Isturisa (Page 4 of 6)

11 DESCRIPTION

ISTURISA (osilodrostat) is a cortisol synthesis inhibitor.

Osilodrostat structural formula

The chemical name of osilodrostat is 4-[(5R)-6,7-Dihydro-5 H -pyrrolo[1,2- c ]imidazol-5-yl]-3-fluorobenzonitrile dihydrogen phosphate.

Molecular formula of osilodrostat salt (phosphate) form on anhydrous basis is: (C 13 H 11 FN 3 ) (H 2 PO 4 ). Relative molecular mass of osilodrostat phosphate salt form is 325.24 g/mol.

ISTURISA tablets for oral administration contains 1 mg, 5 mg, or 10 mg of osilodrostat equivalent to 1.4 mg, 7.2 mg, and 14.3 mg of osilodrostat phosphate respectively, and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, mannitol, microcrystalline cellulose, and magnesium stearate. The film coat is composed of hypromellose, titanium dioxide, ferric oxide (yellow), ferric oxide (red) (1 mg and 10 mg only), ferrosoferric oxide (10 mg only), polyethylene glycol 4000, and talc.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Osilodrostat is a cortisol synthesis inhibitor. It inhibits 11beta-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland. In a Chinese hamster lung cell line V79-4 that overexpresses human CYP11B1, adrenodoxin and adrenodoxin reductase, osilodrostat inhibited the activity of human CYP11B1 dose-dependently with IC50 values of 2.5 ± 0.1 nM (n = 4).

12.2 Pharmacodynamics

A dose dependent increase was observed in 11-deoxycortisol, the cortisol precursor, and ACTH levels in patients with Cushing’s disease.

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)] .

12.3 Pharmacokinetics

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.

Effect of Food

In a healthy volunteer study (N = 20), subjects administered with a single, 30 mg oral dose of ISTURISA film-coated tablets with a high-fat meal resulted in reduction of AUC by 11% and C max by 21%, respectively. The median T max was delayed from 1 to 2.5 hours. These changes are not considered to be clinically significant, therefore ISTURISA can be administered with or without food.

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.

Race/Ethnicity

The relative bioavailability in Asian patients is approximately 20% higher compared to that of non-Asian, along with higher T max and C max , compared to other ethnicities. However, the difference is not clinically significant.

Patients with Renal Impairment

Osilodrostat exposure was similar in the three renal function groups [normal, severe, and end stage renal disease (ESRD) groups] and thus a study was not conducted in mild and moderate renal impairment groups. The results showed that the PK of osilodrostat was not influenced by varying degrees of renal impairment to any clinically significant extent [see Dosage and Administration ( 2.4), Use in Specific Populations ( 8.6)] .

Patients with Hepatic Impairment

There was a trend of increasing AUC inf to osilodrostat in moderate and severe hepatic impaired subjects (geo-mean ratios are 1.44 and 2.66, respectively) as compared to normal subjects. Exposures (C max and AUC) of osilodrostat in the mild hepatic impairment group were similar to those in the normal group [see Dosage and Administration ( 2.5), Use in Specific Populations ( 8.7)] .

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

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).

14 CLINICAL STUDIES

The safety and efficacy of ISTURISA was assessed in a 48-week, multicenter study (called the Core Period) that consisted of four study periods as follows:

  • Period 1: 12-week, open-label, dose titration period
  • Period 2: 12-week, open-label, maintenance treatment period
  • Period 3: 8-week, double-blind, placebo-controlled, randomized withdrawal treatment period which provided the data for the primary efficacy endpoint
  • Period 4: open-label treatment period of 14 to 24 weeks duration

The trial enrolled Cushing’s disease patients with persistent or recurrent disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery. The mean age at enrollment was 41 years; 77% of patients were female. There were 65% Caucasian, 28% Asian, 3% black, and 4% other race. Overall, 96% patients had received previous treatments for Cushing’s disease prior to entering the study, of which 88% had undergone surgery. Persistence or recurrence of Cushing’s disease was evidenced by the mean of three 24-hour UFC (mUFC) > 1.5x upper limit of normal (ULN). The mUFC (SD) at baseline was 1006 nmol/24 hr (1589), which corresponds to approximately 7 x ULN. The median mUFC at baseline was 476 nmol/24 hr, which corresponds to approximately 3.5 x ULN.

Period 1 (Week 1 to 12)

137 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)

130 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 x 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.

Efficacy Assessment

The primary efficacy endpoint of the study was to compare the percentage of complete responders at the end of the 8-week randomized withdrawal period (Period 3) between patients randomized to continue ISTURISA versus the patients switched to placebo. 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 to assess the complete responder rate 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.

Table 3: Percentage of Cushing’s Disease Patients with Normal mUFC at End of Period 3 (8-week randomized withdrawal period)

Primary Endpoint

ISTURISA (N = 36) n (%)

Placebo (N = 34) n (%)

Complete Responder Rate

Difference

(Differences in Percentages)

Complete responder rate at the end of the 8-week randomized withdrawal (RW) period (Week 34)

31 (86)

10 (29)

osilodrostat vs placebo 57 (38, 76)

(95% CI)

(71, 95)

(15, 47)

2-sided p-value < 0.001

Abbreviation: CI, Confidence Interval.

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.

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