Cerliponase alfa (2) – Brineura®

• Clinical trials
  • Study 190-201 was an open-label, single-arm Phase I/II trial divided into two phases: in the first phase, a dose escalation was carried out (initially 30, 100 or 300 mg of cerliponase alfa ICV every 2 weeks for at least 4 weeks each), whilst in the second phase, cerliponase alfa was administered at a stable dose of 300 mg ICV every 2 weeks for at least 48 weeks.
  • Since its marketing authorisation in 2017, data on individuals treated with cerliponase alfa have been collected within the DEM-CHILD registry.

Patients with neuronal ceroid lipofuscinosis (NCL) type 2, also known as tripeptidyl peptidase 1 (TPP1) deficiency

• For patients with neuronal ceroid lipofuscinosis (NCL) type 2, also known as tripeptidyl peptidase 1 (TPP1) deficiency, there is a hint of a major additional benefit.
• Overall, there is a hint of major additional benefit from cerliponase alfa compared with the natural course of the disease.
• mortality
  • No deaths were reported in studies 190-201/202 and 190-203.
  • For the indirect comparison of study 190-201/202 and the external control 190-901 NH3, the results for the 1:1 matching (2 criteria) are presented in the resolution. As no deaths occurred in the intervention study, it is not possible to calculate the hazard ratio adequately. However, a statistically significant difference in favour of the intervention—treatment with cerliponase alfa—is evident.
  • Forty-eight per cent of patients in the external control group died, whilst no deaths were observed in the DEM-CHILD-RX registry study.
  • Despite the uncertainties associated with the historical control presented, a comparison of the objective endpoint of overall survival between the intervention study and the historical control appears plausible given the deterministic and lethal course of the disease. Furthermore, given the magnitude of the observed difference and its consistency in the exploratory analysis, it is assumed that the possibility that the difference is due solely to systematic bias arising from the historical control can be ruled out.
• Morbidity – CLN-2 assessment scale: ML/HML scale
  • To assess disease progression, an HML scale (Hamburg Motor-Language Scale) – developed for neuronal ceroid lipofuscinosis type 2 (CLN2) – was adapted for the single-arm studies 190–201/190–202, in collaboration with the developers of the HML scale, in order, on the one hand, to establish objective reference points and, on the other, to clarify the distinctions between the categories.
  • At week 281, study 190-201/202 showed an average reduction in the ML scale score of 1.2 points.
  • In study 190-203, the ML scale showed an average reduction in score of 0.4 points up to week 145.
  • During the median treatment duration of 286 weeks, 52% of patients in study 190-201/202 experienced, at a median of 272 weeks, an irreversible loss of ≥ 2 points or an irreversible score of 0.
  • Statistically significant differences were observed in favour of treatment with cerliponase alfa.
  • An indirect comparison of Study 190-201/202 with the external control study 190-901 NH3 revealed a statistically significant difference in favour of treatment with cerliponase alfa.
  • In summary, in the morbidity category, there is a clear and consistent advantage of treatment with cerliponase alfa over the untreated control group with regard to motor skills and speech ability (measured using the M/L scale/ HML scale), which is not called into question by the aforementioned uncertainties associated with historical controls.
• quality of life
  • The assessment of general quality of life using the sufficiently validated ‘PedsQL 4.0 Generic Core Scales’ instrument is considered to be relevant to patients.
  • At week 193 of study 190-202 (corresponding to week 242 of the overall study 190–201/202), compared with baseline in study 190–201, an average reduction in the total score of 15.2 points was observed.
  • In summary, no conclusions can be drawn regarding the extent of the additional benefit for the quality of life category.
• Side effects
  • In studies 190-201/202 (N = 24) and 190-203 (N = 14), a descriptive analysis of safety endpoints was carried out for the safety population.
  • In both studies, adverse events (AEs) occurred in all subjects in the safety population; serious adverse events (SAEs) were reported in 86% of subjects in study 190-203 and in approximately 70% in study 190-201/202.
  • As the data are solely from single-arm, non-comparative studies, no conclusions regarding the extent of the additional benefit can be drawn for the category of side effects.
• Overall assessment / Conclusion
  • Despite the aforementioned uncertainties associated with the historical controls, taking these controls into account appears justified overall, given the very rare nature of the disease, the paediatric patient population and the deterministic course of the disease.
  • In the mortality category, there is a clear advantage of treatment with cerliponase alfa over the natural course of the disease. Given the magnitude and consistency of the observed difference, it is assumed that the possibility that the difference is due solely to systematic bias arising from the historical control can be ruled out.
  • Similarly, in the morbidity category, there is a clear and consistent advantage of treatment with cerliponase alfa compared with the untreated control group in terms of motor skills and speech ability (measured using the M/L scale/ HML scale), which is not called into question by the aforementioned uncertainties associated with historical controls.
  • No improvement in quality of life was observed with treatment with cerliponase alfa.
  • As no data on adverse events are available for the historical control cohort, a comparison with the current symptomatic treatment approach for neuronal ceroid lipofuscinosis type 2 remains impossible.
  • The advantages of treatment with cerliponase alfa compared with the natural course of the disease, in terms of the endpoints of overall survival and morbidity, are classified as having a major extent.
  • The G-BA therefore classifies the extent of the additional benefit of cerliponase alfa, based on the criteria in Section 5(7) of the AM-NutzenV and taking into account the severity of the disease and the therapeutic objective in the treatment of neuronal ceroidlipofuscinosis type 2.

Courtesy translation only, please refer to the German original.