Idebenon (2) – Raxone®

• Clinical trials
  • The RHODOS trial is a multicentre, double-blind, randomised, placebo-controlled, parallel-group Phase II trial, which enrolled a total of 85 patients aged between 14 and 65 years with one of the three primary mutations G11778A, G3460A or T14484C, aged between 14 and 65 years, with Leber’s hereditary optic neuropathy (LHON), in a 2:1 ratio. The study investigated the efficacy, safety and tolerability of idebenone compared with placebo.
  • The LEROS study is a prospective, uncontrolled clinical study, which was also conducted as part of the EMA’s marketing authorisation requirements with the aim of assessing the long-term safety and efficacy of idebenone in people with LHON.
  • The PAROS study is a prospective, register-based, uncontrolled clinical study, which was conducted as part of the EMA’s marketing authorisation requirements. The aim was to collect data on the long-term safety and efficacy of idebenone in people with LHON.

Young people and adults with visual impairment due to Leber’s hereditary optic neuropathy (LHON)

• Overall, for adolescents and adults with visual impairment due to LHON, there is a hint of a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• mortality
  • No deaths were observed in the RHODOS study.
• morbidity
  • The pharmaceutical manufacturer has provided various operationalisations of the morbidity endpoint ‘visual acuity’. Of these, the following operationalisations of visual acuity can be taken into account for the present benefit assessment:
  • Best improvement in visual acuity at 24 weeks
  • The ‘best improvement in visual acuity at 24 weeks’, the primary endpoint of the RHODOS study, was defined as the best improvement in visual acuity in one eye of each patient, measured as the change in logMAR between the start of the study and week 24.
  • Neither the continuous data analyses presented nor the responder analyses at the threshold of ≥ 10 ETDRS letters (improvement of at least 0.2 logMAR) showed a statistically significant difference between the study arms.
  • Change in best visual acuity at 24 weeks
  • ‘Change in best visual acuity at 24 weeks’ was defined as the visual acuity of the better eye at week 24 compared with the visual acuity of the better eye at the start of the study.
  • Neither the continuous data analyses presented nor the responder analyses at the threshold of ≥ 10 ETDRS letters (improvement of at least 0.2 logMAR) showed a statistically significant difference between the study arms.
  • Change in visual acuity in the better eye (at baseline) at 24 weeks
  • The change in visual acuity in the better eye at 24 weeks was defined as the change in the eye that had the best visual acuity at the start of the study, as measured at week 24. No statistically significant difference was observed between the study arms with regard to the endpoint of change in visual acuity in the better eye at 24 weeks.
  • In addition, responder analyses are available for the combined assessment as CRR 0.2, operationalised as an improvement in visual acuity from off-chart to on-chart (at least 1.6 logMAR) or an improvement of at least 0.2 logMAR (within the on-chart range). Although these show a statistically significant difference between the treatment groups, it remains unclear whether the improvement of at least 0.2 logMAR was used as a component of ‘Best Improvement in Visual Acuity’ or of ‘Best Visual Acuity’.
  • Overall, with regard to the visual acuity endpoints, it is questionable to what extent the measurement of visual acuity alone (in one eye) in the therapeutic indication comprehensively reflects the symptoms of the condition.
  • Colour contrast sensitivity
  • For this endpoint, colour contrast sensitivity was assessed for the red-green (Protan) and yellow-blue (Tritan) colour pairs. However, the monocentric design leads to limitations in validity: as centre was not a stratification factor in the randomisation, it is unclear to what extent the study arms were fully comparable. The resulting deviation from the ITT population leads to further limitations. Furthermore, unlike an assessment of patients, the evaluation of the eyes complicates the interpretation of results and allows only limited conclusions to be drawn regarding patient-relevant effects. The proportion of patients showing an improvement in colour contrast sensitivity remains unclear.
  • Overall, no usable data on colour contrast sensitivity were available for the benefit assessment.
• quality of life
  • No usable data were available regarding quality of life.
• Side effects
  • No statistically significant differences in side effects were observed between the idebenone- and placebo-treated patient groups.
• Overall assessment
  • The RHODOS RCT provides data on mortality, morbidity and side effects for the benefit assessment of idebenone in the treatment of visual impairment in adolescents and adults with LHON.
  • No deaths occurred during the RHODOS study.
  • In the morbidity category, for the endpoints ‘greatest improvement in visual acuity at 24 weeks’, ‘change in best visual acuity at 24 weeks’ and ‘change in visual acuity in the better eye (at baseline) at 24 weeks’, respectively.
  • No usable data were available regarding quality of life.
  • In the category of side effects, no statistically significant differences were observed between the treatment and control arms.
  • The additional data from the single-arm PAROS and LEROS studies, submitted as part of the renewed benefit assessment following the expiry of the deadline to evaluate long-term effects, do not provide any further information for assessing the extent of the additional benefit beyond the comparative data from the RHODOS study. An overall assessment of the available results does not allow any conclusions to be drawn regarding the extent of the additional benefit. A quantitative assessment of the extent of the effect and a quantification of the additional benefit into one of the categories ‘minor’, ‘considerable’ or ‘major’ is not possible on the basis of the data submitted. Taking into account the severity of the condition, the written submissions and the oral hearing, the G-BA classifies the extent of the additional benefit of idebenone for the treatment of visual impairment in adolescents and adults with LHON, based on the criteria in Section 5(7) of the AM-NutzenV as non-quantifiable, because the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.