Data Demonstrated Significant and Clinically Meaningful Improvements with the Potential to Redefine Narcolepsy Type 1 (NT1) Care Beyond Individual Symptoms
Oveporexton was Generally Well-Tolerated with Safety Profile Consistent with Previous Clinical Studies
Oveporexton is the First and Only Approved Orexin Agonist Designed to Treat the Underlying Cause of NT1 and is Now Approved in the U.S., China and Japan, with Additional Regulatory Submissions Underway

OSAKA, Japan & CAMBRIDGE, Mass.--(BUSINESS WIRE)--Takeda (TSE:4502/NYSE:TAK) announced that the New England Journal of Medicine published results from two Phase 3 studies evaluating oveporexton (ORZEYFUL), an oral orexin receptor 2 (OX2R) agonist, in people with narcolepsy type 1 (NT1).1 Oveporexton is the first and only medicine to treat the underlying cause of NT1.

"People living with narcolepsy type 1 face persistent symptoms across the day and night, which can impact many aspects of daily life,” said Emmanuel Mignot, M.D., Ph.D., principal investigator for the FirstLight (TAK-861-3001) Phase 3 study. “The newly published Phase 3 data reinforce the potential of oveporexton to transform how we approach narcolepsy type 1 in clinical practice, shifting from managing individual symptoms to treating the disease itself.”

NT1 is a chronic, rare neurological disease driven by orexin deficiency. As a result, people experience a range of daytime and nighttime symptoms including excessive daytime sleepiness, cataplexy (sudden loss of muscle tone), disrupted nighttime sleep, sleep paralysis, hallucinations and cognitive symptoms. The persistent, 24 hour-nature of the disease can severely impact many aspects of a person’s life, including work, education and social interactions.

“Leveraging the extensive research we conducted on the impact of narcolepsy type 1, we designed our comprehensive Phase 3 program to reflect the complexity of the disease and the experiences of those living with it,” said Sarah Sheikh, M.Sc., B.M., B.Ch., MRCP, Head, Neuroscience Therapeutic Area Unit and Global Development at Takeda. “The magnitude of effect seen across the full range of symptoms evaluated reinforces the potential of oveporexton to redefine how people feel on treatment. We are grateful to the patients, caregivers and healthcare providers who have participated in our studies and are thrilled to bring the first orexin agonist to the community.”

FirstLight and Radiant Light Phase 3 Study Designs

The FirstLight (TAK-861-3001) study enrolled 168 participants randomized to one of three dosing arms (twice-daily 2mg, twice-daily 1mg and placebo). The RadiantLight (TAK-861-3002) study enrolled 105 participants randomized to two dosing arms (twice-daily 2mg and placebo). The 14 primary and secondary endpoints from the studies assessed the effect of oveporexton on the broad disease impact compared to placebo over 12 weeks. More than 95 percent of the participants who completed the studies enrolled in the ongoing long-term extension (LTE) study.

The data published in the New England Journal of Medicine included primary and key secondary efficacy results along with the safety and tolerability of oveporexton. Results from additional secondary and exploratory endpoints assessing quality of life measures and disease severity were also published.

Efficacy Results:

• The two Phase 3 studies demonstrated consistent, clinically meaningful and statistically significant improvements compared to placebo in wakefulness, sleepiness, cataplexy, disease severity and quality of life measures (p-values of <0.001) across doses over 12 weeks. These improvements were observed at the earliest assessed timepoint for each measure and were sustained throughout the duration of the studies.
• The median percent reductions in weekly cataplexy rate ranged from 79.0% to 88.8% with oveporexton versus 27.7% to 39.1% with placebo at week 12.
• Oveporexton improved disease severity across all domains of the narcolepsy severity scale (NSS-CT) including EDS, cataplexy, hypnagogic hallucinations and sleep paralysis across both doses, and in the disrupted nighttime sleep domain with oveporexton 2mg. More than 70% of treated participants reported the lowest severity level on the NSS-CT (mild; score 0-14) across doses.
• Nearly all treated participants (97%) reported improvements in overall narcolepsy symptoms as assessed by the self-rated Patient Global Impression of Change (PGI-C) scale.
• All dose groups achieved normative thresholds for wakefulness on the Maintenance of Wakefulness Test (MWT) (≥20 minutes) and Epworth Sleepiness Scale (ESS) (score of ≤10). Most participants reached or exceeded normal thresholds for quality of life outcomes as measured by the 36-Item Short Form Survey (SF-36; secondary endpoint) and EuroQol-5 Dimensions 5-Levels (EQ-5D-5L; exploratory endpoint).2.3

Safety Results:

• Consistent across clinical studies to date, the most commonly reported treatment-emergent adverse events (TEAEs) across both studies were transient insomnia, urinary urgency, urinary frequency and excessive saliva.
• Most TEAEs were mild to moderate in intensity, started within two days of treatment and did not require medical intervention.
• Most insomnia events resolved within one week and did not impair or impact daytime functioning, unlike traditional insomnia symptoms. Approximately half of urinary events resolved by week 12 and unresolved events were all mild or moderate in severity.

Oveporexton is the first and only orexin agonist approved in the United States, Japan and China to treat the disease holistically rather than individual symptoms. With additional regulatory submissions underway, Takeda continues to work with health authorities to bring oveporexton to more people living with NT1.

About Oveporexton (ORZEYFUL)

Oveporexton is an oral orexin receptor 2 (OX2R) agonist, which selectively stimulates the OX2R to restore signaling and address the underlying orexin deficiency associated with narcolepsy type 1 (NT1). By activating OX2Rs, oveporexton promotes wakefulness and reduces abnormal rapid eye movement (REM)-sleep like phenomena, including cataplexy (sudden and temporary loss of muscle tone), to address a range of daytime and nighttime symptoms as evaluated in clinical studies and consistent with the approved label.

INDICATION

ORZEYFUL is indicated for the treatment of narcolepsy type 1 (narcolepsy with cataplexy) in adult patients.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

ORZEYFUL is contraindicated in patients taking strong CYP3A inhibitors.

WARNINGS AND PRECAUTIONS

Insomnia: In pooled phase 3 studies in patients with NT1, 60%, 55%, and 1% of patients in the ORZEYFUL 2 mg twice daily, ORZEYFUL 1 mg twice daily, and placebo groups, respectively, developed insomnia. Prior to ORZEYFUL treatment initiation, inform patients about the risk of insomnia at initiation of treatment. If insomnia persists beyond 7 days and significantly impacts daytime functioning or quality of life, consider ORZEYFUL dosage reduction or discontinuation.

Urinary Frequency and Urgency: ORZEYFUL may cause or worsen urinary frequency and urgency. In pooled phase 3 studies in patients with NT1:

• 58%, 53%, and 5% of patients in the ORZEYFUL 2 mg twice daily, ORZEYFUL 1 mg twice daily, and placebo groups, respectively, developed urinary frequency.
• 16%, 15%, and 1% of patients in the ORZEYFUL 2 mg twice daily, ORZEYFUL 1 mg twice daily, and placebo groups, respectively, developed urinary urgency.

These lower urinary tract symptoms are consistent with ORZEYFUL’s mechanism of action through agonism of the orexin receptor 2 (OX2R) on central micturition pathways. Prior to initiation of ORZEYFUL treatment, inform patients about the risk of urinary frequency and urgency and screen for lower urinary tract symptoms. Monitor ORZEYFUL-treated patients with a history of overactive bladder for worsening urinary tract symptoms.

Creatine Phosphokinase Elevations: In pooled phase 3 studies in patients with NT1, asymptomatic creatine phosphokinase elevations >5x ULN were observed in 11% (21/196) of ORZEYFUL-treated patients and 5% (4/76) of placebo treated patients. Two of these cases were characterized by markedly elevated CPK and transaminase levels; both patients discontinued treatment. None of the cases were associated with myoglobinuria or renal impairment. Advise patients to report unexplained muscle pain, weakness, or dark urine, particularly when engaging in vigorous physical activity or taking concomitant drugs associated with myotoxicity.

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥5% and greater than placebo) reported in phase 3 studies with ORZEYFUL were insomnia, pollakiuria, micturition urgency, and salivary hypersecretion.

DRUG INTERACTIONS

• Concomitant use with strong or moderate CYP3A inhibitors increases oveporexton exposures, which may increase the risk of ORZEYFUL-associated adverse reactions.
• Concomitant use of strong and moderate CYP3A inducers can increase oveporexton metabolism and decrease plasma levels of oveporexton, which may decrease the effectiveness of ORZEYFUL.

USE IN SPECIFIC POPULATIONS

Pregnancy: There is a pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to ORZEYFUL during pregnancy. Patients should be encouraged to enroll in the ORZEYFUL pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call 1-877-371-0309. 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.

Lactation: 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.

Hepatic Impairment: Avoid use of ORZEYFUL in patients with severe hepatic impairment (Child-Pugh C), as it has not been studied in this population.

Renal Impairment: Avoid use of ORZEYFUL in patients with severe renal impairment on dialysis (eGFR <15 mL/minute), as it has not been studied in this population.

DRUG ABUSE AND DEPENDENCE

ORZEYFUL contains oveporexton. Controlled substance schedule to be determined after review by the Drug Enforcement Administration.

ORZEYFUL has potential for abuse and misuse. Carefully evaluate patients for a recent history of drug abuse, especially those with a history of CNS stimulant, and follow such patients closely, observing them for signs of misuse or abuse of ORZEYFUL.

Important Note: Prescribing Information is subject to change pending DEA scheduling and final label publication.

Please click for Full Prescribing Information.

About Takeda’s Orexin Franchise

Takeda is the leader in orexin science with a tailored portfolio of investigational orexin agonists in pre-clinical and clinical stages for multiple-sleep wake disorders and other indications where orexin biology plays a role including respiration, mood and metabolism. Oveporexton is the lead orexin receptor 2 (OX2R) agonist in Takeda’s orexin franchise and has been approved by regulatory bodies in China for the treatment of narcolepsy type 1 (NT1) in adolescents aged 16 and older and adults as well as in the United States and Japan for adults with NT1. The company is also investigating other oral orexin agonists, including TAK-360 for the treatment of NT1, narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH), as well as TAK-495.

About Takeda

Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit www.takeda.com.

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References

1. Dauvilliers Y, Mignot E, Antczak J, et al. Oveporexton for Narcolepsy Type 1: Results from Two Phase 3 Trials. New England Journal of Medicine 2026.

2. Jiang R, Bas Janssen MF, Pickard AS. US population norms for the EQ-5D-5L and comparison of norms from face-to-face and online samples. Qual Life Res 2021;30:803-16.

3. Maruish, M. E. User's Manual for the SF-36V2 Health Survey 2011. Lincoln, RI. 3rd ed.