Isturisa

Study 1

The adverse reactions that occurred with frequency higher than 10% during the core 48-week period are shown in Table 1.

Other notable adverse reactions which occurred with a frequency less than 10% were: hirsutism (9.5%), acne (8.8%), dyspepsia (8%), insomnia (8%), anxiety (7.3%), depression (7.3%), gastroenteritis (7.3%), malaise (6.6%), tachycardia (6.6%), alopecia (5.8%), transaminases increased (4.4%), electrocardiogram QT prolongation (3.6%), and syncope (1.5%).

Description of Select Adverse Reactions from the Core 48-week Period of Study 1

Other Abnormal Laboratory Findings

Study 2

The adverse reactions that occurred with frequency higher than 10% and greater than placebo during the 12-week placebo controlled period are shown in Table 2.

Description of Selected Adverse Reactions from the 12-week Placebo-Controlled Period of Study 2

Other Abnormal Laboratory Findings

Risk Summary

There are no available data on osilodrostat use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with active Cushing's Syndrome during pregnancy (see Clinical Considerations).

No adverse developmental outcomes were observed in reproduction studies in pregnant rats and rabbits when exposed to osilodrostat during organogenesis at doses that produced maternal exposures of 7 and 0.5-times the 30 mg twice daily maximum clinical dose, by AUC. In rabbits, exposures associated with maternal toxicity at 7-times the maximum clinical dose resulted in decreased fetal viability. No adverse developmental outcomes were observed in a pre- and postnatal development study with administration of osilodrostat to pregnant rats from organogenesis through lactation at 8-times the 30 mg twice daily maximum clinical dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Clinical Considerations

Data

Risk Summary

There are no available data on the presence of osilodrostat in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions (such as adrenal insufficiency) in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with ISTURISA and for one week after the final dose.

Cardiac Electrophysiology

A thorough QT study in 86 male and female healthy volunteers showed a maximum mean placebo-corrected QTcF interval increase of 1.73 ms [90% confidence interval (CI): 0.15, 3.31] at a 10 mg dose, and 25.38 ms (90% CI: 23.53, 27.22) at a 150 mg dose (up to 2.5 times the maximum recommended dosage) [see Warnings and Precautions (5.2)].

The predicted mean placebo-corrected QTcF change from baseline at the highest recommended dose in clinical practice (30 mg twice daily) was estimated as 5.3 ms (90% CI: 4.2, 6.5), based on an interpolation of the data from the thorough QT Study and population PK analysis [see Warnings and Precautions (5.2)].

Absorption

Osilodrostat is absorbed with a time of maximum observed concentration (T_max) of approximately 1 hour. Exposure (AUC_inf and C_max) slightly increases over dose-proportionally within the therapeutic dose range of 1 mg to 30 mg.

Distribution

The median apparent volume of distribution of osilodrostat is approximately 100 L. Protein binding is low (36.4%). The osilodrostat blood-to-plasma concentration ratio is 0.85.

Elimination

The elimination half-life of osilodrostat is approximately 4 hours.

In an absorption, distribution, metabolism, and excretion study, the majority of the radioactivity dose of osilodrostat is eliminated in the urine (mean: 90.6% of administered dose) with only a minor amount eliminated in the feces (1.58% 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.

Metabolism

Multiple CYP enzymes (i.e., CYP3A4, CYP2B6, and CYP2D6) and UDP-glucuronosyltransferases contribute to osilodrostat metabolism and no single enzyme contributes greater than 25% to the total clearance. The metabolites are not expected to contribute to the pharmacological effect of osilodrostat.

Specific Populations

Age and gender have no significant impact on osilodrostat exposure in adults.

Drug Interaction

In a healthy volunteer study (N = 20) using a single dose of osilodrostat (50 mg) and a probe drugs cocktail, osilodrostat showed inhibition potential on CYP1A2, CYP2C19, CYP2D6, and CYP3A4/5 isozymes with 2.5-, 1.9-, 1.5- and 1.5-fold increase in caffeine, omeprazole, dextromethorphan, and midazolam exposure, respectively [see Drug Interactions (7.1), (7.2)].

There was no significant impact of osilodrostat (30 mg twice daily for 12 days) on the exposure of oral contraceptives containing 0.03 mg estradiol and 0.15 mg levonorgestrel in healthy female subjects.

Carcinogenesis

Carcinogenicity studies were conducted in Wistar Han rats and CD1 mice. Hepatocellular adenomas and carcinomas occurred in male rats at ≥ 10 mg/kg and in females at 30 mg/kg (18- and 65-times the 30 mg twice daily maximum clinical dose, by AUC, respectively). Thyroid follicular adenoma/carcinoma was also observed in male rats at 30 mg/kg. Hepatocellular adenomas and carcinomas occurred in male mice at ≥ 10 mg kg (6 times the maximum clinical dose, by AUC) but not in female mice at any dose ≤ 30 mg/kg (31 times the maximum clinical dose, by AUC). These findings are likely rodent specific and considered not relevant to humans. Genetic profiling studies support activation of hepatic constitutive androstane receptors as the likely tumorigenic mechanism in rodents and is not a significant concern for human risk at clinical exposure to osilodrostat.

Genotoxicity

Genotoxicity assays conducted in vitro in bacterial systems and in vitro and in vivo in mammalian systems with and without metabolic activation indicate that there is no genotoxic risk in humans with osilodrostat.

Impairment of Fertility

In a fertility and early embryonic-development study in Wistar Han rats, doses of 50 mg/kg (118 times the 30 mg twice daily maximum clinical dose, by AUC) resulted in changes to estrous cyclicity and impaired female fertility and embryo viability. No effect on reproductive performance in females was observed at 5 mg/kg (8 times the maximum clinical dose). Fertility and reproductive performance were not affected in male rats up to 50 mg/kg (77 times the maximum clinical dose, by AUC).

Period 1 (Week 1 to 12)

One hundred thirty-seven patients received a starting dose of 2 mg ISTURISA orally twice daily that could be titrated up to a maximum of 30 mg twice daily at no greater than 2-week intervals to achieve a mUFC within the normal range. Individual dose adjustments were based on mUFC. The dose was increased if mUFC was above ULN and was reduced if mUFC was below the lower limit of normal (LLN), or if the patient had symptoms consistent with hypocortisolism and mUFC was in the lower part of the normal range.

Period 2 (Week 13 to 24)

One hundred thirty patients entered Period 2. The daily dose for patients that achieved a mUFC within the normal range in Period 1 was maintained during Period 2. Patients who did not require further dose increase, tolerated the drug, and had a mUFC ≤ ULN at Week 24 (end of Period 2) were to be considered responders and eligible to enter the Randomization Withdrawal phase (Period 3). Patients whose mUFC became elevated during Period 2 could have their dose increased further, if tolerated, up to 30 mg twice daily. These patients were considered non-responders and did not enter Period 3 but continued open-label treatment together with the patients who did not achieve normal mUFC at Week 12 and were followed for long-term safety and response to treatment.

Period 3 (Week 26 to 34)

At Week 26, 71 patients were considered responders and were randomized 1:1 to continue receiving ISTURISA (n = 36) or to switch to placebo (n = 35) for 8 weeks. Patients were stratified at randomization according to dose received at Week 24 (≤ 5 mg twice daily vs 5 mg twice daily) and history of pituitary irradiation (yes/no).

Patients were to remain on their assigned treatment and dose throughout Period 3 if mUFC were within the normal range. Blinded dose reduction or temporary discontinuation for safety or tolerability reasons were permitted. Dose increases were not permitted during Period 3. Patients with mUFC increase > 1.5 × ULN or who required a dose increase were considered non-responders and discontinued from Period 3 but allowed to receive open-label treatment during Period 4.

Period 4 (Week 26 or 34 to 48)

This period included patients who were not eligible for randomization (n = 47) at Week 26, patients who were considered non-responders during Period 3 (n = 29), and patients who were considered responders during Period 3 (n = 41). Open-label treatment with ISTURISA continued in these patients until Week 48 when patients who maintained clinical benefit on ISTURISA, as judged by the Investigator, had an option to enter an extension period of additional 24 weeks.

Efficacy Assessment

The primary efficacy endpoint of the study was the complete response status at the end of the 8-week randomized withdrawal period (Period 3). A complete responder for the primary endpoint was defined as a patient who had mUFC ≤ ULN based on central laboratory result at the end of Period 3 (Week 34), and who neither discontinued randomized treatment or the study nor had any dose increase above their Week 26 dose.

The key secondary endpoint was the complete response status at the end of Period 2 (Week 24). A complete responder for the key secondary endpoint was defined as a patient with mUFC ≤ ULN at Week 24 who did not require an increase in dose above the level established at the end of Period 1 (Week 12). Patients who were missing mUFC assessment at Week 24 were counted as non-responders for the key secondary endpoint.

Results

At the end of Period 3, the percentage of complete responders for the primary endpoint was 86% and 29% in the ISTURISA and placebo groups, respectively (Table 3). The difference in percentage of complete responders between ISTURISA and placebo groups was 57%, with 95% two-sided CI of (38%, 76%). The 95% CI were not presented by individual strata due to the small sample sizes of some of these strata.

The key secondary endpoint, complete responder rate after 24 weeks of treatment with ISTURISA was achieved by 72/137 patients (52.6%) with 95% two-sided CI of (43.9, 61.1). The lower bound of this 95% CI exceeded 30%, the pre-specified threshold for statistical significance and minimum threshold for clinical benefit.

At Week 48, 91/137 patients (66%) had normal mUFC levels.

Variable decreases from baseline for blood pressure, glucose parameters, weight and weight circumference were observed at Week 48. However, because the study allowed initiation of anti-hypertensive and anti-diabetic medications and dose increases in patients already receiving such medications and the absence of a control group, the individual contribution of ISTURISA or of anti-hypertensive and anti-diabetic medication adjustments cannot be clearly established.

Period 1 (Week 1 to 12)

Seventy-three patients received a starting dose of 2 mg twice daily ISTURISA or placebo orally twice daily that could be titrated up at approximately 3-week intervals to achieve a mUFC within the normal range, using the following dose escalation sequence: 2 mg twice daily to 5mg twice daily to 10 mg twice daily up to a maximum of 20 mg twice daily, with intermediate doses used if necessary. Individual dose adjustments were based on mUFC and other relevant data (i.e. serum cortisol, ACTH, chemistry, clinical signs and symptoms of adrenal insufficiency, vitals and study drug dose, tolerability). The dose was increased if mUFC was above ULN and was reduced if mUFC was below the lower limit of normal (LLN), or if the patients had signs and/or symptom consistent with adrenal insufficiency and mUFC was in the lower part of the normal range.

Period 2 (Week 13 to 48)

In this period, all patients who were receiving 2 mg twice daily or more during the double-blind period restarted ISTURISA at a dose of 2 mg twice daily at Week 12. Patients receiving daily dose < 2 mg twice daily during the 12-week double-blind randomized, placebo-controlled period were to continue treatment with their last dose from Period 1. During Period 2, decisions regarding dose titration of ISTURISA were made by the Investigators based on mUFC values and tolerability using the same dose escalation sequence as in the double-blind period. The maximum dose was 30 mg twice daily. Treatment with ISTURISA continued in these patients until Week 48 when patients had an option to enter an extension period of an additional 48 weeks.

Efficacy Assessment

The primary efficacy endpoint of the study was the complete response status at Week 12. A complete responder was defined as a patient who has mUFC ≤ ULN (based on central laboratory result) at Week 12 who neither discontinued during the placebo-controlled period nor had a missing mUFC assessment at Week 12.

Results

At the end of Period 1, the percentage of complete responders for the primary endpoint was 77% and 8% in the ISTURISA and placebo groups, respectively (Table 5).