Idebenone

Idebenone is a synthetic (man-made) short-chain benzoquinone (6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone) and a synthetic analog of coenzyme Q10 (CoQ10) that is used as a substrate for the enzyme NADPH:quinone oxidoreductase (NQO1) capable of stimulating mitochondrial electron transport and supplementing cellular energy levels. Idebenone is believed to possess superior pharmacological and chemical properties compared to coenzyme Q10 (CoQ10). Idebenone exhibits lower hydrophobicity (the property of a substance that repels or is insoluble in water) than natural coenzyme Q10 (CoQ10) and has minimal toxicity ¹, ². Idebenone (Raxone) has been approved for the treatment of individuals ≥12 years old with Leber Hereditary Optic Neuropathy (LHON), a rare inherited mitochondrial eye disease that causes sudden, painless and irreversible vision loss in both eyes, by the European Medicines Agency under exceptional circumstances ³, ⁴, ⁵, ⁶. The current body of evidence indicates some visual benefit in a subgroup of affected individuals treated with idebenone, particularly those treated within the first year of onset of visual loss ⁷, ⁸, ⁹.

Idebenone (Raxone) can only be obtained with a prescription and treatment should be started and supervised by a doctor with experience in LHON (Leber Hereditary Optic Neuropathy). Idebenone (Raxone) is available as 150 mg tablets, and the recommended dose is two tablets taken three times a day with food (300 mg three times a day with meals) ³. Long-term efficacy studies for idebenone in LHON are limited by the lack of direct control data, which are difficult to prospectively compile for rare diseases with an approved treatment. In addition, little data have been collected in the chronic phase (>1 year after onset) ¹⁰, ¹¹.

Idebenone was developed initially as a treatment for Alzheimer’s disease, but has since been explored for Duchenne Muscular Dystrophy (a rare X-linked recessive inherited neuromuscular disorder that is characterized by weakness and wasting [atrophy] of the muscles of the pelvic area followed by the involvement of the shoulder muscles) for the treatment of respiratory dysfunction in patients with Duchenne who are not using glucocorticoid steroids ¹², ¹³, cardiovascular, and skin conditions due to its potent antioxidant properties and ability to influence cellular energy production ¹⁴. Idebenone operates through a multifaceted mechanism involving the enhancement of mitochondrial electron transport chain and direct antioxidant action ¹⁵. Idebenone’s ability to support mitochondrial adenosine triphosphate (ATP = energy) production under oxidative stress and protect against cellular damage by reducing reactive oxygen species (ROS) makes it a versatile therapeutic agent. From neuroprotection to cardioprotection and skin health, the diverse applications of Idebenone underscore its potential in managing various oxidative stress-related conditions. As research continues, new insights into its mechanism and broader therapeutic applications are likely to emerge, solidifying idebenone’s role in modern medicine. A clinical trial involving 41 women showed that skin roughness or dryness, skin hydration, fine lines/wrinkles, and overall global assessment of photodamaged skin were improved after six weeks of using 0.5% and 1.0% idebenone, suggesting the great potential of idebenone to be anti-aging cosmetics ¹⁶. Furthermore, it was proposed that idebenone reduced doxorubicin-mediated heart toxicity by inhibiting ferroptosis via stabilizing of FSP1, making it a promising clinical drug for patients treating with doxorubicin (a chemo drug used to treat leukemia and various other forms of cancer) ¹⁷. In addition, idebenone suppressed platelet aggregation by regulation of thromboxane B2 synthesis ¹⁸ and exerted inhibitory activity on the function of lung fibroblasts ¹⁹.

Idebenone is a synthetic short-chain benzoquinone that is thought to restore mitochondrial function by bypassing the dysfunctional complex I (NADH dehydrogenase) and thus restoring mitochondrial adenosine triphosphate (ATP = energy) production and by acting as a potent antioxidant by reducing reactive oxygen species (ROS) ²⁰, ²¹, ²², ²³. Recently, additional modes of action have been proposed, including effects on apoptosis, mitophagy, and myelination ²⁴, ²⁵.

In the randomized, double-blind, placebo-controlled Rescue of Hereditary Optic Disease Outpatient Study (RHODOS), patients with LHON and disease onset ≤5 years were treated with idebenone (300 mg 3 times/day) or placebo for 6 months ²⁶, ²⁷. A trend toward improved visual acuity (VA) was observed in idebenone-treated patients. In hindsight, the 6-month treatment duration was likely too short to fully capture the potential treatment benefit. An expanded access program allowed for analysis of long-term idebenone treatment in the real world, in subacute/dynamic LHON patients (≤1 year after onset) ²⁸. This noncontrolled study indicated the potential benefit of maintaining idebenone therapy for 24 to 30 months before classifying patients as nonresponders. This approach resulted in a visual acuity (VA) stabilization and/or recovery rate that was higher than expected from limited natural history studies ²⁹, ³⁰. Based on this cumulative clinical evidence, the European Medicines Agency approved idebenone (Raxone) for the treatment of individuals ≥12 years old with LHON ³. Raxone (idebenone) can only be obtained with a prescription and treatment should be started and supervised by a doctor with experience in LHON. Raxone (idebenone) is available as 150 mg tablets, and the recommended dose is two tablets taken three times a day with food ³. Long-term efficacy studies for idebenone in LHON are limited by the lack of direct control data, which are difficult to prospectively compile for rare diseases with an approved treatment. In addition, little data have been collected in the chronic phase (>1 year after onset) ¹⁰, ¹¹.

An open-label, international, multicenter, natural history-controlled LEROS study assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset ³¹, ³². The LEROS study meets its primary endpoint based on clinically relevant benefit at month 12 and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. LEROS confirmed the benefit of idebenone in LHON, including in the chronic phase (1–5 years since onset) with a consistent treatment benefit observed for patients with the most common G11778A (guanine to adenine at position 11778) mutation regardless of disease phase, and for patients with the T14484C (tyrosine to cytosine at position 14484) mutation in the chronic phase. LEROS confirms a favorable safety profile of idebenone in LHON patients. Howver, further study of idebenone use in patients carrying the G3460A (guanine to adenine at position 3460) mutation is needed to clarify treatment benefits. In the meantime, patients carrying G3460A mtDNA mutation who are in the subacute/dynamic phase should be adequately counseled to allow them to make an informed decision as to whether treatment with idebenone should be initiated. The findings of the LEROS study will help guide the clinical management of patients with LHON ³².

Figure 1. Idebenone

[Source ¹⁴ ]

Figure 2. The role of idebenone and coenzyme Q10 (CoQ10) in mitochondrial electron transport chain (ETC)

[Source ¹⁴ ]

Idebenone mechanism of action

Idebenone is a synthetic analog of coenzyme Q10 (CoQ10), a vital molecule involved in the production of cellular energy and the protection against oxidative stress. The mechanism of action of idebenone involves its antioxidant properties and ability to act as a mitochondrial electron carrier. Idebenone overcomes mitochondrial complex I respiratory chain deficiency in patients with Leber Hereditary Optic Neuropathy (LHON) by transferring electrons directly to mitochondrial complex III (by-passing complex I [NADH dehydrogenase]), thereby restoring mitochondrial adenosine triphosphate (ATP = energy) production and re-activating inactive-but-viable retinal ganglion cells, which ultimately prevents further vision loss and promotes vision recovery ³³. Unlike coenzyme Q10 (CoQ10), which accepts electrons from complex I (nicotinamide adenine dinucleotide dehydrogenase [NADH dehydrogenase]), idebenone effectively transfers electrons from complex II (succinate dehydrogenase) to complex III17 (see Figure 2 above) ¹⁴. In the model proposed by King et al ³⁴, idebenone is reduced at the hydrophobic quinone binding site within complex I but dissociates slowly due to its low lipophilicity. Consequently, it competitively inhibits endogenous coenzyme Q10 (CoQ10) function without substituting for its electron transfer function to mitochondrial complex III. Despite early research confirmed that idebenone restored the oxidation of succinate in dogs and rat coenzyme Q10 (CoQ10)-depleted brain mitochondria, NADH oxidation in the presence of idebenone was independent of downstream components of the electron transport chain ³⁵. Experiments using fibroblasts, which oxidized mainly NADH-linked substrates, demonstrated that idebenone was not competent to replace coenzyme Q10 (CoQ10) in the mitochondrial respiratory chain under conditions of coenzyme Q10 deficiency ³⁶.

The approval of idebenone in the treatment of Leber Hereditary Optic Neuropathy (LHON) was based on the overall data from a randomized clinical trial, a follow-up study and real-world data. Taken together, these studies provide convincing evidence that oral idebenone 900 mg/day for 24 weeks has persistent beneficial effects in preventing further vision impairment and promoting vision recovery in patients with Leber Hereditary Optic Neuropathy (LHON) relative to the natural course of the disease. Therefore, idebenone is a valuable agent to treat visual impairment in adolescents and adults with Leber Hereditary Optic Neuropathy (LHON).

At the molecular level, Idebenone functions similarly to coenzyme Q10 (CoQ10) by participating in the mitochondrial electron transport chain (ETC). The electron transport chain (ETC) is a series of complexes located in the mitochondrial inner membrane that facilitate the transfer of electrons from reducing equivalents like NADH to oxygen, culminating in the production of mitochondrial adenosine triphosphate (ATP), the primary energy currency of the cell. Idebenone, like coenzyme Q10 (CoQ10), acts as an electron carrier within this chain, shuttling electrons between complexes I, II, and III, thereby promoting ATP synthesis.

However, Idebenone’s action is unique compared to coenzyme Q10 (CoQ10). Under conditions of oxidative stress, where the normal function of the electron transport chain (ETC) is compromised, Idebenone can bypass dysfunctional complexes and maintain electron flow. This ensures continuous ATP production even under suboptimal conditions. Additionally, Idebenone can act as an antioxidant independent of its role in the electron transport chain (ETC). By directly scavenging reactive oxygen species (ROS), it mitigates oxidative damage to cellular components such as lipids, proteins, and DNA.

The dual role of Idebenone both as an electron carrier and an antioxidant translates into several therapeutic benefits at the cellular level. One of the most significant aspects is its neuroprotective effect. Neurons (nerve cells) are particularly susceptible to oxidative damage due to their high metabolic rate and limited regenerative capacity. By preserving mitochondrial function and reducing oxidative stress, Idebenone helps protect neuronal cells from degeneration, which is especially beneficial in neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and Friedreich’s ataxia.

In the cardiovascular system (heart and blood vessels system), Idebenone’s ability to enhance mitochondrial efficiency and reduce oxidative damage has shown promise in conditions like heart failure and coronary artery disease. The heart, being a highly energy-dependent organ, benefits from the sustained ATP production facilitated by idebenone. Moreover, reducing oxidative stress helps in protecting cardiac tissues from ischemia-reperfusion injury, a common scenario in heart attacks and surgical interventions.

The protective effects of idebenone extend to other tissues as well. In skin, Idebenone is utilized in anti-aging formulations. The skin, constantly exposed to environmental oxidants like UV radiation, benefits from Idebenone’s antioxidant properties. By reducing oxidative stress, Idebenone helps in maintaining skin integrity, reducing wrinkle formation, and improving overall skin health.

Absorption

Food increases the bioavailability of idebenone by approximately 5 to 7-fold and therefore, Raxone should always be administered with food. The tablets should not be broken or chewed. After oral administration of Raxone, idebenone is rapidly absorbed. On repeat dosing, maximum plasma concentrations of idebenone are reached on average within 1 hour (median 0.67 h range:0.33-2.00 h).

Distribution

Experimental data have shown that idebenone passes the blood-brain barrier and is distributed at significant concentrations in cerebral tissue. Following oral administration pharmacologically relevant concentrations of idebenone are detectable in the aqueous humor of the eye.

Biotransformation

Metabolism occurs by means of oxidative shortening of the side chain and by reduction of the quinone ring and conjugation to glucuronides and sulphates. Idebenone shows a high first pass metabolism resulting in conjugates of idebenone [glucuronides and sulphates (IDE-C)) and the Phase I metabolites QS10, QS6, and QS4 as well as their corresponding Phase II metabolites glucuronides and sulphates (QS10+QS10-C, QS6+QS6-C, QS4+QS4-C)]. The main metabolites in plasma are IDE-C and QS4+QS4-C.

The half-life of idebenone varies with age, being approximately 9.4±0.5 hours for children, 10.4±1 hours for adolescents, and 12.7±2 hours for adults ³⁷. Following oral administration, idebenone is rapidly metabolized via oxidative shortening by various cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) to yield QS4, QS6, QS8 and QS10. Idebenone and these metabolites concomitantly undergo conjugation via glucuronidation and sulfatation to yield conjugated moieties represented as idebenone-C, QS4-C, QS6-C, QS8-C and QS10-C ³⁸.

Elimination

Due to the high first-pass effect, the plasma concentrations of idebenone were generally only measurable up to 6 hours after oral administration of 750 mg Raxone, given either as a single oral dose
or after repeated (14 days) three times per day dosing. The main route of elimination is metabolism, with the majority of dose excreted via the kidneys as metabolites. After a single or repeated oral dose of 750 mg Raxone, QS4+QS4-C were the most prominent idebenone-derived metabolites in urine, representing on average between 49.3% and 68.3% of the total administered dose. QS6+QS6 represented 6.45% to 9.46%, whereas QS10+QS10-C and IDE+IDE-C were close to 1% or below.

Idebenone uses

Idebenone (Raxone) is indicated for the treatment of visual impairment in adolescent and adult patients with Leber’s Hereditary Optic Neuropathy (LHON) ³. Treatment should be initiated and supervised by a physician with experience in LHON.

Idebenone dosage

In patients with Leber Hereditary Optic Neuropathy (LHON) still in the subacute/dynamic phase, it is recommended that Idebenone be started as soon as possible at 900 mg/day (300 mg three times a day with meals) ³⁹. Idebenone (Raxone) film-coated tablets should be swallowed whole with water. The tablets should not be broken or chewed. Raxone should be administered with food because food increases the bioavailability of idebenone. Treatment should be continued for at least 1 year to assess the therapeutic response ³⁹. A clinically relevant response (recovery of vision) to treatment should be defined according to an improvement of 2 lines of best-corrected visual acuity on Early Treatment Diabetic Retinopathy Study (ETDRS) charts or from off-chart to on-chart and an automated visual field test (mean deviation) ³⁹. Once a favorable clinically relevant outcome has been confirmed, the treatment should be continued for another year ³⁹.

Elderly

No specific dose adjustment is required for the treatment of LHON in elderly patients.

Liver or kidney impairment

Patients with liver or kidney impairment have been investigated. However, no specific treatment dosage can be made. Caution is advised in treatment of patients with liver or kidney impairment, since adverse events have resulted in temporary interruption or discontinuation of treatment ³³. In the absence of sufficient clinical data, caution should be exercised in patients with kidney impairment.

Children

The safety and efficacy of Idebenone (Raxone) in Leber Hereditary Optic Neuropathy (LHON) patients under 12 years of age have not yet been established ³³.

Pregnancy

The safety of idebenone in pregnant women has not been established. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Idebenone should only be
administered to pregnant women or women of child-bearing potential likely to become pregnant if it is considered that the benefit of the therapeutic effect outweighs any potential risk ³³.

Breast-feeding

Available pharmacodynamic and toxicological data in animals have shown excretion of idebenone in milk ³³. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Idebenone (Raxone) therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman ³³.

Idebenone side effects

The most commonly reported side effects to Idebenone are mild to moderate diarrhea (usually not requiring the discontinuation of the treatment), headache, loss of appetite, and nausea, nasopharyngitis, cough and back pain ³³.

The metabolites of idebenone are colored and may cause a reddish-brown discoloration of the urine (chromaturia). This effect is harmless, not associated with blood in urine (hematuria), and does not require any adaptation of dose or discontinuation of treatment. Caution should be exercised to ensure that the reddish-brown discoloration of the urine (chromaturia) does not mask changes of urine color due to either kidney or blood disorders.

Allergic reactions have been reported. Raxone (idebenone) contains sunset yellow (E110) which may cause allergic reactions.

Overdose

No report of overdose has been received from the RHODOS, the LEROS and the PAROS studies. Doses up to 2,250 mg/day have been administered in clinical studies showing a safety profile consistent with what has been reported ³³. There is no specific antidote for idebenone. When needed, supportive symptomatic treatment should be given.

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