Oveporexton

Available data from clinical trials with ORZEYFUL use during pregnancy are insufficient to identify a drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Animal reproduction studies did not show evidence of embryofetal toxicity or effects on pre- and post-natal development.

The background risk of major birth defects and miscarriage in adults with narcolepsy type 1 is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There are no data available on the presence of oveporexton in human milk, the effects on the breastfed infant, or the effects on milk production. Animal studies indicate that oveporexton was present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ORZEYFUL and any potential adverse effects on the breastfed infant from ORZEYFUL or from the underlying maternal condition.

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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of oveporexton was evaluated in two 12-week placebo-controlled phase 3 studies (Studies 1 and 2) in 196 oveporexton-treated patients with narcolepsy type 1. Patients in the oveporexton group received doses of 1 mg or 2 mg twice in the morning (the two doses were taken at least 3 hours apart with the second dose taken no later than 1 PM) for 12 weeks.

In these studies, the:

• Discontinuation rate due to an adverse reaction was 2.6% in oveporexton-treated patients and 1.3% in placebo-treated patients.
• Most common adverse reactions (incidence ≥5% and greater than placebo) in oveporexton-treated patients were insomnia, pollakiuria, micturition urgency, and salivary hypersecretion.

Table 1 describes the adverse reactions that occurred at a rate of ≥2% in oveporexton-treated patients and more frequently than in placebo-treated patients in Studies 1 and 2.

Table 1. Adverse Reactions Reported in ≥2% of Oveporexton-Treated Patients and Greater than Rate of Placebo in Patients with Narcolepsy Type 1 (Studies 1 and 2):

^* The two oveporexton doses were taken at least 3 hours apart with the second dose taken no later than 1 PM
^** Includes Insomnia, Middle Insomnia, and Initial Insomnia

Insomnia

In Studies 1 and 2, insomnia occurred in 58% of oveporexton-treated patients and severe insomnia occurred in 1.5% of oveporexton-treated patients. Regarding the insomnia events in oveporexton-treated patients:

• Approximately 90% started within the first 2 days of therapy initiation, and 4% began between days 2 and 7 of therapy initiation.
• Approximately 63% resolved within 1 week of onset, and approximately 17% were ongoing at study completion.
• None led to study discontinuation or were classified as serious adverse reactions.

Urinary Adverse Reactions

In Studies 1 and 2, urinary adverse reactions occurred in 63% of oveporexton-treated patients and severe urinary adverse reactions occurred in 1% of oveporexton-treated patients. Two oveporexton-treated patients discontinued treatment, one due to frequent urination and the other due to urinary incontinence.

Vital Sign Changes

In Studies 1 and 2, increases of in-clinic blood pressure (BP) and heart rate (HR) were noted on day 1 with higher frequency in oveporexton-treated patients compared to placebo-treated patients. Increases in systolic and diastolic BP (>20 mm Hg) occurred in 22% and 9% of oveporexton-treated patients and 13% and 7% of placebo-treated patients, respectively and increases in HR (>15 bpm) occurred in 30% of oveporexton-treated patients and 22% of placebo-treated patients. The placebo adjusted mean changes in BP and HR from baseline in oveporexton-treated patients were <5 mm Hg and <2 bpm by Week 12, respectively.

No significant differences in BP or HR were observed at Week 10 compared to baseline with 24-hour ambulatory blood pressure and heart rate monitoring.

Low-Density Lipoprotein Cholesterol Elevations

In Studies 1 and 2, LDL values >160 mg/dL were observed in 32% (62/196) of oveporexton-treated patients and 20% (15/76) of placebo-treated patients. Mean (SD) LDL changes from baseline to Week 12 were +17.6 (21.9) mg/dL and +4.4 (17.5) mg/dL for the pooled oveporexton treatment group (1 mg and 2 mg twice daily combined groups) and the placebo group, respectively.