New Orleans – November 16, 2006 -- Shire plc (Nasdaq: SHPGY, LSE: SHP, TSX: SHQ) announced today that once-daily doses of the investigational medication guanfacine extended release (GXR, also referred to as SPD503), a selective alpha-2A-adrenoceptor agonist, significantly improved symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) in children aged 6 to 17 years when used as a monotherapy. The phase III trial results were presented today at the 2006 U.S. Psychiatric & Mental Health Congress (USPMHC) annual meeting. Two additional studies also released at the meeting report the pharmacokinetic profile of guanfacine extended release.
Shire submitted a New Drug Application (NDA) for guanfacine extended release on August 24, 2006. If approved, guanfacine extended release, which is not a central nervous system stimulant, will be the first once-daily selective alpha-2A-adrenoceptor agonist compound indicated for the treatment of ADHD.
"Guanfacine extended release was developed to allow once-daily dosing through a controlled release formulation," said Eliseo Salinas, MD, Shire EVP and Chief Scientific Officer. "Research studies have shown that the extended-release formulation of guanfacine effectively provided day-long ADHD symptom control with a single daily dose based on several standard symptom measures."
Monotherapy with Once-Daily Guanfacine Extended Release Significantly Improved ADHD Symptoms In this study, investigators randomized 345 subjects to receive placebo or 2 mg, 3 mg or 4 mg guanfacine extended release once daily. The study consisted of three periods: screening (maximum of 14 days), washout (about one week for discontinuation of current ADHD medication) and double-blind treatment (eight weeks). Titration was done in a forced-dose manner by increasing guanfacine extended release in 1 mg increments per week, from 1 mg per day during the first week to a maximum of 4 mg daily in weeks four and five according to randomization. The guanfacine extended release dose was then decreased at the same weekly rate starting in weeks six and seven.
Compared to placebo, children aged 6 to 17 years treated with guanfacine extended release showed significant improvements in the core symptoms of ADHD (hyperactivity, impulsivity and inattention), as reflected by total scores on the primary efficacy measurement, the ADHD Rating Scale (ADHD-RS-IV). The ADHD-RS-IV is a standard test for diagnosing ADHD in children and adolescents and for assessing their response to treatment. The scale, which contains 18 items, is based on the ADHD diagnosis criteria as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision?, a publication of the American Psychiatric Association. A reduction in the ADHD-RS-IV score reflects improvement.
Overall, average reductions in ADHD-RS-IV total scores were 16.7 points for guanfacine extended release and 8.9 for placebo (P <.0001). Investigators observed improvement in ADHD-RS-IV scores as early as two weeks after dosing began, with significant improvement in all guanfacine extended release dose groups occurring at the third week and continuing through the last evaluation at week five. Also, an analysis by weight-adjusted actual dose (mg/kg) showed reductions in ADHD-RS-IV total scores from baseline of 34 percent to 65 percent for guanfacine extended release doses compared with 23 percent for placebo.
Significance was also seen in all secondary efficacy measures, which included scores on the Clinical Global Impression of Improvement (CGI-I), Clinical Global Impression of Severity (CGI-S), Conners' Parent Rating Scale- Revised: Short Form (CPRSR) and Conners' Teacher Rating Scale-Revised: Short Form (CTRS-R).
"As the first selective alpha-2A-adrenoceptor agonist being developed as an ADHD treatment, guanfacine extended release will be a welcomed addition to our armamentarium of ADHD medications. In this clinical trial, guanfacine extended release significantly improved ADHD symptoms based on several standard measures of response," noted Raun Melmed, MD, Medical Director of the Melmed Center in Scottsdale, AZ. "As a practicing physician I can say our community is always interested in expanding the range of ADHD treatment options which need to be used in the context of an overall treatment program, so patients can receive individualized and optimal care."
Guanfacine extended release was generally well-tolerated in this study. The most commonly reported treatment-emergent adverse events were somnolence, headache, fatigue, upper abdominal pain, and sedation. Incidence of sedative events (somnolence, sedation and fatigue) were usually mild or moderate in severity. Modest decreases in mean systolic and diastolic blood pressure and pulse were reported.
Guanfacine Extended Release Formulation and Pharmacokinetics Data Guanfacine extended release, a novel formulation of guanfacine, was developed by incorporating ionic polymers, enteric polymers, and organic acids within the tablet matrix. This formulation was designed to control and prolong the release of guanfacine, in contrast to the immediate, burst-like release provided by the commercially available Immediate Release (IR) formulation of guanfacine, which is indicated as a treatment for hypertension.
In a single-dose, pharmacokinetic study with healthy adults, guanfacine extended release had a doubling of Tmax and a significant reduction in Cmax versus immediate release guanfacine.
Shire Development Inc. supported the three guanfacine extended release studies.
About Guanfacine Extended Release Shire is seeking approval of 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg and 4 mg once-daily guanfacine extended release doses for the control of ADHD symptoms throughout the day in children aged 6 to 17 years. The guanfacine extended release NDA includes data from two placebo-controlled trials in children and adolescents ages 6 to 17 evaluating the compound's safety and efficacy in controlling ADHD symptoms evaluated on a once-weekly basis using the ADHD Rating Scale, which included both hyperactive/impulsive and inattentive subscales.
Guanfacine extended release is a once-daily formulation of the selective alpha-2A-adrenoceptor agonist. Unlike some other ADHD treatments, guanfacine extended release is not a central nervous system stimulant or a controlled substance.
Adrenergic receptors are present on almost all kinds of cells in the body and act as receptors for two neurotransmitters, epinephrine (adrenaline) and norepinephrine, used by nerve cells to communicate. An agonist is a molecule that acts similar to these neurotransmitters by also binding to receptors. It is hypothesized that guanfacine HCl binds to the alpha-2A-adrenergic cell receptor to act directly in the part of the brain called the prefrontal cortex, an area that is associated with working memory, behavioral inhibition, attention and cognitive control, as well as the ability to orchestrate thought and action.
About ADHD Approximately 7.8 percent of all school-age children, or about 4.4 million U.S. children aged 4 to 17 years, have been diagnosed with ADHD at some point in their lives, according to the U.S. Centers for Disease Control and Prevention (CDC). ADHD is one of the most common psychiatric disorders in children and adolescents. ADHD is a neurobiological psychiatric disorder that manifests as a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development. To be properly diagnosed with ADHD, a child needs to demonstrate at least six of nine symptoms of inattention; at least six of nine symptoms of hyperactivity/impulsivity; the onset of such symptoms before age 7 years; that some impairment from the symptoms is present in two or more settings (e.g., at school and home); that the symptoms continue for at least six months; and that there is clinically significant impairment in social, academic or occupational functioning.
Although there is no "cure" for ADHD, there are accepted treatments that specifically target its symptoms. The most common standard treatments include educational approaches, psychological or behavioral modification, and medication.
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Shire's strategic goal is to become the leading specialty pharmaceutical company that focuses on meeting the needs of the specialist physician. Shire focuses its business on attention deficit and hyperactivity disorder (ADHD), human genetic therapies (HGT), gastrointestinal (GI) and renal diseases. The structure is sufficiently flexible to allow Shire to target new therapeutic areas to the extent opportunities arise through acquisitions. Shire believes that a carefully selected portfolio of products with a strategically aligned and relatively small-scale sales force will deliver strong results.
Shire's focused strategy is to develop and market products for specialty physicians. Shire's in-licensing, merger and acquisition efforts are focused on products in niche markets with strong intellectual property protection either in the US or Europe.
For further information on Shire, please visit the Company's website: www.shire.com.
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Statements included herein 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 affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of pharmaceutical research, product development, manufacturing and commercialization; the impact of competitive products, including, but not limited to the impact of those on Shire's Attention Deficit and Hyperactivity Disorder (ADHD) franchise; patents, including but not limited to, legal challenges relating to Shire's ADHD franchise; government regulation and approval, including but not limited to the expected product approval dates of SPD503 (guanfacine extended release) (ADHD), SPD465, extended release triple-bead mixed amphetamine salts (ADHD), MESAVANCE (mesalamine) with MMX technology (SPD 476) (ulcerative colitis), ELAPRASE (idursulfase) (Hunter Syndrome) and NRP104 (lisdexamfetamine dimesylate) (ADHD), including its scheduling classification by the Drug Enforcement Administration in the United States; Shire's ability to secure new products for commercialization and/or development; and other risks and uncertainties detailed from time to time in Shire's and its predecessor registrant Shire Pharmaceuticals Group plc's filings with the Securities and Exchange Commission, particularly Shire plc's Annual Report on Form 10-K for the year ended December 31, 2005.
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