Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Recordati Rare Diseases, Immeuble Le Wilson, 70 avenue du Général de Gaulle, 92800 Puteaux, France
Pharmacotherapeutic group: Anticorticosteroids
ATC code: H02CA02
Osilodrostat is a cortisol synthesis inhibitor. It potently inhibits 11β-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland.
CYP11B1 inhibition is associated with the accumulation of precursors such as 11-deoxycortisol and acceleration of adrenal biosynthesis including androgens. In Cushing’s disease, the fall in plasma cortisol concentration also stimulates ACTH secretion, via the feedback mechanism which accelerates steroid biosynthesis (see section 4.8).
In a thorough QT study (n=86 male and female healthy volunteers) with osilodrostat, the maximum QTcF interval duration differences to placebo were 1.73 ms (90% CI: 0.15, 3.31) at the 10 mg dose and 25.38 ms (90% CI: 23.53, 27.22) at a supratherapeutic dose of 150 mg. Based on an interpolation of these results, the mean maximum prolongation at the highest recommended dose of 30 mg is estimated to be +5.3 ms.
The efficacy and safety of osilodrostat in patients with Cushing’s disease were evaluated in a prospective phase III study (study C2301) that used a randomised withdrawal design. The study consisted of a 26-week open-label period of single-arm osilodrostat treatment, followed by an 8-week randomised withdrawal period in which patients were randomised in 1:1 ratio to either osilodrostat or placebo and a subsequent osilodrostat open-label period.
The eligibility criteria included Cushing’s disease (with confirmation of the pituitary source of excess adrenocorticotrophic hormone), and a mean urinary free cortisol (mUFC, derived from three 24-hour urine collections) value greater than 1.5 times the upper limit of normal (ULN) at screening.
A total of 137 adult patients were enrolled. The mean age was 41.2 years, and the majority of patients were female (77%). Seven patients were aged 65 years or older. Prior therapy included pituitary surgery in 88% of patients and prior medical therapy in 75% of patients. The mean and median baseline mUFC levels were 1006.0 nmol/24 h and 476.4 nmol/24 h, respectively (ULN: 138 nmol/24 h). Co-morbidities at baseline included hypertension (67.9% of patients), obesity (29.9%), diabetes mellitus (21.9%) and osteoporosis (27.7%).
Patients received a starting dose of 2 mg osilodrostat twice daily and the dose could be up-titrated based on individual response and tolerability during an initial 12-week period. Patients with no further dose increases during the following 12 weeks and with a mUFC ≤ULN at week 24 were randomised in a 1:1 ratio at week 26 to receive either osilodrostat or matching placebo for 8 weeks (double-blind randomised withdrawal period), followed by open-label osilodrostat for the remainder of the study. At week 26, 71 patients were randomised in a 1:1 ratio to continue receiving osilodrostat (n=36) or to switch to placebo (n=35). Patients who were not eligible for randomisation at week 24 (n=47) continued on open-label osilodrostat treatment.
The primary objective was to compare the proportion of complete responders at week 34 (the end of the 8-week randomised withdrawal period) between patients randomised to continued active treatment and placebo. For the primary endpoint, a complete response was defined as a mUFC value ≤ULN at week 34. Patients whose dose was increased during the randomised withdrawal period or who discontinued randomised treatment were considered non-responders. The key secondary endpoint was the complete response rate at week 24. Patients with dose increases between weeks 12 and 24 and patients with no valid mUFC assessment at week 24 were counted as non-responders for the key secondary endpoint.
The study met its primary and key secondary endpoints (Table 2).
Median mUFC levels decreased to 62.5 nmol/24 h (-84.1% change from baseline, n=125) at week 12, to 75.5 nmol/24 h (-82.3%, n=125) at week 24 and to 63.3 nmol/24 h (-87.9%, n=108) at week 48.
Table 2. Key results: Phase III study in Cushing’s disease patients (study C2301):
| Osilodrostat n=36 | Placebo n=34 | ||
|---|---|---|---|
| Primary endpoint: Proportion of responders at the end of the randomised withdrawal period (week 34) n () (95 CI) | 31 (86.1) (70.5, 95.3) | 10 (29.4) (15.1, 47.5) | |
| Response rate difference (odds ratio): osilodrostat vs. placebo | 13.7 (3.7, 53.4) 2-sided p value <0.001 | ||
| Secondary endpoints | All patients N=137 | ||
| Key secondary endpoint: Proportion with mUFC ≤ULN at week 24 and no dose increase after week 12 (95% CI) | 72 (52.6%) (43.9, 61.1) | ||
| Complete mUFC response rate (mUFC ≤ULN) at week 48 | 91 (66.4%) (57.9, 74.3) | ||
| Median mUFC value and percentage change at week 48 | 63.3 nmol/24 h (-87.9%) | ||
mUFC: mean urinary free cortisol; ULN: upper limit of normal; CI: confidence interval; response: mUFC ≤ULN.
Improvements were observed in cardiovascular and metabolic parameters (Table 3) and 85.6% of patients with available assessments showed an improvement in at least one physical feature of Cushing’s disease at week 48.
Table 3. Cardiovascular and metabolic parameters:
| Baseline | Week 24 | Week 48 | |
|---|---|---|---|
| Systolic blood pressure (mmHg) | 132.2 | 124.9 (-4.1%) | 121.7 (-6.8%) |
| Diastolic blood pressure (mmHg) | 85.3 | 81.0 (-3.8%) | 78.9 (-6.6%) |
| Body weight (kg) | 80.8 | 77.3 (-3.0%) | 75.5 (-4.6%) |
| Waist circumference (cm) | 103.4 | 99.1 (-2.6%) | 97.4 (-4.2%) |
| HbA1c (%) | 6.0 | 5.6 (-4.6%) | 5.6 (-5.4%) |
Osilodrostat treatment also resulted in an improvement in patient-reported outcomes. Improvements from baseline above the established minimal important difference (MID) were observed for Cushing’s QoL (total score, Physical Problems subscale and Psychosocial Issues subscale), EQ-5D Utility index and BDI-II (depression) scores. The mean Cushing QoL total score improved from 42.2 at baseline to 58.3 (+14.1; +52.4% change from baseline) at week 48.
The efficacy of osilodrostat was also assessed in study C1201 in nine adult Japanese patients with non-pituitary causes of Cushing’s syndrome. The study enrolled patients with adrenal adenoma (n=5), ectopic corticotropin syndrome (n=3) and ACTH-independent macronodular adrenal hyperplasia (n=1), and consisted of a 12-week dose titration period (starting dose 2 mg twice daily), a 36-week maintenance period and an optional long-term extension. At week 12 (primary endpoint) a complete response (mUFC ≤ULN) was observed in 6 patients (66.7%) and a partial response (mUFC decrease by at least 50%) in one additional patient (11.1%). The median average dose used in the study was 2.6 mg/day (range 1.3-7.5 mg/day). The mean duration of treatment in this study was 24 weeks, and long-term exposure was limited.
The European Medicines Agency has deferred the obligation to submit the results of studies with Isturisa in one or more subsets of the paediatric population in adrenal cortical hyperfunction (see section 4.2 for information on paediatric use).
Osilodrostat is a highly soluble, highly permeable compound (BCS class 1). It is rapidly absorbed (tmax ~1 h) and oral absorption in humans is assumed to be nearly complete. Steady state is reached by day 2.
Co-administration with food did not affect absorption to a clinically significant extent. In a healthy volunteer study (n=20), the administration of a single dose of 30 mg osilodrostat with a high-fat meal resulted in a modest reduction of AUC and Cmax by 11% and 21%, respectively, and the median tmax was delayed from 1 to 2.5 hours.
No clinically relevant accumulation was observed in clinical studies. An accumulation ratio of 1.3 was estimated for the 2 to 30 mg dose range.
The median apparent volume of distribution (Vz/F) of osilodrostat is approximately 100 litres. Protein binding of osilodrostat and of its major metabolite M34.5 is low (less than 40%) and concentration-independent. The osilodrostat blood-to-plasma concentration ratio is 0.85. Osilodrostat is not a substrate for OATP1B1 or OATP1B3 transporters.
In a human ADME study in healthy subjects following the administration of a single dose of 50 mg [14C]-osilodrostat, metabolism was deemed the most important clearance pathway for osilodrostat since ~80% of the dose was excreted as metabolites. The three main metabolites in plasma (M34.5, M16.5 and M24.9) represented 51%, 9% and 7% of the dose, respectively. Both M34.5 and M24.9 have longer half-lives than osilodrostat and some accumulation is expected with twice-daily dosing. The decrease in the contribution of osilodrostat to the radioactivity AUC with time post-dose was found to coincide closely with a corresponding increase in the contribution of M34.5.
Thirteen metabolites were characterised in the urine, with the three main metabolites being M16.5, M22 (an M34.5 glucuronide) and M24.9, with 17, 13 and 11% of the dose, respectively. The formation of the major urinary metabolite M16.5 (direct N-glucuronide) was catalysed by UGT1A4, 2B7 and 2B10. Less than 1% of the dose was excreted as M34.5 (di-oxygenated osilodrostat) in the urine but 13% of the dose was identified as M22 (M34.5-glucuronide). The formation of M34.5 was non-CYP-mediated.
Multiple CYP enzymes and UDP glucuronosyltransferases contribute to osilodrostat metabolism and no single enzyme contributes more than 25% to the total clearance. The main CYP enzymes involved in osilodrostat metabolism are CYP3A4, 2B6 and 2D6. Total CYP contribution is 26%, total UGT contribution is 19% and non-CYP non-UGT mediated metabolism was shown to contribute to ~50% of total clearance. In addition, osilodrostat showed a high intrinsic permeability, low efflux ratio and modest impact of inhibitors on the efflux ratio in vitro. This suggests that the potential for clinical drug-drug interactions (DDI) with concomitantly administered medicinal products that inhibit transporters or a single CYP or UGT enzyme is low.
In vitro data indicate that the metabolites do not contribute to the pharmacological effect of osilodrostat.
The elimination half-life of osilodrostat is approximately 4 hours. In an ADME study, the majority (91%) of the radioactive dose of osilodrostat was eliminated in the urine, with only a minor amount eliminated in the faeces (1.6% of dose). The low percentage of the dose eliminated in the urine as unchanged osilodrostat (5.2%) indicates that metabolism is the major clearance pathway in humans.
Exposure (AUCinf and Cmax) increased more than dose-proportionally over the therapeutic dose range.
In vitro data indicate that neither osilodrostat nor its major metabolite M34.5 inhibits the following enzymes and transporters at clinically relevant concentrations: CYP2A6, CYP2C8, CYP2C9, UGT2B7, P-gp, BCRP, BSEP, MRP2, OATP1B3 and MATE2-K. Since the exposure of M34.5 has not yet been determined after repeated dosing, the clinical relevance of the in vitro drug-drug interaction results for M34.5 is unknown.
In a phase I study in 33 subjects with varying degrees of hepatic function using a single dose of 30 mg osilodrostat, AUCinf was 1.4- and 2.7-fold higher in the moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment cohorts, respectively. Cmax was 15 and 20% lower in the moderate and severe cohorts. The terminal half-life increased to 9.3 hours and 19.5 hours in the moderate and severe cohorts. Mild hepatic impairment (Child-Pugh A) did not influence exposure to any significant extent. The absorption rate was not affected by the degree of hepatic impairment.
In a phase I study in 15 subjects with varying degrees of renal function using a single dose of 30 mg osilodrostat, comparable systemic exposure was seen in subjects with severe renal impairment, end-stage renal disease and normal renal function.
The relative bioavailability was approximately 20% higher in Asian patients compared to other ethnicities. Body weight was not shown to be a major determinant of this difference.
Age and gender had no significant impact on osilodrostat exposure in adults. The number of elderly patients in clinical studies was limited (see section 4.2).
In repeat dose toxicity studies conducted in mice, rats and dogs, the central nervous system, liver, female reproductive organs, and the adrenal gland were the primary target organs. The NOAEL for hepatic, reproductive organ and adrenal effects in long-term (26- and 39-week) studies was at least four-fold human clinical exposure based on AUC. CNS findings (aggression, hypersensitivity to touch and increased or decreased activity) were noted in the rat, mouse and dog. The NOAEL for the CNS effects was approximately 2-fold human free Cmax based on the most sensitive species.
Genotoxicity assays conducted in vitro in bacterial systems and in vitro and in vivo in mammalian systems with and without metabolic activation do not indicate a relevant risk in humans. In rat and mice carcinogenicity studies, an increased incidence of hepatocellular adenoma/carcinoma (at lower doses in males than females), and neoplastic changes of thyroid follicular adenoma/carcinoma (in male rats only) were observed. The findings are likely rodent specific and considered not relevant to humans.
Reproductive studies in rabbits and rats demonstrated embryotoxicity, foetotoxicity (increased resorptions and decreased foetal viability, decreased foetal weights, external malformations, and visceral and skeletal variations) and teratogenicity at maternally toxic doses. The NOAEL was 10-fold human exposure (AUC) in a pre- and postnatal developmental study, and 8- to 73-fold human exposure (AUC) in a rat fertility and early embryonic development study. The maternal and foetal NOAEL in the rabbit embryofoetal development study was 0.6-fold human exposure (AUC).
The findings in juvenile rat toxicity studies were largely consistent with those observed in adult rat studies. Delayed sexual maturation was noted at high doses with no effects on overall reproductive performance or parameters after a 6-week recovery period. There were no effects on long bone growth or behavioural performance.
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