Olipudase alfa (1) – Xenpozyme®

• Clinical trials
  • To assess the additional benefit of olipudase alfa for adult patients with manifestations of acid sphingomyelinase deficiency (ASMD) outside the central nervous system (CNS) of type A/B or type B, the pharmaceutical manufacturer submitted the pivotal, multicentre, randomised, double-blind, placebo-controlled Phase II/III ASCEND trial.
  • For the assessment of the additional benefit of olipudase alfa for children and adolescents with manifestations of acid sphingomyelinase deficiency (ASMD) outside the central nervous system (CNS) of type A/B or type B, the pharmaceutical manufacturer submitted the pivotal, multicentre, single-arm Phase I/IIASCEND-Peds study, which formed the basis for the marketing authorisation, to investigate the efficacy and safety of olipudase alfa in paediatric patients aged < 18 years with non-neuronopathic ASMD.

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, as the scientific data do not permit quantification.
• Overall, the strength of the evidence suggests a non-quantifiable additional benefit.
• mortality
  • No deaths occurred in the ASCEND study.
• Morbidity – Pulmonary diffusion capacity for carbon monoxide (DLCO)
  • Lung diffusion capacity for carbon monoxide (DLCO) is a lung function test used to determine changes in the function of the alveolar membrane.
  • The endpoint ‘percentage change in lung diffusion capacity for carbon monoxide (DLCO)’ was assessed as the primary endpoint at week 52 in the ASCEND study.
  • For the endpoint ‘percentage change in DLCO’, the ASCEND study demonstrated a statistically significant advantage of olipudase alfa compared with placebo.
  • The pharmaceutical manufacturer also submitted a pre-specified responder analysis for the ASCEND study. Responders are defined as those participants who achieved an improvement in DLCO of ≥ 15% at week 52. In the intervention arm of the ASCEND study, 5 out of 18 participants showed an improvement in DLCO of ≥ 15%. In the control arm, no participant achieved an improvement in DLCO of ≥ 15%.
  • DLCO is considered a surrogate endpoint. Due to insufficient surrogate validation, the presentation of results for this endpoint is provided only as supplementary information for adults with ASMD.
• Morbidity – spleen volume
  • Spleen volume was measured in the ASCEND study using magnetic resonance imaging (MRI). The endpoint ‘percentage change in spleen volume’ was assessed as the primary endpoint at week 52 in the ASCEND study.
  • For the endpoint ‘percentage change in spleen volume’, the ASCEND study demonstrated a statistically significant advantage of olipudase alfa compared with placebo.
  • The pharmaceutical manufacturer also submitted a pre-specified responder analysis for the ASCEND study. Responders are defined as those participants who achieved a reduction in spleen size of ≥ 30% at week 52. In the intervention arm of the ASCEND study, 17 out of 18 participants showed a reduction in spleen size of ≥ 30 per cent. In the control arm, no participant achieved a reduction in spleen size of ≥ 30 per cent.
  • A sustained reduction in pathologically enlarged spleen volume, combined with a noticeable reduction in debilitating symptoms and an improvement in the patient's quality of life, is considered to be of clinical relevance.
  • However, no improvement in symptoms or quality of life could be demonstrated for olipudase alfa.
  • Nevertheless, a sustained reduction in pathologically enlarged spleen volume is clinically relevant in this therapeutic indication due to the danger of spleen rupture and the risk of splenectomy, with the associated risks of post-splenectomy complications (particularly immunodeficiency or the occurrence of severe bacterial infections).
  • However, due to the lack of improvement in symptoms and quality of life, the extent of the demonstrated advantage for the spleen volume endpoint is non-quantifiable.
• Quality of life – Short Form-36 Health Survey (SF-36)
  • In the ASCEND study, health-related quality of life was assessed using the Short Form-36 Health Survey (SF-36).
  • In the ASCEND study, there was no statistically significant difference between the treatment arms for either the mental health summary score (MCS) or the physical health summary score (PCS).
• Side effects
  • In the ASCEND study, there was no statistically significant difference between olipudase alfa and the control arm for either the endpoints of SUEs or severe adverse events.
  • In the ASCEND study, no participant discontinued treatment due to AEs. Consequently, there was no statistically significant difference between the treatment groups for the endpoint of therapy discontinuation due to AEs.
  • At the SOC (system organ class) and PT (preferred term) levels, there were no statistically significant differences between the treatment groups.
  • In the category of side effects, there are no overall advantages or disadvantages for olipudase alfa compared with placebo.
• Overall assessment
  • To assess the additional benefit of olipudase alfa for adults with extraneural ASMD of type A/B or type B, the pharmaceutical manufacturer submitted the multi-centre, randomised, double-blind, placebo-controlled Phase II/III study ASCEND, which formed the basis for marketing authorisation.
  • The ASCEND study provided data on mortality, morbidity, quality of life and side effects.
  • No deaths occurred in the ASCEND study.
  • For the endpoints in the morbidity category – fatigue (BFI), pain (BPI-SF), health status (EQ-5D-5L-VAS) and PGIS – no statistically significant difference was observed between the treatment groups in any case.
  • For the PGIC endpoint, a statistically significant advantage of olipudase alfa over placebo was demonstrated for the symptom ‘shortness of breath’, although its clinical relevance is unclear. For the PGIC, no statistically significant difference was observed between the treatment arms for the symptoms ‘abdominal problems’, ‘body pain’, ‘fatigue’ and ‘ability to perform daily activities’.
  • For the endpoint ‘percentage change in spleen volume’, the ASCEND study showed a statistically significant advantage of olipudase alfa over placebo, whose extent is non-quantifiable.
  • In the quality of life category, no statistically significant difference was observed between the treatment groups for the SF-36 endpoint.
  • In the ‘Side effects’ category, the overall assessment reveals no advantages or disadvantages for olipudase alfa.
  • Overall, there is a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.

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

• mortality
  • No deaths occurred in the ASCEND-Peds trial.
• Morbidity – Pulmonary diffusion capacity for carbon monoxide (DLCO)
  • Lung diffusion capacity for carbon monoxide (DLCO) is a lung function test used to detect changes in the function of the alveolar membrane.
  • DLCO is considered a surrogate endpoint. Based on the study submitted by the pharmaceutical manufacturer, it cannot be concluded that DLCO is a valid surrogate parameter for patient-relevant endpoints.
  • Due to insufficient surrogate validation, the results for this endpoint are presented for supplementary purposes only.
  • The endpoint ‘percentage change in the diffusion capacity of the lungs for carbon monoxide (DLCO)’ was assessed in the ASCEND-Peds study at week 52. In the single-arm ASCEND-Peds study, an improvement from baseline to week 52 was observed for the endpoint ‘percentage change in DLCO’.
  • However, the certainty and interpretability of the results are very limited due to the open-label study design without a control group; therefore, no conclusions can be drawn regarding the additional benefit of olipudase alfa.
• Quality of life – Paediatric Quality of Life Inventory (PedsQL)
  • Health-related quality of life was assessed in the ASCEND-Peds study using the PedsQL. The PedsQL is a generic instrument for measuring health-related quality of life. The PedsQL for 5- to 18-year-olds consists of 23 items, which are divided into four domains (physical, emotional, social and school-related functioning). For 2- to 4-year-olds, the questionnaire to be completed by parents comprises 21 items covering the same domains. The scores are then converted to a scale of 0 to 100, with higher scores indicating a better quality of life. In this study, the age-appropriate, self-reported and observer-reported versions for the 2 to 4-year-old and 5 to 18-year-old age groups were used, with the version for the 2 to 4-year-old age group being collected exclusively via observer reports. The third-party assessment was carried out by parents or carers. The study documents do not specify the reference period to which the questionnaire relates.
  • In the ASCEND-Peds study, an improvement in quality of life was observed at week 52 compared with baseline for the patient-reported version (5–18 years), both for the total score and for the domains of physical health and psychosocial health. For the parent-reported version (2–4 years), an improvement in quality of life was demonstrated in the Physical Health domain at week 52 compared with baseline.
  • However, due to the absence of a control group, no valid interpretation or assessment of the results for this endpoint can be derived. Overall, no conclusion regarding additional benefit can be drawn with regard to quality of life.
• Side effects
  • In the ASCEND-Peds study, adverse events (SUE) occurred in 5 out of 20 patients (25%). Severe adverse events were observed in 3 out of 20 patients (15%).
  • In the ASCEND-Peds study, no participant discontinued treatment due to AEs.
  • When considering the results on side effects as a whole, no conclusion can be drawn regarding the extent of the additional benefit due to the lack of a control group.
• Overall assessment
  • For the assessment of the additional benefit of olipudase alfa for children and adolescents with manifestations of acid sphingomyelinase deficiency (ASMD) outside the central nervous system (CNS) of type A/B or type B, the pharmaceutical manufacturer submitted the ASCEND-Peds study, a multicentre, single-arm Phase I/II trial forming the basis for marketing authorisation.
  • The ASCEND-Peds study provides data on mortality, morbidity, quality of life and side effects.
  • No control group is available for a comparative assessment in this evaluation.
  • No deaths occurred in the ASCEND-Peds study.
  • In the single-arm ASCEND-Peds study, an increase in age-adjusted height (z-score) was observed at week 52 compared with baseline in an intra-individual analysis. 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 the reference population of children of the same age in the general population.
  • 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 spleen rupture.
  • Administration of olipudase alfa resulted in a significant reduction in spleen volume at week 52 compared with baseline.
  • Overall, however, it is severe to interpret the significance of the data presented on height and spleen volume, as the data provided do not allow for a direct comparison with the natural course of the disease.
  • In the ASCEND-Peds study, endpoints were also collected to assess symptoms using the PedsQL Multidimensional Fatigue Scale and the PedsQL Paediatric Pain Questionnaire. Health-related quality of life was assessed using the PedsQL, a measurement tool suitable for the paediatric patient population. However, in the present evaluation, no valid conclusions can be drawn regarding these endpoints due to the lack of a control group and the open-label study design.
  • With regard to the results on side effects, some serious and severe adverse events occurred during treatment with olipudase alfa. No participant discontinued treatment due to AEs. As there is no comparison with a control group, no valid conclusions can be drawn.
  • Overall, olipudase alfa is found to provide a non-quantifiable added benefit for the treatment of children and adolescents with manifestations of acid sphingomyelinase (ASMD) outside the central nervous system (CNS) of type A/B or type B, as the scientific evidence does not permit quantification of the non-quantifiable additional benefit.

Courtesy translation only, please refer to the German original.