Alipogentiparvovec (1) – Glybera®

• Clinical trials
  • To address the question regarding the extent of the additional benefit, the results of three non-randomised, non-controlled intervention studies – CT-AMT-010-01 (using the predecessor preparation CT-AMT-010), CT-AMT-011-01 and CT-AMT-011-02, as well as two retrospective data review studies, CT-AMT-011-03 (patients from PREP-02 [a pilot study for CT-AMT-011-01], CT-AMT-011-01 and CT-AMT-011-02) and CT-AMT-011-05 (patients from CT-AMT-010-01, PREP-02, CT-AMT-011-01 and CT-AMT-011-02).

Treatment of familial lipoprotein lipase deficiency

• The G-BA assesses the extent of the additional benefit of alipogentiparvovec, which is to be recognised solely from a legal perspective under Section 35a(1), sentence 10, first half-clause, 1 SGB V, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition and the therapeutic objective in treating the condition, as a non-quantifiable additional benefit.
• An additional benefit exists in accordance with Section 35a(1), sentence 10, first half-clause, of SGB V, but is non-quantifiable because the scientific evidence does not permit this.
• In the present case and for this indication, the limited and inconclusive evidence base is particularly relevant to the decision, meaning that a valid assessment of the results to quantify the additional benefit is not possible.
• Consequently, a quantitative assessment of the extent of the effect and a quantification of the additional benefit into one of the categories ‘minor’, ‘considerable’ or ‘major’ is not possible on the basis of the data submitted.
• mortality
  • Mortality was not recorded in the data reviews.
• Morbidity – pancreatitis and abdominal pain
  • In the intervention studies, pancreatitis and abdominal pain were recorded as adverse events (in both outpatients and inpatients).
  • In the retrospective data reviews, data on pancreatitis and abdominal pain in patients included in the intervention and preparatory studies were collected, analysed and compared before and after administration of the study medication.
  • For the data reviews, a blinded panel of experts assessed pancreatitis and abdominal pain events against the revised Atlanta criteria and, based on hospital records, identified severe pancreatitis and multiple episodes of pancreatitis, defined as at least two episodes of pancreatitis of any severity.
  • Only episodes of pancreatitis and abdominal pain associated with hospitalisation were recorded; events occurring in an outpatient setting were not considered.
  • However, the maximum follow-up period of 5 years, the exclusion of outpatient events and the exclusion of events reported to the pharmacovigilance programme for Glybera® after the data cut-off date of the CT-AMT-011-05 are insufficient to support a valid before-and-after comparison of a reduction in pancreatitis.
  • Nor can a partial prevention of pancreatitis as a result of improved dietary compliance among the study patients concerned be ruled out.
  • In the G-BA’s assessment, it therefore remains unclear whether treatment with Glybera® leads to a reduction in the incidence of pancreatitis.
  • It should also be noted that pancreatitis occurs very irregularly.
  • In the European Public Assessment Report (EPAR), the EMA therefore calls for a follow-up period of 15 years for each patient treated.
  • Furthermore, the EMA also points to the lack of evidence for a sustained reduction in triglyceride levels, which was the primary endpoint originally selected for the intervention studies.
  • Nor could the data on the reduction in postprandial chylomicron levels be classified as valid.
  • Taken together, the data on morbidity are not sufficient to draw any conclusions regarding the extent of the additional benefit.
• quality of life
  • Quality of life was assessed for patients in the CT-AMT-011-02 study using the generic Short Form-36 (SF-36) questionnaire.
  • This corresponds to data for only 5 study participants at week 14 and for 3 study participants at week 52.
  • No further assessments of quality of life are available.
  • Valid data cannot be provided due to the incomplete data collection.
  • Consequently, no conclusions can be drawn regarding the extent of the additional benefit in terms of quality of life.
• Side effects
  • A proper before-and-after comparison of side effects is lacking.
  • Of particular note are the adverse events at the application sites, some of which are long-term.
  • Taken together, no conclusions regarding the extent of the additional benefit can be drawn with regard to side effects based on the available results.
• Overall assessment
  • In its overall assessment of the available results, the G-BA arrives at the following evaluation of the extent of the additional benefit: an additional benefit exists in accordance with Section 35a(1), sentence 10, first half-clause, 1 of SGB V, but it is non-quantifiable because the available scientific evidence does not currently permit a quantifiable statement on the extent of the additional benefit for patient-relevant endpoints.

Courtesy translation only, please refer to the German original.