Dublin, Ireland – August 13, 2018 – Shire plc (LSE: SHP, NASDAQ: SHPG) announces that its partner in Japan, Shionogi & Co., Ltd has submitted a New Drug Application (NDA) for the manufacture and marketing in Japan of INTUNIV ® (guanfacine hydrochloride extended release) for the treatment of attention deficit hyperactivity disorder (ADHD) in adults. The Japanese Phase 3 clinical trial was the first ever to evaluate INTUNIV in adult patients (18 years and over) with ADHD.
“This is a key milestone, taking us a step closer to potentially providing INTUNIV to adults in Japan in addition to the approved pediatric indication,” said Brigitte Robertson, M.D., VP and Head of Global Clinical Development, Neuroscience, Shire. “There remains a significant need for new non-stimulant treatment options for adults being diagnosed with ADHD in Japan,” she said.
INTUNIV, a non-stimulant, selective alpha-2A adrenergic receptor agonist2 has been approved as a treatment for child and adolescent patients (6 to 17 years old) with ADHD in Japan since March 2017. INTUNIV is being co-developed and commercialized by Shire and Shionogi under a licensing contract signed in 2011.
ADHD is characterized by 3 core symptoms of inattention, hyperactivity or impulsivity, or a combination of these symptoms,3,4 and can have substantial impact on major areas of life, including: schooling, work and employment, behaviour, and social functioning.5,6,7 Non-stimulant medications are an important alternative to stimulants for some patients with ADHD.8
Topline results from the Phase 3 efficacy trial in adults in Japan showed INTUNIV (4 to 6mg), administered once daily, met its primary endpoint, demonstrating superiority over placebo in the improvement of ADHD symptoms. Results also showed statistically significant improvement over placebo in patients’ global functioning.
This Phase 3 trial was a 12- week, randomized, double-blind, multi-center, parallel-group, placebo-controlled study in 201 adult patients (18 years old and over) with ADHD. The primary efficacy analysis demonstrated that INTUNIV (4 to 6 mg), administered as a once-daily dose, was superior to placebo with respect to the change from baseline to endpoint on a clinician administered ADHD rating scale (ADHD-RS-IV with adults prompts) total score. INTUNIV also demonstrated significance over placebo at the end of treatment on the secondary efficacy analysis of the Clinical Global Impression-Improvement scale (CGI-I), a standardized assessment tool that allows clinicians to rate changes in patients’ clinical condition over time. In this study, clinicians rated more than twice as many patients taking INTUNIV as “improved” and nearly half of patients as “much improved” or “very much improved”.
Treatment-emergent adverse events in the study were generally mild to moderate in severity and similar to those observed in previous INTUNIV studies with no new or unexpected safety findings. Treatment-emergent adverse events reported at more than or equal to 10% for INTUNIV were somnolence, dry mouth, blood pressure decreased, nasopharyngitis, dizziness postural and constipation.
Attention deficit hyperactivity disorder (ADHD) is recognised by the World Health Organization (WHO).3 Although there is no global consensus, a cross-national analysis of WHO World Mental Health (WMH) surveys estimated the mean prevalence of ADHD at 2.8% (range 0.6 to 7.3%) in adults9.
Although the exact origin of ADHD is not fully understood, the area of the brain identified as the prefrontal cortex is known to control several cognitive functions including attention and social behaviours,10,11,12 and has been associated with some structural and functional abnormalities in individuals with ADHD.13,14
ADHD is a complex disorder and approaches to treatment typically include educational methods, psychotherapy and medication.8 When required, either stimulants or non-stimulants are indicated as part of a comprehensive treatment programme for ADHD.8 Non-stimulant medications are an important alternative to stimulants for some ADHD patients.8
INTUNIV (guanfacine hydrochloride extended release) is a once-daily non-stimulant indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents from 6 to 17 years old.2
INTUNIV contains the active substance guanfacine, a selective alpha-2A adrenergic receptor agonist.2 Studies suggest that guanfacine may exert physiological effects by selectively stimulating the alpha-2A adrenergic receptor in the prefrontal cortex.15,16
INTUNIV is currently approved in 36 countries around the world including Australia, Canada, Switzerland, the United States, and Europe. INTUNIV should only be used in accordance with locally approved prescribing information. Please refer to the local label for the approved indication.
INTUNIV Safety Information for Japan
Precautions on Indication
*Diagnostic and Statistical Manual of Mental Disorders
Contraindication (INTUNIV is contraindicated in the following patients.)
This drug is primarily metabolized by the hepatic metabolizing enzymes CYP3A4 and CYP3A5.
Out of 254 patients evaluated for safety before NDA approval, adverse reactions (including abnormal changes in laboratory values) were observed in 190 patients (74.8%). Main adverse reactions were somnolence in 146 patients (57.5%), decreased blood pressure in 39 patients (15.4%), and headache in 31 patients (12.2%).
|Type/ Incidence||≥5%||<5%, ≥1%||<1%||Incidence unknownNote 1|
|Tachycardia, sinus arrhythmia, pallor, hypertensive encephalopathy|
|Psychoneurologic||Somnolence, headache, insomnia, dizziness||Irritability||Nightmare, affect lability, agitation, sedation, asthenia||Anxiety, depression, lethargy, convulsion, hypersomnia|
|Gastrointestinal||Abdominal pain||Decreased appetite, nausea, constipation, diarrhea, thirst, vomiting||Abdominal discomfort, dyspepsia|
|Others||Malaise||Enuresis, increased weight||Pollakiuria, increased
|Asthma, chest pain, dehydration|
Note 1: The incidence of adverse reactions on the basis of overseas clinical studies and spontaneous reports is unknown.
|Christoph Brackmann||[email protected]||+41 41 288 41 29|
|Sun Kim||[email protected]||+1 617 588 8175|
|Scott Burrows||[email protected]||+41 41 288 4195|
|Katie Joyce||[email protected]||+1 781 482 2779|
|Lauren Starr||[email protected]||+41 79 771 5245|
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1 IQVIA MIDAS data, 2018
2 INTUNIV Prescribing Information, Shionogi & Co., Ltd 2017.
3 International Classification of Diseases, 10th ed., (ICD-10). World Health Organization 2007. Chapter 5, F90. http://apps.who.int/classifications/icd10/browse/2010/en#/F90-F98. Last accessed August 2018.
4 American Psychiatric Association. (2013) Diagnostic and statistical manual of mental disorders: DSM-5 (5th ed.). Arlington, VA: American Psychiatric Publishing.
5 DIAMANTOPOULOU S, et al. (2007) Impact of Executive Functioning and Symptoms of Attention Deficit Hyperactivity Disorder on Children's Peer Relations and School Performance. Dev Neuropsychol. 32(1):521-542.
6 BIEDERMAN J, et al. (2006) Functional Impairments in Adults with Self-reports of Diagnosed ADHD: A Controlled Study of 1001 Adults in the Community. J Clin Psychiatry. 67:524-540.
7 SHAW M, et al. (2012) A Systematic Review and Analysis of Long-term Outcomes in Attention Deficit Hyperactivity Disorder: Effects of Treatment and Non-treatment. BMC Medicine. 10:99.
8 Kooij SJ, et al. (2010) European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD. BMC Psychiatry. 10: 67.
9 FAYFED J, et al. (2017) The descriptive epidemiology of DSM-IV Adult ADHD in the world health organization world mental health surveys. ADHD Attention Deficit and Hyperactivity Disorders. Mar 1;9(1):47-65
10 WILKINS AJ, et al. (1987). Frontal lesions and sustained attention. Neuropsychologia. 25:359-365.
11 ANDERSON SW, et al. (1999). Impairment of social and moral behavior related to early damage in human prefrontal cortex. Nature Neuroscience. 2:1032-1037.
12 MANES F, et al. (2002). Decision-making processes following damage to the prefrontal cortex. Brain. 125:624-639.
13 RUBIA K. et al. (1999). Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: a study with functional MRI. American Journal of Psychiatry. 156:891-896.
14 HOEKZEMA E, et al. (2014). An independent components and functional connectivity analysis of resting state FMRI data points to neural network dysregulation in adult ADHD. Human Brain Mapping. 35:1261-1272.
15 REN WW, et al. (2012). Stimulation of α(2A)-adrenoceptors promotes the maturation of dendritic spines in cultured neurons of the medial prefrontal cortex. Molecular and Cellular Neuroscience. 49:205-216.
16 WANG M, et al. (2007). Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 129:397-410.