ORZEYFUL Tablet Ref.[116888] Active ingredients: Oveporexton

Cardiac Electrophysiology

Based on a comprehensive concentration-QTc analysis, there was no clinically relevant effect of ORZEYFUL (i.e., >10 ms) on the QTc interval up to 11 times the mean steady state C_max at the maximum recommended dose.

Oveporexton showed dose proportional increase in exposures (C_max and AUC_0-t) at steady state over the dosage range of 1 mg twice daily to 2 mg twice daily. With two times daily administration, steady state was reached within 5 days, with an accumulation ratio of approximately 1.6 after a ORZEYFUL dosage of 1 mg twice daily to 2 mg twice daily.

Absorption

Oveporexton median (min, max) time to maximum plasma concentration (T_max) is 1.5 hours (1 to 4 hours) at steady state.

Effect of Food: No clinically significant differences in the pharmacokinetics of oveporexton were observed following administration with a high-fat high-calorie meal [see Dosage and Administration (2.1)].

Distribution

The apparent steady state volume of distribution of oveporexton is approximately 325 L. Protein binding is high (>96%) and concentration-independent in human plasma. The whole blood to plasma concentration ratio ranged from 0.61 to 0.90.

Elimination

The mean terminal elimination half-life of oveporexton is approximately 23.2 hours.

Metabolism: Oveporexton is primarily eliminated by hepatic metabolism. CYP3A4 is the predominant CYP enzyme involved in oveporexton metabolism with no major metabolites identified in circulation.

Excretion: After a single 25 mg radiolabeled oral dose of oveporexton, 80.5% of the total dose was recovered in feces and 11.0% was recovered in urine. Renal elimination of unchanged drug accounts for <1% of the total clearance of oveporexton.

Specific Populations

Patients with Hepatic Impairment

Exposure of oveporexton in patients with mild hepatic impairment (HI) (Child-Pugh A) or moderate HI (Child-Pugh B) compared to patients with normal hepatic function is summarized in Figure 1. Changes in oveporexton exposures (AUC_inf) due to HI did not exceed 2-fold compared to patients with normal hepatic function [see Use in Specific Populations (8.6)].

Patients with severe HI (Child-Pugh C) were not evaluated in clinical trials [see Use in Specific Populations (8.6)].

Patients with Renal Impairment

Exposures of oveporexton in patients with severe renal impairment (RI) (eGFR<15 mL/min; not on dialysis) compared to patients with normal renal function is summarized in Figure 1. Changes in oveporexton exposures (AUC_inf) due to RI did not exceed 2-fold compared to patients with normal renal function.

Patients with ESRD (eGFR <15 mL/minute or dialysis patients) were not evaluated in clinical trials.

Figure 1. Effects of Hepatic and Renal Impairment on Oveporexton Pharmacokinetics:

Other Specific Populations

Based on population pharmacokinetic analysis, age, sex, race/ethnicity, and body weight did not have clinically meaningful effects on the pharmacokinetics of oveporexton.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Effects of Other Drugs on ORZEYFUL:

• Strong and Moderate CYP3A Inhibitors: Concomitant use of ORZEYFUL with itraconazole (a strong CYP3A inhibitor) resulted in increases in oveporexton AUC_inf (7.4-fold increase) and C_max (1.7-fold increase), compared to the use of ORZEYFUL alone. The half-life of oveporexton was approximately 5-fold longer in the presence of itraconazole [see Drug Interactions (7)]. Concomitant use of ORZEYFUL with fluconazole (a moderate CYP3A inhibitor) resulted in increases in oveporexton AUC_inf (2.9-fold increase) and C_max (1.5-fold increase), compared to the use of ORZEYFUL alone. The half-life of oveporexton was approximately 2-fold longer in the presence of fluconazole [see Drug Interactions (7)].
• Weak CYP3A Inhibitors: Based on physiologically-based pharmacokinetic (PBPK) modeling, no clinically meaningful interaction is expected during concomitant use of ORZEYFUL with weak CYP3A inhibitors.
• Strong and Moderate CYP3A Inducers: Concomitant use of ORZEYFUL with phenytoin (a strong CYP3A inducer) resulted in decreases in oveporexton AUC_inf and C_max by 81% and 56%, respectively, compared to use of ORZEYFUL alone [see Drug Interactions (7)]. Based on PBPK modeling, concomitant use of ORZEYFUL with a moderate CYP3A inducer is predicted to decrease AUC_inf and C_max by 73% and 55%, respectively, compared to use of ORZEYFUL alone [see Drug Interactions (7)].
• Weak CYP3A Inducers: Based on PBPK modeling, no clinically meaningful interaction is expected during concomitant use of ORZEYFUL with weak CYP3A inducers.

Effects of ORZEYFUL on Other Drugs:

Based on a clinical evaluation of the effect of oveporexton on CYP3A activity assessed by 4β-hydroxycholesterol to cholesterol ratios and PBPK modeling, oveporexton is not expected to affect CYP3A activity or alter systemic exposure of CYP3A substrates at the maximum recommended ORZEYFUL dose.

Based on a clinical evaluation of the effects of oveporexton on OATP1B1/B3 activity assessed by Coproporphyrin I (CPI) and Coproporphyrin III (CPIII), there was no apparent risk of inhibition of these transporters at the maximum recommended ORZEYFUL dose.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes:

In vitro, oveporexton exposures at the maximum recommended ORZEYFUL dose is not expected to directly inhibit or induce CYP enzymes (CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6).

Drug Transporter Systems

• Transporter Inhibition: In vitro, oveporexton did not inhibit P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2K, or MRP2.
• In vitro, oveporexton was an inhibitor of efflux transporters BSEP, MRP3, MRP4, and MDR3. However, inhibition of these transporters by oveporexton is not expected at the maximum recommended ORZEYFUL dose.
• Transporter Substrate: In vitro, oveporexton was not a substrate of P-gp, BCRP, OATP1B1, or OATP1B3.

Carcinogenesis

Oveporexton did not increase the incidence of tumors in rats treated for 2 years at oral doses up to 100 mg/kg/day (>335 times the MRHD based on AUC). Oveporexton did not increase the incidence of tumors in transgenic (TG) ras H2 mice treated for 26 weeks at oral doses up to 600 mg/kg/day (males) and 300 mg/kg/day (females).

Mutagenesis

Oveporexton was not mutagenic in an in vitro bacterial reverse mutation assay (Ames assay). Oveporexton was positive for genotoxic potential in an in vitro micronucleus assay; however, no genotoxic effects were observed in an in vivo bone marrow micronucleus assay or a liver comet assay in rats.

Impairment of Fertility

In a male and female fertility study, rats were treated orally with oveporexton at 10, 100, and 750 mg/kg/day (approximately 68, 311, 747 and 120, 455, 1499 times the MRHD based on AUC in males and females, respectively). Males were treated for 9 weeks prior to mating and 28 days through mating. Females were treated 2 weeks prior to mating, through mating, and through Gestation Day 6. In males, there were no effects on fertility or reproductive performance at any dose. In females, decreases in the number of corpora lutea followed by decreased numbers of implantations and live embryos were observed at 750 mg/kg/day.

The efficacy of ORZEYFUL for the treatment of narcolepsy type 1 (NT1) was evaluated in two randomized, multicenter, double-blind placebo controlled 12-week parallel group studies (Study 1 [NCT06470828] and Study 2 [NCT06505031]). Patients enrolled in both studies had a diagnosis of NT1 according to the International Classification of Sleep Disorders (ICSD-3) or International Classification of Sleep Disorders-Text Revision (ICSD-3-TR) criteria.

• In Study 1, 168 patients were randomized 2:3:3 to receive oral placebo (N=41) twice in the morning, ORZEYFUL 1 mg (N=61) twice in the morning, or ORZEYFUL 2 mg (N=66) twice in the morning. In all dosing groups, the two doses were taken at least 3 hours apart with the second dose taken no later than 1 PM.
• In Study 2, 105 patients were randomized 1:2 to receive oral placebo (N=35) or ORZEYFUL 2 mg (N=70) twice, in the morning. The two doses were taken at least 3 hours apart with the second dose taken no later than 1 PM.

Key Efficacy Endpoints

The primary efficacy endpoint in Studies 1 and 2 was the change from baseline to Week 12 in the mean sleep latency from the Maintenance of Wakefulness Test (MWT). MWT measures a patient's ability to remain awake during the daytime in a darkened, quiet environment. Patients were instructed to remain awake for as long as possible during 40-minute test sessions, and sleep latency was determined as the mean number of minutes patients could remain awake across the four test sessions. A normative mean sleep latency is defined as ≥20 minutes, with a clinically significant improvement defined to be an increase from baseline of more than 2 minutes.

Pre-specified secondary endpoints in Studies 1 and 2 included the:

• Epworth Sleepiness Scale (ESS) total score. ESS is an 8-item questionnaire by which patients rate their perceived likelihood of falling asleep during daily activities. A score of ≤10 is considered within the normative range, and a reduction of 2 points from baseline is defined as a clinically significant improvement.
• Weekly Cataplexy Rate (WCR). WCR is calculated from patients' self-reported cataplexy events in a daily diary. A reduction of at least 25% in the frequency of daily or weekly episodes, based on diary entries, is defined as a clinically significant improvement.
• Narcolepsy Severity Scale for Clinical Trials (NSS-CT) total score. NSS-CT is a 15-item self-administered questionnaire that assesses the overall severity of narcolepsy symptoms: daytime sleepiness, cataplexy, sleep paralysis, hallucinations, and disrupted nighttime sleep (DNS).
• Patient Global Impression of Change (PGI-C) score. The PGI-C is a self-administered questionnaire that assesses the overall global impression of the narcolepsy symptoms by the patient as the change due to treatment relative to baseline. The PGI-C was evaluated on a 7-point scale, centered at no change, and ranging from "very much worse" to "very much improved".

Important Baseline Disease Characteristics and Demographics

In Study 1, the mean age was 31 years (range 16 to 65 years of age), 58% were female; 35% were White, 16% were Asian, 4% were Black or African American, <1% were multiple races, and 44% were not known or reported; 45% were not of Hispanic or Latino ethnicity, 8% were of Hispanic or Latino ethnicity, and 47% the ethnicity was not known or reported.

In Study 2, the mean age was 31 years (range 18 to 62 years), 48% were Female, 45% were White, and 20% were Asian, and 35% had an unknown race; 65% were not of Hispanic or Latino ethnicity and 35% the ethnicity was not known or reported.

Efficacy Results

In Studies 1 and 2, ORZEYFUL 1 mg and 2 mg two times daily treatment groups, compared to the placebo treatment groups, demonstrated statistically significant improvements in the:

• Change from baseline to Week 12 in the:
  • Mean sleep latency from the MWT (primary efficacy endpoint).
  • ESS total score and the NSS CT total score.
• WCR and the PGI-C score at Week 12.

Efficacy results MWT, ESS, and WCR for Studies 1 and 2 are summarized in Table 3 below. In Studies 1 and 2:

• Examination of efficacy in males and females did not reveal clear evidence of differences in efficacy due to sex.
• There was insufficient data to examine if there were differences in efficacy by race/ethnicity.

Table 3. Efficacy Results for Maintenance of Wakefulness Test, Epworth Sleepiness Scale, and Weekly Cataplexy Rate in Patients with Narcolepsy Type 1 at 12 Weeks (Studies 1 and 2):

SD = standard deviation; SE = standard error; LS Mean = least square mean; CI = confidence interval
^* Two times daily, at least 3-5 hours apart
^† Statistically significantly superior to the placebo group after adjusting for multiplicity