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Takeda Launches ORZEYFUL(TM) (oveporexton), the First and Only Medicine of Its Kind for Narcolepsy Type 1 Now Available in the United States

Takeda Pharmaceutical Company Limited

• Adults Living with NT1 Can Now be Prescribed ORZEYFUL, a New First-in-Class Orexin Medicine that Treats the Disease Holistically
• ORZEYFUL has the Potential to Redefine the Standard of Care by Targeting the Underlying Orexin Deficiency Associated with NT1

OSAKA, Japan & CAMBRIDGE, Mass.--BUSINESS WIRE--

Takeda (TSE:4502/NYSE:TAK) announced that ORZEYFUL™ (oveporexton) CIV is now available in the U.S. by prescription for the treatment of narcolepsy type 1 (NT1, narcolepsy with cataplexy) in adults, bringing the first and only orexin agonist to this community. Learn more at ORZEYFUL.com.

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“Living with narcolepsy type 1 is an ongoing struggle to keep it together – from scheduling naps and anticipating sleep attacks to figuring out how to be present as a mom and a professional,” said Emily P., clinical trial participant with NT1. “With ORZEYFUL, I feel more confident planning my day because my narcolepsy has become more manageable.”

Driven by orexin deficiency, the persistent 24-hour nature of NT1 affects far more than daytime sleepiness; it shapes how people plan their days and navigate many parts of their lives. What others might do without thinking can require careful planning, endless calculations and constant balancing to get through the day. Now, for the first time, people living with NT1 have a new option that targets the underlying orexin deficiency to treat the disease holistically rather than individual symptoms.

“Clinical trials showed ORZEYFUL improved the full range of symptoms, and now we can bring those results into real-world practice,” said Dr. Emmanuel Mignot, M.D., Ph.D., principal U.S. investigator in the ORZEYFUL Phase 3 program. “Using ORZEYFUL to target the underlying cause of narcolepsy type 1 is a welcome and exciting development in sleep medicine. I can now start a new conversation with my patients about their symptoms and how using this new treatment approach may make a real difference for them.”

“We work for decades toward the defining moments that have the potential to make a real difference for patients,” said Rhonda Pacheco, president of Takeda’s U.S. Business Unit. “Bringing ORZEYFUL, a first-in-class medicine, to people living with narcolepsy type 1 in the U.S. is one of those moments. We’re incredibly proud to be here, and equally focused on what comes next: supporting care and access for patients prescribed ORZEYFUL.”

ORZEYFUL is available by prescription from a licensed healthcare providers and will be dispensed across the U.S. through Accredo Specialty Pharmacy, part of Evernorth Health Services. Takeda offers patient support programs to help eligible adult patients prescribed ORZEYFUL get started, including help understanding coverage steps and connecting to available assistance options. For more information about ORZEYFUL, including prescribing information and available patient support visit ORZEYFUL.com.

About Narcolepsy Type 1 (NT1, narcolepsy with cataplexy), an Underdiagnosed Neurological Disease

NT1 is a rare, chronic neurological disease driven by a loss of orexin that affects an estimated 3 million people worldwide and 120,000 in the U.S. NT1 is characterized by excessive daytime sleepiness, cataplexy (sudden loss of muscle tone), cognitive symptoms and disrupted nighttime sleep that can severely impact daily life, including work, education and social relationships.

More than half of treated NT1 patients remain symptomatic. NT1 also remains significantly underdiagnosed, with only an estimated 50% diagnosed in the U.S., a process that can take an average of 10 years. This diagnostic gap is partly due to symptom overlap with other sleep-wake and comorbidity disorders as well as the limited availability of easy-to-use diagnostic tools. Takeda is working to potentially address these challenges through development of biomarker solutions and digital tools that support earlier identification and differentiation of NT1.

About ORZEYFUL (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, ORZEYFUL 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. The most common side effects include trouble sleeping (insomnia), urinary urgency, urinary frequency and excessive saliva.

The U.S. Food and Drug Administration approved ORZEYFUL in August 2026 pending controlled substance classification. ORZEYFUL has since been classified as a schedule IV controlled substance (CIV).

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, a Schedule IV controlled substance.

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.

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 plays a role including respiration, mood and metabolism. ORZEYFUL (oveporexton) is the lead orexin receptor 2 (OX2R) agonist asset in Takeda’s orexin franchise and has been approved by regulatory bodies in China, Japan and the United States for the treatment of narcolepsy type 1 (NT1). The company is also investigating other oral orexin agonists, including TAK-360 being investigated 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 takeda.com.

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