Pasireotid (2) – Signifor®

• Clinical trials
  • To address the question regarding the extent of the additional benefit, the results of study C2404 – the main study on which the marketing authorisation is based – are available. This is a multicentre, randomised, three-arm Phase III trial to evaluate the efficacy and safety in adult patients with inadequately controlled acromegaly.
  • In addition, the results of study C2305 are taken into account. Study C2305 is a multicentre, randomised, two-arm, double-blind study designed to evaluate the efficacy and safety in adult patients with acromegaly who have not previously received treatment.

Treatment of adult patients with acromegaly in whom surgical treatment has been unsuccessful or is not an option, and who have not responded adequately to treatment with another somatostatin analogue

• Taking into account the available results on mortality, morbidity, quality of life and side effects, the G-BA classifies the extent of the additional benefit of pasireotide as minor, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the condition.
• mortality
  • No deaths were observed in the study.
  • With regard to mortality, no conclusion can be drawn regarding the extent of the additional benefit due to the short study duration.
  • Taking these aspects into account, it is not proven that the active ingredient pasireotide has a positive effect on mortality in the indication of acromegaly.
• Morbidity – Biochemical control
  • The primary endpoint of study C2402 was the proportion of patients achieving biochemical control, defined as a reduction in the mean GH level to below 2.5 μg/l and normalisation of the age- and sex-adjusted IGF-1 level after 24 weeks.
  • For this composite endpoint, a significant effect in favour of the intervention was observed, with 15 per cent of patients on the lower dose and 20 per cent on the higher dose of pasireotide achieving control, compared with 0 per cent in the control group.
  • The significant effect in favour of the intervention is also evident when the two components (GH and IGF-1) are considered individually.
  • These analyses each show a higher response rate among patients treated with the higher dose of pasireotide.
  • These findings are supported by the results from the C2305 study twelve months after crossover.
  • The G-BA considers the surrogate endpoint of biochemical control to be only of limited validity for the endpoint of mortality – which was not assessed in the study – due to methodological limitations.
  • Post-hoc analyses using this stricter threshold show a significant effect for pasireotide LAR 60 mg, but no significant effect for pasireotide LAR 40 mg.
  • During the commenting procedure, the pharmaceutical manufacturer submitted a further retrospective analysis of patients with acromegaly. This analysis is not suitable for use in validating the ‘biochemical control’ endpoint.
• Morbidity – Reduction in tumour volume
  • In patients with acromegaly, complete surgical removal of the tumour is the first-line treatment. The tumour’s space-occupying effects can lead to serious damage to surrounding brain structures. A reduction in tumour mass is therefore a surrogate parameter for preventing such damage.
  • A reduction of 25 % was selected as the cut-off value for defining a response within the study. The validity of the threshold value of >25 % reduction in tumour mass is unclear and its clinical relevance is questionable.
  • In study C2402, the proportion of patients with at least a 25% reduction in tumour volume was higher in the pasireotide groups than in the control group. The difference was statistically significant (in a one-sided test), but with a wide confidence interval.
• Morbidity – symptoms of acromegaly
  • Patient-relevant symptoms – headache, fatigue, sweating, paraesthesia and osteoarthralgia – were assessed by patients on a 5-point scale.
  • Due to the lack of blinding, a high potential for bias must be assumed for these endpoints, particularly in the case of subjective endpoints.
  • There was no significant difference in the symptoms of fatigue, sweating, paraesthesia, osteoarthralgia and ring size.
  • With regard to changes in headache symptoms, there was a statistically significant effect in favour of the intervention groups (pasireotide LAR 40 mg: –0.7 ± 1.1 points; pasireotide LAR 60 mg: –0.5 ± 1.0 points; control group 0.0 ± 1.2 points; P < 0.05). However, the clinical relevance of this difference (less than 1 point on a 5-point scale) is unclear, as there is a lack of evidence regarding both validity and the minimum clinically important difference (MID).
• Health-related quality of life
  • Health-related quality of life is a patient-relevant endpoint. Quality of life was assessed using the disease-specific Acromegaly Quality of Life (AcroQoL) questionnaire.
  • Due to the lack of blinding, a high potential for bias must be assumed for this endpoint.
  • There were no significant differences between the treatment groups in terms of quality of life as assessed by the AcroQoL.
  • Symptoms improved slightly in all treatment groups over time. On individual scales of the AcroQoL, there were statistically significant improvements over time in the patient groups treated with pasireotide, but not in the control group.
  • The results on quality of life do not allow any conclusions to be drawn regarding an improvement in treatment-related benefit.
• Side effects
  • The desired effects of pasireotide are offset by adverse events (AEs).
  • In particular, hyperglycaemia was more common in patients treated with pasireotide than in the control groups: 33.3% and 30.6% of patients treated with 40 mg and 60 mg pasireotide, respectively, compared with 13.6% in the control group.
  • Overall, 36% of patients in the pasireotide group started antidiabetic therapy (usually with oral antidiabetics) during the study, compared with 4.4% in the octreotide group.
  • Study discontinuations due to the study medication were rare (5% and 7% for pasireotide LAR 40 mg and 60 mg, respectively, in C2402), but occurred more frequently in the pasireotide groups than in the control group (0%).
  • There were no deaths in study C2402; in study C2305, there were four deaths (myocardial infarction, septic shock, suicide, aortic aneurysm), two each in the intervention and control groups, which, in the opinion of the investigators and the EMA, were not related to the study medication.
  • The incidence of hyperglycaemia and diabetes was higher in the pasireotide groups than in the control group. However, patients in the control group had been receiving their medication in accordance with the inclusion criteria for at least six months prior to the start of the study, meaning that habituation to the drug or a selection of patients who are more likely to tolerate it is possible.

Courtesy translation only, please refer to the German original.