TOKYO & PRINCETON, N.J.--(BUSINESS WIRE)-- Otsuka Pharmaceutical Co., Ltd. and its U.S. subsidiary, Otsuka Pharmaceutical Development & Commercialization, Inc., today announced positive results of two, 6-week, Phase 3 clinical trials that evaluated the efficacy, safety, and tolerability of centanafadine for the treatment of adolescents and children with attention-deficit/hyperactivity disorder (ADHD). Centanafadine is a first-in-class norepinephrine, dopamine, and serotonin reuptake inhibitor.

• The first trial (NCT05257265) was a pivotal Phase 3, randomized, double-blind, three-arm, fixed-dose trial to evaluate the efficacy, safety, and tolerability of centanafadine for adolescents with ADHD from the ages of 13 to 17 years.²
• The second trial (NCT05428033) was a pivotal Phase 3, randomized, double-blind, 3-arm, fixed-dose trial to evaluate the efficacy, safety, and tolerability of centanafadine for children with ADHD from the ages of 6 to 12 years.³

The trials were similar in design; both were three-arm, double-blind, fixed-dose trials in which patients were randomized to receive either low-dose centanafadine, high-dose centanafadine, or placebo.^2,3

“Otsuka is committed to finding novel solutions for complex, underserved medical needs,” said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka Pharmaceutical Development & Commercialization, Inc. “We are pleased these pivotal Phase 3 results demonstrate centanafadine has the potential to offer a new treatment option for children and adolescents who live with ADHD, a condition that can affect every aspect of life.”

Topline Results

The primary outcome in both trials was the change from baseline to week 6 in the ADHD Rating Scale (ADHD-RS-5) symptoms total score.

The first trial (NCT05257265) in adolescents aged 13-17 met its primary endpoint by demonstrating improvements from baseline on the ADHD-RS-5 scale. Patients receiving centanafadine saw statistically significant improvements compared to placebo for both the average effect of the high and low dose ([p=0.0099]) and for the high dose ([p=0.0006]) centanafadine-treated groups. The low-dose centanafadine-treated group did not reach statistical significance.

The second trial (NCT05428033) in children aged 6-12 met its primary endpoint by demonstrating improvements from baseline on the ADHD-RS-5 scale. Patients receiving centanafadine saw statistically significant improvements compared to placebo for both the average effect of the high and low dose ([p=0.0039]) and for the high dose ([p=0.0008]) centanafadine-treated group. The low-dose centanafadine-treated group did not reach statistical significance.

In both trials, the high dose centanafadine showed separation from placebo as early as week 1, the first post-baseline timepoint, with the effect maintained throughout the study period.

In a pooled analysis across the two studies, the most frequently observed side effects for centanafadine (>2 percent and more frequent than placebo) included decreased appetite, nausea, rash, fatigue, upper abdominal pain and somnolence. Overall, the safety and tolerability results were consistent with the profile of centanafadine seen within the wider clinical development program.

Full study results are not yet available. The trial results are planned to be submitted for scientific publication at a later date. Clinical pharmacology studies and long-term stability studies are underway, and the NDA will be filed in the U.S. as soon as these are completed.

Otsuka is incredibly appreciative to all the children and adolescents with ADHD, their families and caregivers, as well as the investigators and site staff who participated in the trial(s) and contributed greatly to this research.

About Centanafadine and the Phase 3 Program

Centanafadine is a first-in-class norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI) being developed for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. NCT05257265 and NCT05428033 were designed to evaluate the efficacy, safety, and tolerability of centanafadine in adolescents and children with ADHD. The trial populations included male and female patients, aged 13-17 years (inclusive) and 4-12 years (inclusive), respectively, with a primary diagnosis of ADHD based on DSM-5 criteria and confirmed with the MINI-KID. The topline data announced from NCT05428033 is from participants aged 6-17 years. The trial has a separate cohort of children aged 4-5 years that has not yet started.^2,3

Both trials consisted of six weeks of double-blind randomized treatment with a 7-day follow-up. Both trials were three-arm, double-blind, fixed-dose trials in which study participants were randomized to receive low-dose centanafadine, high-dose centanafadine, or placebo. The dose for each patient was determined by body weight.^2,3

The primary outcome in both trials was the change from baseline to week 6 in the ADHD Rating Scale – ADHD-RS-5 symptoms total score. Trials were conducted in the United States and Canada.^2,3

In 2020, Otsuka announced positive topline results from two, six-week, Phase 3 clinical trials that evaluated the efficacy, safety, and tolerability of oral centanafadine for the treatment of adult patients with attention-deficit/hyperactivity disorder. In both studies, centanafadine demonstrated statistically significant improvements vs. placebo for primary and key secondary efficacy endpoints in both studies. Centanafadine was well tolerated in adults, in the combined analysis across the two studies, no adverse event was reported by more than 7 percent of patients.⁴

About ADHD-RS-5

The Attention-Deficit/Hyperactivity Disorder Rating Scale Version 5 (ADHD-RS-5) is a tool used to evaluate the severity of ADHD symptoms in children and adolescents.⁵ The scale assessment was conducted by a clinician with the study participant’s caregiver.

About Attention-Deficit/Hyperactivity Disorder (ADHD)

According to the Attention Deficit Disorder Association, an estimated 9.8 percent (six million) of children and adolescents in the U.S. have attention-deficit/hyperactivity disorder (ADHD).¹ ADHD is a neurodevelopmental disorder defined by impairing levels of inattention, disorganization, and/or hyperactivity-impulsivity [DSM-5].^1,6

These brain operations include important functions such as attention, concentration, memory, motivation and effort, learning from mistakes, impulsivity, hyperactivity, organization, and social skills. ADHD has no known cure and the majority of people do not outgrow it. Approximately two-thirds or more of children with ADHD continue to have symptoms and challenges in adulthood.⁷

For additional information on ADHD, please visit the National Institute of Mental Health website.

About Otsuka

Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: Otsuka–people creating new products for better health worldwide. Otsuka researches, develops, manufactures, and markets innovative products, with a focus on pharmaceutical products to meet unmet medical needs and nutraceutical products for the maintenance of everyday health.

In pharmaceuticals, Otsuka is a leader in the challenging areas of mental, renal, and cardiovascular health and has additional research programs in oncology and on several under-addressed diseases including tuberculosis, a significant global public health issue. These commitments illustrate how Otsuka is a “big venture” company at heart, applying a youthful spirit of creativity in everything it does.

Otsuka established a presence in the U.S. in 1973 and today its U.S. affiliates include Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Otsuka America Pharmaceutical, Inc. (OAPI). These two companies’ 2,000 employees in the U.S. develop and commercialize medicines in the areas of mental health and nephrology, using cutting-edge technology to address unmet healthcare needs.

OPDC and OAPI are indirect subsidiaries of Otsuka Pharmaceutical Company, Ltd., which is a subsidiary of Otsuka Holdings Co., Ltd. headquartered in Tokyo, Japan. The Otsuka group of companies employed 47,000 people worldwide and had consolidated sales of approximately USD 13.1 billion in 2022.

All Otsuka stories start by taking the road less traveled. Learn more about Otsuka in the U.S. at www.otsuka-us.com and connect with us on LinkedIn and X at @OtsukaUS. Otsuka Pharmaceutical Co., Ltd.’s global website is accessible at https://www.otsuka.co.jp/en/.

References

1. Bitsko RH, Claussen AH, Lichstein J, et al. Mental Health Surveillance Among Children - United States, 2013-2019. MMWR Suppl. 2022;71(2):1-42.
2. ClinicalTrials.gov. National Library of Medicine (U.S.). A Trial of Centanafadine Efficacy and Safety in Adolescents With Attention- Deficit/Hyperactivity Disorder. Identifier: NCT05257265. https://classic.clinicaltrials.gov/ct2/show/NCT05257265.
3. ClinicalTrials.gov. National Library of Medicine (U.S.). A Trial of Centanafadine Efficacy and Safety in Children With Attention-deficit/ Hyperactivity Disorder (ADHD). Identifier: NCT05428033. https://classic.clinicaltrials.gov/ct2/show/NCT05428033.
4. Adler LA, Adams J, Madera-McDonough J, et al. Efficacy, Safety, and Tolerability of Centanafadine Sustained-Release Tablets in Adults With Attention-Deficit/Hyperactivity Disorder: Results of 2 Phase 3, Randomized, Double-blind, Multicenter, Placebo-Controlled Trials. J Clin Psychopharmacol. 2022;42(5):429-439.
5. Markowitz JT, Oberdhan D, Ciesluk A, Rams A, Wigal SB. Review of Clinical Outcome Assessments in Pediatric Attention-Deficit/Hyperactivity Disorder. Neuropsychiatr. Dis Treat. 2020;16:1619-1643.
6. Wolraich ML, Hagan JF Jr, Allan C, et al. Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents [published correction appears in Pediatrics. 2020 Mar;145(3):]. Pediatrics. 2019;144(4):e20192528.
7. Attention deficit Disorder Association. ADHD: The Facts. (n.d.) Available at: https://add.org/adhd-facts/ (last accessed 24 Oct 2023).

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