Cerliponase alfa (1) – Brineura®

• Clinical trials
  • The pivotal study 190-201 is a first-in-human Phase 1/2 trial – a multicentre, open-label, single-arm intervention study divided into two phases.
  • Study 190-202 is an ongoing, multicentre, open-label, single-arm extension study of study 190-201, which is expected to end in December 2020 (study duration 239 weeks).
  • The results of the uncontrolled registration trials 190-201/190-202 were compared with a historical control group of untreated patients.

Patients with type 2 neuronal ceroid lipofuscinosis (NCL)

• For patients with type 2 neuronal ceroid lipofuscinosis (NCL), there is a non-quantifiable additional benefit.
• In summary, the G-BA recognises an additional benefit of cerliponase alfa on the basis of the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective; however, the extent of this additional benefit cannot be quantified.
• mortality
  • No patients died in study 190-201.
  • The updated analysis of the natural course of the disease based on the DEM-CHILD dataset (190-901) does not contain any data on overall survival.
• Morbidity – M/L scale / HML scale
  • Responder analysis: The proportion of patients in whom the decline, scaled over 48 weeks, was less than two was 100% (n=22/22) among patients treated with cerliponase alfa, compared with 45 per cent (n=10/22) of patients in the historical control group. The difference is statistically significant in favour of treatment with cerliponase alfa (p=0.0009).
  • Slope analysis: The ML/HML score, scaled to 48 weeks, fell by an average of 2.0 points in patients in study 190-901, compared with 0.34 points in patients in study 190-201/202, corresponding to a difference of 1.66 points (p<0.0001), scaled to 48 weeks.
  • Time-to-event analysis: The hazard ratio (HR) was 0.10 ([95% CI 0.03; 0.38], p=0.0005) for an observation period of up to 72 weeks. This results in a relative risk reduction of 90% in disease progression, as measured by the linearly estimated decline on the ML scale, for patients receiving cerliponase alfa compared with patients in the historical control group.
  • The median time to disease progression was 285 days (95% CI: 210; 420) in the historical control group, whilst the median has not yet been reached in the treated patients.
  • Consequently, given the magnitude and consistency of the observed differences in changes on the M/L scale and HML scale, treatment with cerliponase alfa demonstrates an exceptionally pronounced effect compared with the untreated control group, which is not called into question by the uncertainties mentioned.
• Morbidity – Further morbidity data from study 201/202
  • At both week 48 and week 80, the responder rate remained unchanged at 87%.
• Health-related quality of life – PedsQL
  • For study 190-201, the PedsQL data in the ITT population (N=23) showed an average improvement in the total score of 2.6 points from the study baseline to the final observation in the study (week 49).
  • Only in the ‘Physical Competence’ dimension was a deterioration observed at the end of the study compared with baseline values (by an average of 6.1 points).
  • In the extension study 190-202, a deterioration was observed in all dimensions compared with the baseline values from the main study (week 98). The total score fell by an average of 14.1 points, whilst physical competence declined by an average of 27.9 points by week 98.
• Side effects
  • No comparative data on side effects are available for the benefit assessment.
  • Information on long-term effects is available up to the data cut-off date of 3 June 2016, with a median treatment duration of 95 weeks. There were no discontinuations due to AEs and no deaths in the study. A total of 51 SUEs were recorded in 79% of patients, and AEs of NCI-CTCAE grade 3 or higher were recorded in 54% of patients.
  • The most common (> 20%) side effects observed included fever, reduced CSF protein, ECG abnormalities, vomiting, upper respiratory tract infections and hypersensitivity reactions.
• Overall assessment
  • Taking the historical control into account appears justified overall, given the very rare nature of the disease, the paediatric patient population and the deterministic course of the disease.
  • The results of the historical control show statistically significant effects in favour of cerliponase alfa in the morbidity category for the ML scale analyses, with regard to the preservation of patient-relevant motor and speech abilities, which are exceptionally pronounced. However, the aforementioned uncertainties regarding the historical comparison cohort and the primary endpoint remain. However, it can be virtually ruled out that a bias caused by these uncertainties alone is solely responsible for the large differences observed in the changes on the ML/HML scale in favour of cerliponase alfa.
  • No comparable data are available for the categories of quality of life and side effects. No improvement in quality of life was observed during treatment with cerliponase alfa. In this condition, where therapeutic success is defined by the absence or slowing of disease progression, it cannot necessarily be assumed that patients’ quality of life will improve.
  • As no data on adverse events are available for the historical control cohort, a comparison with the previous symptomatic treatment approach for type 2 neuronal ceroid lipofuscinosis is not possible. From the perspective of a comparative benefit assessment, the adverse effect profile cannot be reliably assessed given the lack of comparative data and the short observation period of the 190-201/202 study, which is brief for a therapy being tested in humans for the first time. Further long-term data are required to assess the side effects.
  • Due to the uncertainties mentioned, it is not possible to reliably assess the extent of the additional benefit of cerliponase alfa.
• Conclusion
  • The uncertainties associated with this historical control and the limited validation of the assessment tool must be taken into account. At the same time, due to a lack of comparative data or data that can only be assessed to a limited extent regarding quality of life and the safety profile of cerliponase alfa, there are relevant uncertainties that do not allow for a conclusive assessment of the extent of the treatment-related benefit of cerliponase alfa based on the currently available scientific data.

Courtesy translation only, please refer to the German original.