LIFYORLI Capsule Ref.[116441] Active ingredients:

Exposure-Response Relationships

Relacorilant exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.

Cardiac Electrophysiology

At 3.8 times the mean maximal relacorilant concentration of the recommended dosage, clinically significant QTc interval prolongation was not observed.

Relacorilant pharmacokinetics were observed in adult patients at the approved recommended dosage and are presented as mean (CV%), unless otherwise specified. Relacorilant maximum concentration (C_max) is 720 (68%) ng/mL and systemic exposure (AUC) is 5,686 (84%) ng*h/mL following the third consecutive daily dose.

Absorption

Relacorilant median (min, max) time to maximum plasma concentration (T_max) is 2.5 hours (1.2, 5.5).

Effect of Food

Relacorilant C_max increased 1.7-fold, AUC increased 2-fold, and T_max was delayed 0.5 hours following administration with a low-fat meal (approximately 400 to 500 calories, 25% fat content).

Relacorilant C_max increased 1.9-fold, AUC increased 2.4-fold, and T_max was delayed 0.25 hours following administration with a high-fat meal (approximately 800 to 1,000 calories, 50% fat content).

Distribution

Relacorilant apparent volume of distribution (V_z/F) is 2490 (54%) L after a single 150 mg dose under fasted conditions. Protein binding of relacorilant in human plasma is >99% in vitro.

Elimination

Relacorilant terminal half-life is 27 (30%) hours with an apparent total clearance of 52 (69%) L/h under fasted conditions.

Metabolism

Relacorilant is primarily metabolized by cytosolic reductases and CYP3A. An active metabolite, CORT125295, with functional activity approximately 5-fold lower than relacorilant, represents 75% of the parent AUC.

Excretion

After a single oral dose of radiolabeled relacorilant 250 mg to healthy participants, about 73% (<1% unchanged) of the dose was recovered in feces and 17% (<2% unchanged) in urine.

Specific Populations

No clinically significant differences in the pharmacokinetics of relacorilant were observed based on age (26 to 85 years), body weight (35 to 128 kg), race (White [81%], Asian [9%]), ethnicity (Non-Hispanic [93%], Hispanic [7%]), CLcr 30 to <90 mL/min, or mild hepatic impairment (total bilirubin > ULN to ≤1.5 × ULN or AST > ULN and total bilirubin ≤ ULN).

The effect of CLcr <30 mL/min or end-stage renal disease undergoing hemodialysis or severe hepatic impairment (total bilirubin >3 to 10 × ULN and any AST) on the pharmacokinetics of relacorilant is unknown.

Patients with Hepatic Impairment

Relacorilant AUC increased 1.3-fold in participants with moderate hepatic impairment (Child-Pugh Class B).

Drug Interaction Studies

Clinical Studies

Nab-paclitaxel: Dose-normalized paclitaxel (CYP2C8 and CYP3A4 substrate) C_max increased 2-fold and dose-normalized AUC increased 1.7-fold following coadministration of nab-paclitaxel with LIFYORLI 150 mg.

No clinically significant differences in the pharmacokinetics of relacorilant were observed when given in combination with nab-paclitaxel.

Strong CYP3A Inhibitors: Relacorilant (300 mg once daily for 10 days under fasted conditions) steady state C_max increased 1.2-fold and steady state AUC increased 1.5-fold following coadministration of itraconazole (strong CYP3A inhibitor) 200 mg once daily for 10 days.

CYP3A Substrates: Midazolam (CYP3A substrate) C_max increased 3.1-fold and AUC increased 8.9-fold following coadministration of LIFYORLI 350 mg under fasted conditions (1.8 times the relacorilant exposure at the recommended dosage) once daily for 10 days.

CYP2C8 Substrates: Pioglitazone (CYP2C8 substrate) C_max decreased to 78% and AUC to 75% following coadministration of LIFYORLI 350 mg under fasted conditions (1.8 times the relacorilant exposure at the recommended dosage) once daily for 11 days.

Other Drugs: No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with relacorilant: metoprolol (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), or dabigatran etexilate (P-gp).

In vitro Studies

CYP450 Enzymes: Relacorilant and CORT125295 are inducers of CYP1A2.

Transporter Systems: Relacorilant and CORT125295 are inhibitors of BCRP.

Carcinogenesis

In a 6-month carcinogenicity study, transgenic rasH2 mice were orally administered up to 100 mg/kg/day relacorilant. In a 2-year carcinogenicity study, rats were orally administered up to 10 mg/kg/day in male rats (1.3 times the human exposure based on AUC at the recommended dose) and 3 mg/kg/day in female rats (0.7 times the human exposure based on AUC at the recommended dose). There was no evidence of relacorilant-induced carcinogenicity in either study.

Mutagenesis

Relacorilant was not genotoxic in the bacterial reverse mutation (Ames) assay, an in vitro human lymphocyte micronucleus assay, or an in vivo micronucleus assay in rats.

Impairment of Fertility

In a fertility study, relacorilant was administered orally to male rats prior to and throughout mating and to female rats prior to mating and up to the implantation day (gestation day 7). Relacorilant had no effect on fertility or reproductive function in male or female rats at doses up to 40 mg/kg/day (≥4.5 times the human exposure based on AUC at the recommended dose).

The efficacy of LIFYORLI in combination with nab-paclitaxel was evaluated in ROSELLA (NCT05257408), a multicenter, open-label, active-controlled, randomized, two-arm, trial in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients were permitted to receive up to three prior lines of systemic therapy and prior bevacizumab was required. The trial excluded patients who required chronic or frequent use of glucocorticoids.

A total of 381 patients were randomized (1:1) to receive:

• LIFYORLI 150 mg orally the day before, the day of, and the day after administration of nab-paclitaxel 80 mg/m² intravenous infusion on Days 1, 8 and 15 of each 28-day cycle (188) or
• nab-paclitaxel 100 mg/m² intravenous infusion on Days 1, 8 and 15 of each 28-day cycle (193)

Treatment was administered until disease progression or unacceptable toxicity. Tumor response assessments occurred every 8 weeks for the first 40 weeks and every 12 weeks thereafter. Randomization was stratified by the following factors: number of prior lines of therapy (1 vs. >1) and region (North America vs. Europe vs. Korea/Australia/Latin America).

The major efficacy outcome measures were progression-free survival (PFS) assessed by blinded independent central review (BICR) and overall survival (OS). PFS was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

The median age was 62 years (range: 26 to 86); 71% were White, 13% were Asian, 1.3% were Black or African American, and 13% did not have race reported. Nine percent of patients were Hispanic or Latino, 76% were non-Hispanic, and 15% had ethnicity not reported or unknown. Nearly all patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 (69%) or 1 (30%). Nine percent of patients had received 1 prior line of systemic therapy, 48% of patients had received 2 prior lines of systemic therapy, and 44% of patients had received 3 prior lines of systemic therapy. Thirty-nine percent of patients received prior systemic therapy for platinum-resistant disease. All patients received prior bevacizumab, 99.5% had received a prior taxane (19% in the last line of therapy and 4% in the platinum-resistant setting) and 61% had received a prior PARP inhibitor. Of patients who had received a prior PARP inhibitor, 78% had radiographic progression while receiving the PARP inhibitor.

LIFYORLI demonstrated a statistically significant improvement in PFS and OS for patients randomized to LIFYORLI in combination with nab-paclitaxel compared to nab-paclitaxel monotherapy.

Efficacy results for ROSELLA are summarized in Table 7, Figure 1 and Figure 2.

Table 7. Efficacy Results in ROSELLA:

BICR = Blinded Independent Central Review; CI = Confidence Interval
^a Results at the pre-specified final PFS analysis.
^b Based on the stratified Cox proportional hazard model.
^c Two-sided p-value based on stratified log-rank test (compared to a significance level of 0.04).
^d Results at the pre-specified final OS analysis.
^e Two-sided p-value based on stratified log-rank test (compared to a significance level of 0.0499).

Figure 1. Kaplan-Meier Curve for Progression-Free Survival in ROSELLA:

Figure 2. Kaplan-Meier Curve for Overall Survival in ROSELLA: