Idebenone (DB09081): A Comprehensive Monograph on its Pharmacology, Clinical Trajectory, and Therapeutic Potential

Executive Summary

Idebenone (CAS: 58186-27-9; DrugBank ID: DB09081) is a synthetic small molecule, structurally analogous to the endogenous antioxidant Coenzyme Q10 (CoQ10). Initially developed for Alzheimer's disease with limited success, its therapeutic journey is a compelling case study in pharmaceutical repurposing, driven by a mechanistic rationale centered on mitochondrial support and antioxidant activity. This report provides a comprehensive, evidence-based analysis of Idebenone, covering its physicochemical properties, multifaceted pharmacology, complex clinical development history, divergent global regulatory status, and future therapeutic potential.

Pharmacologically, Idebenone possesses a dual mechanism. It functions as a mitochondrial electron carrier, capable of bypassing a defective Complex I in the electron transport chain to restore cellular ATP production. This specific action is the cornerstone of its efficacy in its sole approved indication: the treatment of visual impairment in adolescent and adult patients with Leber's Hereditary Optic Neuropathy (LHON), a rare mitochondrial disease characterized by Complex I deficiency. Concurrently, Idebenone is a potent antioxidant that inhibits lipid peroxidation and scavenges free radicals. Emerging research also points to a novel anti-inflammatory role through the inhibition of the NLRP3 inflammasome.

Despite this promising mechanistic profile, Idebenone's clinical history is marked by a singular success amidst numerous setbacks. While it secured marketing authorization from the European Medicines Agency (EMA) for LHON under "exceptional circumstances," it has failed to gain approval from the U.S. Food and Drug Administration (FDA) for any indication. Its investigational paths for Friedreich's Ataxia (FA), Duchenne Muscular Dystrophy (DMD), Alzheimer's disease, and Primary Progressive Multiple Sclerosis (PPMS) have been fraught with challenges, including inconsistent efficacy and terminated clinical trials.

A critical factor influencing these outcomes is the drug's challenging pharmacokinetic profile, characterized by low oral bioavailability, high inter-subject variability, and extensive first-pass metabolism. This suggests that clinical failures may, in part, represent a failure of adequate drug exposure in target tissues rather than a failure of the underlying mechanism.

The drug is generally well-tolerated, with the most common adverse effects being mild-to-moderate diarrhea, nasopharyngitis, and cough. A notable, harmless side effect is chromaturia (reddish-brown urine). Clinically relevant drug interactions exist, primarily as a mild inhibitor of CYP3A4 and a potential inhibitor of P-glycoprotein, necessitating caution with co-administered drugs that have a narrow therapeutic index.

In conclusion, Idebenone occupies a well-defined but narrow therapeutic niche in LHON, where its mechanism directly counters the disease's core pathophysiology. Its broader potential remains constrained by its pharmacokinetic limitations. Future prospects may lie in the development of novel formulations or analogues with improved bioavailability, as well as the exploration of its newly identified anti-inflammatory and ferroptosis-inhibiting properties in other disease contexts.

1.0 Introduction: The Journey of a Coenzyme Q10 Analogue

1.1 Developmental Origins and Initial Therapeutic Goals

The history of Idebenone is a quintessential example of pharmaceutical repurposing, a journey that began with ambitious goals in a prevalent neurodegenerative disorder and culminated in a niche application for a rare genetic disease. The compound was first developed by Takeda Pharmaceutical Company under the code CV-2619.[1] The initial therapeutic target was Alzheimer's disease and other cognitive defects, a strategy predicated on the hypothesis that the drug's antioxidant properties could ameliorate the oxidative stress and mitochondrial dysfunction implicated in age-related neurodegeneration.[1]

This early research led to its first regulatory approval in Japan in 1986, where it was marketed under the trade name Avan® for the "improvement of decreased volition and emotional disturbance due to chronic cerebrovascular circulation disorder".[5] However, its performance in Alzheimer's disease proved inconsistent in clinical trials, ultimately failing to demonstrate a significant and reliable benefit. This lack of proven efficacy led to the cancellation of its approval for this indication in Japan in 1998.[3]

Despite this initial setback, the foundational mechanistic rationale for Idebenone—supporting mitochondrial energy production and protecting against oxidative damage—remained plausible for a host of other pathologies. This allowed the compound to embark on a "second life" of clinical investigation. Researchers pivoted from the complex, multifactorial landscape of Alzheimer's to rare diseases with more clearly defined pathophysiology linked to mitochondrial dysfunction. This strategic shift led to extensive clinical trials in conditions such as Friedreich's Ataxia (FA), Leber's Hereditary Optic Neuropathy (LHON), and Duchenne Muscular Dystrophy (DMD), all of which involve primary or secondary mitochondrial impairment.[3] This trajectory from a failed blockbuster candidate to a specialized orphan drug illustrates a common and important strategy in modern drug development, where a compound with a favorable safety profile and a broad, plausible mechanism is systematically tested in populations with high unmet medical need.

1.2 Chemical Identity as a Short-Chain Benzoquinone

At its core, Idebenone is a synthetic small molecule belonging to the benzoquinone chemical class.[2] It was rationally designed as a structural analogue of the endogenous antioxidant ubiquinone, more commonly known as Coenzyme Q10 (CoQ10).[1] CoQ10 is a vital component of the mitochondrial electron transport chain (ETC) and a critical lipid-soluble antioxidant in cellular membranes.

The defining structural feature of Idebenone, which differentiates it from CoQ10, is its shorter and less complex side chain. Whereas CoQ10 possesses a long polyisoprenoid tail, Idebenone has a 10-hydroxydecyl side chain.[2] This modification was a deliberate design choice intended to alter its physicochemical properties. Specifically, the shorter chain makes Idebenone less lipophilic than CoQ10. This was hypothesized to improve its oral absorption and, crucially, its ability to permeate the blood-brain barrier, a significant limitation for the larger CoQ10 molecule.[11] This fundamental structural difference is central to Idebenone's entire pharmacological profile, influencing its pharmacokinetics and its capacity to exert effects within the central nervous system and other tissues.

2.0 Physicochemical Profile and Pharmaceutical Formulation

A precise understanding of a drug's physicochemical properties is fundamental to interpreting its pharmacology, formulation, and clinical behavior. Idebenone is well-characterized across multiple chemical and pharmaceutical databases.

2.1 Chemical Identifiers and Structural Properties

Idebenone is chemically designated by the IUPAC name 2-(10-Hydroxydecyl)-5,6-dimethoxy-3-methyl-p-benzoquinone.[1] Throughout its development and marketing, it has been known by several synonyms and trade names, including idebenona, idébénone, CV-2619, and the brand names Raxone®, Catena®, and Sovrima®.[1]

Its molecular formula is C19​H30​O5​, corresponding to an average molecular weight of 338.44 g/mol and a precise monoisotopic mass of 338.209324066 Da.[1] This places it firmly in the category of a "small molecule" drug. The key database identifiers that uniquely define the compound are summarized in Table 1.

2.2 Solubility, Stability, and Physical Appearance

Physically, Idebenone presents as an orange or yellow-orange crystalline solid powder.[1] A critical property influencing its formulation and biological activity is its solubility. It is practically insoluble in water, a characteristic typical of lipophilic quinone structures.[2] However, it demonstrates good solubility in organic solvents such as dimethyl sulfoxide (DMSO) and ethanol, where concentrations of up to 100 mM (approximately 68 mg/mL) can be achieved for research purposes.[7]

The melting point of Idebenone is consistently reported within the range of 51°C to 55°C.[13] For storage, research-grade material is often kept at -20°C, though it can be shipped at ambient temperatures and the final product is stored at room temperature, preferably in a cool, dark place.[7]

2.3 The Raxone® Formulation: Composition and Excipients

The commercially available, EMA-approved formulation of Idebenone is marketed as Raxone®. It is supplied as a 150 mg orange, round, film-coated tablet, engraved with '150' on one side.[17] The composition of the tablet includes excipients that are clinically relevant. Each tablet contains 46 mg of lactose monohydrate, which is a contraindication for patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.[17] Additionally, the tablet's coating contains the coloring agent sunset yellow FCF (E110), which has the potential to cause allergic reactions in susceptible individuals.[17] These formulation details are critical for safe prescribing and patient counseling.

Table 1: Key Physicochemical and Identification Properties of Idebenone

Property	Value	Source(s)
IUPAC Name	2-(10-hydroxydecyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione	1
Synonyms	Idebenona, Idébénone, CV-2619, Raxone, Catena, Sovrima, Mnesis, Avan	1
CAS Number	58186-27-9	1
DrugBank ID	DB09081	6
PubChem ID	3686	7
Molecular Formula	C19​H30​O5​	1
Molecular Weight	338.44 g/mol (Average)	3
Appearance	Orange or yellow-orange crystalline solid powder	1
Melting Point	51-55 °C	13
Solubility (Water)	Insoluble	2
Solubility (Organic)	Soluble to 100 mM in DMSO and ethanol	7

3.0 Molecular Pharmacology: A Multifaceted Mechanism of Action

The therapeutic rationale for Idebenone rests on a combination of well-established and emerging mechanisms of action, primarily centered on mitochondrial bioenergetics and cellular protection. Its ability to function as both a mitochondrial electron carrier and a potent antioxidant underpins its development across a range of neurodegenerative and neuromuscular disorders.

3.1 The Mitochondrial Electron Carrier: Bypassing Complex I

The principal and most clinically validated mechanism of action for Idebenone is its function as a mobile electron carrier within the mitochondrial electron transport chain (ETC).[3] In a healthy mitochondrion, electrons flow sequentially from Complex I and Complex II to Coenzyme Q10, then to Complex III, cytochrome c, and finally to Complex IV, where they reduce oxygen to water. This process pumps protons across the inner mitochondrial membrane, creating an electrochemical gradient that drives ATP synthesis.

In diseases where Complex I is dysfunctional, such as Leber's Hereditary Optic Neuropathy (LHON), this electron flow is blocked. This leads to a catastrophic failure of energy production and a buildup of damaging reactive oxygen species (ROS).[20] Idebenone's unique property is its ability to circumvent this blockage. It can accept electrons from other sources and transfer them directly to Complex III of the ETC.[6] By acting as a "bypass," it restores the flow of electrons through the latter part of the chain, thereby re-establishing the proton gradient and enabling the continued production of ATP.[5]

This mechanism is not merely theoretical; it is the direct explanation for Idebenone's clinical success in LHON. The disease is caused by specific mitochondrial DNA (mtDNA) mutations that cripple Complex I function in retinal ganglion cells (RGCs).[6] By restoring ATP production and reducing oxidative stress, Idebenone is thought to reactivate "inactive-but-viable" RGCs, leading to the observed stabilization and recovery of vision.[9] This represents a powerful and elegant example of a targeted molecular therapy where the drug's action precisely counteracts the primary pathophysiological defect of the disease.

3.2 The Antioxidant: Scavenging Free Radicals and Inhibiting Lipid Peroxidation

Independent of its role in the ETC, Idebenone is a powerful antioxidant.[2] The quinone structure allows it to accept and donate electrons, enabling it to directly neutralize harmful free radicals, such as superoxide.[2] A key consequence of this activity is the inhibition of lipid peroxidation, a destructive process where ROS attack lipids in cellular membranes, leading to membrane damage, loss of function, and cell death.[2]

By protecting mitochondrial and other cellular membranes from this oxidative damage, Idebenone helps preserve cellular integrity.[5] This antioxidant mechanism was the original basis for its investigation in diseases like Alzheimer's and Friedreich's Ataxia, where oxidative stress is considered a significant contributor to the pathology.[7] Some in vitro studies have suggested that its antioxidant capacity, particularly in topical applications, may be superior to that of other well-known antioxidants like CoQ10 and vitamin E.[11]

3.3 Emerging Mechanisms: Modulation of Neuroinflammatory Pathways

More recent preclinical research has begun to uncover a third, distinct mechanism of action for Idebenone, positioning it not just as a mitochondrial support agent but also as an active immunomodulator. Studies have demonstrated that Idebenone can suppress neuroinflammatory pathways by directly inhibiting the activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome.[27] The NLRP3 inflammasome is a multiprotein complex that, when activated by cellular stress or pathogens, triggers the maturation and release of potent pro-inflammatory cytokines, most notably interleukin-1β (IL-1β).[27]

This inhibitory effect was observed in cellular and animal models of neuroinflammation triggered by both lipopolysaccharide (LPS) and amyloid-beta (Aβ), the peptide central to Alzheimer's pathology.[27] In these models, Idebenone downregulated the entire NLRP3/caspase-1/IL-1β axis, reduced glial cell activation (gliosis), and improved cognitive function.[27] Complementary in vitro work has shown that Idebenone can also suppress the production of other inflammatory mediators, including nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), in activated microglial cells.[1]

This discovery represents a significant paradigm shift in the understanding of Idebenone's biology. It suggests that its therapeutic potential may extend to diseases where neuroinflammation is a primary pathological driver. This new mechanistic insight could help re-contextualize the results of past clinical trials. For instance, the failures in Alzheimer's or PPMS, previously seen as a failure of the antioxidant strategy, might instead be viewed as a failure to achieve sufficient CNS concentrations to exert a meaningful anti-inflammatory effect. This opens up compelling new avenues for future research, potentially involving higher doses, improved formulations, or investigation in earlier stages of neuroinflammatory diseases.

4.0 Clinical Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The clinical utility of a drug is fundamentally determined by its pharmacokinetic (PK) profile—how the body absorbs, distributes, metabolizes, and excretes it. For Idebenone, its ADME characteristics are complex and present significant challenges that have likely influenced its varied clinical trial outcomes.

4.1 Absorption Dynamics and the Critical Impact of Food

Following oral administration, Idebenone is absorbed, but plasma concentrations of the pharmacologically active parent drug are typically very low and demonstrate high inter-subject variability.[5] This suggests that oral bioavailability is limited. One of the most critical factors governing its absorption is a pronounced food effect. Administration with food, and particularly a high-fat meal, has been shown to increase the bioavailability, as measured by peak plasma concentration (Cmax) and area under the curve (AUC), of the parent drug by approximately five-fold.[28] This substantial increase is likely due to the drug's lipophilic nature, with the presence of dietary fats enhancing its solubilization and absorption. This finding has direct clinical relevance, mandating that Idebenone be administered with food to ensure adequate and more consistent systemic exposure.[17]

4.2 Distribution and High Plasma Protein Binding

Once absorbed into the bloodstream, Idebenone's lipophilicity dictates its distribution. It is highly bound to plasma proteins, with binding reported to be over 99% in preclinical models.[5] This high degree of binding means that only a small fraction of the drug in circulation is free and available to exert a pharmacological effect. The drug distributes widely into tissues, with the highest concentrations typically found in the gastrointestinal tract, liver, and kidneys following oral administration.[5]

Critically for its intended use in neurological disorders, Idebenone does cross the blood-brain barrier. While conjugated metabolites are the predominant species found in most peripheral tissues, studies have shown that unconjugated (active) metabolites are the main form found in the brain and cerebrospinal fluid. Furthermore, unchanged parent Idebenone has been detected in the mitochondrial fraction of brain homogenates, confirming that the active drug reaches its subcellular target within the central nervous system.[5]

4.3 Extensive First-Pass Metabolism and Key Metabolite Profile

The most defining feature of Idebenone's pharmacokinetics is its extensive first-pass metabolism in the liver.[5] After absorption from the gut, the drug is rapidly and substantially metabolized before it reaches systemic circulation, which explains the very low plasma levels of the parent compound. Metabolism proceeds along two major pathways [5]:

1. Phase I (Oxidation): The long hydroxydecyl side chain undergoes oxidative shortening. This process is mediated by a broad range of cytochrome P450 (CYP) enzymes, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.[5] This yields a series of shorter-chain metabolites designated QS10, QS8, QS6, and QS4. These metabolites are generally considered to be pharmacologically inactive.[10]
2. Phase II (Conjugation): The parent Idebenone molecule and its Phase I metabolites undergo conjugation, primarily with glucuronides and sulfates, to form more water-soluble compounds that can be easily excreted.[5]

The consequence of this extensive metabolism is that the metabolic products dominate the plasma profile. The main metabolites detected in plasma are conjugated Idebenone (IDE-C) and conjugated QS4 (QS4+QS4-C).[6] The plasma concentrations of total Idebenone (parent drug plus its conjugates) are 420- to 650-fold higher than that of the parent drug alone. Furthermore, the plasma concentrations of total QS4 are three to four times higher than those of total Idebenone, making it the most abundant metabolic fraction in circulation.[28] This quantitative relationship, summarized in Table 2, underscores the profound impact of first-pass metabolism on the drug's disposition.

4.4 Route of Elimination

Metabolism is the main route of elimination for Idebenone. The vast majority of an administered dose is excreted via the kidneys in the form of its metabolites.[5] Elimination is relatively rapid, with most of the drug-derived material cleared within 48 hours. The major metabolite found in urine is the conjugated form of QS4.[5]

This challenging pharmacokinetic profile—low parent drug exposure, high variability, and extensive metabolism—is a plausible explanation for Idebenone's inconsistent clinical efficacy. While the drug may achieve sufficient local concentrations in more accessible tissues like the eye to be effective in LHON, it may fail to reach and sustain therapeutic concentrations in the brain and spinal cord to meaningfully impact the widespread pathology of diseases like PPMS or Alzheimer's. The dose-dependent neurological effects observed in younger FA patients further support this hypothesis, as their different metabolism or body mass might allow for a higher relative exposure, pushing them into a therapeutic window that adults do not reach.[3] This strongly implies that the drug's efficacy is limited not by its mechanism, but by its delivery, and that future development of similar molecules must prioritize improving bioavailability and CNS penetration.

Table 2: Summary of Pharmacokinetic Parameters of Idebenone and its Major Metabolites

Parameter	Parent Idebenone	Total Idebenone (IDE + IDE-C)	Total QS4 (QS4 + QS4-C)	Source(s)
Time to Peak (tmax)	~1-2 hours	Not specified	Not specified	5
Terminal Half-life (t½)	Short (levels below LOQ after ~4h)	Not specified	Not specified	5
Food Effect	~5-fold increase in AUC/Cmax	Not specified	Not specified	28
Relative Plasma Exposure	1x (Baseline)	420-650x higher than parent	3-4x higher than Total Idebenone	28
Primary Elimination Route	Metabolism, then renal excretion of metabolites	Metabolism, then renal excretion	Renal excretion	5
Major Metabolites	QS10, QS6, QS4 (Phase I); IDE-C (Phase II)	N/A	N/A	5

5.0 Clinical Efficacy and Investigational History: A Tale of Mixed Fortunes

The clinical development of Idebenone has been a long and arduous journey, characterized by a single, clear success in a rare disease set against a backdrop of mixed results and definitive failures in several other neurological and neuromuscular conditions. This history provides critical lessons on the importance of matching a drug's mechanism to a disease's specific pathophysiology.

5.1 Leber's Hereditary Optic Neuropathy (LHON): The Sole Approved Indication

The approval of Idebenone for LHON represents the pinnacle of its clinical success, where its molecular mechanism aligned perfectly with the genetic cause of the disease.

5.1.1 Pivotal Trial Evidence (RHODOS)

The European Medicines Agency (EMA) marketing authorization was primarily supported by the RHODOS (Rescue of Hereditary Optic Disease Outpatient Study) trial, a 24-week, randomized, double-blind, placebo-controlled study involving 85 LHON patients.[20] The study evaluated a daily dose of 900 mg of Idebenone. Analysis of the primary endpoint—the best recovery of visual acuity in either eye—showed a numerical improvement for Idebenone over placebo but did not achieve statistical significance (p=0.291).[31]

However, the totality of the evidence, including key secondary and post-hoc analyses, was compelling enough for regulators. A significantly greater proportion of patients treated with Idebenone experienced a "clinically relevant recovery" of vision in at least one eye compared to those on placebo (30% vs. 10%).[20] This was defined as either an improvement from being unable to read any letters on an eye chart ("off-chart") to reading at least one line, or a significant improvement for those already "on-chart." The therapeutic benefit was found to be most pronounced in patients who had different levels of visual acuity between their two eyes at the start of the trial and in those carrying the m.11778G>A and m.3460G>A mitochondrial DNA mutations.[32]

5.1.2 Long-Term Efficacy (LEROS and Real-World Data)

The positive signals from RHODOS were substantiated by long-term data. The LEROS (Long-term Efficacy and safety of Raxone in a broad Open-label population of LHON patients) study (NCT02774005) was an open-label, natural history-controlled trial that assessed the efficacy of 900 mg/day Idebenone over a 24-month period in a broader population of 199 LHON patients, including those up to 5 years post-symptom onset.[33] The LEROS study successfully met its primary endpoint, confirming the long-term efficacy of Idebenone in both the subacute and chronic phases of the disease.[33]

Further support came from real-world evidence, including data from an Expanded Access Program (EAP) and retrospective analyses. These studies consistently showed that the proportion of patients achieving vision recovery increased with the duration of treatment, with some analyses suggesting that at least two years of continuous therapy may be needed to maximize the probability of recovery.[20]

5.2 Duchenne Muscular Dystrophy (DMD): Targeting Respiratory Decline

In DMD, Idebenone was investigated not for its effect on muscle strength, but for its potential to preserve respiratory function, a major cause of mortality in the disease.

5.2.1 Analysis of the DELOS and SIDEROS Trials

The Phase III DELOS trial (NCT01027884) was a pivotal study in 64 DMD patients (aged 10-18) who were not taking concomitant glucocorticoids.[35] The trial successfully met its primary endpoint, demonstrating that Idebenone at 900 mg/day significantly reduced the rate of decline in respiratory function, as measured by peak expiratory flow percent predicted (PEF%p), over 52 weeks compared to placebo.[35] A post-hoc analysis of the DELOS data also revealed that patients treated with Idebenone had a significantly lower risk of bronchopulmonary adverse events (BAEs), such as respiratory infections, and required fewer courses of systemic antibiotics.[37]

Building on this success, the SIDEROS trial (NCT02814019) was launched. This was a larger Phase III study designed to confirm the respiratory benefits in a broader population of 255 DMD patients who were taking concomitant glucocorticoids, the standard of care.[38] However, the SIDEROS trial was terminated early in 2020, and its open-label extension (SIDEROS-E) was also terminated.[38] The termination implies that the trial failed to demonstrate the expected benefit in this steroid-treated population, a significant setback for the DMD program.

5.2.2 Long-Term Outcomes from the SYROS Study

Despite the SIDEROS outcome, long-term data from the SYROS study provided a more positive picture for a specific patient subset. SYROS was a retrospective collection of real-world data from 18 patients who had completed the original DELOS trial and continued to receive Idebenone through an EAP for up to 6 years.[41] The analysis compared periods when patients were on Idebenone versus periods when they were off treatment. The results showed that long-term Idebenone treatment was associated with a 50% reduction in the annual rate of decline of forced vital capacity (FVC%p) and fewer BAEs and respiratory-related hospitalizations.[41] This suggests a durable benefit in the steroid-naïve population, but the failure of SIDEROS raises critical questions about potential negative interactions with steroids or differences in disease pathology that limit Idebenone's efficacy in the majority of treated DMD patients.

5.3 Friedreich's Ataxia (FA): A Dichotomy of Cardiac and Neurological Outcomes

The investigation of Idebenone in FA, another mitochondrial disease, has yielded a frustratingly mixed and ultimately disappointing set of results.

5.3.1 Review of Efficacy on Cardiomyopathy

A hallmark of FA is hypertrophic cardiomyopathy. Numerous small-scale, and often open-label, clinical studies reported that low-dose Idebenone (typically 5 mg/kg/day) could significantly reduce cardiac hypertrophy, as measured by a decrease in left ventricular mass on echocardiograms.[3] This was one of the most consistent signals in the early FA research. However, the effect on actual cardiac

function, such as ejection fraction, was inconsistent. Some studies reported modest improvements, while at least one long-term follow-up noted a worsening of function despite the reduction in heart muscle mass, suggesting the drug could not overcome the underlying disease progression.[29]

5.3.2 Analysis of Inconsistent Neurological Benefits and Dose-Response

The primary challenge in FA has been demonstrating a benefit for the progressive neurological symptoms, particularly ataxia. The evidence here has been overwhelmingly inconclusive or negative.[3] While some early, small studies hinted at benefits in fine motor skills, especially in younger patients [3], these findings were not replicated in larger, more rigorous trials. The placebo-controlled IONA trial, for example, failed to show a statistically significant effect of Idebenone on validated ataxia rating scales like the ICARS and FARS.[44]

A Phase II dose-ranging study suggested a potential dose-dependent effect, with intermediate and high doses appearing more effective than low doses on neurological endpoints.[29] This prompted larger Phase III trials like MICONOS (NCT00537680), but this study was ultimately terminated.[47] The cumulative weight of these negative neurological findings led to the voluntary withdrawal of the drug's conditional approval for FA in Canada in 2013.[3]

5.4 Failed and Discontinued Indications: Alzheimer's Disease and Primary Progressive Multiple Sclerosis (PPMS)

Idebenone's history is also defined by its definitive failures in two major CNS disorders.

• Alzheimer's Disease: As the original indication, Idebenone was extensively studied for its potential to improve cognitive function. Despite some encouraging signals in early, smaller studies [48], larger, well-controlled trials ultimately failed to demonstrate a consistent or meaningful benefit on cognitive decline. This lack of efficacy led to the abandonment of this indication and the cancellation of its approval for this use in Japan.[1]
• Primary Progressive Multiple Sclerosis (PPMS): Based on the hypothesis that mitochondrial dysfunction contributes to axonal loss in MS, the NIH sponsored the Phase I/II IPPoMS trial (NCT00950248).[50] This study tested a high dose of Idebenone (2,250 mg/day) against placebo. While the drug proved to be safe and well-tolerated at this dose, it completely failed to show any benefit. There was no difference between the Idebenone and placebo groups in the primary endpoint (a composite disability score called CombiWISE) or in any secondary clinical or MRI measures of disease progression.[51]

5.5 Current and Future Investigational Frontiers

Despite its mixed history, research into Idebenone continues. A Phase 3 clinical trial is currently recruiting to investigate its potential as a preventive treatment for migraine disorders (NCT04151472), a novel application for the drug.[56] Separately, its antioxidant properties have made it a component in some topical cosmetic products for anti-aging purposes, an area of commercial interest outside of regulated pharmaceuticals.[3]

Table 3: Summary of Major Clinical Trials of Idebenone by Indication

Indication	Trial Name/ID	Phase	N	Patient Population	Key Outcome/Result	Source(s)
LHON	RHODOS	III	85	LHON patients, ≤5 years onset	Failed primary endpoint but showed significant benefit in clinically relevant recovery (30% vs 10% placebo). Supported EMA approval.	20
LHON	LEROS (NCT02774005)	IV	199	LHON patients, ≤5 years onset	Met primary endpoint, confirming long-term (24-month) efficacy and safety.	33
DMD	DELOS (NCT01027884)	III	64	Steroid-naïve DMD patients	Met primary endpoint: significantly reduced decline in respiratory function (PEF%p) vs placebo.	35
DMD	SIDEROS (NCT02814019)	III	255	Steroid-treated DMD patients	Terminated. Did not confirm benefit in this population.	38
DMD	SYROS	N/A	18	Long-term follow-up of DELOS patients	Long-term (up to 6 years) treatment reduced rate of respiratory function decline by 50% vs off-treatment periods.	41
FA	IONA	III	70	FA patients	Failed to show statistically significant improvement in ataxia scores (ICARS/FARS) vs placebo.	44
FA	MICONOS (NCT00537680)	III	N/A	FA patients	Terminated.	47
PPMS	IPPoMS (NCT00950248)	I/II	77	PPMS patients	Failed to show any benefit in slowing disability progression vs placebo.	52

6.0 The Global Regulatory Maze: A Comparative Analysis

The regulatory journey of Idebenone is as complex as its clinical history, with markedly different outcomes in major global markets. This divergence reflects varying regulatory philosophies, particularly concerning the evidentiary standards for rare diseases with high unmet medical need.

6.1 European Medicines Agency (EMA): Approval Under "Exceptional Circumstances"

In the European Union, Idebenone, under the brand name Raxone®, achieved its most significant regulatory success. On September 8, 2015, the EMA granted it a marketing authorization for the treatment of visual impairment in adolescent (aged 12 and over) and adult patients with Leber's Hereditary Optic Neuropathy (LHON).[6]

This approval was granted via the "exceptional circumstances" pathway.[20] This pathway is reserved for situations where the applicant cannot provide a comprehensive set of efficacy and safety data under normal conditions of use, typically because the condition to be treated is extremely rare. In the case of LHON, the EMA acknowledged that conducting large-scale, long-term clinical trials was not feasible.[20] The decision was therefore based on the totality of the available evidence, which included the RHODOS trial, data from an Expanded Access Program, and a case record survey of untreated patients. While the pivotal RHODOS trial did not meet its primary endpoint with statistical significance, the collective data showed a consistent pattern of clinical benefit, which the agency deemed sufficient given the devastating nature of the disease and the complete lack of alternative treatments.[20] As a condition of this approval, the marketing authorization holder (initially Santhera, now Chiesi Group) is obligated to conduct post-authorization studies, such as the PAROS patient registry, to continue gathering long-term safety and efficacy data.[20]

6.2 U.S. Food and Drug Administration (FDA): A Path Fraught with Challenges

In stark contrast to its status in Europe, Idebenone is not approved by the U.S. FDA for any indication.[6] Its journey through the U.S. regulatory system has been met with significant hurdles.

• For LHON: Despite receiving Orphan Drug Designation from the FDA for LHON in October 2006, a marketing application has not been approved.[61] This suggests that the data package that was sufficient for an "exceptional circumstances" approval in the EU did not meet the FDA's evidentiary requirements.
• For Duchenne Muscular Dystrophy (DMD): Santhera actively pursued an approval for DMD in the U.S., and the program was granted Fast Track Designation by the FDA, acknowledging the serious nature of the condition.[36] However, the regulatory strategy hit a critical roadblock. Santhera had hoped to file for an accelerated approval based on the positive results of the DELOS trial in steroid-naïve patients. The FDA, however, concluded that this was insufficient and required that the results from the larger SIDEROS trial, which was studying the drug in the more common population of steroid-treated patients, be included in any New Drug Application (NDA).[62] The subsequent termination of the SIDEROS trial effectively closed the regulatory pathway for Idebenone in DMD in the U.S. In response to the unmet need, an Expanded Access Program (EAP) named BreatheDMD was launched to provide the investigational drug to eligible U.S. patients outside of a clinical trial setting.[63]

6.3 Other Key Jurisdictions: The Canadian and Japanese Experiences

The regulatory story in other major markets further illustrates the drug's mixed fortunes.

• Canada: Idebenone (marketed as Sovrima) was granted a conditional approval by Health Canada in 2008 for the treatment of Friedreich's Ataxia.[3] This approval was contingent upon the manufacturer providing further clinical trial data to confirm its efficacy. When subsequent, more rigorous trials failed to provide this confirmatory evidence of a neurological benefit, the manufacturer voluntarily recalled the drug from the Canadian market in April 2013.[3] It is not currently approved for any use in Canada.[6]
• Japan: Japan was the first country to approve Idebenone. It was approved in 1986 under the name Avan® for symptoms associated with chronic cerebrovascular disorders.[5] It was also investigated for Alzheimer's disease, but this indication was later cancelled due to a lack of proven efficacy.[3]

Table 4: Comparative Global Regulatory Status of Idebenone

Agency	Country/Region	Indication	Status	Key Dates & Notes	Source(s)
EMA	European Union	Leber's Hereditary Optic Neuropathy (LHON)	Approved	Sep 2015: Approved under "exceptional circumstances".	6
FDA	United States	Leber's Hereditary Optic Neuropathy (LHON)	Not Approved	Oct 2006: Orphan Drug Designation granted.	61
FDA	United States	Duchenne Muscular Dystrophy (DMD)	Not Approved	FDA required SIDEROS trial data for NDA; trial was terminated.	60
Health Canada	Canada	Friedreich's Ataxia (FA)	Withdrawn	2008: Conditional approval. 2013: Voluntarily recalled due to lack of efficacy in confirmatory trials.	3
PMDA	Japan	Cerebrovascular Disorders	Approved	1986: Approved as Avan®.	5
PMDA	Japan	Alzheimer's Disease	Indication Cancelled	1998: Approval for this indication cancelled due to lack of proven effect.	3

7.0 Comprehensive Safety, Tolerability, and Risk Management

A thorough understanding of a drug's safety profile is paramount for its clinical use. Idebenone is generally regarded as a safe and well-tolerated compound, a characteristic that has been consistently observed across numerous clinical trials, even at high doses up to 2,250 mg per day.[2]

7.1 Profile of Adverse Drug Reactions

The safety profile of Idebenone has been characterized through clinical trials and post-marketing surveillance.

• Common and Very Common Adverse Events: Based on the European Summary of Product Characteristics (SmPC) for Raxone®, the most frequently reported adverse drug reactions are nasopharyngitis and cough (very common, affecting >1 in 10 people) and mild-to-moderate diarrhea and back pain (common, affecting up to 1 in 10 people). The diarrhea is typically not severe enough to necessitate treatment discontinuation.[6]
• Post-Marketing and Less Common Events: A wider range of adverse events has been reported with unknown frequency, primarily from post-marketing experience in various indications. These include gastrointestinal disturbances (nausea, vomiting, dyspepsia), nervous system effects (dizziness, headache, agitation, seizure), and skin reactions (rash, pruritus).[19]
• Serious Potential Risks and Hematological Effects: The formal Risk Management Plan (RMP) for Raxone® identifies two important potential risks that require monitoring: abnormal liver function tests (including elevated transaminases and, rarely, hepatitis) and blood count abnormalities.[19] Hematological effects reported with unknown frequency include leukocytopenia (low white blood cells), neutropenia (low neutrophils), agranulocytosis (severe lack of neutrophils), and thrombocytopenia (low platelets).[19] A case of transient neutropenia that resolved upon discontinuation of the drug was reported in a clinical trial for Friedreich's Ataxia.[29]
• Chromaturia: A unique and benign side effect of Idebenone is chromaturia—a reddish-brown discoloration of the urine.[17] This is caused by the colored metabolites of the drug being excreted and is not associated with hematuria (blood in the urine) or any renal pathology. It is considered harmless and does not require dose adjustment or discontinuation. However, it is important that both clinicians and patients are aware of this effect to avoid unnecessary alarm and to ensure that it does not mask a true underlying renal or urological issue.

7.2 Clinically Significant Drug-Drug Interactions

Idebenone has a relatively low potential for significant drug-drug interactions, but two key mechanisms warrant clinical attention.

• CYP450 System: In vitro studies indicate that Idebenone and its primary metabolite, QS10, do not cause significant inhibition or induction of the major cytochrome P450 enzymes at clinically relevant concentrations.[66] However, in vivo data from a drug-drug interaction study showed that after repeated dosing, Idebenone acts as a mild inhibitor of CYP3A4. This interaction led to a modest increase (28-34%) in the exposure of midazolam, a sensitive CYP3A4 substrate.[66] Therefore, caution is advised when co-administering Idebenone with CYP3A4 substrates that have a narrow therapeutic index. Examples include certain immunosuppressants (cyclosporine, tacrolimus, sirolimus), opioids (fentanyl, alfentanil), and ergot alkaloids (ergotamine).[18]
• P-glycoprotein (P-gp): Idebenone has the potential to inhibit P-glycoprotein, an important efflux transporter protein that pumps drugs out of cells. Inhibition of P-gp could lead to increased plasma concentrations and potential toxicity of P-gp substrates. Caution is therefore recommended when Idebenone is used concurrently with drugs like dabigatran etexilate, digoxin, or aliskiren.[66]

7.3 Contraindications, Warnings, and Special Populations

• Contraindications: The only absolute contraindication is known hypersensitivity to Idebenone or to any of the excipients in the formulation, such as lactose or the sunset yellow (E110) coloring agent.[17]
• Special Populations:
• Pregnancy and Lactation: The safety of Idebenone in pregnant or breastfeeding women has not been established. Animal studies show that the drug is excreted into maternal milk. Therefore, it should only be used if the potential therapeutic benefit to the mother is judged to outweigh the potential risk to the fetus or infant. A decision may be needed to either discontinue breastfeeding or discontinue the drug.[19]
• Pediatric Use: For its approved indication of LHON, the Raxone® SmPC does not recommend use in children under the age of 12, as safety and efficacy have not been established in this group.[18] However, the drug has been studied in clinical trials for other conditions in children as young as 7 or 8 years old.[45]
• Hepatic and Renal Impairment: There is limited clinical data in patients with significant hepatic or renal impairment. Therefore, caution should be exercised when prescribing Idebenone to these populations, and monitoring of liver and kidney function may be appropriate.[17]

7.4 The Raxone® Risk Management Plan (RMP)

As required by the EMA, a formal RMP exists for Raxone® to ensure its benefits outweigh its risks.[58] The RMP summarizes the safety profile and outlines the pharmacovigilance and risk minimization activities. It formally lists no

important identified risks but designates important potential risks that require ongoing monitoring, specifically "Abnormal liver function test and hepatitis" and "Blood count abnormalities." It also identifies areas of missing information, including its use in children under 14, patients with hepatic or renal impairment, and pregnant or breastfeeding women, which are addressed through standard SmPC warnings and ongoing data collection.[58]

8.0 Synthesis and Critical Analysis: Unifying the Evidence

The extensive data on Idebenone, spanning over three decades of research, paints a picture of a drug with a compelling mechanism but a challenging clinical and regulatory history. A critical synthesis of this evidence reveals key themes that explain its trajectory and inform its future potential. The story of Idebenone is not merely one of success or failure, but a nuanced narrative about the evolution of drug development, highlighting the increasing importance of targeted mechanisms, optimized pharmacokinetics, and adaptive regulatory pathways.

8.1 Reconciling Mechanism with Clinical Outcomes: Why Success in LHON?

The central question in the Idebenone story is why a drug with a broad, fundamental mechanism—mitochondrial support and antioxidation—succeeded so clearly in one specific niche while faltering in many others. The answer lies in the near-perfect alignment between its primary mechanism of action and the precise molecular defect in LHON. The disease is caused by a monogenic defect in mitochondrial Complex I. Idebenone's ability to act as an electron carrier that bypasses Complex I provides a direct, targeted biochemical rescue. This "lock and key" scenario is not present in the other conditions where it was tested. Diseases like Alzheimer's, PPMS, and even FA are genetically and pathologically far more complex. They involve multiple pathways, including inflammation, protein aggregation, and diverse metabolic disturbances, for which a single-mechanism agent like Idebenone may be insufficient. The success in LHON, therefore, was not just a victory for the drug, but a validation of a targeted therapeutic approach.

Furthermore, a discernible pattern emerges from the clinical data: Idebenone's limited efficacy signals appear strongest in younger patient populations or in earlier stages of disease. In FA, the only hints of neurological benefit were in children and adolescents.[3] In DMD, the benefit was shown in patients who still had respiratory function to preserve.[35] Conversely, trials in older, more advanced patient populations, such as adults with FA, PPMS, and Alzheimer's, have consistently failed.[3] This suggests the existence of a "therapeutic window." Idebenone may function best as a disease-modifying or protective agent that can support cells that are metabolically stressed but still viable, rather than as a regenerative agent capable of reversing extensive, established neurodegeneration.

8.2 The Role of Pharmacokinetics and Bioavailability in Therapeutic Efficacy

A critical analysis strongly suggests that Idebenone's challenging pharmacokinetic profile is a central protagonist in its story of mixed clinical fortunes. The data consistently show very low oral bioavailability of the active parent drug, extensive and rapid first-pass metabolism, and high inter-patient variability.[5] This means that achieving sustained, therapeutic concentrations of the active drug in target tissues, particularly the central nervous system, is a major challenge.

This pharmacokinetic reality likely underpins many of the clinical failures. For LHON, the eye is a relatively accessible compartment, and it is plausible that the approved dosing regimen (900 mg/day with food) achieves sufficient local concentrations to rescue the retinal ganglion cells. However, for diseases with widespread CNS pathology like PPMS and Alzheimer's, it is highly probable that these same doses failed to produce adequate drug exposure in the brain and spinal cord to exert a meaningful effect. The dose-dependent responses seen in some FA studies further reinforce this point.[29] Therefore, many of Idebenone's clinical failures may not be a refutation of its cellular mechanism, but rather a straightforward failure of drug delivery and exposure.

8.3 Future Directions: Novel Formulations, Analogues, and Therapeutic Targets

Despite its limitations, the story of Idebenone is not over. The market for the compound is projected to grow, driven by its established use in LHON and its increasing adoption in the cosmetics industry as a topical antioxidant for anti-aging skincare products.[57] The key to unlocking its broader therapeutic potential lies in overcoming its inherent weaknesses and exploring its newly discovered biological activities.

• Novel Formulations and Analogues: The most pressing need is to improve its pharmacokinetic profile. Future research will likely focus on developing novel drug delivery systems (e.g., nanoparticle encapsulation) to enhance bioavailability and targeted delivery.[57] Concurrently, medicinal chemists are exploring the synthesis of new Idebenone analogues with modified side chains or redox cores, designed to improve stability, solubility, and CNS penetration while retaining or enhancing the desired biological activity.[49]
• New Therapeutic Targets: The recent discovery of Idebenone's ability to inhibit the NLRP3 inflammasome is a significant development.[27] This positions it as a potential anti-inflammatory agent and opens up entirely new avenues for investigation in neuroinflammatory disorders. Its characterization as a ferroptosis inhibitor—a form of iron-dependent programmed cell death—is another exciting frontier, relevant to a range of diseases from cancer to neurodegeneration.[8] These new mechanistic insights could spark a renaissance for Idebenone or its derivatives, leading to a new wave of clinical trials targeting these more specific pathways.

9.0 Expert Recommendations

Based on the comprehensive analysis of the available evidence, the following recommendations are provided for key stakeholders:

For Clinicians:

• Idebenone (Raxone®) remains the only approved and evidence-supported treatment for visual impairment in LHON. Its use should be initiated and supervised by a physician experienced with the disease, in accordance with the approved label.
• Patient counseling is critical. Clinicians should emphasize the importance of administration with food to maximize absorption and should inform patients about the expected, harmless side effect of chromaturia to prevent undue alarm.
• The potential for long-term benefit, with vision recovery sometimes taking up to two years, should be communicated to set realistic expectations for patients and encourage treatment adherence.
• For off-label use in other conditions, clinicians should exercise extreme caution. The evidence for neurological benefit in FA is poor, and trials in DMD (in steroid-treated patients), PPMS, and Alzheimer's have failed. Its use in these conditions is not supported by the current body of evidence.

For Researchers:

• The most promising avenues for future research involve addressing the drug's primary limitations and exploring its novel mechanisms.
• Pharmacokinetics: A high-priority area is the development of novel formulations or pro-drug strategies to dramatically improve the oral bioavailability and CNS penetration of Idebenone.
• Medicinal Chemistry: The synthesis and screening of new Idebenone analogues with optimized ADME properties and enhanced potency against specific targets (e.g., Complex I, NLRP3) is warranted.
• New Mechanisms: The anti-inflammatory effects via NLRP3 inhibition and the role as a ferroptosis inhibitor deserve rigorous preclinical investigation in relevant disease models (e.g., Alzheimer's, Parkinson's, inflammatory disorders). This could lead to a rational repurposing of the compound or its derivatives.
• Clinical Trial Design: Future clinical trials, should they be pursued, must learn from past failures. They should incorporate PK/PD modeling, consider enrichment strategies for patient populations most likely to respond (e.g., early-stage disease), and utilize biomarkers to confirm target engagement.

For Industry and Regulatory Bodies:

• The commercial potential of Idebenone itself is likely limited to its niche in LHON and its use in the non-regulated cosmetics market. The significant investment required to overcome its PK challenges for major CNS indications may be prohibitive.
• The development of next-generation analogues with superior properties represents a more viable long-term strategy. These new chemical entities could leverage the mechanistic understanding gained from Idebenone while possessing a more favorable clinical and commercial profile.
• The divergent regulatory outcomes between the EMA and FDA highlight the ongoing global conversation about evidentiary standards for rare diseases. The Idebenone case serves as a valuable precedent for companies developing orphan drugs, emphasizing the need to engage with regulatory agencies early and to understand their different approaches to risk-benefit assessment, particularly when relying on data packages that fall short of traditional standards.

10.0 References

[1]

Works cited

1. Idebenone | CV 2619 | CAS#58186-27-9 - MedKoo Biosciences, accessed August 6, 2025, https://www.medkoo.com/products/14736
2. Chemistry, toxicology, pharmacology and pharmacokinetics of idebenone: a review - PubMed, accessed August 6, 2025, https://pubmed.ncbi.nlm.nih.gov/15374467/
3. Idebenone - Wikipedia, accessed August 6, 2025, https://en.wikipedia.org/wiki/Idebenone
4. Idebenone: When an antioxidant is not an antioxidant - PMC - PubMed Central, accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7708875/
5. (PDF) Pharmacokinetic evaluation of idebenone - ResearchGate, accessed August 6, 2025, https://www.researchgate.net/publication/47458120_Pharmacokinetic_evaluation_of_idebenone
6. Idebenone: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 6, 2025, https://go.drugbank.com/drugs/DB09081
7. Idebenone | CAS 58186-27-9 | Quinone antioxidant - StressMarq Biosciences Inc., accessed August 6, 2025, https://www.stressmarq.com/products/small-molecules/antioxidant/idebenone-sih-150/
8. Idebenone | C19H30O5 | CID 3686 - PubChem, accessed August 6, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Idebenone
9. Idebenone: A Review in Leber's Hereditary Optic Neuropathy, accessed August 6, 2025, https://pubmed.ncbi.nlm.nih.gov/27071925/
10. Pharmacokinetic properties and metabolism of idebenone - BOC Sciences, accessed August 6, 2025, https://www.bocsci.com/blog/pharmacokinetic-properties-and-metabolism-of-idebenone/
11. Current Status and Future Prospects of Idebenone in Treatment of Mitochondrial Diseases: Literature Review, accessed August 6, 2025, https://clinmedjournals.org/articles/ijsrp/international-journal-of-surgery-research-and-practice-ijsrp-6-102.php?jid=ijsrp
12. Evaluating the therapeutic potential of idebenone and related quinone analogues in Leber hereditary optic neuropathy - PubMed Central, accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5644719/
13. Idebenone 58186-27-9 | TCI AMERICA - TCI Chemicals, accessed August 6, 2025, https://www.tcichemicals.com/US/en/p/I0848
14. Idebenone, antioxidant and neuroprotective agent (CAS 58186-27-9) (ab142522) | Abcam, accessed August 6, 2025, https://www.abcam.com/en-us/products/biochemicals/idebenone-antioxidant-and-neuroprotective-agent-ab142522
15. Idebenone Datasheet - Selleck Chemicals, accessed August 6, 2025, https://www.selleckchem.com/datasheet/idebenone-S260503-DataSheet.html
16. Idebenone SDS, 58186-27-9 Safety Data Sheets - ECHEMI, accessed August 6, 2025, https://www.echemi.com/sds/idebenone-pd1805103571.html
17. Raxone, INN-idebenone - EMA, accessed August 6, 2025, https://www.ema.europa.eu/en/documents/product-information/raxone-epar-product-information_en.pdf
18. Raxone 150 mg film-coated tablets - Patient Information Leaflet (PIL) - (emc) | 2269, accessed August 6, 2025, https://www.medicines.org.uk/emc/product/2269/pil
19. Raxone, INN-idebenone, accessed August 6, 2025, https://ec.europa.eu/health/documents/community-register/2017/20170719138454/anx_138454_en.pdf
20. Raxone | European Medicines Agency (EMA), accessed August 6, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/raxone
21. Leber's hereditary optic neuropathy – current status of idebenone and gene replacement therapies - PMC - PubMed Central, accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11831234/
22. Idebenone: A Review in Leber's Hereditary Optic Neuropathy. - National Genomics Data Center (CNCB-NGDC), accessed August 6, 2025, https://ngdc.cncb.ac.cn/openlb/publication/OLB-PM-27071925
23. Idebenone for Leber's hereditary optic neuropathy - PubMed, accessed August 6, 2025, https://pubmed.ncbi.nlm.nih.gov/27186591/
24. Idebenone | CAS 58186-27-9 - Tocris Bioscience, accessed August 6, 2025, https://www.tocris.com/products/idebenone_3002
25. Study Details | Idebenone to Treat Friedreich's Ataxia | ClinicalTrials.gov, accessed August 6, 2025, https://clinicaltrials.gov/study/NCT00229632?term=Friedreich's%20Ataxia&viewType=Table&rank=7
26. Study Details | Idebenone to Treat Friedreich's Ataxia | ClinicalTrials.gov, accessed August 6, 2025, https://clinicaltrials.gov/study/NCT00229632
27. Idebenone Regulates Aβ and LPS-Induced Neurogliosis and Cognitive Function Through Inhibition of NLRP3 Inflammasome/IL-1β Axis Activation - Frontiers, accessed August 6, 2025, https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.749336/full
28. Pharmacokinetic properties and metabolism of idebenone - ProQuest, accessed August 6, 2025, https://search.proquest.com/openview/1b7584859acdbb1100b8bfcbdd15cc3f/1?pq-origsite=gscholar&cbl=47196
29. Clinical experience with high-dose idebenone in Friedreich ataxia ..., accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4277883/
30. Idebenone in Friedreich's ataxia - PubMed, accessed August 6, 2025, https://pubmed.ncbi.nlm.nih.gov/18710357/
31. AWMSG SECRETARIAT ASSESSMENT REPORT Idebenone (Raxone®) 150 mg film-coated tablets Reference number: 807 FULL SUBMISSION, accessed August 6, 2025, https://awttc.nhs.wales/files/appraisals-asar-far/appraisal-report-idebenone-raxone-807/
32. What treatments are available? - LHON Society, accessed August 6, 2025, https://www.lhonsociety.org/information/what-treatments-are-available
33. Therapeutic benefit of idebenone in patients with Leber hereditary ..., accessed August 6, 2025, https://pubmed.ncbi.nlm.nih.gov/38428428/
34. Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy - PubMed Central, accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7657145/
35. Idebenone Reduces Loss of Respiratory Function in Duchenne Muscular Dystrophy - Outcome of a Phase III Double Blind, Randomised, Placebo-Controlled Trial (DELOS) (PL2.003), accessed August 6, 2025, https://www.neurology.org/doi/10.1212/WNL.84.14_supplement.PL2.003
36. Santhera receives FDA Fast Track Designation for Raxone /Catena (idebenone) for the Treatment of Duchenne Muscular Dystrophy (D, accessed August 6, 2025, https://www.santhera.com/assets/files/press-releases/680846_apr_9_2015.pdf
37. Idebenone reduces respiratory complications in patients with Duchenne muscular dystrophy, accessed August 6, 2025, https://pubmed.ncbi.nlm.nih.gov/27238057/
38. A Phase III Double-blind Study With Idebenone in Patients With Duchenne Muscular Dystrophy (DMD) Taking Glucocorticoid Steroids | ClinicalTrials.gov, accessed August 6, 2025, https://www.clinicaltrials.gov/study/NCT02814019
39. A Phase III Double-blind Study With Idebenone in Patients With Duchenne Muscular Dystrophy (DMD) Taking Glucocorticoid Steroids | ClinicalTrials.gov, accessed August 6, 2025, https://clinicaltrials.gov/study/NCT02814019
40. Phase III Study With Idebenone in Patients With Duchenne Muscular Dystrophy (SIDEROS-E) | ClinicalTrials.gov, accessed August 6, 2025, https://www.clinicaltrials.gov/study/NCT03603288
41. Effect of long-term idebenone treatment on respiratory morbidity and hospitalization rate in patients with Duchenne muscular dystrophy (DMD) - MDA Clinical & Scientific Conference 2025, accessed August 6, 2025, https://www.mdaconference.org/abstract-library/effect-of-long-term-idebenone-treatment-on-respiratory-morbidity-and-hospitalization-rate-in-patients-with-duchenne-muscular-dystrophy-dmd/
42. Santhera's SYROS Study Shows Long-term Efficacy with Idebenone ..., accessed August 6, 2025, https://www.parentprojectmd.org/santheras-syros-study-shows-long-term-efficacy-with-idebenone-in-slowing-respiratory-function-loss-in-patients-with-duchenne-muscular-dystrophy/
43. Santhera announces idebenone study results - Action Duchenne, accessed August 6, 2025, https://www.actionduchenne.org/santhera-announces-idebenone-study-results/
44. Idebenone in Friedreich ataxia and Leber's hereditary optic neuropathy: close mechanisms, similar therapy? | Brain | Oxford Academic, accessed August 6, 2025, https://academic.oup.com/brain/article/139/7/e39/2464210
45. IDEBENONE: Overview, Uses, Side Effects, Precautions ... - WebMD, accessed August 6, 2025, https://www.webmd.com/vitamins/ai/ingredientmono-1078/idebenone
46. Antioxidants Don't Seem to Benefit Friedreich's Ataxia Symptoms, Reviewers Conclude, accessed August 6, 2025, https://friedreichsataxianews.com/news/antioxidants-friedreichs-ataxia-symptoms-clinical-trial-idebenone/
47. A Phase III Double-Blind, Randomised, Placebo-Controlled Study of the Efficacy, Safety and Tolerability of Idebenone in the Treatment of Friedreich's Ataxia Patients (MICONOS) - Orphanet, accessed August 6, 2025, https://www.orpha.net/en/research-trials/clinical-trial/188575?name=&mode=&country=&recruiting=0&terminated=0
48. Idebenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in age-related cognitive disorders - PubMed, accessed August 6, 2025, https://pubmed.ncbi.nlm.nih.gov/7981485/
49. Idebenone: Novel Strategies to Improve Its Systemic and Local Efficacy - MDPI, accessed August 6, 2025, https://www.mdpi.com/2079-4991/8/2/87
50. Study Details | Clinical Trial of Idebenone in Primary Progressive Multiple Sclerosis (IPPoMS) | ClinicalTrials.gov, accessed August 6, 2025, https://www.clinicaltrials.gov/study/NCT00950248
51. Disseminated Sclerosis Completed Phase 1 / 2 Trials for Idebenone (DB09081) - DrugBank, accessed August 6, 2025, https://go.drugbank.com/indications/DBCOND0044732/clinical_trials/DB09081?phase=1%2C2&status=completed
52. Santhera Reports Outcome of Exploratory Trial with Idebenone in PPMS Conducted at the NIH, accessed August 6, 2025, https://www.santhera.com/assets/files/press-releases/2018-03-05_PR_PPMS_e_final.pdf
53. Idebenone (Raxone) Fails in Exploratory MS Trial - Medscape, accessed August 6, 2025, https://www.medscape.com/viewarticle/893524
54. Investigational Primary Progressive MS Drug Shows Safety, But No Efficacy Benefits, accessed August 6, 2025, https://www.pharmacytimes.com/view/investigational-primary-progressive-ms-drug-shows-safety-but-no-efficacy-benefits
55. Idebenone does not inhibit disability progression in primary progressive MS - PubMed, accessed August 6, 2025, https://pubmed.ncbi.nlm.nih.gov/32784117/
56. Migraine Disorders Recruiting Phase 3 Trials for Idebenone (DB09081) | DrugBank Online, accessed August 6, 2025, https://go.drugbank.com/indications/DBCOND0031562/clinical_trials/DB09081?phase=3&status=recruiting
57. Pure Idebenone Powder Future-proof Strategies: Trends, Competitor Dynamics, and Opportunities 2025-2033, accessed August 6, 2025, https://www.datainsightsmarket.com/reports/pure-idebenone-powder-1088497
58. idebenone (Raxone)® RMP Summary - Swissmedic, accessed August 6, 2025, https://www.swissmedic.ch/dam/swissmedic/de/dokumente/marktueberwachung/rmp/idebenone-raxone-rmp-summary.pdf.download.pdf/idebenone_Raxone_RMP-Summary.pdf
59. Chiesi Group Enters into License Agreement with Santhera for a treatment for LHON, accessed August 6, 2025, https://www.chiesi.com/en/chiesi-group-enters-into-license-agreement-with-santhera-for-a-treatment-for-lhon/
60. Idebenone: What is it and is it FDA approved? - Drugs.com, accessed August 6, 2025, https://www.drugs.com/history/idebenone.html
61. Search Orphan Drug Designations and Approvals - FDA, accessed August 6, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=232006
62. FDA Turns Down Santhera Pharmaceuticals' Request for Accelerated Approval for Idebenone to Treat DMD | Muscular Dystrophy Association, accessed August 6, 2025, https://www.mda.org/press-releases/fda-turns-down-santhera-pharmaceuticals%E2%80%99-request-accelerated-approval-idebenone-treat
63. Santhera Launches U.S. Expanded Access Program with Idebenone ..., accessed August 6, 2025, https://www.santhera.com/assets/files/press-releases/2018-02-06_EAP_e_fina.pdf
64. Study Details | Expanded Access Program for Idebenone in Participants With Duchenne Muscular Dystrophy (DMD) | ClinicalTrials.gov, accessed August 6, 2025, https://www.clinicaltrials.gov/study/NCT03433807
65. What are the side effects of Idebenone? - Patsnap Synapse, accessed August 6, 2025, https://synapse.patsnap.com/article/what-are-the-side-effects-of-idebenone
66. This medicinal product is subject to additional monitoring. This will allow quick identification of - Raxone, INN-idebenone, accessed August 6, 2025, https://ec.europa.eu/health/documents/community-register/2020/20200504148094/anx_148094_en.pdf
67. Idebenone - Uses, Dosage, Side Effects, Price, Composition | Practo, accessed August 6, 2025, https://www.practo.com/medicine-info/idebenone-1923-api
68. Idebenone as a novel, therapeutic approach for Duchenne muscular dystrophy: results from a 12 month, double-blind, randomized placebo-controlled trial - PubMed, accessed August 6, 2025, https://pubmed.ncbi.nlm.nih.gov/21435876/
69. Global Hydroxydecyl Ubiquinone (Idebenone) Market Outlook: Trends, Developments & Forecast to 2032 - 24ChemicalResearch, accessed August 6, 2025, https://www.24chemicalresearch.com/blog/7122/hydroxydecyl-ubiquinone-market
70. Current Status and Future Prospects of Idebenone in Treatment of Mitochondrial Diseases: Literature Review - ClinMed International Library, accessed August 6, 2025, https://clinmedjournals.org/articles/ijsrp/international-journal-of-surgery-research-and-practice-ijsrp-6-102.php
71. Predicted MS/MS Spectrum - 40V, Positive (Annotated) (DB09081, accessed August 6, 2025, https://go.drugbank.com/spectra/ms_ms/761349
72. Idebenone: Health Benefits, Side Effects, Uses, Dose & Precautions - RxList, accessed August 6, 2025, https://www.rxlist.com/supplements/idebenone.htm
73. Idebenone (3002) by Tocris, Part of Bio-Techne, accessed August 6, 2025, https://www.bio-techne.com/cn/p/small-molecules-peptides/idebenone_3002
74. Safety Study of Idebenone to Treat Friedreich's Ataxia | ClinicalTrials.gov, accessed August 6, 2025, https://clinicaltrials.gov/study/NCT00015808
75. Friedreich's ataxia: clinical features, pathogenesis and management - Oxford Academic, accessed August 6, 2025, https://academic.oup.com/bmb/article/124/1/19/4557846
76. Impact on respiratory decline resulting from idebenone treatment in patients with Duchenne muscular dystrophy (DMD): Results of Meta-analysis (P5.432) - Neurology.org, accessed August 6, 2025, https://www.neurology.org/doi/10.1212/WNL.90.15_supplement.P5.432
77. RAXONE 150 mg (idébénone) - Haute Autorité de Santé, accessed August 6, 2025, https://www.has-sante.fr/jcms/p_3315494/en/raxone-150-mg-idebenone
78. Santhera Signs Distribution and Supply Agreement for Raxone® (idebenone) with Pharmathen for Greece and Cyprus, accessed August 6, 2025, https://www.santhera.com/assets/files/press-releases/2017-05-02_PR_Pharmathen_e_final.pdf
79. Primary Progressive Multiple Sclerosis (PPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (PERSEUS) - UCSD Clinical Trials, accessed August 6, 2025, https://clinicaltrials.ucsd.edu/trial/NCT04458051
80. Failed, Interrupted, or Inconclusive Trials on Neuroprotective and Neuroregenerative Treatment Strategies in Multiple Sclerosis: Update 2015–2020 - PubMed Central, accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8217012/
81. idebenone emerging insight market forecast - DelveInsight, accessed August 6, 2025, https://www.delveinsight.com/report-store/idebenone-emerging-insight-market-forecast
82. Study Details | Clinical Trial of Idebenone in Primary Progressive ..., accessed August 6, 2025, https://clinicaltrials.gov/study/NCT00950248