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
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
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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:
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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.
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29. DoF INT/SPD503-020/v2, Shire Pharmaceuticals, July 2015