CRENESSITY Capsule / Oral solution Ref.[115529] Active ingredients: Crinecerfont

Exposure-Response Relationships

Model based exposure-response analyses for adults and pediatric patients with CAH demonstrated that, within the studied exposures of CRENESSITY in Phase 3 trials, relatively flat exposure-response relationships were observed for androstenedione reduction from baseline to Week 4 for both adults and pediatric patients and percent glucocorticoid daily dose reduction from baseline to Week 24 for adults and to Week 28 for pediatric patients.

Adrenocorticotropic Hormone (ACTH) Reduction

In 8 adults with classic CAH (NCT0352886) who received the recommended CRENESSITY dosage for 2 weeks, the median percent reduction from baseline in ACTH was 62%.

In the Phase 3 clinical trials of adults and pediatric patients with classic CAH, administration of the recommended CRENESSITY dosage for 4 weeks during the initial glucocorticoid stable period led to a reduction in ACTH levels.

In Study 1, the median percent reduction from baseline to Week 4 in ACTH was 65%.

In Study 2, the median percent reduction from baseline to Week 4 in ACTH was 72%.

Cardiac Electrophysiology

At a dose 4 times the maximum approved recommended dosage, CRENESSITY does not prolong the QT interval to any clinically relevant extent.

Crinecerfont maximum plasma concentration (C_max) and area under the time concentration curve (AUC_{0-24 hours}) increases dose-proportionally over the approved recommended dosage range. Upon twice daily dosing, steady state conditions are achieved in approximately 7 days with an accumulation ratio of 1.4.

Absorption

Crinecerfont median time to reach C_max (T_max) is 4 hours following oral administration of CRENESSITY.

No clinically significant differences in crinecerfont C_max or AUC were observed following administration of CRENESSITY oral capsules and oral solution.

Steady state exposures for crinecerfont in adults and pediatric patients following oral administration of CRENESSITY are presented in Table 6.

Table 6. Geometric Mean (CV%) for AUC_24,ss and C_max in Adults and Pediatric Patients with Classic Congenital Adrenal Hyperplasia Following Oral Administration of CRENESSITY:

CV%, coefficient of variation expressed as a percentage; bid, twice daily; steady-state exposure parameters are generated from simulation of 500 subjects based on population pharmacokinetic modeling and weight band appropriate formulation

Effect of Food

Following administration of CRENESSITY capsule, crinecerfont C_max increased 4.9-fold and AUC increased 3.3-fold with a high-fat meal (800 to 1000 calories, 50% fat), compared to fasted conditions [see Dosage and Administration (2.2)].

Following administration of CRENESSITY oral solution, crinecerfont C_max increased 8.6-fold and AUC increased 8.3-fold with a high-fat meal (800 to 1000 calories, 50% fat), compared to fasted conditions [see Dosage and Administration (2.2)]

Distribution

Mean apparent volume of distribution (CV%) of crinecerfont in adults with CAH is 852 L (31%). Crinecerfont plasma protein binding is greater than or equal to 99.9%.

Elimination

Crinecerfont's effective half-life is approximately 14 hours with a mean (CV%) apparent clearance of 3.5 L/h (37%).

Metabolism

Crinecerfont is metabolized primarily by CYP3A4 and to a lesser extent by CYP2B6 in vitro. Additionally, CYP2C8 and CYP2C19 may also have minor contributions to crinecerfont metabolism.

Excretion

Following a single oral 100 mg dose of radiolabeled crinecerfont, approximately 47.3% (2.7% as unchanged) of the dose was recovered in feces and 2% (amount as unchanged is undetectable) in urine.

Specific Populations

No clinically significant differences in the pharmacokinetics of crinecerfont were observed based on age (range: 5 to 54 years), sex (58.7% male), race (4.8% Asian, 9.7% Black, 77.5% White), mild to severe hepatic impairment (Child Pugh Class A to C), or mild to moderate renal impairment (estimated glomerular filtration rate: equal to or greater than 44 mL/min/1.73 m²; CKD-EPI 2009 formula for adults and bedside Schwartz formula for pediatric patients).

Crinecerfont has not been studied in patients with severe renal impairment or end-stage renal disease.

Drug Interaction Studies

Clinical Studies

Effect of Strong CYP3A4 Inducers on Crinecerfont: Crinecerfont C_max decreased by 23% and AUC decreased by 62% following concomitant use with rifampin (strong CYP3A4 inducer) [see Dosage and Administration (2.3) and Drug Interactions (7.1)].

Effect of Strong CYP3A4 Inhibitors on Crinecerfont: Crinecerfont C_max and AUC increased by 25% and 45%, respectively, when used concomitantly with ketoconazole (strong CYP3A4 inhibitor).

Effect of Crinecerfont on CYP3A Substrates: No clinically significant differences in the pharmacokinetics of midazolam (CYP3A4 substrate) were observed when co-administered with crinecerfont. Concomitant use of crinecerfont did not affect the pharmacokinetics of oral contraceptives containing ethinyl estradiol and levonorgestrel.

In Vitro Studies

Cytochrome P450 Enzymes: Crinecerfont does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. Crinecerfont does not induce CYP2C8, CYP3A4, CYP1A2 and CYP2B6.

Transporter Systems: Crinecerfont does not inhibit P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), bile salt export pump (BSEP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, multidrug and toxin extrusion protein (MATE)1, or MATE2-K.

Carcinogenesis

In a 2-year carcinogenicity study, rats were administered daily crinecerfont doses of 5, 15, and 100 mg/kg/day via oral gavage. An increased incidence of thyroid follicular cell combined adenomas and carcinomas was observed in female rats at the 100 mg/kg/day dose level (approximately 4-fold higher than human exposure at the MRHD based on AUC). Thyroid follicular cell tumors can occur in rats from excessive thyroid stimulating hormone (TSH) secondary to liver enzyme induction, which is not thought to commonly occur in humans. No evidence of increased tumorigenicity was seen in male rats up to approximately 5-fold higher than human exposure at the MRHD based on AUC or in female rats up to approximately 2-fold higher than human exposure at the MRHD based on AUC.

In a 6-month study in Tg.rasH2 mice, daily crinecerfont doses of 15, 50, 500, and 1500 mg/kg/day were administered via oral gavage. Crinecerfont did not increase the incidence of tumors in male or female transgenic mice (approximately 4-fold higher than human exposure at the MRHD based on AUC).

Mutagenesis

Crinecerfont was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay.

Impairment of Fertility

There were no crinecerfont-related effects on male or female fertility or female reproductive performance in rats treated orally with up to 1000 mg/kg/day crinecerfont at 2-fold higher than human exposure at the MRHD by AUC exposure.

14.1 Adults with Classic Congenital Adrenal Hyperplasia

The efficacy of CRENESSITY to reduce androgen levels and enable a reduced glucocorticoid dose while maintaining androgen control in adults with classic CAH was evaluated in a randomized, double-blind, placebo-controlled study (Study 1; NCT#04490915). This study enrolled 182 adults with classic CAH due to 21-hydroxylase deficiency on supraphysiological glucocorticoid doses and with androgen concentrations in the normal range or with inadequate androgen control.

Subjects were randomized to receive CRENESSITY 100 mg twice daily (N=122) or placebo (N=60) for 24 weeks. During the first 4 weeks of CRENESSITY treatment, subjects maintained a stable glucocorticoid regimen except for stress dosing as needed. During Weeks 4 to 12, the glucocorticoid dose was reduced as frequently as every 2 weeks without regard to androstenedione levels, with the goal to achieve a glucocorticoid dose of 8 to 10 mg/m²/day in hydrocortisone dose equivalents adjusted for body surface area by Week 12. From Weeks 12 to 20, the glucocorticoid dose was further adjusted, if needed, to achieve androstenedione control by Week 24.

The mean (range) age was 31 (18 to 58) years, 51% were male, 90% were White, and 8% were Hispanic or Latino. At baseline, the mean (SD) glucocorticoid total daily dose in hydrocortisone equivalents was 32 (9) mg/day (18 [5] mg/m²/day), with mean (SD) androstenedione levels of 620 (729) ng/dL prior to the morning glucocorticoid dose.

The efficacy of CRENESSITY was assessed by the least-squares (LS) mean (SEM) percent change from baseline in the total glucocorticoid daily dose while androstenedione was controlled (≤120% of baseline or ≤upper limit of normal [ULN]) after 24 weeks. The LS mean percent change from baseline in daily glucocorticoid dose was statistically significantly greater in the CRENESSITY group at -27% compared to -10% in the placebo group, as shown in Table 7.

Table 7. Primary Change From Baseline in Glucocorticoid Daily Dose While Maintaining Androstenedione Control at Week 24 in Adults with Classic Congenital Adrenal Hyperplasia (Study 1):

CI=confidence interval; LS mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean
^* In hydrocortisone equivalents (4x equivalency factor for (methyl)predniso(lo)ne, 60x for dexamethasone) adjusted for body surface area.

At Week 24, there was a statistically significantly greater percentage of subjects achieving a reduction to a physiologic glucocorticoid daily dose (≤11 mg/m²/day hydrocortisone equivalents) while androstenedione was controlled (≤120% of baseline or ≤ULN) with CRENESSITY compared to placebo (63% vs 18%, p<0.0001).

At Week 4, following a treatment period at a stable glucocorticoid dose regimen, the LS mean change from baseline in serum androstenedione in the CRENESSITY group was statistically significantly different at -299 ng/dL compared to the LS mean increase from baseline in the placebo group of 46 ng/dL, as shown in Table 8.

Table 8. Change From Baseline in Serum Androstenedione (ng/dL) at Week 4* in Adults with Classic Congenital Adrenal Hyperplasia(Study 1):

CI=confidence interval; LS mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean
^* End of glucocorticoid stable period.
^† Obtained prior to the morning glucocorticoid dose.

14.2 Pediatric Patients with Classic Congenital Adrenal Hyperplasia

The efficacy of CRENESSITY to improve androgen control and enable a reduced glucocorticoid dose while maintaining androgen control in pediatric patients with classic CAH was evaluated in a Phase 3 randomized, double-blind, placebo-controlled study (Study 2; NCT#04806451). This study enrolled 103 pediatric subjects 4 to 17 years of age with classic CAH due to 21-hydroxylase deficiency and inadequate androgen control on supraphysiological glucocorticoid doses.

Subjects were randomized to receive either CRENESSITY twice daily (N=69) or placebo (N=34) for 28 weeks, using weight-based dosing (50 mg twice daily via oral solution for subjects 20 to <55 kg [CRENESSITY N=37; placebo N=14 ], or 100 mg twice daily via oral capsules for subjects ≥55 kg [CRENESSITY N=32; placebo N=20]).

During the first 4 weeks of CRENESSITY treatment, subjects were maintained on a stable glucocorticoid regimen except for stress dosing, as needed. The primary efficacy endpoint was the change from baseline in serum androstenedione at Week 4. From Weeks 4 to 20, the glucocorticoid dose could be reduced as frequently as every 4 weeks provided androstenedione levels were controlled. The goal was to achieve a glucocorticoid dose of 8 to 10 mg/m²/day (hydrocortisone dose equivalents adjusted for body surface area) by Week 28 while maintaining androstenedione control.

The mean (range) age was 12 (4 to 17) years, 41% were Tanner Stage 1 or 2, 52% were male, 63% were White, and 11% were Hispanic or Latino. With respect to concurrent glucocorticoid use at baseline, 92% of patients were receiving hydrocortisone alone and 8% were receiving prednisone [or equivalent] (with or without hydrocortisone). At baseline, subjects were receiving a mean (SD) glucocorticoid total daily dose in hydrocortisone equivalents of 16 (4) mg/m²/day, and had a mean (SD) androstenedione level of 431 (461) ng/dL and mean (SD) serum 17-hydroxyprogesterone level of 8682 (6847) ng/dL prior to the morning glucocorticoid dose.

At Week 4, following a treatment period at a stable glucocorticoid dose regimen, the LS mean reduction from baseline in serum androstenedione in the CRENESSITY group was statistically significantly different at -197 ng/dL compared to the increase of 71 ng/dL in the placebo group, as shown in Table 9.

Table 9. Change From Baseline in Serum Androstenedione (ng/dL) at Week 4* in Pediatric Subjects with Classic Congenital Adrenal Hyperplasia (Study 2):

CI=confidence interval; LS mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean
^* End of glucocorticoid stable period.
^† Obtained prior to the morning glucocorticoid dose.

At Week 4, following a treatment period at a stable glucocorticoid regimen, the LS mean reduction (SEM) from baseline in serum 17-hydroxyprogesterone in the CRENESSITY group was statistically significantly different at -5865 (572) ng/dL compared to the increase of 556 (818) ng/dL in the placebo group (LS Mean Treatment Difference -6421, 95% CI -8387, -4454, p<0.0001).

The LS mean percent change from baseline in the total glucocorticoid daily dose while androstenedione was controlled (≤120% of baseline or ≤ULN) at Week 28 in the CRENESSITY group was statistically significantly different at -18% compared to the increase of 6% in the placebo group, as shown in Table 10.

Table 10. Percent Change From Baseline in Glucocorticoid Daily Dose While
Maintaining Androstenedione Control at Week 28 in Pediatric Subjects with Classic Congenital Adrenal Hyperplasia (Study 2):

CI=confidence interval; LS mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean;
^* In hydrocortisone equivalents (4x equivalency factor for (methyl)predniso(lo)ne) adjusted for body surface area.