• SIMTRIYO is the first and only norepinephrine, dopamine, serotonin reuptake inhibitor (NDSRI) approved for the treatment of ADHD in adults and pediatric patients aged 6 years and older weighing at least 20kg
• SIMTRIYO will be commercially available later this year following scheduling by the U.S. Drug Enforcement Administration (DEA)
• Approval is supported by results from four pivotal Phase 3 clinical trials in adults and pediatric patients demonstrating statistically significant and clinically meaningful improvements in ADHD symptoms and a well-characterized safety profile
• ADHD is a chronic neurodevelopmental disorder that affects approximately 22.5 million children, adolescents, and adults in the U.S.

Otsuka Pharmaceutical Development & Commercialization, Inc. and Otsuka Pharmaceutical Co., Ltd. (Otsuka) today announced that the U.S. Food and Drug Administration (FDA) has granted approval of SIMTRIYO^® (centanafadine), a once-daily extended-release capsule for the treatment of attention-deficit hyperactivity disorder (ADHD) in adults and pediatric patients aged 6 years and older weighing at least 20kg. As the first and only approved norepinephrine, dopamine, serotonin reuptake inhibitor (NDSRI), SIMTRIYO introduces a new treatment approach for patients and healthcare professionals managing this complex and highly individualized condition. By inhibiting the reuptake of norepinephrine, dopamine, and serotonin, SIMTRIYO increases the availability of these neurotransmitters in pathways involved in attention and behavioral regulation. SIMTRIYO, an NDSRI and central nervous system (CNS) stimulant, is expected to be available later this year following scheduling by the U.S. Drug Enforcement Administration (DEA).

The approval is supported by results from four pivotal Phase 3 clinical trials evaluating the efficacy and safety of SIMTRIYO across adult, adolescent, and pediatric patients. In these Phase 3 clinical studies, SIMTRIYO demonstrated statistically significant and clinically meaningful improvements in ADHD symptoms compared with placebo, as measured by the ADHD Rating Scale-5 (ADHD-RS-5) in children and adolescents and the Adult ADHD Investigator Symptom Rating Scale (AISRS) in adults. In pediatric and adult studies, improvements in ADHD symptoms were seen as early as week 1. The most common adverse events include decreased appetite, nausea, rash, headache, and abdominal pain in children and adolescents, and headache, decreased appetite, insomnia, nausea, dry mouth, and diarrhea in adults.

“The approval of SIMTRIYO marks an important milestone for people living with ADHD, as it introduces a novel treatment approach for this condition,” said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka. “ADHD is a complex and highly individualized disorder that can affect people throughout childhood, adolescence, and adulthood. Today’s approval reflects our commitment to advancing innovative treatment options that address the diverse needs of patients and families managing ADHD. We are deeply grateful to the patients, caregivers, investigators, and clinical teams whose participation made this achievement possible.”

Additional clinical research continues to expand the evidence base for centanafadine. In a recently completed Phase 3b study in adults with ADHD and comorbid anxiety, centanafadine demonstrated statistically significant improvements in ADHD symptoms compared with placebo, providing additional insight into its clinical profile. Full study results will be presented at an upcoming scientific meeting.

ADHD is a chronic neurodevelopmental disorder characterized primarily by impairments in attention, hyperactivity, and impulsivity¹. The disorder can affect academic performance, occupational functioning, social relationships, and challenges that impact patients’ daily lives¹. Although ADHD is often diagnosed during childhood, symptoms frequently persist into adolescence and adulthood¹.

“ADHD can significantly affect many aspects of daily life across school, work, and relationships,” said Dr. Lenard A. Adler, director of the adult ADHD program at NYU Langone Health. “Even when on treatment, because of the heterogenic nature of ADHD, many patients continue to experience symptoms that can interfere with daily functioning. The approval of SIMTRIYO introduces a novel mechanism of action and expands the range of options available to healthcare professionals and patients. Having more therapeutic choices is important because ADHD is a highly individualized condition and treatment decisions should reflect the unique needs of each patient.”

Data Supporting Approval
The FDA approval of SIMTRIYO is supported by results from four randomized, double-blind, placebo-controlled Phase 3 clinical trials evaluating the efficacy and safety of centanafadine in children, adolescents, and adults with ADHD.

In the two pivotal adult studies (NCT03605680 and NCT03605836), both centanafadine dose groups demonstrated statistically significant improvements in Adult ADHD Investigator Symptom Rating Scale (AISRS) total scores compared with placebo. Improvements were observed as early as Week 1 and maintained throughout the six-week treatment period. In the pivotal pediatric and adolescent studies (NCT05428033 and NCT05257265), high-dose centanafadine demonstrated statistically significant improvements in ADHD Rating Scale-5 (ADHD-RS-5) total scores compared with placebo. Improvements were observed as early as Week 1.

Across the Phase 3 clinical development program, centanafadine was generally well-tolerated. Clinical and preclinical data demonstrated a well-studied and consistent safety profile. The most common adverse reactions were rash and decreased appetite in children 6 to 12 years of age; decreased appetite, nausea, rash, headache and abdominal pain in adolescents 13 to 17 years of age; and headache, decreased appetite, insomnia, nausea, dry mouth, and diarrhea in adults.

About Attention-Deficit Hyperactivity Disorder (ADHD)
ADHD is a chronic neurodevelopmental disorder characterized primarily by impairments in attention, hyperactivity, and impulsivity¹. It affects approximately 7 million children in the U.S. and an estimated 15.5 million adults, according to the Centers for Disease Control and Prevention (CDC)^2,3.

About SIMTRIYO^® (Centanafadine)
SIMTRIYO^® (centanafadine) is a first-in-class norepinephrine, dopamine, serotonin reuptake inhibitor (NDSRI) and CNS stimulant. Clinical studies have shown that SIMTRIYO significantly reduced symptoms of ADHD in adults and pediatric patients aged 6 years and older weighing at least 20kg. Clinical data suggest SIMTRIYO has demonstrated a well-studied and consistent safety profile.

INDICATION and IMPORTANT SAFETY INFORMATION for SIMTRIYO^® (centanafadine)

INDICATION

Simtriyo is a norepinephrine-dopamine-serotonin reuptake inhibitor and central nervous system stimulant indicated for the treatment of ADHD in adults and pediatric patients 6 years of age and older weighing at least 20 kg.

Limitations of Use

The use of Simtriyo is not recommended in pediatric patients younger than 6 years of age, because this pediatric subpopulation had a higher incidence of weight loss than pediatric patients 6 years of age and older, or in pediatric patients weighing less than 20 kg, because of a lack of data for this subpopulation and the risk of weight loss.

IMPORTANT SAFETY INFORMATION

WARNING: SUICIDAL IDEATION AND BEHAVIORS IN PEDIATRIC PATIENTS AGED 6 YEARS AND OLDER

Higher rates of suicidal ideation and behaviors occurred in Simtriyo-treated patients aged 6 to 12 years with attention-deficit/hyperactivity disorder (ADHD) than in placebo-treated patients. Closely monitor all pediatric patients for suicidal ideation and behaviors. Consider stopping Simtriyo in patients who experience emergent suicidal ideation and behavior.

WARNING: ABUSE, MISUSE, AND ADDICTION

Simtriyo has a potential for abuse and misuse. Abuse of central nervous system (CNS) stimulants, including Simtriyo, can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including Simtriyo, can result in overdose and death. Before prescribing Simtriyo, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of Simtriyo, and proper disposal of any unused drug. Throughout treatment, reassess each patient’s risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

Contraindications: Simtriyo is contraindicated in patients with a known hypersensitivity to centanafadine or any of the excipients of Simtriyo, taking or within 14 days of stopping a monoamine oxidase inhibitor, or with pheochromocytoma or a history of pheochromocytoma.

Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

Increased Blood Pressure and Heart Rate: Assess heart rate and blood pressure following increases in dosage, and periodically while on therapy.

Psychiatric Adverse Reactions: If new psychotic or manic symptoms occur, consider discontinuing Simtriyo.

Hypersensitivity Reactions: Serious hypersensitivity, including anaphylaxis and angioedema, have been reported. If a clinically significant hypersensitivity reaction occurs, immediately discontinue Simtriyo and initiate appropriate therapy.

Long-Term Suppression of Growth in Pediatric Patients: Closely monitor height, body mass index and linear growth in pediatric patients. Consider treatment interruption in patients not growing or gaining height or weight as expected.

Peripheral Vasculopathy Including Raynaud’s Phenomenon: Carefully assess for digital changes during Simtriyo treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy.

Serotonin Syndrome: Use of Simtriyo with other serotonergic drugs may cause serotonin syndrome. If occurs, discontinue Simtriyo and/or concomitant serotonergic drug.

Motor and Verbal Tics and Worsening of Tourette’s Syndrome: Regularly monitor patients for the emergence or worsening of tics or Tourette's syndrome. Discontinue Simtriyo if clinically appropriate.

Most commonly observed adverse reactions (≥5% and greater than placebo):

The most common adverse reactions in pediatric patients (aged 6 to 12 years) were rash and decreased appetite, and (aged 13 to 17 years) decreased appetite, nausea, rash, headache, and abdominal pain. The most common adverse reactions in adults were headache, decreased appetite, insomnia, nausea, dry mouth, and diarrhea.

Pregnant women exposed to Simtriyo and healthcare providers are encouraged to contact the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/research/pregnancyregistry/adhd-medications/

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNINGS.

About Otsuka
Otsuka Pharmaceutical Co., Ltd. is a total healthcare company that focuses on each individual's potential to enhance their well-being. Our medical-related business provides treatments and diagnostics for both physical and mental health. Our nutraceutical business supports daily health maintenance and improvement. Otsuka's unique products and services are based on scientific evidence, under the guidance of our corporate philosophy: Otsuka-people creating new products for better health worldwide.  

Otsuka America Pharmaceutical, Inc. and Otsuka Pharmaceutical Development & Commercialization, Inc. are the US-based indirect subsidiaries of the global healthcare company Otsuka Pharmaceutical Co. Ltd. Otsuka’s US companies share a deep commitment to the development and commercialization of innovative products in the spaces of neuroscience, nephrology, and immunology. At our core is perseverance—a fierce determination to overcome any obstacle, regardless of setbacks, on behalf of patients, caregivers, and their loved ones. We will not be bound by doing what’s been done before. Learn more at www.otsuka-us.com.

References

1. American Psychiatric Association (2022). Diagnostic and Statistical Manual of Mental Disorders (5th ed., text rev).
2. Staley, Brook S, et al. Attention-Deficit/Hyperactivity Disorder Diagnosis, Treatment, and Telehealth Use in Adults — National Center for Health Statistics Rapid Surveys System, United States, October–November 2023. US Centers for Disease Control and Prevention.
3. Data and Statistics on ADHD. Attention-Deficit/ Hyperactivity Disorder (ADHD). November 19. 2024. U.S. Centers for Disease Control and Prevention. https://www.cdc.gov/adhd/data/index.html.

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