Lumasiran (1) – Oxlumo®

• Clinical trials
  • ILLUMINATE-A is a Phase III trial with a randomised, double-blind treatment phase designed to investigate the efficacy and safety of lumasiran in adults, adolescents and children (aged ≥ 6 years) with a documented diagnosis of primary hyperoxaluria type 1 (PH1). In the trial, a total of 39 adults and children were randomised in a 2:1 ratio to the treatment arms (lumasiran:placebo).
  • ILLUMINATE-B is a single-arm, open-label Phase III trial designed to investigate the efficacy, safety, pharmacodynamics and pharmacokinetics of lumasiran in children (< 6 years) with a documented diagnosis of PH1.

Children, adolescents and adults with primary hyperoxaluria type 1 (PH1)

• mortality
  • In the ILLUMINATE-A and ILLUMINATE-B studies, the number of deaths occurring during the course of the study was recorded as part of the safety monitoring. No deaths occurred in the studies.
  • No conclusions regarding the extent of the additional benefit can be drawn for the mortality category.
• Morbidity – urinary oxalate concentration
  • Urinary oxalate concentration is a clinically relevant parameter in this therapeutic indication, used in particular for diagnosis and treatment monitoring in patients with preserved renal function. Reducing the supersaturation of calcium oxalate in the urine is considered a therapeutic goal in order to reduce the risk of kidney damage.
  • The sometimes significantly elevated oxalate level in urine represents the first immediate manifestation of PH1 and, as a pathogenic factor, is responsible for the symptoms of the disease. However, the severity of symptoms in patients with PH1 varies from patient to patient. No valid data could be identified to show what effects a specific change in urinary oxalate concentration has on the symptoms experienced by individual patients or on the risk of kidney damage.
  • In the ILLUMINATE-A study, a statistically significant difference in favour of lumasiran compared with the control group was observed for the endpoint of oxalate concentration in 24-hour urine at months 3 to 6 compared with baseline.
  • In the ILLUMINATE-B study, the oxalate-to-creatinine ratio (mmol/mmol) was statistically significantly reduced at months 3 to 6 compared with baseline.
• Quality of life – Paediatric Quality of Life Inventory (PedsQL)
  • In the ILLUMINATE-A study, the PedsQL and the disease-specific PedsQL End-Stage Renal Disease (ESRD) module were used to assess health-related quality of life. In the ILLUMINATE-B study, this endpoint was not assessed.
  • The PedsQL 4.0 assesses general health-related quality of life in children and adolescents, whilst the disease-specific ESRD 3.0 module assesses health-related quality of life in chronic kidney disease.
  • There was no statistically significant difference between the study arms in the changes from baseline to month 6 in the PedsQL total score. Similarly, no significant differences were observed between the treatment arms in the individual domains of the PedsQL (not shown in the resolution).
  • The suitability of the PedsQL-ESRD module for the study population in question, which consists of patients with largely preserved renal function, remains unclear. Furthermore, only a total score for the module was calculated, which, according to the available literature, is not intended. The ‘PedsQL-ESRD module’ endpoint is not taken into account in the benefit assessment.
  • With regard to health-related quality of life, as measured using the PedsQL and KDQOL-36, no conclusions can be drawn from the data of the ILLUMINATE-A study regarding the extent of the additional benefit of lumasiran compared with the control group.
• Side effects
  • In the ILLUMINATE-A study, 22 out of 26 participants (84.6%) in the lumasiran arm and 9 out of 13 participants (69.2%) in the placebo arm experienced at least one AE during the 6-month double-blind treatment phase. No severe AEs or SAEs occurred in either study arm. In the lumasiran arm, one participant discontinued the study medication due to an AE.
  • In the ILLUMINATE-B study, all children experienced an AE during the study; however, no child experienced a severe AE or an AE that led to discontinuation of the study medication. One child experienced a SAE.
  • For AEs occurring in ≥ 10 % of participants in a study arm, the pharmaceutical manufacturer provides post-hoc calculated relative risks and associated p-values. As information on the possible adjustment of the stratification factor is lacking, the data in the resolution are presented in a purely descriptive manner.
  • In the system organ class ‘General disorders and administration site conditions’, an AE occurred in 11 subjects (42 %) in the lumasiran arm, but in no subjects in the placebo arm. Similarly, in the system organ classes ‘Psychiatric disorders’ and ‘Skin and subcutaneous tissue disorders’, ADRs occurred only in subjects in the Lumasiran arm.
  • Similarly, no conclusions regarding the extent of the additional benefit can be drawn from the results for the endpoint category ‘side effects’.
• Overall assessment / Conclusion
  • For the benefit assessment of lumasiran for the treatment of children, adolescents and adults with primary hyperoxaluria type 1, results from the 6-month randomised, double-blind and placebo-controlled treatment phase of the ILLUMINATE-A study and the results of the single-arm, uncontrolled ILLUMINATE-B study.
  • In the morbidity category, the ILLUMINATE-A, a statistically significant difference in favour of Lumasiran compared with the control group was observed for the endpoint of oxalate concentration in 24-hour urine compared with baseline; this is supported by a significant reduction in oxalate concentration in spontaneous urine compared with baseline in the ILLUMINATE-B.
  • The results on urinary oxalate concentration suggest that the pathologically altered accumulation of oxalate in the urine caused by the genetic defect is stabilised during treatment with Lumasiran. Urinary oxalate concentration is a clinically relevant parameter in this therapeutic indication, used for diagnosis and to guide treatment. However, no valid data could be identified to show what effects a specific change in urinary oxalate concentration has in patients with PH1 on their individual symptoms or on the risk of kidney damage.
  • In summary, no conclusions regarding the extent of the additional benefit can be drawn from the morbidity data.
  • In its overall assessment of the available results on patient-relevant endpoints, the G-BA classifies the extent of the additional benefit of lumasiran for the treatment of children, adolescents and adults with primary hyperoxaluria type 1, on the basis of the criteria in Section 5(8), sentence 1, 2 in conjunction with Section 5(7), first sentence, number 4 of the AM-NutzenV, as non-quantifiable, because the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.