Eliglustat (1) – Cerdelga®

• Clinical trials
  • The ENCORE trial is a randomised, active-controlled, multicentre, open-label, non-inferiority Phase III trial with a parallel-group design, which investigated the efficacy and safety of eliglustat compared with treatment with imiglucerase in patients with a stable health status who had previously received enzyme replacement therapy, over a period of 52 weeks.

Eliglustat for the long-term treatment of adult patients with type 1 Gaucher disease (GD1) who are, in terms of cytochrome P450 type 2D6 (CYP2D6), poor metabolisers (poor metabolisers, PMs),intermediate metabolisers(IMs) orextensive metabolisers(EMs)

• In summary, the extent of the additional benefit of eliglustat is assessed as follows:
• For the long-term treatment of adult patients with Gaucher disease type 1 (GD1) who, with regard to cytochrome P450 type 2D6 (CYP2D6), are slow metabolisers (poor metabolisers, PMs), intermediate metabolisers (IMs) orextensive metabolisers(EMs), there is a non-quantifiable additional benefit.
• The G-BA classifies the extent of the additional benefit of eliglustat as non-quantifiable on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• There is an additional benefit, but it is non-quantifiable because the scientific evidence does not permit this.
• In the present case and for this indication, the decisive factor is that the non-inferiority of eliglustat compared with imiglucerase could not be adequately demonstrated.
• The non-inferiority margin of 25% chosen by the pharmaceutical manufacturer for the composite endpoint (spleen volume, liver volume, haemoglobin level, platelet count) in the ENCORE study is deemed inappropriate by the G-BA, as it was previously by the EMA.
• The non-inferiority margin of 15 per cent for the endpoint ‘percentage change in spleen volume’ is also based on data that are not sufficiently valid.
• Furthermore, the open-label study design represents a limitation.
• A valid and meaningful assessment of the results to quantify the additional benefit is therefore not possible.
• Consequently, a quantitative comparative assessment of the extent of the effect and a quantification of the additional benefit based on the data submitted are not possible.
• mortality
  • No deaths were observed in the ENCORE study; mortality was not an efficacy endpoint.
  • With regard to mortality, no conclusions regarding the extent of the additional benefit can be drawn from the available results.
• Morbidity – Percentage change in spleen volume
  • The pre-specified non-inferiority margin of 15% in the ENCORE study was met; however, this must be regarded as critical for the reasons already outlined.
  • The slight improvement in the reduction in spleen volume showed no statistically significant difference between treatment with eliglustat and treatment with imiglucerase.
  • A sustained reduction in pathologically enlarged spleen volume, combined with a reduction in debilitating symptoms that is noticeable to the patient and an improvement in quality of life, is clinically relevant.
  • A long-lasting reduction in pathologically enlarged spleen volume is clinically relevant in this therapeutic indication due to the risk of splenectomy and the danger of spleen rupture.
• Morbidity – mobility and bone pain
  • For the endpoints of mobility and bone pain, only descriptive data are available.
• quality of life
  • The change in quality of life from baseline to week 52 was measured using the non-disease-specific Medical Outcome Study 36-Item Short Form Health Survey (SF-36).
  • The results after 52 weeks of treatment are summarised as the physical summary scale and the mental health summary scale.
  • In the ENCORE study, patients described their health-related quality of life on the physical summary scale at the start of the study as ranging between 48.47 and 53.57 points (mean values for the eliglustat and imiglucerase groups).
  • By week 52, all patients showed a trend towards improvement (absolute change in mean: 2.91 for eliglustat vs. 1.39 for imiglucerase).
  • The difference between the Eliglustat and Imiglucerase treatment arms is not statistically significant in the analysis of the Eliglustat group, neither on the mental nor on the physical summary scale.
• Side effects
  • Adverse events (AEs) occurred in 33 (97.1%) patients in the Eliglustat arm, compared with 42 (79.2%) patients in the Imiglucerase arm.
  • This difference is statistically significant (RR: 1.22; 95% CI: [1.05; 1.42]; p = 0.0242).
  • Most AEs could be classified into the following four MedDRA System Organ Classes (SOCs): infections, musculoskeletal, connective tissue and bone disorders, gastrointestinal disorders, and nervous system disorders.
  • Serious AEs occurred exclusively in the eliglustat arm in 4 patients (11.8%).
  • This difference is statistically significant (p = 0.0208).
  • These involved disorders of the gastrointestinal tract, injury, poisoning and procedural complications, benign, malignant and unspecified neoplasms, and infections and parasitic diseases.
  • No serious SAE of particular interest occurred.
  • No patient in the eliglustat group discontinued treatment due to AEs.
  • The available results regarding side effects indicate that treatment with Eliglustat is associated with harm compared with imiglucerase.
  • However, due to the open-label study design and the fact that patients in the control arm had been receiving imiglucerase therapy for an average of 10 years, there are uncertainties regarding the interpretation of this endpoint.
  • Overall, in the present case scenario, no conclusion can be drawn regarding the extent of the additional benefit in terms of side effects.
• Conclusion
  • Taking the available results as a whole, the G-BA arrives at the following assessment of the extent of the additional benefit: there is an additional benefit, but it is non-quantifiable, as the available scientific data do not currently permit a quantifiable statement on the extent of the additional benefit for patient-relevant endpoints.

Courtesy translation only, please refer to the German original.