Ponesimod (2) – Ponvory®

• Clinical trials
  • To assess the additional benefit of ponesimod, the pharmaceutical manufacturer has submitted the randomised, double-blind OPTIMUM trial, in which ponesimod was compared with teriflunomide.

a1) Adults with relapsing-remitting multiple sclerosis (RRMS) who have not yet received disease-modifying therapy, or adults previously treated with disease-modifying therapy whose disease is not highly active; EDSS score ≤ 3.5

• Overall, therefore, there is an indication of a minor additional benefit of ponesimod compared with teriflunomide in adults with an EDSS score ≤ 3.5.
• mortality
  • The findings on overall mortality are based on data on fatal adverse events. No statistically significant difference was observed between the treatment groups.
• Morbidity – Confirmed relapses (EDSS-based)
  • For the endpoint of confirmed relapses, operationalised as the annual relapse rate, there is a statistically significant advantage in favour of ponesimod compared with teriflunomide.
  • Whilst a statistically significant advantage in favour of ponesimod continues to be observed for adults with an EDSS score ≤ 3.5 (mild disability), no statistically significant difference between the treatment groups can be demonstrated for adults with an EDSS score > 3.5 (more severe disability), no statistically significant difference between the treatment groups can be demonstrated.
• Morbidity – Confirmed disability progression (EDSS-based)
  • No statistically significant difference between the treatment groups was observed for the endpoint of confirmed disability progression.
• Morbidity – Severity of disability (Multiple Sclerosis Functional Composite [MSFC])
  • For the endpoint of severity of disability, assessed using the MSFC z-score, there is a statistically significant advantage of ponesimod over teriflunomide. However, the 95% confidence interval for Hedges’ g does not lie entirely above the irrelevance threshold of 0.20. It cannot therefore be concluded that the effect is clinically relevant.
• Morbidity – Fatigue (Patient Global Impression of Severity [PGI-S])
  • For the endpoint of fatigue, assessed using the PGI-S, there is no statistically significant difference between the treatment groups.
• Health-related quality of life – Short Form-36 Health Survey Version 2 (SF-36v2)
  • Whilst a statistically significant advantage in favour of ponesimod over teriflunomide continues to be observed for adults with an EDSS score ≤ 3.5 (mild disability), no statistically significant difference between the treatment groups can be demonstrated for adults with an EDSS score > 3.5 (more severe disability), no statistically significant difference between the treatment groups can be demonstrated.
  • For the mental health summary score (MCS) of the SF-36v2, there is no statistically significant difference between the treatment groups in terms of either improvement or deterioration compared with the start of the study.
• Side effects – SUEs
  • No statistically significant difference was observed between the treatment groups for the SUEs endpoint.
• Side effects – discontinuation due to AEs
  • For the endpoint ‘withdrawal due to AEs’, no statistically significant difference was observed between the treatment groups.
• Side effects – bradycardia (PT, AE)
  • For the endpoint ‘bradycardia’, there was a statistically significant difference between the treatment groups, with a disadvantage for ponesimod compared with teriflunomide.
• Side effects – Infections and parasitic diseases (SOC, SAE)
  • For the endpoint ‘infections and parasitic diseases’, there was no statistically significant difference between the treatment groups.
• Side effects – alopecia (PT, AE)
  • For the endpoint alopecia, there is a statistically significant advantage for ponesimod over teriflunomide.
• Overall assessment
  • In adults with an EDSS score ≤ 3.5 (mild disability), ponesimod showed an advantage over teriflunomide in terms of morbidity (confirmed relapses) and health-related quality of life (SF-36v2, physical summary score). However, these observed advantages are not reflected in other patient-relevant endpoints such as disability progression or fatigue.
  • Based on the adverse reaction profile, it cannot be concluded that ponesimod causes either greater or minor harm overall.
  • The effects of ponesimod are therefore assessed, in adults with an EDSS score ≤ 3.5, as a moderate—rather than merely minor—improvement in treatment-related benefit compared with the appropriate comparator therapy, which has not been achieved to date, and the extent of the additional benefit is classified as minor.
  • Overall, therefore, for ponesimod in the treatment of adults with relapsing-remitting multiple sclerosis who have not yet received disease-modifying therapy, or adults previously treated with disease-modifying therapy whose disease is not highly active, and who have an EDSS score of ≤ 3.5, a minor additional benefit compared with teriflunomide.

a2) Adults with relapsing-remitting multiple sclerosis (RRMS) who have not yet received disease-modifying therapy, or adults who have previously been treated with disease-modifying therapy and whose disease is not highly active; EDSS score > 3.5

• Overall, therefore, no additional benefit of ponesimod over teriflunomide can be established in adults with an EDSS score > 3.5.
• The additional benefit is not proven.
• mortality
  • The findings on overall mortality are based on data on fatal adverse events. No statistically significant difference was observed between the treatment groups.
• Morbidity – Confirmed relapses (EDSS-based)
  • Whilst a statistically significant advantage in favour of ponesimod continues to be observed for adults with an EDSS score ≤ 3.5 (mild disability), no statistically significant difference between the treatment groups can be demonstrated for adults with an EDSS score > 3.5 (more severe disability), no statistically significant difference between the treatment groups can be demonstrated.
• Morbidity – Confirmed disability progression (EDSS-based)
  • For the endpoint of confirmed disability progression, no statistically significant difference was observed between the treatment groups.
• Morbidity – Severity of disability (Multiple Sclerosis Functional Composite [MSFC])
  • For the endpoint of severity of disability, assessed using the MSFC z-score, there is a statistically significant advantage of ponesimod over teriflunomide. However, the 95% confidence interval for Hedges’ g does not lie entirely above the irrelevance threshold of 0.20. It cannot therefore be concluded that the effect is clinically relevant.
• Morbidity – Fatigue (Patient Global Impression of Severity [PGI-S])
  • For the endpoint of fatigue, assessed using the PGI-S, there is no statistically significant difference between the treatment groups.
• Health-related quality of life – Short Form-36 Health Survey Version 2 (SF-36v2)
  • Whilst a statistically significant advantage in favour of ponesimod over teriflunomide continues to be observed for adults with an EDSS score ≤ 3.5 (mild disability), no statistically significant difference between the treatment groups can be demonstrated for adults with an EDSS score > 3.5 (more severe disability), no statistically significant difference between the treatment groups can be demonstrated.
  • For the mental health summary score (MCS) of the SF-36v2, there is no statistically significant difference between the treatment groups in terms of either improvement or deterioration compared with baseline.
• Side effects – SUEs
  • No statistically significant difference was observed between the treatment groups for the SUEs endpoint.
• Side effects – discontinuation due to AEs
  • For the endpoint ‘withdrawal due to AEs’, no statistically significant difference was observed between the treatment groups.
• Side effects – bradycardia (PT, AE)
  • For the endpoint ‘bradycardia’, there was a statistically significant difference between the treatment groups, with a disadvantage for ponesimod compared with teriflunomide.
• Side effects – Infections and parasitic diseases (SOC, SAE)
  • For the endpoint ‘infections and parasitic diseases’, there was no statistically significant difference between the treatment groups.
• Side effects – alopecia (PT, AE)
  • For the endpoint alopecia, there is a statistically significant advantage for ponesimod over teriflunomide.
• Overall assessment
  • In adults with an EDSS score > 3.5 (more severe disability), no statistically significant differences were observed between the treatment groups for the endpoints of mortality, morbidity and health-related quality of life.
  • With regard to side effects, no overall increase or minor decrease in harm attributable to ponesimod can be inferred for this patient group either.
  • Overall, the additional benefit of ponesimod over teriflunomide in adults with an EDSS score > 3.5 is not proven.

Courtesy translation only, please refer to the German original.