Osilodrostat (1) – Isturisa®

• Clinical trials
  • Study C2301 is a multicentre study comprising four phases and featuring a randomised withdrawal design.
  • Study C1201 is an open-label, single-arm, multicentre Phase II study involving 9 Japanese adults with Cushing’s syndrome.

Adult patients with endogenous Cushing’s syndrome

• mortality
  • No deaths occurred during the 8-week comparison of osilodrostat versus placebo in the randomised withdrawal period (RW period) of study C2301.
  • During the subsequent open-label treatment phase with osilodrostat, two patients died by week 48.
  • No deaths occurred up to week 12 in the randomised phase of study C2302.
  • For the endpoint category of mortality, no conclusion regarding additional benefit can be drawn on the basis of the study data presented.
• Morbidity – mean free cortisol in 24-hour urine (mUFC response)
  • In study C2301, for the endpoint of complete response – defined as mUFC ≤ ULN without therapy discontinuation during the open-label period – a statistically significant difference was observed at the end of the open-label period (week 34) in favour of osilodrostat compared with placebo (91.7% vs. 47.1%; RR = 1.9, 95% CI [1.35; 2.82]; p < 0.001).
  • At week 48, 66.4% of patients achieved a complete response (open-label treatment phase with osilodrostat).
  • In the randomised phase of the C2302 study, a statistically significant difference in favour of osilodrostat compared with placebo was observed for the endpoint of complete response, defined as mUFC ≤ ULN without therapy discontinuation by week 12 (77.1% vs. 8.0%; RR = 9.64, 95% CI [2.53; 36.73]; p < 0.0001).
  • The results of both studies suggest that treatment with osilodrostat brings cortisol levels within the normal range and stabilises pathologically altered cortisol levels.
• Quality of life – CushingQoL
  • The results of the CushingQoL cannot be taken into account for the 8-week comparison of osilodrostat versus placebo during the RW period of the C2301 study.
  • The results from the open-label treatment phase with osilodrostat show that the mean CushingQoL scores at week 48 had increased by approximately 14 points from the approximately 42 points recorded at the start of the study. Similar results are observed for the ‘Physical Problems’ and ‘Psychosocial Issues’ subscales. However, in the absence of a comparator arm, it is not possible to assess the effect.
  • In study C2302, the mean CushingQoL total scores at the start of the study were approximately 49 and 57 points, respectively. Following the 12-week treatment period, an improvement in quality of life was observed in both study arms (56 points in the osilodrostat arm and 66 points in the control arm). However, the differences in results between the treatment groups are not statistically significant. Similar changes were observed in the ‘Physical Problems’ and ‘Psychosocial Issues’ subscales.
  • No advantage or disadvantage resulting from treatment with osilodrostat could be identified with regard to mortality or disease-specific quality of life.
• Side effects
  • In the analysis of the uncontrolled data from study C2301, adverse events (AEs) that occurred during the randomised (RW) period whilst on placebo were not taken into account.
  • Both in the randomised phase (RW period) and in the open-label treatment phase of the C2301 study, the following common AEs (AEs of any severity with an incidence ≥ 10 %) occurred according to MedDRA SOC: Gastrointestinal disorders, general disorders and administration site conditions, infections and infestations, and investigations; however, no statistically significant differences were observed between the treatment groups during the randomised phase. Furthermore, endocrine disorders (SOC) occurred very frequently during the open-label treatment phase with osilodrostat.
  • In study C2302, the following AEs of any severity occurred more frequently in the osilodrostat arm: cardiac disorders (PT tachycardia, 7 events (14.6%) in the osilodrostat arm vs. no events in the control arm), endocrine disorders (in particular PT adrenal insufficiency: 7 (14.6%) vs. 0 events), gastrointestinal disorders (in particular PT diarrhoea: 10 (20.8%) vs. 0 events), General disorders and administration site conditions (in particular, PT asthenia: 11 (22.9%) vs. 0 events), musculoskeletal, connective tissue and bone disorders (in particular, PT arthralgia: 17 (35.4%) vs. 2 events (8.0%) and PT myalgia 11 (22.9%) vs. 1 event (4.0%)). These results show a statistically significant difference between the treatment groups, to the detriment of osilodrostat.
• Overall assessment
  • For the benefit assessment, the pivotal, multicentre C2301 study (using a randomised withdrawal design) and the multicentre C2302 study were available; these investigated the efficacy and safety of osilodrostat compared with placebo over 8 and 12weeks in patients with confirmed Cushing’s disease. In addition, data from the open-label treatment phase of study C2301 up to week 48 are available.
  • For the endpoint category of mortality, no conclusion regarding additional benefit can be drawn on the basis of the study data presented.
  • With regard to disease-specific quality of life (CushingQoL), no comprehensible analyses were available for the comparative data in study C2301. The results from the open-label treatment phase with osilodrostat show an improvement in quality of life at week 48 compared with the start of the study; however, in the absence of a comparator arm, it is not possible to assess the effect. In study C2302, an improvement in quality of life was observed in both study arms following the 12-week treatment period. However, the results do not differ in a statistically significant manner.
  • In the endpoint category of side effects, no statistically significant differences were observed between the treatment groups during the 8-week randomised period and up to the end of the open-label treatment phase with osilodrostat in study C2301. In study C2302, there were statistically significantly more AEs of all severity grades in the osilodrostat arm. With regard to severe and serious AEs, as well as AEs leading to discontinuation of treatment, there were no statistically significant differences between the treatment groups. In detail, among the AEs of particular interest in study C2302, there were statistically significantly more AEs associated with hypocortisolism.

Courtesy translation only, please refer to the German original.