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RWE Decision Alert

UK HTA Recommends KANUMA® in Pediatric Patients Based Partly on Comparative RWD

KANUMA® (sebelipase alfa), manufactured by Alexion Pharmaceuticals, underwent a recent appraisal by the United Kingdom (UK)’s National Institute for Health and Care Excellence (NICE) for the treatment of Wolman disease in children aged two years and under. After reviewing submitted data from two single arm, open label, multicenter trials and retrospective real-world data (RWD) as a comparator arm, the NICE committee concluded that KANUMA improves survival and disease-related outcomes in Wolman disease.
NICE Appraisal

KANUMA (sebelipase alfa), manufactured by Alexion Pharmaceuticals, was recently evaluated by the NICE and recommended as an option for long-term enzyme replacement therapy in Wolman disease for children two years and under. Wolman disease is a rare genetic condition in which there is a complete loss in lysosomal acid lipase (LAL) enzyme activity. The disease causes a build-up of fat in cells in the liver, heart, blood vessels, and digestive system. Without treatment, the child has no chance of survival. Kanuma serves as an enzyme replacement treatment alongside a restricted diet, allowing the patient to receive a hematopoietic stem cell transplant (HSCT).

Numerous clinical uncertainties surround HSCTs, particularly regarding HSCTs’ impact on KANUMA treatment, such as potential dosage reduction, timing of transplants, and the proportion of patients undergoing these procedures. The NICE committee and the External Assessment Group (EAG) identified these uncertainties as having significant implications for assessing the potential of KANUMA to improve the treatment pathway for Wolman disease patients and for evaluating its cost-effectiveness. Long-term data is limited due to the rare nature of Wolman disease. Alexion Pharmaceuticals provided all available data on UK patients treated for LAL deficiency, including patients who received HSCTs. This included comprehensive follow-up data from a retrospective natural history study spanning over ten years, a duration typically not anticipated in Highly Specialized Technology evaluations.

The NICE committee and EAG grounded their evaluation on clinical effectiveness data drawn from two single arm, open label, multicenter trials conducted by Alexion Pharmaceuticals, supported by the retrospective natural history study. The first clinical trial, a Phase II study, enrolled ten pediatric patients diagnosed at eight months or younger, with significant clinical concerns; its primary outcome was drug safety. The second trial, a Phase II/III study, enrolled nine participants diagnosed at two years or younger; the primary outcome was the proportion of individuals alive at 12 months of age. Lastly, the retrospective natural history study followed 35 pediatric patients diagnosed with Wolman disease from 1985 to 2012. Participants in this study either underwent an HSCT, had a liver transplant, or received no treatment. For the comparator arm, which focused on clinical management without KANUMA, the company utilized data from 21 pediatric patients who did not receive any treatment.

The company presented a naïve, unadjusted comparison of survival outcomes from the two clinical trials and the natural history study. The analysis of the Phase II trial revealed that 90% of participants treated with KANUMA were alive at 12 months, and 80% were alive at 24 months. In stark contrast, the natural history study showed that all pediatric patients who received no treatment died before reaching 12 months of age. While the committee agreed that the clinical trial evidence indicated an improvement in survival and in other disease-related outcomes, they also emphasized uncertainties about the long-term effectiveness of the treatment.

RWD was also used in the economic evaluation of KANUMA, specifically to assess the health-related quality of life (HRQoL). Alexion Pharmaceuticals referred to a retrospective cohort study by Demaret et al. in 2021, where HRQoL outcomes for five French patients with Wolman disease were reported utilizing the Pediatric Quality of Life Inventory questionnaire. The company’s analysis assumed that the HRQoL for individuals treated with KANUMA was the same as the age-matched general UK population. This assumption was also applied to those who received KANUMA followed by an HSCT. Both the NICE Committee and the EAG raised concerns about the potential overestimation of HRQoL in this analysis. The EAG particularly noted that the frequent infusions required for KANUMA treatment, similar to other enzyme replacement therapies, might affect the HRQoL. Consequently, the EAG requested a scenario analysis incorporating a 20% HRQoL reduction compared to the age-matched general UK population. Furthermore, the EAG conducted a survey comparing function and HRQoL in 15 children, both with and without Wolman disease, using the preferred EQ-5D tool. The results of this survey were employed to establish utility values in the final economic analysis.


While the NICE committee acknowledged the limited scope of the long-term data and the small-scale, non-comparative nature of the clinical trials for KANUMA, the evidence provided was considered adequate to recommend it for treating Wolman disease in patients aged two years and younger. The RWD, including the retrospective study and HRQoL assessment, were important in supporting the clinical trial data, particularly in providing a comparator to evaluate the treatment’s effectiveness in terms of survival and disease-related outcomes. This combination of clinical and real-world evidence supported NICE’s decision, leading to the approval of KANUMA as a viable enzyme replacement therapy option for this specific patient group.

Author: Rithvik Badinedi, Consultant, Market Access and Real-World Evidence


  1. Demaret, T., Lacaille, F., Wicker, C., Arnoux, J.-B., Bouchereau, J., Belloche, C., Gitiaux, C., Grevent, D., Broissand, C., Adjaoud, D., Abi Warde, M.-T., Plantaz, D., Bekri, S., de Lonlay, P., & Brassier, A. (2021). Sebelipase alfa enzyme replacement therapy in Wolman disease: A nationwide cohort with up to ten years of follow-up. Orphanet Journal of Rare Diseases, 16(1), 507.
  2. NICE, UK. (2024, January 10). Sebelipase alfa for treating Wolman disease | Guidance | NICE. NICE.
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