Cipaglucosidase alfa (1) – Pombiliti®

• Clinical trials
  • The pharmaceutical manufacturer presents the results of the PROPEL trial. This was a double-blind, randomised trial with treatment arms comprising cipaglucosidase alfa (20 mg/kg every 2 weeks) plus miglustat (195 or 260 mg, depending on body weight) (n = 85) and alglucosidase alfa (20 mg/kg every 2 weeks) plus placebo (n = 38), which was conducted at 62 centres worldwide.

Adults with late-onset Pompe disease (acid α-glucosidase [GAA] deficiency)

• Overall, there is a hint of a minor additional benefit of cipaglucosidase alfa compared with the appropriate comparator therapy.
• Overall, therefore, a minor additional benefit is identified for the active ingredient cipaglucosidase alfa in combination with miglustat compared with alglucosidase alfa in the treatment of adults with Pompe disease.
• mortality
  • No deaths occurred in the study.
• Morbidity – Physical functioning assessed using the Rasch-built Pompe-specific activity (R-PAct)
  • The Rasch-built Pompe-specific activity (R-PAct) instrument is a patient-reported questionnaire designed to measure the impact of Pompe disease on activities of daily living and social participation.
  • In this indication, the responder analyses for deterioration at the week 52 assessment point are relevant. The response threshold for deterioration was defined as a decrease of 15% of the scale range, i.e. by ≥ 15 points compared with baseline.
  • There is a high proportion of missing values (27.1% in the cipaglucosidase alfa arm and 15.8% in the alglucosidase alfa arm), which the pharmaceutical manufacturer replaces using imputation methods; the results can be used for the assessment of additional benefit.
• Morbidity – Physical functioning, fatigue, dyspnoea, upper limb function using PROMIS
  • PROMIS (Patient Reported Outcome Measurement Information System) is a generic system comprising various instruments for assessing physical, mental and social health.
  • For the benefit assessment, the data submitted by the pharmaceutical manufacturer during the commenting procedure are taken into account; these data have been transformed in accordance with the conversion tables in the relevant PROMIS manuals.
  • Under this procedure, patients with missing values cannot be included in the analysis; for this reason, the pharmaceutical manufacturer replaced the missing values using imputation methods.
  • For the questionnaires on physical functioning, fatigue and limb function, the proportion of imputed values ranges from 7 to 30 per cent; the results can be used for the assessment of additional benefit.
  • For the endpoint of dyspnoea, approximately 60 per cent of values are missing; consequently, the results are not suitable for assessment and are not taken into account.
  • In the present indication, the responder analyses for deterioration at the week 52 evaluation point are relevant. The response threshold for deterioration was defined as a 15 per cent decrease in the respective scale range compared with the start of the study.
  • There are no statistically significant differences in the results for the endpoints of fatigue and upper limb function.
• quality of life
  • Endpoints relating to health-related quality of life were not assessed in the PROPEL study.
• Side effects
  • For the endpoints of severe adverse events and discontinuation due to adverse events, no statistically significant difference was observed between the treatment groups in either case.
  • In the study, infusion-related reactions were also recorded using a predefined set of symptoms that occurred between 2 and 96 hours after the infusion.
  • It can be assumed that infusion-related reactions were also included in the analyses of adverse events; consequently, they are not considered separately.
  • It should also be noted that there was no statistically significant difference between the treatment arms.
• Overall assessment
  • For cipaglucosidase alfa in combination with miglustat as a long-term enzyme replacement therapy, to be used in combination with the enzyme stabiliser miglustat for the treatment of adults with Pompe disease (acid α-glucosidase [GAA] deficiency) of the late-onset form (late-onset Pompe disease, LOPD), the PROPEL study provides results for the endpoint categories of mortality, morbidity and side effects, each compared with the appropriate comparator therapy, alglucosidase alfa.
  • No deaths occurred in the study.
  • In the morbidity category, patient-relevant endpoints relating to physical functioning (as measured by R-PAct and the PROMIS questionnaire), fatigue, dyspnoea, upper limb function (PROMIS), changes in general physical well-being, respiratory effort, muscle strength, muscle function, ability to move, activities of daily living, energy levels and muscle pain (using the SGIC), physical endurance (using the 6-minute walk test), motor function (GSGC test) and health status (EQ-5D VAS).
  • Statistically significant differences in favour of cipaglucosidase alfa were observed in the endpoints of energy levels and ability to move, as assessed using the SGIC.
  • Data on quality of life were not collected as part of the PROPEL study.
  • With regard to side effects, there were no statistically significant differences between the comparison arms in terms of the overall rates of serious adverse events.
  • Overall, statistically significant advantages of cipaglucosidase alfa in combination with miglustat compared with alglucosidase alfa were therefore demonstrated in the morbidity category (energy levels and ability to move, both assessed using the SGIC).
  • The additional benefit is determined on the basis of these endpoints assessed using the SGIC; however, the results for the other endpoints relating to physical functioning and motor function must also be taken into account in the overall assessment.
  • In this regard – particularly for endpoints assessed using the more complex instruments R-PAct and PROMIS – there are no data indicating an opposite effect that would call the observed advantages into question.
  • However, as the statistically significant advantages in the endpoints of energy levels and ability to move are not confirmed in the morbidity endpoints that were also assessed, and in particular not in the endpoints relating to physical functioning and motor function, the extent of the additional benefit must be regarded as minor at most.

Courtesy translation only, please refer to the German original.