Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Psychoanaleptics, Other psychostimulants and nootropics; ATC code: N06BX13

Mechanism of action

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 efficacy and safety

Clinical safety and efficacy of idebenone in LHON have been assessed in one double-blind, randomised, placebo-controlled study (RHODOS). Long term efficacy and safety have been studied in a post-approval open-label study (LEROS). Long term safety has been studied in a non-interventional post-authorisation safety study (PAROS).

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 Idebenone or placebo for a period of 24 weeks (6 months). Raxone Idebenone 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 Idebenone          Placebo (N=29) (N=53)
Primary endpoint:                             logMAR* –0.135 ± 0.041    logMAR –0.071 ± 0.053 Best recovery of VA                                    logMAR –0.064, 3 letters (–0.184; 0.055) (mean ± SE; 95%CI)                                                   p=0.291 Main secondary endpoint:                      logMAR –0.035 ± 0.046     logMAR 0.085 ± 0.060 Change in best VA                                      logMAR –0.120, 6 letters (–0.255; 0.014) (mean ± SE; 95% CI)                                                  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 Idebenone 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 Idebenone 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 Raxone
RHODOS (ITT)                                      RHODOS Placebo (N=29) Idebenone (N=53)
Responders (N, %)      16 (30.2 %)                  3 (10.3 %)
EAP-Raxone Idebenone
EAP and CRS                                         CRS-untreated (N=94) (N=62)
Responders (N, %)      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 LEROS; a total of 199 LHON patients were enrolled in this open – label study. Over half (112 [56.6%]) had the G11778A mutation, whereas 34 (17.2%) had the T14484C mutation and 35 (17.7%) had the G3460A mutation. The mean age at Baseline (BL) was 34.2 years. Patients received 900 mg/day Raxone Idebenone for a period of 24 months. Raxone Idebenone was given as 3 doses of 300 mg daily, each with meals.

The primary endpoint in LEROS was the proportion of eyes that achieved a Clinically Relevant Benefit (CRB) (that is, in which there was either a Clinically Relevant Recovery [CRR] of VA from Baseline or a Clinically Relevant Stabilization [CRS]) at Month 12 in those patients that started treatment with Raxone Idebenone ≤1 year after the onset of symptoms, compared to eyes of patients from an external Natural History (NH) control group. CRB was observed in 42.3% of eyes from LEROS patients, in contrast to 20.7% eyes from NH patients. Clinically, this represents a relevant 104% relative improvement compared to spontaneous CRB that may occur in the control NH eyes. The estimated difference between treatment and control was statistically significant (p-value 0.0020) in favor of Raxone Idebenone presenting an Odds Ratio (OR) of 2.286 (95% confidence limits 1.352, 3.884).

One of the secondary endpoints in LEROS was the proportion of eyes with CRB in patients treated with Raxone Idebenone >1 year after the onset of symptoms, with CRR of VA from Baseline or CRS in which Baseline VA better than 1.0 logMAR was maintained at Month 12 compared to an external NH control group. CRB was observed in 50.3% eyes of LEROS patients and 38.6% eyes of NH patients. The difference between the two groups was statistically significant in favor of Raxone Idebenone presenting a p-value of 0.0087 and OR [95% CI] of 1.925 [1.179, 3.173].

A total of 198 patients received treatment with Raxone Idebenone and were included in the Safety Population. The mean duration of treatment in the Safety Population was 589.17 days (range: 1 – 806 days), which was equivalent to a total exposure of 319.39 person-years. A total of 154 (77.8%) of the patients undertook treatment for >12 months. A total of 149 (75.3%) patients underwent treatment at the >18-month timeframe; at the >24-month timeframe, this was 106 (53.5%). A total of 154 (77.8%) patients reported Treatment Emergent Adverse Events. The Adverse Events (AE) reported were mainly of mild or moderate severity; 13 (6.6%) patients who received Raxone Idebenone treatment reported severe AEs. Forty-nine (24.7%) patients reported AEs that were considered by the Investigator to be treatment-related. Twenty-seven (13,6%) patients experienced Serious Adverse Events and ten (5.1%) had AEs that led to permanent discontinuation of study treatment. No new safety concerns have emerged in patients with LHON enrolled in the LEROS study.

PAROS was a post-authorization non-interventional safety study designed to collect longitudinal safety and effectiveness data in routine clinical settings in patients prescribed with Raxone Idebenone for the treatment of LHON. This study was conducted at 26 centres in 6 European countries (Austria, France, Germany, Greece, Italy and The Netherlands).

In the long-term safety study PAROS, a total of 224 LHON patients with a median age of 32.2 years at baseline received treatments with Raxone Idebenone and were included in the Safety population. Over half of the patients (52.2%) had the G11778A mutation; 17.9% had the T14484C mutation, 14.3% had the G3460A mutation, and 12.1% had other mutations. Time in treatment of these patients is displayed in the table 3 below.

Table 3: Time in treatment (Safety Population)
Time in              Idebenone-naïve      Idebenone non-naïve at                       All treatment                   at            baseline baseline
N                             39                           185                         224 Day 1                  39 (100.0%)                  185 (100.0%)                224 (100.0%) ≥ 6 months             35 (89.7%)                   173 (93.5%)                  208 (92.9%) ≥ 12 months            30 (76.9%)                   156 (84.3%)                  186 (83.0%) ≥ 18 months            20 (51.3%)                   118 (63.8%)                  138 (61.6%) ≥ 24 months            14 (35.9%)                    93 (50.3%)                  107 (47.8%) ≥ 30 months            8 (20.5%)                     68 (36.8%)                  76 (33.9%) ≥ 36 months           8 (20.5%)                    54 (29.2%)                    62 (27.7%) The mean duration of exposure is of 765.4 days (SD 432.6 days)

The long-term safety profile of Raxone Idebenone in the treatment of patients with LHON was evaluated when used under conditions of routine clinical care.

A total of 130 patients (58.0% of the Safety population) reported 382 Treatment Emergent Adverse Events (TEAEs). Eleven (4.9%) patients reported severe Adverse Events (AEs). Fifty (22.3%) patients reported 82 TEAEs that were considered by the Investigator to be drug-related.
Thirty-four (15.2%) patients had 39 TEAEs that led to discontinuation of Raxone Idebenone treatment. Twenty-five (11.2%) patients experienced 31 serious TEAEs.
There was one death in the study, in an 81-year-old male patient who died of terminal prostate carcinoma, which was assessed by the Investigator as unrelated to Raxone Idebenone.

No new safety concerns have been identified with long-term treatment with Raxone Idebenone in patients with LHON when used under conditions of routine clinical care in the PAROS study.
The safety profile of Raxone Idebenone observed in PAROS was similar to that from a previous open-label study (the LEROS study).

Paediatric population

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.
In PAROS, only nine patients under 14 years of age were included and received Raxone Idebenone at 900 mg/day.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties
Absorption

Food increases the bioavailability of idebenone by approximately 5-7-fold and therefore, Raxone Idebenone should always be administered with food. The tablets should not be broken or chewed.

After oral administration of Raxone Idebenone, 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.

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 Idebenone, 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 Idebenone, 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.

Linearity/non-linearity
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 time-dependent pharmacokinetics.

Hepatic or renal impairment

No data are available in these populations.
Paediatric population

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.