Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Santhera Pharmaceuticals (Deutschland) GmbH, Marie-Curie Strasse 8, 79539 Lörrach, Germany, Tel: +49 (0) 7621 1690 200, Fax: +49 (0) 7621 1690 201, Email: office@santhera.com
Pharmacotherapeutic group: Psychoanaleptics, Other psychostimulants and nootropics
ATC code: N06BX13
Idebenone, a short-chain benzoquinone, is an anti-oxidant assumed to be capable of transferring electrons directly to complex III of the mitochondrial electron transport chain, thereby circumventing complex I and restoring cellular energy (ATP) generation under experimental conditions of complex I deficiency. Similarly, in LHON idebenone can transfer electrons directly to complex III of the electron transport chain, thereby bypassing complex I which is affected by all three primary mtDNA mutations causing LHON, and restoring cellular ATP generation.
According to this biochemical mode of action, idebenone may re-activate viable-but-inactive retinal ganglion cells (RGCs) in LHON patients. Depending on the time since symptom onset and the proportion of RGCs already affected, idebenone can promote recovery of vision in patients who experience vision loss.
Clinical safety and efficacy of idebenone in LHON have been assessed in one double-blind, randomised, placebo-controlled study (RHODOS).
In RHODOS a total of 85 LHON patients, 14-66 years of age, with any of the 3 primary mtDNA mutations (G11778A, G3460A or T14484C) and disease duration of not more than 5 years were enrolled. Patients received either 900 mg/day Raxone or placebo for a period of 24 weeks (6 months). Raxone was given as 3 doses of 300 mg daily, each with meals.
The primary endpoint “best recovery of visual acuity (VA)” was defined as the result from the eye experiencing the most positive improvement in VA from baseline to week 24 using ETDRS charts. The main secondary endpoint “change in best VA” was measured as the difference between best VA in either the left or right eye at 24 weeks compared to baseline (Table 1).
Table 1. RHODOS: Best recovery of VA and change in best VA from baseline to week 24:
| Endpoint (ITT) | Raxone (N=53) | Placebo (N=29) |
|---|---|---|
| Primary endpoint: Best recovery of VA (mean ± SE; 95%CI) | logMAR* –0.135 ± 0.041 | logMAR -0.071 ± 0.053 |
| logMAR –0,064, 3 letters (–0.184; 0.055) p=0.291 | ||
| Main secondary endpoint: Change in best VA (mean ± SE; 95% CI) | logMAR -0.035 ± 0.046 | logMAR 0.085 ± 0.060 |
| logMAR -0,120, 6 letters (-0.255; 0.014) p=0.078 | ||
Analysis according to Mixed Model of Repeated Measures
One patient in the placebo group presented with ongoing spontaneous recovery of vision at baseline. Exclusion of this patient yielded similar results as in the ITT population; as could be expected, the difference between idebenone and placebo arm was slightly larger.
* logMAR – Logarithm of the Minimum Angle of Resolution
A pre-specified analysis in RHODOS determined the proportion of patients with an eye with baseline VA of ≤0.5 logMAR in whom the VA deteriorated to ≥1.0 logMAR. In this small subgroup of patients (n=8), 0 of 6 patients in the idebenone group deteriorated to ≥1.0 logMAR whereas 2 of 2 patients in the placebo group showed such a deterioration.
In a single-visit observational follow-up study of RHODOS VA assessments from 58 patients obtained on average 131 weeks after discontinuation of treatment indicates that the effect of Raxone may be maintained.
A post-hoc responder analysis was performed in RHODOS evaluating the proportion of patients who had a clinically relevant recovery of VA from baseline in at least one eye, defined as either: (i) improvement in VA from unable to read a single letter to able to read at least 5 letters on the ETDRS chart; or (ii) improvement in VA by at least 10 letters on the ETDRS chart. Results are shown in Table 2 including supporting data from 62 LHON patients using Raxone in an Expanded Access Programme (EAP) and from 94 untreated patients in a Case Record Survey (CRS).
Table 2. Proportion of patients with clinically relevant recovery of VA after 6 months from baseline:
| RHODOS (ITT) | RHODOS Raxone (N=53) | RHODOS Placebo (N=29) |
|---|---|---|
| Responders (Ν, %) | 16 (30.2%) | 3 (10.3%) |
| EAP and CRS | EAP-Raxone (N=62) | CRS-untreated (N=94) |
| Responders (Ν, %) | 19 (30.6%) | 18 (19.1%) |
In the EAP the number of responders increased with longer treatment duration, from 19 out of 62 patients (30.6%) at 6 months to 17 out of 47 patients (36.2%) at 12 months.
In clinical trials in Friedreich’s Ataxia, 32 patients between the ages of 8 and 11 years and 91 patients between the ages of 12 and 17 years received idebenone at ≥900 mg/day for up to 42 months. In RHODOS and the EAP in LHON, a total of 3 patients between the ages of 9 and 11 years and 27 patients between the ages of 12 and 17 years received idebenone at 900 mg/day for up to 33 months.
This medicinal product has been authorised under ‘exceptional circumstances’.
This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
Food increases the bioavailability of idebenone by approximately 5-7-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).
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.
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.
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) t.i.d 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.
In phase I pharmacokinetic studies, proportional increases in plasma concentrations of idebenone were observed for doses from 150 mg to 1050 mg. Neither idebenone nor its metabolites showed timedependent pharmacokinetics.
No data are available in these populations.
Whilst clinical trials experience in paediatrics with LHON is limited to patients of 14 years of age and above, pharmacokinetic data from population pharmacokinetic studies, which included paediatric Friedreich’s Ataxia patients of age 8 years and above, did not reveal any significant differences in the pharmacokinetics of idebenone.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
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