Ocrelizumab (1) – Ocrevus®

• Clinical trials
  • To demonstrate the additional benefit, the pharmaceutical manufacturer has submitted analyses from two double-blind, randomised, controlled trials, OPERA I and OPERA II, which had an identical study design.
  • In these studies, intravenous ocrelizumab was compared with subcutaneous interferon beta-1a over a treatment period of 96 weeks.
  • The ORATORIO study is used to demonstrate additional benefit in the patient group ‘patients with early PPMS’. This study is a randomised, double-blind trial in which ocrelizumab was compared with placebo in adults with early PPMS.

a) Adult patients with relapsing-remitting multiple sclerosis (RRMS) with active disease who have not yet received any disease-modifying therapy, or adult patients previously treated with disease-modifying therapy whose disease is not highly active

• Consequently, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, the G-BA concludes that ocrelizumab offers a minor additional benefit compared with interferon beta-1a in patient population a) adult patients with relapsing-remitting multiple sclerosis who have not yet received disease-modifying therapy, or adult patients previously treated with disease-modifying therapy whose disease is not highly active.
• On the basis of two studies of sufficient size and methodological quality, the G-BA classifies the certainty of the evidence as ‘proof’ based on the available data.
• mortality
  • Apart from the mortality recorded as part of the AE, no further deaths attributable to the course of the disease occurred in the OPERA I and OPERA II studies. The difference between the treatment groups is not statistically significant.
• Morbidity – relapses (EDSS-based)
  • The meta-analysis for the relevant patient population showed a statistically significant difference in favour of ocrelizumab compared with interferon beta-1a.
  • The additional operationalisations presented – the annual relapse rate for moderate and severe relapses, and the time to the first confirmed relapse – also show a statistically significant advantage for ocrelizumab in the meta-analysis.
  • Subgroup analyses revealed an effect modification for the characteristic of age (pre-specified cut-off point < 40 years and ≥ 40 years). In both patient populations, a statistically significant difference was observed in favour of ocrelizumab compared with interferon beta-1a; however, the extent of the effect was greater in the population of patients aged < 40 years than in the population aged ≥ 40 years.
• Morbidity – Confirmed disability progression (EDSS-based)
  • For this endpoint, the time to the first confirmed progression of disability, as measured by the EDSS, is used. A statistically significant difference in favour of ocrelizumab compared with treatment with interferon beta-1a was observed, regardless of age.
• Morbidity – Severity of disability (MSFC z-score)
  • For this benefit assessment, the mean difference from the covariance analysis from the start of the study to week 96 is used, which shows a statistically significant difference in favour of ocrelizumab. However, the confidence interval for the standardised mean difference (in the form of Hedges’ g) does not lie entirely outside the irrelevance range; consequently, the clinical relevance of the measured effect cannot be inferred.
• Morbidity – impairment due to fatigue (mFIS)
  • For this benefit assessment, the mean change (adjusted covariance analysis) from the start of the study to week 96 is used, which shows no statistically significant difference.
• Morbidity – Health status (EQ-5D VAS)
  • For the benefit assessment in this case, therefore, it is not the responder analyses that are presented, but the pre-specified analysis based on the mean difference from the covariance analysis from the start of the study to week 96, which shows no statistically significant difference between the treatment groups.
• Health-related quality of life – SF-36
  • The mean difference from the start of the study to week 96, as determined by the covariance analysis, shows a statistically significant difference between the treatment groups for the PCS in favour of ocrelizumab. However, the confidence interval for the standardised mean difference (in the form of Hedges’ g) does not lie entirely outside the irrelevance range; consequently, the clinical relevance of the measured effect cannot be inferred.
  • Thus, in the meta-analysis of the OPERA studies, the analysis of the PCS without imputation shows a statistically significant difference in favour of ocrelizumab, which is not confirmed when missing values are imputed.
• Side effects – Serious adverse events (SAEs)
  • In the meta-analysis of the two OPERA studies, no statistically significant difference was observed between the treatment groups with regard to SAEs.
  • However, for the characteristic of age (in the study, the cut-off point was pre-specified as age < 40 years and ≥ 40 years), the subgroup analyses revealed an effect modification. A statistically significant difference in favour of ocrelizumab was observed for patients aged < 40 years.
• Side effects – discontinuation due to AEs
  • Treatment discontinuations due to AEs were documented in fewer patients in the ocrelizumab arm than in the interferon beta-1a arm. For the endpoint ‘discontinuation due to AEs’, the meta-analysis showed a statistically significant difference in favour of ocrelizumab.
• Side effects – Specific side effects – Influenza-like illness and injection site reaction
  • For the endpoints of flu-like illness and injection site reaction, the meta-analysis showed a statistically significant difference in favour of ocrelizumab in each case.
• Side effects – Specific side effects – Infusion-related reactions
  • For the endpoint ‘infusion-related reactions’, the meta-analysis shows a statistically significant difference to the detriment of ocrelizumab.
• Side effects – Specific AEs – Infections and parasitic diseases, and depression
  • For the endpoints ‘infections and parasitic diseases’ and ‘depression’, the meta-analysis showed no statistically significant difference between the treatment groups in either case.
• Overall assessment
  • In the morbidity category, there is a minor but statistically significant advantage for ocrelizumab over interferon beta-1a for the endpoint ‘relapses’. Furthermore, there is a statistically significant difference in favour of ocrelizumab for the endpoint ‘confirmed disability progression’.
  • Overall, the advantage observed in the quality of life category for the SF-36 endpoint, when considering the responder analysis (deterioration of ≥ 5 points) without imputing missing values, cannot be conclusively assessed with sufficient certainty.
  • In the ‘side effects’ category, ocrelizumab shows an advantage for the endpoint ‘discontinuation due to side effects’. With regard to specific adverse events, the benefits and disadvantages of ocrelizumab compared with interferon beta-1a are repealed in the risk-benefit assessment, and there is no statistically significant difference for the endpoint ‘serious adverse events’. The advantages of ocrelizumab in the ‘side effects’ category are classified as minor in extent.

b) Adult patients with relapsing-remitting multiple sclerosis (RRMS) with highly active disease despite treatment with a disease-modifying therapy

• The additional benefit is not proven.
• For the benefit assessment in patient population b) Adult patients with relapsing-remitting multiple sclerosis (RRMS) with highly active disease despite treatment with a disease-modifying therapy, the pharmaceutical manufacturer has submitted analyses of a patient population from the OPERA I and OPERA II studies, in which ocrelizumab was compared with interferon beta-1a.
• On the basis of the data submitted during the commenting procedure and following the oral hearing, it emerged that the patient population selected by the pharmaceutical manufacturer in the dossier did not correspond to the relevant patient population for the question relating to patient population b).
• The proportion of patients pre-treated with interferon beta-1a in the submitted patient population from the OPERA studies ranged between 23.3 and 39.3 per cent. This proportion was therefore higher than originally assumed for the benefit assessment. Patients who had previously been treated with interferon beta-1a should, as part of the correct implementation of the appropriate comparator therapy, have been switched to interferon beta-1b or glatiramer acetate.
• Furthermore, following the oral hearing, the pharmaceutical manufacturer submitted an analysis of a single endpoint (annual relapse rate) from the meta-analysis of the OPERA studies for the patient population that was actually relevant, namely only those patients who had been pre-treated with glatiramer acetate or interferon beta-1b. Particularly given that, for the assessment of additional benefit, all other patient-relevant endpoints, as well as the results on mortality, quality of life and side effects, are equally relevant, no conclusions regarding additional benefit can be drawn from the results of a selectively reported endpoint.

c) Adult patients with early primary progressive multiple sclerosis (PPMS), characterised by disease duration and degree of disability, as well as imaging features typical of inflammatory activity

• Consequently, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, the G-BA concludes that there is a minor additional benefit for ocrelizumab + best standard care (BSC) compared with BSC in the patient population of ‘adult patients with early PPMS’.
• Against this background, the level of certainty is downgraded from ‘indication’ to ‘hint’.
• mortality
  • The difference between the treatment groups is not statistically significant.
• Morbidity – Confirmed disability progression (EDSS-based)
  • Under replacement strategy 1, patients for whom confirmation of disability progression was lacking due to withdrawal from the study were classified as unconfirmed progressors. When applying this replacement strategy 1, no statistically significant difference between the treatment groups is observed for any of the endpoints.
  • Under replacement strategy 2, however, these patients are classified as having confirmed progression on the day of therapy discontinuation. When applying this replacement strategy 2, a statistically significant difference in favour of ocrelizumab is observed.
  • Overall, the additional benefit for the endpoint of disability progression is assessed as minor.
• Morbidity – Severity of disability (MSFC z-score)
  • For the endpoint ‘severity of disability’, the mean difference from the MMRM analysis between baseline and week 120 is considered. No statistically significant difference is observed between the treatment groups.
• Morbidity – impairment due to fatigue (mFIS) and health status (EQ-5D VAS)
  • For the endpoints ‘impairment due to fatigue’ and ‘health status’, no usable data are available in either case, as the proportion of patients excluded from the relevant analyses exceeds 30 per cent.
• Health-related quality of life – SF-36
  • No usable data are available for the endpoint health-related quality of life (assessed using the SF-36), as the proportion of patients excluded from the relevant analyses was > 30%.
• Side effects – SUEs and discontinuation due to AEs
  • For the endpoints SUEs and discontinuation due to AEs, there was no statistically significant difference between the treatment groups in either case.
• Side effects – Specific AEs – Infusion-related reaction
  • For the endpoint ‘infusion-related reaction’, a statistically significant difference was observed to the detriment of ocrelizumab.
• Side effects – Specific AEs – Infections and parasitic diseases
  • No statistically significant difference was observed for the endpoint ‘infections and parasitic diseases’.
• Side effects – Specific side effects – Depression
  • For the endpoint ‘depression’, a statistically significant difference was observed in favour of ocrelizumab.
• Overall assessment
  • In the morbidity category, for the endpoint of confirmed disability progression (EDSS-based), there is a statistically significant difference in favour of ocrelizumab when using substitution strategy 2. In view of the results in patients who remained in the study following initial progression and the progressive course of PPMS, an advantage of ocrelizumab + BSC over BSC alone is assumed, the extent of which is assessed as minor.
  • In the category of side effects, neither an advantage nor a disadvantage for ocrelizumab + BSC compared with BSC can be inferred.

Courtesy translation only, please refer to the German original.