Enable AccessibilityEnable Accessibility

Shire receives CHMP Positive Opinion in Europe for INTUNIV®▼ (guanfacine hydrochloride extended release) as a non-stimulant ADHD treatment for children and adolescents

July 23, 2015

ZUG, Switzerland – Shire plc (LSE: SHP, NASDAQ: SHPG) today announced that the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending the approval of the once-daily, non-stimulant INTUNIV® (guanfacine hydrochloride extended release; GXR) for the treatment of attention deficit/hyperactivity disorder (ADHD) in children and adolescents.

The CHMP’s positive opinion is based on results from three Phase 3 pivotal studies investigating the short- and long-term safety and efficacy of INTUNIV® in children and adolescents with ADHD.1-3

“This positive opinion from the CHMP is an important step towards providing physicians with a new therapeutic option for children and adolescents with ADHD,” said Philip J. Vickers, Ph.D., Head of Research and Development, Shire. “Due to the varying needs of patients and the different manifestations of ADHD, non-stimulant medications are an important treatment option for some patients in Europe.”

The European Commission will now consider the CHMP positive opinion in its decision of whether to grant marketing authorisation for INTUNIV® in Europe.

About ADHD in children and adolescents
ADHD is a common psychiatric disorder in children and adolescents4,5 and is recognised by the World Health Organization (WHO).6 The core symptoms are inattention, hyperactivity and impulsivity.6-8 In Europe, the prevalence of ADHD is estimated to be approximately 5% for children and adolescents (<18 years).4,5 While the exact origin of ADHD is not known, studies have indicated that ADHD could be associated with certain structural and functional brain abnormalities.9-21

About INTUNIV®
If approved in Europe, INTUNIV® will be indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents 6 to 17 years old for whom stimulants are not suitable, not tolerated or have been shown to be ineffective.
If approved, INTUNIV® must be used as a part of a comprehensive ADHD treatment programme, typically including psychological, educational and social measures.

INTUNIV® contains the active substance guanfacine, a selective alpha-2A adrenergic receptor agonist.22 Studies have suggested that guanfacine may exert physiological effects by stimulating the alpha-2A adrenergic receptor in the prefrontal cortex.23,24 This region is known to control several cognitive functions including attention and social behaviours,25-27 and has been associated with some structural and functional abnormalities in individuals with ADHD.10-12

Summary of the safety outcomes of the three Phase 3 pivotal studies

Hervas et al.1

The majority of treatment-emergent adverse events (TEAEs) reported across all treatment groups were mild-to-moderate in intensity. The most common TEAEs in the GXR group included somnolence, headache and fatigue. The most common TEAEs reported in the placebo group were headache, fatigue and somnolence. TEAEs leading to study discontinuation were reported in 7.9% and 0.9% of subjects in the GXR and placebo groups, respectively. There were no clinically meaningful changes in ECG and QTc events detected, and the impact on blood pressure and pulse were consistent with known effects and were unremarkable.1

Wilens et al.2,28

The majority of adverse events (AEs) were mild-to-moderate in severity, with the most common TEAEs among those receiving GXR being somnolence, headache, fatigue and dizziness. TEAEs that led to study discontinuation were reported by 9 patients receiving GXR and 3 patients receiving placebo. There were no clinically meaningful differences between GXR and placebo on the impact on blood pressure, pulse, ECG results or QTc-related parameters. With GXR, non-significant improvements were observed in child-rated daytime sleepiness on the PDSS and non-significant child-rated improvements in behavioural and emotional symptoms on the BPRS-C scale at endpoint.2,28

Newcorn et al.3,29

TEAEs in the open-label phase led to discontinuation in 8.0% of patients. Sedative events (somnolence, sedation and hypersomnia) were reported by 53.6% of the patients. 8.7% of sedative events led to dose reduction, and 2.7% of sedative events led to study discontinuation. At the end of the randomised double-blind treatment period, the majority of reported TEAEs were mild-to-moderate in intensity. The most common TEAEs included headache and somnolence. TEAEs that led to study discontinuation were reported by 3 (1.9%) patients receiving GXR (grand mal convulsion, sedation and somnolence) and 2 (1.3%) patients receiving placebo. Blood pressure and pulse observed in this study were consistent with the known profile of GXR and GXR was not associated with any clinically significant changes in ECG parameters, height or weight.3

For further information please contact:

Investor Relations    
Scott Santiamo [email protected] +1 484 343 2576
Deborah Hibbett [email protected] +41 41 288 4359

NOTES TO EDITORS

Shire enables people with life-altering conditions to lead better lives.

Our strategy is to focus on developing and marketing innovative specialty medicines to meet significant unmet patient needs.

We focus on providing treatments in Rare Diseases, Neuroscience, Gastrointestinal and Internal Medicine and we are developing treatments for symptomatic conditions treated by specialist physicians in other targeted therapeutic areas, such as Ophthalmics.

www.shire.com

THE “SAFE HARBOR” STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995

Statements included in this announcement that are not historical facts are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, Shire’s results could be materially adversely affected. The risks and uncertainties include, but are not limited to, that:

  • Shire’s products may not be a commercial success;
  • product sales from ADDERALL XR® and INTUNIV® are subject to generic competition;
  • the failure to obtain and maintain reimbursement, or an adequate level of reimbursement, by third-party payers in a timely manner for Shire's products may affect future revenues, financial condition and results of operations;
  • Shire conducts its own manufacturing operations for certain of its products and is reliant on third-party contract manufacturers to manufacture other products and to provide goods and services. Some of Shire’s products or ingredients are only available from a single approved source for manufacture. Any disruption to the supply chain for any of Shire’s products may result in Shire being unable to continue marketing or developing a product or may result in Shire being unable to do so on a commercially viable basis for some period of time;
  • the manufacture of Shire’s products is subject to extensive oversight by various regulatory agencies. Regulatory approvals or interventions associated with changes to manufacturing sites, ingredients or manufacturing processes could lead to significant delays, an increase in operating costs, lost product sales, an interruption of research activities or the delay of new product launches;
  • Shire has a portfolio of products in various stages of research and development. The successful development of these products is highly uncertain and requires significant expenditures and time, and there is no guarantee that these products will receive regulatory approval;
  • the actions of certain customers could affect Shire's ability to sell or market products profitably. Fluctuations in buying or distribution patterns by such customers can adversely affect Shire’s revenues, financial condition or results of operations;
  • investigations or enforcement action by regulatory authorities or law enforcement agencies relating to Shire’s activities in the highly regulated markets in which it operates may result in significant legal costs and the payment of substantial compensation or fines;
  • adverse outcomes in legal matters and other disputes, including Shire’s ability to enforce and defend patents and other intellectual property rights required for its business, could have a material adverse effect on Shire’s revenues, financial condition or results of operations;
  • Shire faces intense competition for highly qualified personnel from other companies and organizations. Shire is undergoing a corporate reorganization and was the subject of an unsuccessful acquisition proposal and the consequent uncertainty could adversely affect Shire’s ability to attract and/or retain the highly skilled personnel needed for Shire to meet its strategic objectives;
  • failure to achieve Shire’s strategic objectives with respect to the acquisition of NPS Pharmaceuticals Inc. may adversely affect Shire’s financial condition and results of operations;
  • and other risks and uncertainties detailed from time to time in Shire’s filings with the U.S. Securities and Exchange Commission, including its most recent Annual Report on Form 10-K.

REFERENCES:

1. HERVAS, et al. (2014). Efficacy and safety of extended-release guanfacine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder: a randomized, controlled, phase III trial. Eur Neuropsychopharmacol. 24(12):1861-72.
2. WILENS, TE. et al. A multicentre, placebo-controlled trial of guanfacine extended release in adolescents with attention- deficit/hyperactivity disorder. Poster presented at the 3rd EUNETHYDIS International Conference on ADHD; Istanbul, Turkey. 2014. 
3. NEWCORN, JH. et al. Long-term maintenance of efficacy of extended-release guanfacine hydrochloride (GXR) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD): double-blind, placebo-controlled, multicentre, Phase 3 randomized withdrawal study. Poster presented at 22nd European Congress of Psychiatry, Munich, Germany. 2014. 
4. POLANCZYK G, et al. (2007). The Worldwide Prevalence of ADHD: A Systematic Review and Metaregression Analysis. Am J Psych. 164:942-948.
5. WILLCUTT, EG. (2012). The Prevalence of DSM-IV Attention-deficit/Hyperactivity Disorder: A Meta-analytic Review. Neurotherapeutics. 9:490-499.
6. 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 May 2015.
7. MCCARTHY, S. et al. (2012). The Epidemiology of Pharmacologically Treated Attention Deficit Hyperactivity Disorder (ADHD) in Children, Adolescents and Adults in UK Primary Care. BMC Pediatr 12:78. 
8. Diagnostic and statistical manual of mental disorders, 5th ed., (DSM-5th). American Psychiatric Association. 2013. 
9. SHAW, P. et al. (2007). Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proceedings of the National Academy of Sciences USA. 104:19649-19654.
10. DICKSTEIN, SG. et al. (2006). The neural correlates of attention deficit hyperactivity disorder: an ALE meta-analysis. Journal of Child Psychology and Psychiatry. 47:1051-1062.
11. 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.
12. 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.
13. DAVENPORT, ND. et al. (2010). Differential fractional anisotropy abnormalities in adolescents with ADHD or schizophrenia. Psychiatry Research.181:193-198.
14. ELLISON-WRIGHT, I. et al. (2008). Structural brain change in Attention Deficit Hyperactivity Disorder identified by meta-analysis. BMC Psychiatry. 8:51.
15. FAIR, DA. et al. (2010). Atypical default network connectivity in youth with attention-deficit/hyperactivity disorder. Biological Psychiatry. 68:1084-1091.
16. IVANOV, I. et al. (2010). Morphological abnormalities of the thalamus in youths with attention deficit hyperactivity disorder. American Journal of Psychiatry. 167:397-408.
17. KOBEL, M. et al. (2010). Structural and functional imaging approaches in attention deficit/hyperactivity disorder: does the temporal lobe play a key role? Psychiatry Research. 183:230-236.
18. NAKAO, T. et al. (2011). Gray Matter Volume Abnormalities in ADHD: Voxel-Based Meta-Analysis Exploring the Effects of Age and Stimulant Medication. American Journal of Psychiatry. 168:1154-1163.
19. PAVULURI, MN. et al. (2009). Diffusion Tensor Imaging Study of White Matter Fiber Tracts in Pediatric Bipolar Disorder and Attention-Deficit/Hyperactivity Disorder. Biological Psychiatry. 65:586-593.
20. SHAW, P. et al. (2012). Development of Cortical Surface Area and Gyrification in Attention-Deficit/Hyperactivity Disorder. Biological Psychiatry. 72:191-197.
21. VALERA, EM. et al. (2007). Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder. Biological Psychiatry. 61:1361-1369.
22. UHLÉN, S & WIKBERG, J. (1991). Delineation of rat kidney α-2A and α-2B-adrenoceptors with [3H]RX821002 radiology and binding: Computer modelling reveals that guanfacine is an α-2A-selective compound. European Journal of Pharmacology. 202:235-243.
23. REN, WW. et al. (2012). Stimulation of (2A)-adrenoceptors promotes the maturation of dendritic spines in cultured neurons of the medial prefrontal cortex. Mol Cell Neurosci 49:205-216. 
24. WANG, M. et al. (2007). Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 129:397-410. 
25. MANES, F. et al. (2002). Decision-making processes following damage to the prefrontal cortex. Brain. 125:624-639.
26. WILKINS, AJ. et al. (1987). Frontal lesions and sustained attention. Neuropsychologia. 25:359-365. 
27. ANDERSON, SW. et al. (1999). Impairment of social and moral behavior related to early damage in human prefrontal cortex. Nat Neurosci. 2:1032-1037. 
28. Safety and Efficacy of SPD503 in Treating Attention-Deficit/Hyperactivity Disorder (ADHD) in Children Aged 6-17. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/results/NCT00152009?term=SPD503&rank=1. Last accessed July 2015.
29. DoF INT/SPD503-020/v2, Shire Pharmaceuticals, July 2015

Copyright 1995-2023 Takeda Pharmaceutical Company Limited. All rights reserved.