Olipudase alfa (2) – Xenpozyme®

• Clinical trials
  • The ASCEND trial was a completed, double-blind Phase III trial that investigated the safety and efficacy of Olipudase alfa compared with placebo.
  • The ASCEND-Peds study was a completed, open-label, single-arm Phase I/II study that primarily investigated the safety and tolerability of Olipudase alfa.
  • The 64-week treatment phase of the ASCEND-Peds trial was followed by the open-label, single-arm LTS13632 trial.

a) Adults with manifestations of acid sphingomyelinase deficiency (ASMD) outside the central nervous system (CNS) of type A/B or type B

• Hint for a non-quantifiable additional benefit.
• Overall, therefore, olipudase alfa is considered to provide non-quantifiable added benefit in adults with acid sphingomyelinase deficiency (ASMD) outside the central nervous system (CNS) with Type A/B or Type B, a non-quantifiable additional benefit is identified on the basis of the demonstrated advantage in reducing spleen volume.
• The overall interpretability of the results is limited due to the minor number of patients included in the study.
• mortality
  • No deaths occurred in the ASCEND study.
• Morbidity – symptoms associated with splenomegaly
  • No suitable data are available for the endpoint ‘splenomegaly-associated symptoms’.
• Morbidity – Fatigue: Brief Fatigue Inventory (BFI)
  • For the endpoint ‘most severe fatigue’ (BFI Item 3), there is no statistically significant difference between the treatment groups.
  • No data are available on the total BFI score, which would be suitable for reflecting the endpoint of fatigue as a whole.
• Morbidity – Pain: Brief Pain Inventory – Short Form (BPI-SF)
  • As the response rates for the BPI-SF differed by more than 15% between the treatment groups even at the start of the study, the analyses presented are not suitable for inclusion in the benefit assessment.
• Morbidity – Health status: EQ-5D-5L-VAS (visual analogue scale of the European Quality of Life Questionnaire – 5 Dimensions)
  • For the EQ-5D VAS, the ASCEND study shows no statistically significant difference between the treatment groups.
• Morbidity – Percentage change in spleen volume
  • For the endpoint ‘percentage change in spleen volume’, the ASCEND study shows a statistically significant advantage in favour of olipudase alfa compared with placebo.
  • Furthermore, the results from the long-term treatment phase of the ASCEND study show that, over the course of the study, spleen volume continued to decrease, resulting in mild splenomegaly on average.
• Morbidity – Diffusion capacity of the lungs for carbon monoxide (DLCO)
  • For the endpoint ‘percentage change in DLCO’, the ASCEND study demonstrated a statistically significant advantage of olipudase alfa over placebo at week 52.
  • DLCO is considered a surrogate endpoint. Due to insufficient validation of the surrogate endpoint, the results for this endpoint are presented for supplementary purposes only.
• Morbidity – Liver volume
  • For the endpoint ‘percentage change in liver volume’, the ASCEND study demonstrated a statistically significant advantage of olipudase alfa compared with placebo at week 52.
  • Although a reduction in liver volume was demonstrated in the study, it therefore remains unclear to what extent the reduction in liver volume achieved with olipudase alfa therapy is relevant for patients. The results for this endpoint are therefore presented for supplementary information only.
• Morbidity – Patient Global Impression of Symptom Severity (PGIS)/Patient Global Impression of Change (PGIC)
  • No statistically significant differences were observed between the treatment arms for either the PGIS or the PGIC.
• Quality of life – Short Form-36 Health Survey (SF-36)
  • In the ASCEND study, there was no statistically significant difference between the treatment groups for either the physical composite score (PCS) or the mental composite score (MCS) of the SF-36.
• Side effects
  • In the ASCEND study, no statistically significant differences were observed between the treatment groups for the endpoints of adverse events (AEs), severe adverse events (SAEs) and discontinuation due to adverse events.
  • With regard to the available data on severe AEs, it should be noted that these were defined in the ASCEND study as AEs which, in the opinion of the investigator, prevent daily activities and require treatment. This operationalisation is not suitable for reliably distinguishing severe AEs from non-severe AEs.
• Overall assessment
  • The results of the ASCEND study are used for benefit assessment of olipudase alfa in adults with acid sphingomyelinase deficiency (ASMD) outside the central nervous system (CNS) of type A/B or type B.
  • No deaths occurred in the ASCEND study.
  • For the morbidity endpoint category, there was no statistically significant difference between the treatment groups for the endpoint ‘severe fatigue’ (assessed using BFI Item 3), the endpoint ‘health status’ (assessed using the EQ-5D VAS), or for the PGIS and PGIC endpoints.
  • In the health-related quality of life endpoint category, there was no statistically significant difference between the treatment groups for either the physical composite score (PCS) or the mental composite score (MCS) of the SF-36.
  • For the endpoint category of side effects, there was no statistically significant difference between the treatment groups for the endpoints SUEs, severe AEs and discontinuation due to AEs.
  • Overall, therefore, for olipudase alfa in adults with a deficiency of acid sphingomyelinase (ASMD) outside the central nervous system (CNS) with Type A/B or Type B, based on the demonstrated advantage in reducing spleen volume, a non-quantifiable additional benefit has been established.

b) Children and adolescents with manifestations of acid sphingomyelinase deficiency (ASMD) outside the central nervous system (CNS) of type A/B or type B

• Hint for a non-quantifiable additional benefit.
• Based on the single-arm data, it is generally not possible to make any comparative statements regarding the natural course of the disease under best supportive care for the paediatric patient population.
• Overall, a non-quantifiable additional benefit is identified for olipudase alfa in the treatment of children and adolescents with manifestations of acid sphingomyelinase deficiency (ASMD) outside the central nervous system (CNS) of type A/B or type B.
• The interpretability of the results is generally limited due to the single-arm, non-comparative study design.
• mortality
  • No deaths occurred in the ASCEND-Peds study and the associated LTS13632 study.
  • However, the non-comparative data presented do not allow for an assessment in comparison with the natural course of the disease under best supportive care.
• Morbidity – Percentage change in spleen volume
  • In children and adolescents, the results of the ASCEND-Peds study and the associated long-term study LTS13632 also show an improvement in splenomegaly, with 60% (n = 12) of patients, progressing to, on average, moderate splenomegaly by week 157.
  • Taken together, the present data show a significant reduction in spleen volume at week 52 compared with baseline following administration of olipudase alfa; however, the extent of this reduction is non-quantifiable.
• Morbidity – Height (z-score)
  • In the ASCEND-Peds study and the associated long-term study LTS13632, an increase in age-adjusted height and a convergence towards the values of the reference population were observed.
  • Taken together, the data show that administration of olipudase alfa resulted in a significant increase in height at week 52 compared with baseline; however, the extent of this increase is non-quantifiable.
• Morbidity – Pulmonary Diffusion Capacity for Carbon Monoxide (DLCO)
  • In the single-arm ASCEND-Peds study, an improvement from baseline to week 52 was observed for the endpoint ‘percentage change in DLCO’.
  • DLCO is considered a surrogate endpoint. Due to insufficient surrogate validation, the results for this endpoint are presented for supplementary purposes only.
• Morbidity – Liver volume
  • Although a reduction in liver volume was demonstrated in the study, it remains unclear to what extent the reduction in liver volume achieved with olipudase alfa therapy is relevant to patients. The results for this endpoint are therefore presented for supplementary purposes only.
• Quality of life – Paediatric Quality of Life Inventory (PedsQL)
  • The single-arm data presented do not allow for any conclusions to be drawn regarding the assessment of health-related quality of life in comparison with the natural course of the disease under best supportive care. The results are therefore presented for supplementary purposes only.
• Side effects
  • Of 20 patients, 5 (25%) experienced SUEs and 3 (15%) experienced severe AEs. No patient discontinued treatment due to AEs.
  • Overall, however, no conclusions can be drawn from the single-arm data regarding the evaluation of olipudase alfa compared with the natural course of the disease under best supportive care.
• Overall assessment
  • For the benefit assessment of the patient population of children and adolescents, the pharmaceutical manufacturer presents the multicentre, single-arm ASCEND-Peds study and the associated long-term study LTS13632. In the ASCEND-Peds study, data were collected on mortality, morbidity, quality of life and side effects.
  • Based on the single-arm data, it is generally not possible to make any comparative statements regarding the natural course of the disease under best supportive care for the paediatric patient population.
  • No deaths occurred in the ASCEND-Peds study.
  • In the morbidity endpoint category, treatment with olipudase alfa showed a significant reduction in spleen volume. A sustained reduction in pathologically enlarged spleen volume is clinically relevant in this therapeutic indication due to the risk of splenectomy and the danger of splenic rupture. Based on the data presented, it is not possible to make a direct comparative assessment of the effect of olipudase alfa against the natural course of the disease. However, in the case of this condition and with such a severe extent of splenomegaly as was initially observed in the ASCEND-Peds study, it cannot be assumed that an improvement or spontaneous remission of the enlarged spleen volume can be expected with treatment using best supportive care. For this reason, in this specific situation, the results of the single-arm study in children and adolescents can be used to derive an additional benefit for the endpoint ‘percentage change in spleen volume’.
  • Similarly, with regard to the development of age-adjusted height (z-score), it is not possible to make a direct comparative assessment of the effect of olipudase alfa against the natural course of the disease. Whilst the baseline values predominantly suggest below-average physical development in the children compared with the general population, by the end of the ASCEND-Peds study the anthropometric values had converged with those of children of the same age in the general population.
  • For both the endpoint category of health-related quality of life and the endpoint category of side effects, no conclusions can be drawn regarding the evaluation of olipudase alfa compared with the natural course of the disease under best supportive care, due to the single-arm nature of the data.
  • Overall, the extent of the advantages demonstrated in the endpoints ‘reduction in spleen volume’ and height (z-score) cannot be quantified, as the data provided do not allow for a direct comparison with the natural course of the disease.
  • On balance, a non-quantifiable additional benefit is identified for olipudase alfa in the treatment of children and adolescents with manifestations of acid sphingomyelinase deficiency (ASMD) outside the central nervous system (CNS) of type A/B or type B.

Courtesy translation only, please refer to the German original.