idebenone

Idebenone improved learning and memory in experiments with mice.{{cite journal | vauthors = Liu XJ, Wu WT | title = Effects of ligustrazine, tanshinone II A, ubiquinone, and idebenone on mouse water maze performance | journal = Zhongguo Yao Li Xue Bao = Acta Pharmacologica Sinica | volume = 20 | issue = 11 | pages = 987–990 | date = November 1999 | pmid = 11270979 }} In humans, evaluation of Surrogate endpoints like electroretinography, auditory evoked potentials and visual analogue scales also suggested positive nootropic effects,{{cite journal | vauthors = Schaffler K, Hadler D, Stark M | title = Dose-effect relationship of idebenone in an experimental cerebral deficit model. Pilot study in healthy young volunteers with piracetam as reference drug | journal = Arzneimittel-Forschung | volume = 48 | issue = 7 | pages = 720–726 | date = July 1998 | pmid = 9706371 }} 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.{{cite journal | vauthors = Gutzmann H, Kühl KP, Hadler D, Rapp MA | title = Safety and efficacy of idebenone versus tacrine in patients with Alzheimer's disease: results of a randomized, double-blind, parallel-group multicenter study | journal = Pharmacopsychiatry | volume = 35 | issue = 1 | pages = 12–18 | date = January 2002 | pmid = 11819153 | doi = 10.1055/s-2002-19833 }}{{cite journal | vauthors = Parnetti L, Senin U, Mecocci P | title = Cognitive enhancement therapy for Alzheimer's disease. The way forward | journal = Drugs | volume = 53 | issue = 5 | pages = 752–768 | date = May 1997 | pmid = 9129864 | doi = 10.2165/00003495-199753050-00003 | s2cid = 46987059 }} 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.

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.{{cite journal | vauthors = Di Prospero NA, Baker A, Jeffries N, Fischbeck KH | title = Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial | journal = The Lancet. Neurology | volume = 6 | issue = 10 | pages = 878–886 | date = October 2007 | pmid = 17826341 | doi = 10.1016/S1474-4422(07)70220-X | s2cid = 24749816 | url = https://zenodo.org/record/1260260 }} The latter was only significantly improved in young patients.{{cite journal | vauthors = Tonon C, Lodi R | title = Idebenone in Friedreich's ataxia | journal = Expert Opinion on Pharmacotherapy | volume = 9 | issue = 13 | pages = 2327–2337 | date = September 2008 | pmid = 18710357 | doi = 10.1517/14656566.9.13.2327 | s2cid = 73285881 }} 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.{{cite journal | vauthors = Buyse G, Mertens L, Di Salvo G, Matthijs I, Weidemann F, Eyskens B, Goossens W, Goemans N, Sutherland GR, Van Hove JL | display-authors = 6 | title = Idebenone treatment in Friedreich's ataxia: neurological, cardiac, and biochemical monitoring | journal = Neurology | volume = 60 | issue = 10 | pages = 1679–1681 | date = May 2003 | pmid = 12771265 | doi = 10.1212/01.wnl.0000068549.52812.0f | s2cid = 36556782 }}

The drug was approved for Friedreich's ataxia in Canada in 2008 under conditions including proof of efficacy in further clinical trials.{{cite web|url=http://www.hc-sc.gc.ca/dhp-mps/prodpharma/notices-avis/conditions/catena_fs_fd_117672-eng.php|title=Heath Canada Fact Sheet - Catena|archive-url=https://web.archive.org/web/20140619110910/http://www.hc-sc.gc.ca/dhp-mps/prodpharma/notices-avis/conditions/catena_fs_fd_117672-eng.php|archive-date=19 June 2014|url-status=dead}} However, in February 2013, Health Canada announced that idebenone would be voluntarily recalled as of April 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.[http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/23509a-eng.php Voluntary Withdrawal of Catena from the Canadian Market] In 2008, the European Medicines Agency (EMA) refused a marketing authorisation for this indication. As of 2013 the drug was not approved for FA in EuropeMargaret Wahl for Quest Magazine, 28 May 2010. [http://quest.mda.org/news/fa-research-idebenone-strikes-out-again FA Research: Idebenone Strikes Out Again] {{Webarchive|url=https://web.archive.org/web/20170927202244/http://quest.mda.org/news/fa-research-idebenone-strikes-out-again |date=27 September 2017 }} nor in the US, where, as of February 2023, there is only one approved treatment.[https://web.archive.org/web/20230301015303/https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-friedreichs-ataxia#:~:text=FDA%20has%20approved%20Skyclarys%20(omaveloxolone,recommended%20dosage%20of%20150%20mg. FDA approves first treatment for Friedreich's ataxia]

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,{{cite journal | vauthors = Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Garip A, Kernt M, Petraki D, Rummey C, Leinonen M, Metz G, Griffiths PG, Meier T, Chinnery PF | display-authors = 6 | title = A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy | journal = Brain | volume = 134 | issue = Pt 9 | pages = 2677–2686 | date = September 2011 | pmid = 21788663 | pmc = 3170530 | doi = 10.1093/brain/awr170 }} and submitted an application to market the drug to European regulators in July 2011.{{cite web|author=Staff|website=European Biotechnology News|date=26 July 2011|url=http://www.eurobiotechnews.eu/news/messages-archive/archive/article/santhera-publishes-pivotal-trial-results-of-idebenone-and-goes-for-eu-approval.html|title=Santhera publishes pivotal trial results of idebenone and goes for EU approval|archive-url=https://archive.today/20130217112149/http://www.eurobiotechnews.eu/news/messages-archive/archive/article/santhera-publishes-pivotal-trial-results-of-idebenone-and-goes-for-eu-approval.html|archive-date=17 February 2013|url-status=dead}} It is approved by EMA for this indication and was designated an orphan drug in 2007.

After experiments in mice{{cite journal | vauthors = Buyse GM, Van der Mieren G, Erb M, D'hooge J, Herijgers P, Verbeken E, Jara A, Van Den Bergh A, Mertens L, Courdier-Fruh I, Barzaghi P, Meier T | display-authors = 6 | title = Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance | journal = European Heart Journal | volume = 30 | issue = 1 | pages = 116–124 | date = January 2009 | pmid = 18784063 | pmc = 2639086 | doi = 10.1093/eurheartj/ehn406 }} and preliminary studies in humans, idebenone has entered Phase II clinical trials in 2005 and Phase III trials in 2009.{{ClinicalTrialsGov|NCT01027884|Phase III Study of Idebenone in Duchenne Muscular Dystrophy (DMD) (DELOS)}}

Phase I and II clinical trial for the treatment of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) was conducted.{{ClinicalTrialsGov|NCT00887562|Study of Idebenone in the Treatment of Mitochondrial Encephalopathy Lactic Acidosis & Stroke-like Episodes (MELAS)}} Phase I/II trial for primary progressive multiple sclerosis concluded that Idebenone did not inhibit disability progression.{{ClinicalTrialsGov|NCT00950248|Double Blind Placebo-Controlled Phase I/II Clinical Trial of Idebenone in Patients With Primary Progressive Multiple Sclerosis (IPPoMS)}}{{cite journal | vauthors = Kosa P, Wu T, Phillips J, Leinonen M, Masvekar R, Komori M, Wichman A, Sandford M, Bielekova B | display-authors = 6 | title = Idebenone does not inhibit disability progression in primary progressive MS | journal = Multiple Sclerosis and Related Disorders | volume = 45 | pages = 102434 | date = October 2020 | pmid = 32784117 | pmc = 9386688 | doi = 10.1016/j.msard.2020.102434 }}

As of 2022, a phase III clinical trial is ongoing for the treatment of Parkinson's disease.{{cite journal | vauthors = McFarthing K, Rafaloff G, Baptista M, Mursaleen L, Fuest R, Wyse RK, Stott SR | title = Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2022 Update | journal = Journal of Parkinson's Disease | volume = 12 | issue = 4 | pages = 1073–1082 | date = 2022 | pmid = 35527571 | pmc = 9198738 | doi = 10.3233/JPD-229002 }}

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.{{cite journal | vauthors = McDaniel DH, Neudecker BA, DiNardo JC, Lewis JA, Maibach HI | title = Clinical efficacy assessment in photodamaged skin of 0.5% and 1.0% idebenone | journal = Journal of Cosmetic Dermatology | volume = 4 | issue = 3 | pages = 167–173 | date = September 2005 | pmid = 17129261 | doi = 10.1111/j.1473-2165.2005.00305.x | s2cid = 2394666 }}

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.{{cite journal | vauthors = Suno M, Nagaoka A | title = [Effect of idebenone and various nootropic drugs on lipid peroxidation in rat brain homogenate in the presence of succinate] | language = ja | journal = Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica | volume = 91 | issue = 5 | pages = 295–299 | date = May 1988 | pmid = 3410376 | doi = 10.1254/fpj.91.295 | doi-access = free }} Clinical relevance of these findings has not been established.

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.

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