Between 7 January and 26 July 2013, 19 patients were enrolled: four in the follow-up cohort (starting dose: 4 mg/day, n = 1; 20 mg/day, n = 3) and 15 in the expansion cohort (starting dose: 4 mg/day, n = 9; 10 mg/day, n = 6; Table 1). Seventeen patients (89.5 %) completed the 22-week treatment period. One patient discontinued at the end of the 22-week treatment period, and 16 patients entered the optional extension phase.
Response to osilodrostat
After 10 weeks of osilodrostat treatment, 84.2 % (n/N = 16/19) of patients were controlled and 5.3 % (n/N = 1/19) were partially controlled (Table 2); overall response rate was 89.5 % (n/N = 17/19). Two patients discontinued during the first 10 weeks, one because of a non-treatment-related administrative issue and one because of an adverse event (AE; grade 3 papular rash); see Supplementary Appendix for more details. At week 22, the overall response rate was 78.9 % (n/N = 15/19; Table 2); all responders were controlled responders. The details of the two patients who were responders at week 10 but not at week 22 are described in the Supplementary Appendix; one of these patients might have experienced an ‘escape’ from response.
Effect of osilodrostat on cortisol levels
UFC levels decreased in all patients and were within the normal range in 15/17 patients (88.2 %) who reached week 22 (Fig. 2); decreases in the remaining two patients were 48.6 and 47.4 %. Overall mean UFC levels decreased rapidly from baseline (1371 ± 2734 nmol/24 h) to within the normal range by week 4 and remained suppressed through to week 22 (92 ± 124 nmol/24 h; Fig. 3); the decrease from baseline to week 22 was from 398 ± 176 to 98 ± 92 nmol/24 h in the follow-up cohort and from 1630 ± 3043 to 90 ± 136 nmol/24 h in the expansion cohort.
Changes in mean morning serum and salivary cortisol levels generally followed those of UFC, rapidly decreasing to within the normal range and remaining so until week 22 (Fig. 3). There was no change (from 10 ± 5 at baseline to 10 ± 11 nmol/L at week 22) in morning salivary cortisol levels in the follow-up cohort (levels were already within the normal range at baseline), while levels decreased from 28 ± 46 to 4 ± 3 nmol/L in the expansion cohort; the change for the overall population was from 24 ± 41 nmol/L at baseline to 5 ± 6 nmol/L at week 22. Late-night salivary cortisol levels also decreased, although the changes were more variable and measured levels remained above normal throughout treatment (Fig. 3). Of the 17 patients who completed the study: baseline serum cortisol levels were >ULN in 11 patients and, by week 22, levels had normalized in eight, remained >ULN in two, and fell to <LLN in one patient; baseline morning salivary cortisol levels were ≥ULN in five patients and, by week 22, had normalized in four patients and remained >ULN in one; baseline late-night salivary cortisol levels were >ULN in all 17 patients and, by week 22, had normalized in seven and remained >ULN in 10 patients.
Effect of osilodrostat on other hormone levels
Mean baseline ACTH levels in the overall population were >ULN (20.2 pmol/L; normal range 1.8–9.2) and increased four-fold at week 22 (Fig. 4; Supplementary Table 1). The increase in ACTH was greater in the expansion than in the follow-up cohort (Supplementary Figure 1) and was primarily driven by two patients; see Supplementary Appendix for further details.
Overall mean baseline 11-deoxycortisol levels were 4.5 nmol/L (normal range 0–3.92) and levels increased markedly (11-fold at week 22) during treatment (Fig. 4; Supplementary Table 1). Similarly, overall 11-deoxycorticosterone levels increased (24-fold) and were >ULN at week 22 (6.3 nmol/L; normal range 0.05–0.39) (Fig. 4; Supplementary Table 1).
Overall mean aldosterone levels were within the normal range at baseline (157 pmol/L; normal range 55–250) and decreased during treatment (Fig. 4; Supplementary Table 1); mean levels were below the LLN at week 22 (41.7 pmol/L). Notably, renin levels decreased in the follow-up cohort (0.8-fold to 57.1 ± 98.2 mU/L) and increased in the expansion cohort (2.8-fold to 66.6 ± 148.7 mU/L) during osilodrostat treatment (Fig. 4; Supplementary Table 1).
At baseline, mean testosterone levels in female patients were 1.2 ± 0.7 nmol/L; levels increased to >ULN during treatment (4.0 ± 3.4 nmol/L at week 22; normal range 0.1–1.6 nmol/L). Baseline levels were >ULN in 5/14 (35.7 %) female patients, all of whom had post-baseline values >ULN. Of the 12 female patients who completed 22 weeks, testosterone levels at week 22 were >ULN in nine (75.0 %) (Supplementary Figure 2). New or worsening hirsutism (n = 2) and/or acne (n = 3) were reported among four female patients during the study, all of whom had increased testosterone levels. Baseline mean testosterone levels in males were slightly below normal (7.4 ± 3.5 nmol/L; normal range 8.7–38.2) and increased to within the normal range during osilodrostat treatment (13.2 ± 5.7 nmol/L at week 22). At baseline, two males had low testosterone levels and three had levels slightly greater than LLN (Supplementary Figure 2); during treatment, all male patients had increases to the mid-normal range. See Supplementary Appendix for data on estradiol, LH, and FSH (Supplementary Table 2).
Changes in clinical and laboratory parameters
Mean body weight (–1.5 ± 3.8 kg) and body mass index (–0.5 ± 1.4 kg/m2) in the overall population did not show a clinically meaningful change from baseline to week 22 (Table 3). Of the 17 patients who completed the study, 12 had a decrease in weight and five had an increase. Edema (generalized and peripheral) was reported as an AE in two patients. One patient had a weight gain from 127 kg on day 1 to 137 kg on day 70 and lower extremity swelling on day 86. The other patient had a history of diabetes insipidus and reported generalized edema on day 31; weight was 129 kg on day 1 and 127 kg on day 28. Both patients had similar 11-deoxycorticosterone levels to the population mean and no history of congestive heart failure. However, the first patient had a history of intermittent lower extremity swelling since 2001.
There was little mean change from baseline in systolic or diastolic blood pressure at week 22, either in the overall population (–1.0 ± 16.2 and 1.3 ± 9.7 mmHg, respectively) or in the 13 patients with a baseline history of hypertension (–0.8 ± 19.0 and 1.9 ± 11.2 mmHg, respectively; Table 3). Five patients who completed the study had elevated baseline systolic blood pressure (defined as >139 mmHg ); levels normalized at week 22 in two patients and remained elevated in three. One patient with normal baseline levels had elevated systolic blood pressure at week 22. Four patients who completed the study had elevated diastolic blood pressure at baseline (defined as >89 mmHg); levels remained elevated at week 22 in all four patients. Another four patients with normal baseline levels had elevated diastolic blood pressure at week 22. There were no notable increases in systolic (defined as ≥180 mmHg) or diastolic (defined as ≥105 mmHg) blood pressure. One patient was reported to have an AE of hypertension.
Decreases from baseline to week 22 were observed in fasting plasma glucose (FPG; –14.9 ± 28.9 mg/dL) and HbA1c levels (–0.2 ± 0.3 %) (Table 3); the improvements in FPG were greater (–33.3 ± 41.0 mg/dL) in the eight patients who had a baseline history of diabetes mellitus. There were also clinically relevant decreases to within the normal range in cholesterol and triglyceride levels from baseline to week 22 (Table 3). There were no clinically relevant changes in mean vital signs [although one patient had a notably elevated pulse rate (defined as ≥120 bpm) on one occasion during treatment] or notable electrocardiogram measurements over the study period (except for the patient with a reported serious AE of QT prolongation). Overall, there were no clinically meaningful changes from baseline to week 22 in mean sodium (140.6 ± 2.7 to 141.0 ± 2.1 mmol/L) or potassium (4.1 ± 0.4 to 3.8 ± 0.4 mmol/L) levels. Based on laboratory assessment, nine patients developed mild hypokalemia (range 3.0–3.4 mmol/L), although only one case was reported as an AE by the investigator; two patients with hypokalemia received potassium supplementation. One patient developed hyperkalemia; a laboratory value of 4.6 mmol/L (laboratory normal range was 3.5–4.5 mmol/L) was reported 2 weeks after initiation of osilodrostat therapy and it was reported as an AE 15 days later. Potassium levels were subsequently within the normal range from week 4 to week 22.
Changes in pituitary tumor size
Data on each individual patient with measurable tumor size are summarized in Supplementary Table 4. Tumor size was not evaluable in 13/19 patients because the tumor was too small to be visualized, or anatomical changes post-pituitary surgery and/or radiation obscured the measurement. Two patients discontinued from the study before week 22 and therefore had no follow-up imaging. In the six patients with measurable tumors (Supplementary Table 3), diameter changes of 1.0–1.7 mm were observed from baseline to week 22; these changes are not considered to be clinically meaningful (i.e. <2.0 mm [21–23]). Two patients had an increase in the maximal tumor diameter at week 22 (range 1.0–1.7 mm). One patient had no change, and three patients had a decrease in maximal tumor diameter (1.0 mm each). See Supplementary Appendix for further details. Only one patient had measureable tumor volume at both baseline and week 22; volume increased from 13.7 mm3 at baseline to 17.5 mm3 at week 22 (change of 3.8 mm3, +28 %), which suggests a clinically meaningful change [23–25].
Safety and tolerability of osilodrostat
Safety was assessed over a median period of 26.7 weeks’ treatment (range 2–50). Nearly all patients (18/19; 94.7 %) experienced at least one AE; the AEs most commonly reported by the investigator are shown in Table 4.
Three serious AEs were reported in two patients: one patient had QT prolongation (suspected to be drug related) in the context of an acute hospitalization for a serious AE of gastroenteritis (not suspected to be drug related) with dehydration; the other patient had uncontrolled Cushing’s disease as reported by the investigator (not suspected to be drug related); see Supplementary Appendix for further details. Adrenal insufficiency was reported as an AE in six patients. Mean UFC and morning serum cortisol values were <LLN at the time the AE was reported in four and three of the six patients, respectively (Supplementary Table 4); no other patients had UFC < LLN during the study. Osilodrostat treatment was decreased in five patients with adrenal insufficiency (two of these patients also had treatment interrupted at a different time point), and one further patient received replacement therapy with dexamethasone. One patient had syncope associated with adrenal insufficiency; no arrhythmia was documented in this patient.