Sebelipase alfa (2) – Kanuma®

• Clinical trials
  • The LAL-CL03 study is an open-label, multicentre, single-arm Phase II/III dose-escalation study in which 9 infants with growth failure due to LAL deficiency were enrolled and treated with sebelipase alfa for up to 5 years.
  • The LAL-CL08 study is an open-label, multicentre, single-arm Phase II study with a treatment period of up to 3 years with sebelipase alfa, in which 10 children with rapidly progressive LAL deficiency (aged ≤ 8 months at the start of sebelipase dosing).
  • The LAL-CL02 (ARISE) is a multicentre, randomised, double-blind, placebo-controlled Phase III study lasting 20 weeks, designed to assess the efficacy and safety of sebelipase alfa in children and adults with LAL deficiency.
  • The LAL-CL06 study is a multicentre, single-arm, open-label Phase II study primarily designed to investigate the safety of sebelipase alfa in paediatric and adult patients with LAL deficiency over a treatment duration of up to 144 weeks.

a) Patients with rapidly progressive LAL deficiency already present in infancy (< 6 months)

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• On balance, despite the methodological shortcomings described above, an advantage in overall survival – and thus an additional benefit – can be inferred in light of the high mortality rate among untreated infants with rapidly progressive LAL deficiency, as well as the extent of the effect.
• The additional benefit of sebelipase alfa is therefore classified as non-quantifiable, as the scientific evidence does not permit quantification.
• mortality
  • The natural history study LAL-1-NH01 shows a high overall mortality rate among untreated infants with rapidly progressive disease.
  • Of the 25 infants with Wolman-type LAL deficiency included in the study who were not required to meet the criterion of early growth failure (study cohort 2), only one survived beyond 12 months of age.
  • In the LAL-CL03 study, 6 out of 9 patients survived to 12 months of age, and in the LAL-CL08 study, 9 out of 10 patients survived to 12 months of age.
  • Comparisons of the intervention studies with the historical control group showed a very clear, statistically significant survival benefit for infants treated with sebelipase alfa compared with the historical control group.
• Morbidity – Anthropometric parameters: weight, weight-for-length, body mass index
  • In both single-arm studies, an increase in age-adjusted weight, weight relative to height/length and age-adjusted BMI was observed in intra-individual comparisons with baseline.
  • Whilst the baseline values predominantly suggest, particularly in the LAL-CL08 study, that the children’s physical development was below average compared with the general population, by the end of the studies the anthropometric values were within the range of children of the same age in the general population.
  • However, it is severe to interpret the significance of the data presented, as the disease is generally fatal if left untreated, and it is therefore not possible to assess the course of the disease in comparison with its natural progression in the present patient population.
• Morbidity – Denver II Developmental Test
  • The Denver II Developmental Test was administered to infants with rapidly progressive LAL deficiency in both intervention studies.
  • No suitable baseline data are available due to the minor response rate.
  • At the last available observation point, the children who survived in the LAL-CL03 study showed no abnormalities in the various domains of the Denver II Developmental Test compared with the general population, whereas in the LAL-CL08 study, 3 out of 5 children showed abnormalities based on the total score.
  • However, given the unclear validity of the measurement instrument, the data presented can only be assessed to a limited extent, as the disease is usually fatal if left untreated, and it is therefore not possible to make a comparison with the natural course of the disease in the present patient population.
• quality of life
  • No data on quality of life are available.
• Side effects
  • For infants with rapidly progressive LAL deficiency, the summary data on severe adverse events (AEs), severe AEs and AEs leading to discontinuation of study medication are taken from the LAL-CL03 and LAL-CL08 studies, as well as the ALX-LALD-501 patient registry.
  • However, as there is no control group due to the high mortality rate among untreated patients, it is severe to interpret the significance of the results.
  • Overall, no conclusion can be drawn regarding the extent of the additional benefit.
• Overall assessment
  • For patients with rapidly progressive LAL deficiency already present in infancy (< 6 months), data are available from two single-arm intervention studies (LAL-CL03 (VITAL), LAL-CL08), a patient registry (ALX-LALD-501) and a historical control study (LAL-1-NH01).
  • With regard to overall survival, sebelipase alfa demonstrated an advantage compared with the natural course of the disease.
  • With regard to morbidity and side effects, it is not possible to assess the additional benefit of sebelipase alfa, as suitable comparative data cannot be collected due to the usually fatal course of the disease in untreated patients.
  • However, the data on anthropometric parameters and the Denver II Developmental Test, when compared with the age-adjusted standard population, suggest that, with treatment with sebelipase alfa, at least some of the children may develop normally.
  • No data on quality of life are available.
  • There is additional benefit; however, the actual magnitude of the difference between patients treated with sebelipase alfa and those who are untreated cannot be determined from the data provided.
  • The additional benefit of sebelipase alfa is therefore classified as non-quantifiable, as the scientific evidence does not permit this.

b) Patients with LAL deficiency (not rapidly progressive in infancy (<6 months))

• There is a hint of a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• In its overall assessment of these results relating to patient-relevant endpoints, the G-BA classifies the extent of the additional benefit of sebelipase alfa in the treatment of patients with LAL deficiency (not already rapidly progressive in infancy (<6 months)), as non-quantifiable on the basis of the criteria set out in Section 5(8), sentences 1 and 2, in conjunction with Section 5(7), sentence 1, number 4 of the AM-NutzenV, because the scientific evidence does not permit quantification.
• mortality
  • In the LAL-CL02 and LAL-CL06 studies, deaths were recorded as safety endpoints.
  • No deaths occurred during the study period.
  • Given that the randomised comparison from the LAL-CL02 study is only available for 20 weeks, a definitive assessment of long-term mortality is not possible.
• Morbidity – Anthropometric parameters: age-adjusted weight, body mass index (BMI)
  • The anthropometric parameters age-adjusted weight and BMI (percentiles) were assessed in the LAL-CL06 study in patients aged ≤ 18 years.
  • With regard to the anthropometric parameters, only minor increases in age-adjusted weight and age-adjusted BMI were observed in the intra-individual comparison in the single-arm LAL-CL06 study.
  • However, due to the uncontrolled study design, it is not possible to assess the additional benefit on the basis of the data presented.
• Morbidity – daytime tiredness (fatigue)
  • Daytime fatigue was assessed in the LAL-CL02 and LAL-CL06 studies using the FACIT Fatigue questionnaire.
  • The results from the double-blind phase of the LAL-CL02 study for the total score or the individual domains did not differ significantly between the sebelipase alfa and placebo groups, either at the start of treatment or at the end of the study.
  • For the LAL-CL06 study, the response rates were too minor for the data to be included in the benefit assessment.
• Morbidity – Denver II Developmental Test
  • The Denver II Developmental Test was administered in the LAL-CL06 study to children aged ≤ 6 years.
  • At week 96, the total score for all children (n = 6) was within the range of demographic normal values.
  • It is particularly severe to interpret these data given the absence of a control group.
• Quality of life – Paediatric Quality of Life Inventory (PedsQL)
  • The PedsQL measures general health-related quality of life in children and adolescents with chronic conditions and was used in the LAL-CL02 and LAL-CL06 studies among participants aged between 5 and ≤ 18 years.
  • For the double-blind phase of the LAL-CL02 study, there were no statistically significant differences across the various domains – including the total score – between patients treated with sebelipase alfa and those receiving placebo.
  • Due to the uncontrolled design of the open-label phase of the LAL-CL02 and LAL-CL06 studies, no conclusions can be drawn regarding the additional benefit of sebelipase alfa.
• Quality of life – Chronic Liver Disease Questionnaire (CLDQ)
  • The CLDQ is a disease-specific instrument for assessing health-related quality of life in adult patients with chronic liver disease.
  • For the present benefit assessment, data on the CLDQ questionnaire with sufficient response rates are available from the LAL-CL02 study involving patients aged 17 years and over.
  • In the double-blind phase, there was no significant difference between the treatment arms (sebelipase alfa vs placebo) for the total score or the domains at week 20.
• Side effects
  • For individuals with non-rapidly progressive LAL deficiency in infancy, data on side effects are available from the LAL-CL02 and LAL-CL06 studies, as well as the ALX-LALD-501 patient registry.
  • Overall, only a few adverse events (AEs) were reported.
  • In the LAL-CL02 study, no statistically significant differences were observed between the treatment arms during the 20-week double-blind phase for the composite of severe AEs, serious AEs and AEs leading to therapy discontinuation.
  • Overall, the available data do not suggest either an advantage or a disadvantage of sebelipase alfa compared with placebo in the ‘side effects’ category.
• Overall assessment
  • For patients with LAL deficiency (not rapidly progressive in infancy (< 6 months)), data are available from the LAL-CL02 and LAL-CL06 studies, as well as the ALX-LALD-501 patient registry.
  • Based on the data from the single-arm study LAL-CL06 and the open-label phase of LAL-CL02, no conclusions regarding additional benefit can be drawn due to the high potential for bias in single-arm studies and the lack of a control group.
  • The results relating to patient-relevant endpoints from the double-blind, controlled phase of the LAL-CL02 study at week 20 are therefore of primary relevance to decision-making.
  • With regard to overall survival, neither an advantage nor a disadvantage can be identified from treatment with sebelipase alfa compared with placebo.
  • For the morbidity endpoint category, results are available for the endpoint ‘fatigue’. No statistically significant difference was observed between sebelipase alfa and placebo.
  • No benefits or disadvantages can be inferred with regard to health-related quality of life.
  • Similarly, no statistically significant differences between sebelipase alfa and placebo were found in the ‘side effects’ endpoint category.

Courtesy translation only, please refer to the German original.