone, Sovrima, among others) is a drug that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease and other cognitive defects.[1] This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of neuromuscular diseases. In 2010, early clinical trials for the treatment of Friedreich's ataxia[2] and Duchenne muscular dystrophy[3] have been completed. As of December 2013 the drug is not approved for these indications in North America or Europe. It is approved by the European Medicines Agency (EMA) for use in Leber's hereditary optic neuropathy (LHON) and was designated an orphan drug in 2007.[4]

Idebenone
Clinical data
Trade namesCatena, Raxone, Sovrima
AHFS/Drugs.comInternational Drug Names
License data
  • EU EMA: by INN
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability<1% (high first pass effect)
Protein binding>99%
Elimination half-life18 hours
ExcretionUrine (80%) and feces
Identifiers
  • 2-(10-hydroxydecyl)-5,6-dimethoxy-3-methyl-
    cyclohexa-2,5-diene-1,4-dione
CAS Number
  • 58186-27-9 Y
PubChem CID
  • 3686
ChemSpider
  • 3558 Y
UNII
  • HB6PN45W4J
KEGG
  • D01750 Y
ChEBI
  • CHEBI:31687
ChEMBL
  • ChEMBL252556 Y
CompTox Dashboard (EPA)
  • DTXSID0040678
Chemical and physical data
FormulaC19H30O5
Molar mass338.444 g·mol−1
3D model (JSmol)
  • Interactive image
  • O=C1/C(=C(\C(=O)C(\OC)=C1\OC)C)CCCCCCCCCCO
  • InChI=1S/C19H30O5/c1-14-15(12-10-8-6-4-5-7-9-11-13-20)17(22)19(24-3)18(23-2)16(14)21/h20H,4-13H2,1-3H3 Y
  • Key:JGPMMRGNQUBGND-UHFFFAOYSA-N Y
  (verify)

Chemically, idebenone is an organic compound of the quinone family. It is also promoted commercially as a synthetic analog of coenzyme Q10 (CoQ10).

Uses

Indications that are or were approved in some territories

Nootropic effects and Alzheimer's disease

Idebenone improved learning and memory in experiments with mice.[5] In humans, evaluation of Surrogate endpoints like electroretinography, auditory evoked potentials and visual analogue scales also suggested positive nootropic effects,[6] but larger studies with hard endpoints are missing.

Research on idebenone as a potential therapy of Alzheimer's disease have been inconsistent, but there may be a trend for a slight benefit.[7][8] In May 1998, the approval for this indication was cancelled in Japan due to the lack of proven effects. In some European countries, the drug is available for the treatment of individual patients in special cases.[1]

Friedreich's ataxia (Sovrima)

Preliminary testing has been done in humans and found idebenone to be a safe treatment for Friedreich's ataxia (FA), exhibiting a positive effect on cardiac hypertrophy and neurological function.[9] The latter was only significantly improved in young patients.[10] In a different experiment, a one-year test on eight patients, idebenone reduced the rate of deterioration of cardiac function, but without halting the progression of ataxia.[11]

The drug was approved for FA in Canada in 2008 under conditions including proof of efficacy in further clinical trials.[12] However, on February 27, 2013, Health Canada announced that idebenone would be voluntarily recalled as of April 30, 2013 by its Canadian manufacturer, Santhera Pharmaceuticals, due to the failure of the drug to show efficacy in the further clinical trials that were conducted.[13] In 2008, the European Medicines Agency (EMA) refused a marketing authorisation for this indication.[1] As of 2013 the drug was not approved for FA in Europe[14] nor in the US, where there is no approved treatment.[15]

Leber's hereditary optic neuropathy (Raxone)

Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited (mother to all offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. Santhera completed a Phase III clinical trial in this indication in Europe with positive results,[16] and submitted an application to market the drug to European regulators in July 2011.[17] It is approved by EMA for this indication and was designated an orphan drug in 2007.[4]

Indications being explored

Duchenne muscular dystrophy (Catena)

After experiments in mice[18] and preliminary studies in humans, idebenone has entered Phase II clinical trials in 2005[3] and Phase III trials in 2009.[19]

Other neuromuscular diseases

Phase I and II clinical trials for the treatment of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)[20] and primary progressive multiple sclerosis[21] are ongoing as of December 2013.

As of 2022, a phase III clinical trial is ongoing for the treatment of Parkinson's disease.[22]

Life style

Idebenone is claimed to have properties similar to CoQ10 in its antioxidant properties, and has therefore been used in anti-aging on the basis of free-radical theory. Clinical evidence for this use is missing. It has been used in topical applications to treat wrinkles.[23]

Pharmacology

In cellular and tissue models, idebenone acts as a transporter in the electron transport chain of mitochondria and thus increases the production of adenosine triphosphate (ATP) which is the main energy source for cells, and also inhibits lipoperoxide formation. Positive effects on the energy household of mitochondria has also been observed in animal models.[1][24] Clinical relevance of these findings has not been established.

Pharmacokinetics

Idebenone is well absorbed from the gut but undergoes excessive first pass metabolism in the liver, so that less than 1% reach the circulation. This rate can be improved with special formulations (suspensions) of idebenone and by administering it together with fat food; but even taking these measures bioavailability still seems to be considerably less than 14% in humans. More than 99% of the circulating drug are bound to plasma proteins. Idebenone metabolites include glucuronides and sulfates, which are mainly (~80%) excreted via the urine.[1]

References

  1. ^ a b c d e CHMP Assessment Report for Sovrima (PDF) (Report). European Medicines Agency. 20 November 2008. pp. 6, 9–11, 67f.
  2. ^ Clinical trial number NCT00229632 for "Idebenone to Treat Friedreich's Ataxia" at ClinicalTrials.gov
  3. ^ a b Clinical trial number NCT00654784 for "Efficacy and Tolerability of Idebenone in Boys With Cardiac Dysfunction Associated With Duchenne Muscular Dystrophy (DELPHI)" at ClinicalTrials.gov
  4. ^ a b "Raxone". www.ema.europa.eu. Retrieved 12 July 2019.
  5. ^ Liu XJ, Wu WT (November 1999). "Effects of ligustrazine, tanshinone II A, ubiquinone, and idebenone on mouse water maze performance". Zhongguo Yao Li Xue Bao = Acta Pharmacologica Sinica. 20 (11): 987–990. PMID 11270979.
  6. ^ Schaffler K, Hadler D, Stark M (July 1998). "Dose-effect relationship of idebenone in an experimental cerebral deficit model. Pilot study in healthy young volunteers with piracetam as reference drug". Arzneimittel-Forschung. 48 (7): 720–726. PMID 9706371.
  7. ^ Gutzmann H, Kühl KP, Hadler D, Rapp MA (January 2002). "Safety and efficacy of idebenone versus tacrine in patients with Alzheimer's disease: results of a randomized, double-blind, parallel-group multicenter study". Pharmacopsychiatry. 35 (1): 12–18. doi:10.1055/s-2002-19833. PMID 11819153.
  8. ^ Parnetti L, Senin U, Mecocci P (May 1997). "Cognitive enhancement therapy for Alzheimer's disease. The way forward". Drugs. 53 (5): 752–768. doi:10.2165/00003495-199753050-00003. PMID 9129864. S2CID 46987059.
  9. ^ Di Prospero NA, Baker A, Jeffries N, Fischbeck KH (October 2007). "Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial". The Lancet. Neurology. 6 (10): 878–886. doi:10.1016/S1474-4422(07)70220-X. PMID 17826341. S2CID 24749816.
  10. ^ Tonon C, Lodi R (September 2008). "Idebenone in Friedreich's ataxia". Expert Opinion on Pharmacotherapy. 9 (13): 2327–2337. doi:10.1517/14656566.9.13.2327. PMID 18710357. S2CID 73285881.
  11. ^ Buyse G, Mertens L, Di Salvo G, Matthijs I, Weidemann F, Eyskens B, et al. (May 2003). "Idebenone treatment in Friedreich's ataxia: neurological, cardiac, and biochemical monitoring". Neurology. 60 (10): 1679–1681. doi:10.1212/01.wnl.0000068549.52812.0f. PMID 12771265. S2CID 36556782.
  12. ^ . Archived from the original on 19 June 2014.
  13. ^ Voluntary Withdrawal of Catena from the Canadian Market
  14. ^ Margaret Wahl for Quest Magazine, MAY 28, 2010. FA Research: Idebenone Strikes Out Again
  15. ^ NINDS Fact Sheet
  16. ^ Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, et al. (September 2011). "A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy". Brain. 134 (Pt 9): 2677–2686. doi:10.1093/brain/awr170. PMC 3170530. PMID 21788663.
  17. ^ Staff (26 July 2011). "Santhera publishes pivotal trial results of idebenone and goes for EU approval". European Biotechnology News. Archived from the original on 2013-02-17.
  18. ^ Buyse GM, Van der Mieren G, Erb M, D'hooge J, Herijgers P, Verbeken E, et al. (January 2009). "Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance". European Heart Journal. 30 (1): 116–124. doi:10.1093/eurheartj/ehn406. PMC 2639086. PMID 18784063.
  19. ^ Clinical trial number NCT01027884 for "Phase III Study of Idebenone in Duchenne Muscular Dystrophy (DMD) (DELOS)" at ClinicalTrials.gov
  20. ^ Clinical trial number NCT00887562 for "Study of Idebenone in the Treatment of Mitochondrial Encephalopathy Lactic Acidosis & Stroke-like Episodes (MELAS)" at ClinicalTrials.gov
  21. ^ Clinical trial number NCT00950248 for "Double Blind Placebo-Controlled Phase I/II Clinical Trial of Idebenone in Patients With Primary Progressive Multiple Sclerosis (IPPoMS)" at ClinicalTrials.gov
  22. ^ McFarthing K, Rafaloff G, Baptista M, Mursaleen L, Fuest R, Wyse RK, Stott SR (2022). "Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2022 Update". Journal of Parkinson's Disease. 12 (4): 1073–1082. doi:10.3233/JPD-229002. PMC 9198738. PMID 35527571.
  23. ^ McDaniel DH, Neudecker BA, DiNardo JC, Lewis JA, Maibach HI (September 2005). "Clinical efficacy assessment in photodamaged skin of 0.5% and 1.0% idebenone". Journal of Cosmetic Dermatology. 4 (3): 167–173. doi:10.1111/j.1473-2165.2005.00305.x. PMID 17129261. S2CID 2394666.
  24. ^ Suno M, Nagaoka A (May 1988). "[Effect of idebenone and various nootropic drugs on lipid peroxidation in rat brain homogenate in the presence of succinate]". Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica (in Japanese). 91 (5): 295–299. doi:10.1254/fpj.91.295. PMID 3410376.

January 20, 2023
idebenone, pronounced, known, trade, names, catena, raxone, sovrima, among, others, drug, that, initially, developed, takeda, pharmaceutical, company, treatment, alzheimer, disease, other, cognitive, defects, this, been, with, limited, success, swiss, company,. Idebenone pronounced eye deb eh known trade names Catena Raxone Sovrima among others is a drug that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer s disease and other cognitive defects 1 This has been met with limited success The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of neuromuscular diseases In 2010 early clinical trials for the treatment of Friedreich s ataxia 2 and Duchenne muscular dystrophy 3 have been completed As of December 2013 update the drug is not approved for these indications in North America or Europe It is approved by the European Medicines Agency EMA for use in Leber s hereditary optic neuropathy LHON and was designated an orphan drug in 2007 4 IdebenoneClinical dataTrade namesCatena Raxone SovrimaAHFS Drugs comInternational Drug NamesLicense dataEU EMA by INNATC codeN06BX13 WHO Legal statusLegal statusIn general Prescription only Pharmacokinetic dataBioavailability lt 1 high first pass effect Protein binding gt 99 Elimination half life18 hoursExcretionUrine 80 and fecesIdentifiersIUPAC name 2 10 hydroxydecyl 5 6 dimethoxy 3 methyl cyclohexa 2 5 diene 1 4 dioneCAS Number58186 27 9 YPubChem CID3686ChemSpider3558 YUNIIHB6PN45W4JKEGGD01750 YChEBICHEBI 31687ChEMBLChEMBL252556 YCompTox Dashboard EPA DTXSID0040678Chemical and physical dataFormulaC 19H 30O 5Molar mass338 444 g mol 13D model JSmol Interactive imageSMILES O C1 C C C O C OC C1 OC C CCCCCCCCCCOInChI InChI 1S C19H30O5 c1 14 15 12 10 8 6 4 5 7 9 11 13 20 17 22 19 24 3 18 23 2 16 14 21 h20H 4 13H2 1 3H3 YKey JGPMMRGNQUBGND UHFFFAOYSA N Y verify Chemically idebenone is an organic compound of the quinone family It is also promoted commercially as a synthetic analog of coenzyme Q10 CoQ10 Contents 1 Uses 1 1 Indications that are or were approved in some territories 1 1 1 Nootropic effects and Alzheimer s disease 1 1 2 Friedreich s ataxia Sovrima 1 1 3 Leber s hereditary optic neuropathy Raxone 1 2 Indications being explored 1 2 1 Duchenne muscular dystrophy Catena 1 2 2 Other neuromuscular diseases 1 3 Life style 2 Pharmacology 2 1 Pharmacokinetics 3 ReferencesUses EditIndications that are or were approved in some territories Edit Nootropic effects and Alzheimer s disease Edit Idebenone improved learning and memory in experiments with mice 5 In humans evaluation of Surrogate endpoints like electroretinography auditory evoked potentials and visual analogue scales also suggested positive nootropic effects 6 but larger studies with hard endpoints are missing Research on idebenone as a potential therapy of Alzheimer s disease have been inconsistent but there may be a trend for a slight benefit 7 8 In May 1998 the approval for this indication was cancelled in Japan due to the lack of proven effects In some European countries the drug is available for the treatment of individual patients in special cases 1 Friedreich s ataxia Sovrima Edit Preliminary testing has been done in humans and found idebenone to be a safe treatment for Friedreich s ataxia FA exhibiting a positive effect on cardiac hypertrophy and neurological function 9 The latter was only significantly improved in young patients 10 In a different experiment a one year test on eight patients idebenone reduced the rate of deterioration of cardiac function but without halting the progression of ataxia 11 The drug was approved for FA in Canada in 2008 under conditions including proof of efficacy in further clinical trials 12 However on February 27 2013 Health Canada announced that idebenone would be voluntarily recalled as of April 30 2013 by its Canadian manufacturer Santhera Pharmaceuticals due to the failure of the drug to show efficacy in the further clinical trials that were conducted 13 In 2008 the European Medicines Agency EMA refused a marketing authorisation for this indication 1 As of 2013 the drug was not approved for FA in Europe 14 nor in the US where there is no approved treatment 15 Leber s hereditary optic neuropathy Raxone Edit Leber s hereditary optic neuropathy LHON is a mitochondrially inherited mother to all offspring degeneration of retinal ganglion cells RGCs and their axons that leads to an acute or subacute loss of central vision this affects predominantly young adult males Santhera completed a Phase III clinical trial in this indication in Europe with positive results 16 and submitted an application to market the drug to European regulators in July 2011 17 It is approved by EMA for this indication and was designated an orphan drug in 2007 4 Indications being explored Edit Duchenne muscular dystrophy Catena Edit After experiments in mice 18 and preliminary studies in humans idebenone has entered Phase II clinical trials in 2005 3 and Phase III trials in 2009 19 Other neuromuscular diseases Edit Phase I and II clinical trials for the treatment of MELAS mitochondrial encephalomyopathy lactic acidosis and stroke like episodes 20 and primary progressive multiple sclerosis 21 are ongoing as of December 2013 update As of 2022 a phase III clinical trial is ongoing for the treatment of Parkinson s disease 22 Life style Edit Idebenone is claimed to have properties similar to CoQ10 in its antioxidant properties and has therefore been used in anti aging on the basis of free radical theory Clinical evidence for this use is missing It has been used in topical applications to treat wrinkles 23 Pharmacology EditIn cellular and tissue models idebenone acts as a transporter in the electron transport chain of mitochondria and thus increases the production of adenosine triphosphate ATP which is the main energy source for cells and also inhibits lipoperoxide formation Positive effects on the energy household of mitochondria has also been observed in animal models 1 24 Clinical relevance of these findings has not been established Pharmacokinetics Edit Idebenone is well absorbed from the gut but undergoes excessive first pass metabolism in the liver so that less than 1 reach the circulation This rate can be improved with special formulations suspensions of idebenone and by administering it together with fat food but even taking these measures bioavailability still seems to be considerably less than 14 in humans More than 99 of the circulating drug are bound to plasma proteins Idebenone metabolites include glucuronides and sulfates which are mainly 80 excreted via the urine 1 References Edit a b c d e CHMP Assessment Report for Sovrima PDF Report European Medicines Agency 20 November 2008 pp 6 9 11 67f Clinical trial number NCT00229632 for Idebenone to Treat Friedreich s Ataxia at ClinicalTrials gov a b Clinical trial number NCT00654784 for Efficacy and Tolerability of Idebenone in Boys With Cardiac Dysfunction Associated With Duchenne Muscular Dystrophy DELPHI at ClinicalTrials gov a b Raxone www ema europa eu Retrieved 12 July 2019 Liu XJ Wu WT November 1999 Effects of ligustrazine tanshinone II A ubiquinone and idebenone on mouse water maze performance Zhongguo Yao Li Xue Bao Acta Pharmacologica Sinica 20 11 987 990 PMID 11270979 Schaffler K Hadler D Stark M July 1998 Dose effect relationship of idebenone in an experimental cerebral deficit model Pilot study in healthy young volunteers with piracetam as reference drug Arzneimittel Forschung 48 7 720 726 PMID 9706371 Gutzmann H Kuhl KP Hadler D Rapp MA January 2002 Safety and efficacy of idebenone versus tacrine in patients with Alzheimer s disease results of a randomized double blind parallel group multicenter study Pharmacopsychiatry 35 1 12 18 doi 10 1055 s 2002 19833 PMID 11819153 Parnetti L Senin U Mecocci P May 1997 Cognitive enhancement therapy for Alzheimer s disease The way forward Drugs 53 5 752 768 doi 10 2165 00003495 199753050 00003 PMID 9129864 S2CID 46987059 Di Prospero NA Baker A Jeffries N Fischbeck KH October 2007 Neurological effects of high dose idebenone in patients with Friedreich s ataxia a randomised placebo controlled trial The Lancet Neurology 6 10 878 886 doi 10 1016 S1474 4422 07 70220 X PMID 17826341 S2CID 24749816 Tonon C Lodi R September 2008 Idebenone in Friedreich s ataxia Expert Opinion on Pharmacotherapy 9 13 2327 2337 doi 10 1517 14656566 9 13 2327 PMID 18710357 S2CID 73285881 Buyse G Mertens L Di Salvo G Matthijs I Weidemann F Eyskens B et al May 2003 Idebenone treatment in Friedreich s ataxia neurological cardiac and biochemical monitoring Neurology 60 10 1679 1681 doi 10 1212 01 wnl 0000068549 52812 0f PMID 12771265 S2CID 36556782 Heath Canada Fact Sheet Catena Archived from the original on 19 June 2014 Voluntary Withdrawal of Catena from the Canadian Market Margaret Wahl for Quest Magazine MAY 28 2010 FA Research Idebenone Strikes Out Again NINDS Fact Sheet Klopstock T Yu Wai Man P Dimitriadis K Rouleau J Heck S Bailie M et al September 2011 A randomized placebo controlled trial of idebenone in Leber s hereditary optic neuropathy Brain 134 Pt 9 2677 2686 doi 10 1093 brain awr170 PMC 3170530 PMID 21788663 Staff 26 July 2011 Santhera publishes pivotal trial results of idebenone and goes for EU approval European Biotechnology News Archived from the original on 2013 02 17 Buyse GM Van der Mieren G Erb M D hooge J Herijgers P Verbeken E et al January 2009 Long term blinded placebo controlled study of SNT MC17 idebenone in the dystrophin deficient mdx mouse cardiac protection and improved exercise performance European Heart Journal 30 1 116 124 doi 10 1093 eurheartj ehn406 PMC 2639086 PMID 18784063 Clinical trial number NCT01027884 for Phase III Study of Idebenone in Duchenne Muscular Dystrophy DMD DELOS at ClinicalTrials gov Clinical trial number NCT00887562 for Study of Idebenone in the Treatment of Mitochondrial Encephalopathy Lactic Acidosis amp Stroke like Episodes MELAS at ClinicalTrials gov Clinical trial number NCT00950248 for Double Blind Placebo Controlled Phase I II Clinical Trial of Idebenone in Patients With Primary Progressive Multiple Sclerosis IPPoMS at ClinicalTrials gov McFarthing K Rafaloff G Baptista M Mursaleen L Fuest R Wyse RK Stott SR 2022 Parkinson s Disease Drug Therapies in the Clinical Trial Pipeline 2022 Update Journal of Parkinson s Disease 12 4 1073 1082 doi 10 3233 JPD 229002 PMC 9198738 PMID 35527571 McDaniel DH Neudecker BA DiNardo JC Lewis JA Maibach HI September 2005 Clinical efficacy assessment in photodamaged skin of 0 5 and 1 0 idebenone Journal of Cosmetic Dermatology 4 3 167 173 doi 10 1111 j 1473 2165 2005 00305 x PMID 17129261 S2CID 2394666 Suno M Nagaoka A May 1988 Effect of idebenone and various nootropic drugs on lipid peroxidation in rat brain homogenate in the presence of succinate Nihon Yakurigaku Zasshi Folia Pharmacologica Japonica in Japanese 91 5 295 299 doi 10 1254 fpj 91 295 PMID 3410376 Retrieved from https en wikipedia org w index php title Idebenone amp oldid 1109695705, wikipedia, wiki, book, books, library,

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