SAN DIEGO – MAY 23, 2007 – Shire plc (LSE: SHP, NASDAQ: SHPGY, TSX: SHQ) announced that DAYTRANATM (methylphenidate transdermal system), the first and only non-oral medication approved for treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children aged 6 to 12 years, provided significant improvement in symptom control and tolerability, according to results of a 12-month open-label study presented at the American Psychiatric Association (APA) annual meeting in San Diego.
"We documented that children with ADHD experienced effective ADHD treatment with use of DAYTRANA for 12 months, sustaining the improvements in their ability to maintain focus and concentration," said investigator Oscar Bukstein, M.D., M.P.H ,Associate Professor of Psychiatry, University of Pittsburgh School of Medicine. "More importantly, Daytrana maintained a favorable safety profile, meeting the study's primary endpoint, and demonstrating an incidence of adverse events that is consistent with previous trials and other stimulants in this class."
Shire's DAYTRANA is the first and only patch medication approved by the U.S. Food and Drug Administration (FDA) to treat the symptoms of ADHD in children aged 6 to 12 years. DAYTRANA is available in four dosage strengths – 10 mg, 15 mg, 20 mg and 30 mg – all designed for once-daily use. When worn for the recommended nine hours, efficacy has been demonstrated from the first time point measured (two hours) through the 12-hour time point. Because DAYTRANA is a patch, physicians may recommend that patients shorten the wear time if shorter duration of effect is desired or to help manage the potential for late-day side effects.
Bukstein added, "DAYTRANA's novel patch delivery system offers physicians and parents of children with ADHD a convenient, non-oral option to individualize ADHD treatment to meet their children's changing schedules."
This study was an open-label extension of four clinical trials. Those children not optimized on DAYTRANA from the previous trials entered a four-week stepwise DAYTRANA dose-optimization phase. All children then entered an 11-month DAYTRANA dose maintenance phase. DAYTRANA was applied each morning to the hip area and worn for approximately nine hours daily. During the dose-optimization phase, titration to a higher dose was permitted after a minimum of three days. Tapering to a lower dose was permitted throughout the dose optimization period and dose adjustments were also permitted during the dose maintenance period.
All of the children in this open-label, flexible-dose trial participated in one of four trials in which the children previously received DAYTRANA, OROS methylphenidate or a placebo. All of the children previously used DAYTRANA for at least a minimum of three days and a maximum of 37 months. While this study evaluated the safety and effectiveness of DAYTRANA for up to 12 months, DAYTRANA has not been studied versus placebo for longer than 7 weeks. Physicians, who prescribe DAYTRANA for long-term use, should periodically re-evaluate patients to assess the usefulness of DAYTRANA for the individual patient.
Children were diagnosed with ADHD using DSM-IV-TR® criteria. Researchers assessed safety and tolerability, through physical exams, skin evaluations, laboratory tests, and monitoring of vital signs, including ECGs throughout the study.
The ADHD-RS-IV assesses 18 individual symptoms of ADHD as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR®), a publication of the American Psychiatric Association.
Of the 327 children enrolled, 157 completed the study. Investigators used data from the intent-to-treat population (324 children) for the efficacy evaluations. Of the safety population (326 children) 7 percent withdrew due to skin irritation at the patch application site, and 9 percent withdrew due to adverse events. The highest percentage of discontinuations were due to withdrawn consent or lost to follow-up (12 percent and 11 percent, respectively).
The most commonly reported treatment-emergent adverse events reported throughout the study (≥10 percent) included decreased appetite, headache, upper respiratory tract infection, cough, pyrexia and decreased weight. Most (98 percent) adverse events were mild or moderate in severity and consistent with known effects of methylphenidate. Three serious adverse events were reported and all were considered unrelated to DAYTRANA use.
DAYTRANA Demonstrated Significant Improvements in ADHD-RS-IV, CGI-I and PGA Scores
In the study, the children experienced a significant overall mean reduction in their ADHD Rating Scale-IV (ADHD-RS-IV) total score. When the study began, the mean total score on the ADHD-RS-IV was 25.0. When using Daytrana, the mean ADHD-RS-IV total scores declined, with children averaging 15.4 at study end. The overall mean change in ADHD-RS-IV total score from study start to end was -9.3 (+/- 16.29) and was statistically significant (p<.0001). The total scores also declined significantly from study start to end on both the inattentiveness and hyperactivity/impulsivity ADHD-RS-IV subscales (P<.0001).
Investigators evaluated DAYTRANA's overall effectiveness using the Clinical Global Impressions-Improvement (CGI-I) and Parent Global Assessment (PGA) scales, both of which yielded significant ratings of improvement at study end, with 83 and 78 percent, respectively, reporting DAYTRANA "very much improved" or "much improved" the children's ADHD symptoms (P<.0001).
The study was supported by funding from Shire.
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; and/or at least six of nine symptoms of hyperactivity/impulsivity; the onset of which appears 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 and the symptoms cannot be better explained by another psychiatric disorder.
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.
Shire ADHD Portfolio
Shire's portfolio of ADHD treatments includes VYVANSE™ (lisdexamfetamine dimesylate), the first prodrug stimulant, which is planned to launch June 2007, DAYTRANA™ (methylphenidate transdermal system), the first and only ADHD patch, and ADDERALL XR® (mixed salts of a single-entity amphetamine product), a long-acting formulated stimulant. Additional ADHD treatments under development by Shire include SPD465 (triple-bead mixed amphetamine salts) and SPD503 (guanfacine HCl extended release).
For further information please contact:
Porter Novelli for Shire
Marion E. Glick
212.601.8273
917.301.4206 (on site at APA)
marion.glick@porternovelli.com
Jennifer Anello
212.601.8132
203.470.0836 (on site at APA)
jennifer.anello@porternovelli.com
APA # NR664
May 23, 2007; 12:00 p.m. PDT (3:00 p.m. EDT)
Sails Pavilion, Upper Level, San Diego Convention Center
12-Month Efficacy and Tolerability of MTS in Children with ADHD
Frank A. López, MD; Oscar G. Bukstein, MD; Robert L. Findling, MD; John M. Turnbow, MD; Liza Squires, MD
Children's Developmental Center, Maitland, FL; Western Psychiatric Institute and Clinic, Pittsburgh, PA; University Hospitals of Cleveland, Cleveland, OH; Westex Clinical Investigations, Lubbock, TX ; Shire US Inc., Wayne, PA
About DAYTRANA
DAYTRANA should not be used in patients with allergy to methylphenidate or patch components; marked anxiety, tension and agitation; glaucoma; tics, diagnosis or a family history of Tourette's syndrome; seizures; or during or within 14 days after treatment with monoamine oxidase inhibitors (MAOIs).
Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses in ADHD. Physicians should take a careful patient history, including family history, and physical exam, to assess the presence of cardiac disease. Patients who report symptoms of cardiac disease such as exertional chest pain and unexplained syncope should be promptly evaluated. Use with caution in patients whose underlying medical condition might be affected by increases in blood pressure or heart rate.
New psychosis, mania, aggression, growth suppression, and visual disturbances have been associated with the use of stimulants. Use with caution in patients with a history of: psychosis; EEG abnormalities; bipolar disorder; depression. Growth and hematologic monitoring is advised during prolonged treatment. Patients should avoid applying external heat to the DAYTRANA patch. Skin irritation or contact sensitization may occur.
DAYTRANA should be given cautiously to patients with a history of drug dependence and alcoholism. Chronic abuse can lead to marked tolerance and psychological dependence. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder.
Common adverse events reported by patients who received DAYTRANA in clinical trials were decreased appetite, insomnia, nausea, vomiting, decreased weight, tics, affect lability, and anorexia, consistent with adverse events commonly associated with the use of methylphenidate.
For Full Prescribing Information go to www.DAYTRANA.com.
About VYVANSE and ADDERALL XR
VYVANSE or ADDERALL XR should not be taken by patients who have advanced arteriosclerosis; symptomatic cardiovascular disease; moderate to severe hypertension; hyperthyroidism; known hypersensitivity or idiosyncrasy to sympathomimetic amines; agitated states; glaucoma; a history of drug abuse; or during or within 14 days after treatment with monoamine oxidase inhibitors (MAOIs).
Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses in ADHD. Physicians should take a careful patient history, including family history, and physical exam, to assess the presence of cardiac disease. Patients who report symptoms of cardiac disease such as exertional chest pain and unexplained syncope should be promptly evaluated. Use with caution in patients whose underlying medical condition might be affected by increases in blood pressure or heart rate.
New psychosis, mania, aggression, growth suppression, and visual disturbances have been associated with the use of stimulants. Use with caution in patients with a history of psychosis, seizures or EEG abnormalities, bipolar disorder, or depression. Growth monitoring is advised during prolonged treatment.
Amphetamines have a high potential for abuse. Administration of amphetamines for prolonged periods of time may lead to drug dependence. Particular attention should be paid to the possibility of subjects obtaining amphetamines for non-therapeutic uses or distribution to others and the drugs should be prescribed or dispensed sparingly. Misuse of amphetamine may cause sudden death and serious cardiovascular adverse events.
The most common adverse events reported in clinical studies of VYVANSE included: pediatric - loss of appetite, insomnia, abdominal pain, and irritability. The most common adverse events reported in clinical studies of ADDERALL XR included: pediatric - loss of appetite, insomnia, abdominal pain, and emotional lability; adolescent - loss of appetite, insomnia, abdominal pain, and weight loss; adult - dry mouth, loss of appetite, insomnia, headache, and weight loss.
About SPD465 (triple-bead mixed amphetamine salts):
SPD465 recently received an approvable letter from U.S. Food and Drug Administration (FDA) for the treatment of ADHD in adults. SPD465, a single entity, mixed amphetamine salt formulation was studied to determine if it provides symptom control for up to 16 hours in adults with ADHD. The most commonly reported treatment-emergent adverse events were decreased appetite, insomnia, dry mouth, headache, upper abdominal pain and anorexia.
About SPD503 (guanfacine HCl extended release):
SPD503 is currently under review with FDA for the treatment of ADHD in children aged 6 to 17 years. SPD503 is a once-daily formulation of the selective alpha-2A-adrenoceptor agonist guanfacine and was studied to determine if it provided control of ADHD symptoms throughout the day in children aged 6 to 17 years. The most commonly reported treatment-emergent adverse events were headache, somnolence, fatigue, upper abdominal pain and sedation
Notes to editors
SHIRE PLC
Shire's strategic goal is to become the leading specialty biopharmaceutical company that focuses on meeting the needs of the specialist physician. Shire focuses its business on 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
THE "SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995
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) and SPD465 (extended release triple-bead mixed amphetamine salts) (ADHD); Shire's ability to secure new products for commercialization and/or development; Shire's ability to benefit from its acquisition of New River Pharmaceuticals Inc.; and other risks and uncertainties detailed from time to time in Shire 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, 2006.
Daytrana™ is a trademark of Shire Pharmaceuticals Ireland Limited.