Siponimod (1) – Mayzent®

• Clinical trials
  • The EXPAND trial is a randomised, double-blind, placebo-controlled, multicentre trial.

a) Adult patients with secondary progressive multiple sclerosis (SPMS) with active disease, defined by clinical findings or imaging evidence of inflammatory activity, and with relapses.

• An additional benefit is not proven.
• The pharmaceutical manufacturer has not provided any data for the patient population under assessment, meaning that no conclusions can be drawn regarding the additional benefit of siponimod compared with the appropriate comparator therapy.

b) Adult patients with secondary progressive multiple sclerosis (SPMS) with active disease, defined by clinical findings or imaging evidence of inflammatory activity, without active relapses.

• The additional benefit is not proven.
• mortality
  • No time-to-event analyses are available for the endpoint of overall mortality. However, in the present situation, a statistically significant difference can be ruled out due to the minor incidence of events (one person died in each treatment arm).
• Morbidity – Confirmed disability progression (EDSS-based)
  • For the endpoint of confirmed disability progression (EDSS-based), assessments over a 6-month period are used for confirmation. No statistically significant difference is observed between the two treatment arms.
• Morbidity – Confirmed relapses (EDSS-based)
  • For the additional analysis of the time to the first confirmed relapse, a statistically significant advantage for siponimod + BSC was also observed.
• quality of life
  • The endpoint of health-related quality of life was not assessed in the EXPAND study.
• Side effects
  • In its benefit assessment, the IQWiG criticised the fact that, for the relevant patient population, only analyses covering the period of blinded treatment with the randomly assigned study medication were presented, and no analyses covering the entire study period.
  • Furthermore, no information is available on how events that could be either symptoms or side effects were handled, nor was any analysis presented in which these events were excluded from the calculations. Consequently, the analyses submitted regarding adverse events cannot be assessed with sufficient certainty due to the resulting uncertainty as to whether all safety events were included in the analysis.
• Overall assessment
  • The benefit assessment was based on the randomised, double-blind, placebo-controlled EXPAND trial, which compared siponimod plus best standard care (BSC) with placebo plus BSC in adult patients with secondary progressive multiple sclerosis.
  • Patients with SPMS were included in the study regardless of whether they showed disease activity. However, the authorised therapeutic indication for siponimod covers only SPMS patients with disease activity, as demonstrated by relapses or imaging evidence of inflammatory activity. Patient population b) furthermore comprises only patients with SPMS and active disease who do not have ongoing relapses. Consequently, those patients in patient population b) who, two years prior to study inclusion, had no clinical relapse, but who did have evidence of disease activity on imaging (magnetic resonance imaging) in the form of contrast-enhancing (gadolinium) T1 lesions. These patients represent a small patient population of the EXPAND study. Consequently, only 11.6% of patients in the intervention arm (128 patients) and 11.2% of patients in the comparator arm (61 patients) were included in the analysis of patient population b).
  • In the morbidity endpoint category, no statistically significant differences were observed between the two treatment arms in the endpoints relating to the progression of disability or the severity of disability. This result is also reflected in the endpoints of cognitive functioning, visual acuity, walking ability, physical and mental function, and health status, in which no relevant advantage for siponimod could be identified either. By contrast, a statistically significant advantage in favour of siponimod was observed at the endpoint of confirmed relapses.
  • The pharmaceutical manufacturer did not collect any data in the endpoint category of health-related quality of life. In the endpoint category of side effects, the pharmaceutical manufacturer did not provide any evaluable data for the relevant patient population, meaning that the side effect profile of siponimod cannot be assessed in comparison with best standard care (BSC).
  • In secondary progressive multiple sclerosis, the focus is on the progressive course of the disease, which is particularly evident in the progression of disability. The primary therapeutic goal in SPMS is therefore to halt disease progression. However, no statistically significant advantage could be demonstrated for siponimod, particularly with regard to the endpoint of disability progression.
  • Given the clinical characteristics of SPMS, relapse prevention is not usually the primary focus of treatment for SPMS. This is also evident from the fact that the patients included in the analysis had not experienced any relapses for at least two years prior to the start of the study, and that during the course of the study, relapses occurred in only a small number of patients (approximately 13 per cent). Although relapses can still occur even in the SPMS stage of the disease and are associated with limitations for patients, they do not contribute significantly to long-term disease progression. This finding is also evident from the results of the patient population of the EXPAND study, as the advantage of siponimod in reducing the annual relapse rate is not reflected in the progression of disability or the severity of disability.
  • Furthermore, the prior treatment of SPMS patients represents a potential source of uncertainty regarding the potential effect of siponimod on reducing the relapse rate. Of the total of 189 patients included in the analysis of patient population b), approximately 75% had received disease-modifying MS therapy prior to the start of the study. Subgroup analyses of this characteristic show that the relapses observed in the EXPAND study occurred almost exclusively in patients who had received disease-modifying MS therapy prior to the start of the study (DMT pre-treatment). This may suggest that the relapses observed during the course of the study are relapses that had been successfully suppressed by previous MS treatment.
  • Overall, therefore, no statistically significant advantage for siponimod could be demonstrated for the primary treatment objective in SPMS, as measured by the endpoint of confirmed disability progression. The potential effect of siponimod on reducing the relapse rate cannot be conclusively assessed due to insufficient data regarding the influence of previous disease-modifying MS therapies on the relapses that occurred during the study. Furthermore, no evaluable data on the adverse reaction profile of siponimod are available.

Courtesy translation only, please refer to the German original.