Pasireotid (1) – Signifor®

• Clinical trials
  • The assessment of the extent of the additional benefit of pasireotide is based on study B2305.
  • Study B2305 is a randomised, two-arm, blinded, Phase III study without a control group.
  • In the two study arms, pasireotide was tested at two different doses: 0.6 milligrams twice daily (1.2 mg daily dose, ‘1.2 mg group’) and 0.9 milligrams twice daily (1.8 mg daily dose, ‘1.8 mg group’).

adult patients with Cushing’s disease for whom surgery is not an option or in whom surgery has failed

• For adult patients with Cushing’s disease for whom surgical intervention is not an option or in whom surgical intervention has failed, there is a minor additional benefit.
• The G-BA classifies the extent of the additional benefit of pasireotide as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• In accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this constitutes a moderate improvement in treatment-related benefit that has not previously been achieved, as a reduction in non-serious symptoms of the disease (the ‘morbidity’ endpoint) is achieved.
• Due to the limited study duration, no data are available to demonstrate the sustainability of the effect or to permit an assessment of pasireotide for long-term use.
• However, a high proportion of patients do not respond, or do not respond sufficiently, to treatment with pasireotide (non-responders) or discontinue treatment due to adverse events.
• The occurrence of hyperglycaemia, diabetes mellitus and cardiac adverse events must be assessed critically.
• mortality
  • No deaths occurred in the B2305 study.
  • The endpoint ‘mean urinary free cortisol (mUFC)’ is not sufficiently validated as a surrogate for the patient-relevant endpoint ‘overall survival’.
  • No conclusions can be drawn regarding the extent of the additional benefit of pasireotide for the endpoint ‘overall survival’.
• Morbidity – mean free cortisol in urine
  • With regard to the endpoint ‘morbidity’, the G-BA assesses the extent of the additional benefit of pasireotide as minor.
  • This represents a moderate improvement in treatment-related benefit that has not previously been achieved, as a reduction in mUFC is achieved.
  • A sustained reduction in pathologically elevated serum cortisol levels, as measured by mUFC, is clinically relevant for patients.
  • Apart from the occurrence of adverse events, an unsatisfactory response to treatment was the most common reason for discontinuation of the study according to the intention-to-treat principle.
  • The study withdrawal rate was strikingly high.
  • Valid conclusions regarding the correlation between the clinical mUFC response (responders, reducers, non-responders) and the secondary morbidity parameters cannot be drawn on the basis of the available data.
• Morbidity – blood pressure, LDL cholesterol
  • The endpoints ‘blood pressure’ and ‘LDL cholesterol’ are surrogate endpoints that are not directly relevant to patients.
  • The validity of these patient-relevant endpoints in the present therapeutic indication is not proven.
  • Consequently, these endpoints cannot be used to assess the extent of the additional benefit of pasireotide.
• Morbidity – Body weight
  • With regard to the endpoint ‘body weight’, in Cushing’s disease the altered fat distribution characteristic of the condition and the reduction in muscle mass are of greater significance than absolute body weight.
  • However, the therapeutic relevance of the results for these endpoints can only be assessed to a limited extent, due to the fact that results for the respective endpoints are not available for all patients included in the analysis (59 and 57 patients, respectively), as well as due to the operationalisation of the respective endpoints.
• Morbidity – Depression
  • The endpoint ‘depression’ was assessed as a patient-reported outcome using a patient questionnaire (BDI (Beck Depression Inventory)-II test, maximum total score: 63 points).
  • The value reported after 6 months is on average 4.6 points (1.2 mg group) and 5.5 points (1.8 mg group) lower than the baseline value.
  • The clinical relevance of the reduction in BDI-II scores cannot be assessed due to the aforementioned limitations of study B2305.
  • The extent of the additional benefit for the endpoint ‘depression’ cannot therefore be assessed.
• quality of life
  • Data on the additional benefit with regard to quality of life for pasireotide are available from the CushingQoL (Quality-Of-Life) patient questionnaire, a new disease-specific quality-of-life questionnaire used for the first time in this study (maximum total score: 100 points).
  • The CushingQoL score reported at 6 months (data are available for 56 patients in each group) is on average 7.1 points (1.2 mg group) and 11.5 points (1.8 mg group), respectively, higher than the average baseline value of 41.6 and 40.5 points (data are available for 81 and 78 patients, respectively).
  • The clinical relevance of the difference in CushingQoL scores cannot be assessed due to the aforementioned limitations of study B2305 (in particular, the absence of a control group and the high dropout rate).
  • The available data are insufficient to assess the minimum value for a clinically relevant change.
  • The postulated minimum clinically relevant change of 10.1 points (Nelson, 2012) is based on the B2305 registration trial itself and is derived solely from the standard deviation of the patients’ measured values.
  • The extent of the additional benefit for the ‘quality of life’ endpoint cannot therefore be assessed.
• Side effects
  • The positive effects of pasireotide are offset by adverse events.
  • In the B2305 trial, 98.1 per cent of patients experienced at least one adverse event, and around a quarter of patients were affected by at least one serious adverse event.
  • 17.3 per cent of patients discontinued treatment with pasireotide due to adverse events.
  • The most common adverse events were gastrointestinal in nature, particularly diarrhoea and nausea, as well as hyperglycaemia and gallstones.
  • Given the increased risk of diabetes and cardiac complications associated with Cushing’s disease, or the presence of such comorbidities, the frequent occurrence of hyperglycaemia and diabetes mellitus (13 per cent and 7 per cent respectively) observed in the B2305 study as well as cardiac adverse events (QT prolongation in 3.7% and sinus bradycardia in 4.3% of patients) must be viewed critically.
  • The assessment of adverse events is limited due to the absence of a control group.

Courtesy translation only, please refer to the German original.