Sebelipase alfa (1) – Kanuma®

• Clinical trials
  • The LAL-CL03 study is an uncontrolled trial with a treatment phase of up to 4 years involving sebelipase alfa, in which 9 infants with LAL deficiency and failure to thrive (known as Wolman’s disease) were studied.
  • The second registration study, the LAL-1-NH01 study, is a retrospective observational study designed to characterise survival and the key aspects of the clinical course of LAL deficiency/Wolman phenotype (N=25).
  • To demonstrate the efficacy and safety of sebelipase alfa for patients with LAL deficiency (not rapidly progressive in infancy (<6 months)), the results of the randomised, placebo-controlled LAL-CL02 study (ARISE; N = 66) are available; the study duration was 20 weeks and the median patient age was 16.8 years at the time of informed consent.

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

• In summary, the extent of the additional benefit of sebelipase alfa for patients with rapidly progressive LAL deficiency already present in infancy (<6 months) is assessed as follows: For patients with rapidly progressive LAL deficiency already present in infancy (< 6 months), there is a non-quantifiable additional benefit.
• Due to the methodological limitations of the study and the historical control, as well as the overall limited evidence base, the G-BA classifies the extent of the additional benefit for sebelipase alfa, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the condition is non-quantifiable.
• mortality
  • Experience to date shows that infants with Wolman disease die at a median age of 3.7 months.
  • In the LAL-CL03 study, of the 9 patients, at the time of the written statement (data cut-off 31 December 2015), 3 patients had died before the age of 12 months and a further patient before the age of 24 months. Five of the nine patients had survived for more than 24 months at the time of the data cut-off.
  • Given the differences in survival duration between the LAL-CL03 study and the historical control, an overall additional benefit of sebelipase alfa can be inferred. Owing to the uncertainties already discussed regarding the availability of a historical control, the results do not permit a quantitative assessment of the positive effects in terms of the extent of the additional benefit.
• morbidity
  • It is evident that age-adjusted weight (relative to the respective published percentiles) increases steadily over the course of treatment. Although relative weight gain is an important parameter in cases of failure to thrive in infants and young children, its significance in the present context cannot be conclusively assessed in view of the aforementioned confounding factors and the lack of comparative data from the control cohort.
• quality of life
  • No data on quality of life are available for the LAL-CL03 study. It is therefore not possible to draw conclusions regarding the extent of the additional benefit for this endpoint.
• Side effects
  • Data on serious adverse events are available for a large proportion of the LAL-CL03 study population; these are predominantly gastrointestinal side effects, infections and reactions at the site of administration.
  • The infusion-related events and the hypersensitivity reactions described in the summary of product characteristics (SmPC) are clearly attributable to treatment with sebelipase alfa. These side effects appear generally tolerable given the severity of the disease.
  • As there is no control group, it is severe to interpret the significance of the adverse events. Overall, no conclusion can be drawn regarding the extent of the additional benefit.
• Conclusion
  • In the present case scenario and indication, the results on overall mortality—which demonstrate an additional benefit for sebelipase alfa—are particularly relevant to the decision-making process.
  • Assuming that the natural course of the disease in patients with rapidly progressive LAL deficiency already present in infancy (< 6 months), is associated with a high mortality rate – partly due to the lack of adequate treatment options to date – it is considered appropriate, despite the uncertainties associated with a historical control and single-arm studies, to use the study results on overall mortality to determine the additional benefit.
  • Due to the methodological limitations of the study and the historical control, as well as the generally limited evidence base, the G-BA classifies the extent of the additional benefit for sebelipase alfa, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease, is non-quantifiable.

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

• In summary, the extent of the additional benefit of sebelipase alfa for patients with LAL deficiency (not already rapidly progressive in infancy (< 6 months)) is assessed as follows: For patients with LAL deficiency (not rapidly progressive in infancy (<6 months)), there is a non-quantifiable additional benefit.
• Taking the results as a whole, the G-BA classifies the extent of the additional benefit of sebelipase alfa for patients with LAL deficiency (not already rapidly progressive in infancy (<6 months)) as non-quantifiable, because the available scientific evidence does not currently permit a quantifiable assessment of the extent of the additional benefit for patient-relevant endpoints.
• mortality
  • No deaths occurred in the study. With regard to mortality, no conclusion regarding the extent of the additional benefit can be drawn from the available results.
• Morbidity – low-density lipoprotein cholesterol (LDL-C) concentration
  • For the endpoint of low-density lipoprotein cholesterol (LDL-C) concentration, the sebelipase alfa group showed a statistically significant reduction over the course of the study (28.4% compared with 6.2%, in each case relative to the baseline value; p < 0.001). In this therapeutic indication, LDL-C concentration is a surrogate parameter of unclear validity.
• Morbidity – Alanine aminotransferase (ALT) normalisation
  • A reduction in ALT concentration was observed in the group of patients treated with sebelipase alfa. Elevated ALT levels are generally regarded as a sign of liver damage; however, ALT normalisation has not been validated as a surrogate marker for morbidity and mortality in patients with LAL deficiency.
• Morbidity – Daytime fatigue
  • Daytime fatigue was assessed using the FACIT Fatigue Questionnaire. Fatigue can generally be regarded as a patient-relevant endpoint.
  • Regardless of this, there were no significant differences in the results between the sebelipase alfa and placebo groups, either at the start of treatment or at the end of the study.
• quality of life
  • For the LAL-CL03 study, quality of life data are available from both the Chronic Liver Disease Questionnaire (CLDQ) and the Paediatric Quality of Life Inventory (PedsQL). Both questionnaires are, in principle, validated for various conditions, but not for LAL deficiency.
  • No significant differences were observed for either questionnaire.
  • With regard to quality of life, no conclusions can be drawn from the available results regarding the extent of the additional benefit.
• Side effects
  • The number of side effects observed in the study did not differ significantly between the treatment groups: 3 severe adverse events (AEs) occurred in the sebelipase alfa group and only 1 in the placebo group.
  • For AEs classified according to the Medical Dictionary for Regulatory Activities (MedRA), no significant differences were observed, although some results were contradictory.
• Conclusion
  • Taking the results as a whole, the G-BA, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, classifies the extent of the additional benefit of sebelipase alfa for patients with LAL deficiency (not rapidly progressive in infancy (<6 months)) as non-quantifiable, because the available scientific data do not currently permit a quantifiable assessment of the extent of the additional benefit for patient-relevant endpoints.

Courtesy translation only, please refer to the German original.