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Investigational Data Presented For INTUNIV™ (Guanfacine) Extended-Release Tablets When Coadministered With Stimulants Showed ADHD Symptom Improvement In Overall, Morning And Evening Assessments

October 28, 2010

Shire plc (LSE: SHP, NASDAQ: SHPGY), the global specialty biopharmaceutical company, today presented research results of once-daily INTUNIV™ (guanfacine) Extended-Release Tablets, coadministered with stimulants in children and adolescents diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) who had suboptimal response to treatment with a long-acting stimulant alone.  At study end point, patients receiving INTUNIV coadministered with a stimulant had significantly reduced symptoms on the ADHD Rating Scale IV (ADHD-RS-IV) compared with those receiving placebo with a stimulant, regardless of morning or evening dosing.  These data were presented in a poster session at a major national scientific meeting of psychiatry in New York, NY.

“This study looked at patients who were taking a stable dose of a long-acting stimulant medicine but who continued to experience ADHD symptoms,” said Timothy Wilens, MD, Staff in the Pediatric Psychopharmacology Unit at Massachusetts General Hospital and Associate Professor of Psychiatry at Harvard Medical School, who led the study.  “These findings provide greater insight into the use of INTUNIV when combined with a stimulant.”

INTUNIV is a selective alpha-2A agonist approved for the treatment of ADHD in children and adolescents ages 6 to 17.  Efficacy was based on two pivotal studies (8 and 9 weeks in duration) of INTUNIV administered as monotherapy.  INTUNIV is indicated as an integral part of a total treatment program that may include counseling or other measures.

These data presented today were included as part of a supplemental New Drug Application (sNDA) submitted to the Food and Drug Administration (FDA) on April 28, 2010, seeking approval for INTUNIV as an ADHD treatment combined with stimulants in this same patient population.  The application is currently under review.  The target FDA action date is February 28, 2011.

In This Investigational Study, Coadministration of INTUNIV With a Stimulant Showed Significant ADHD Symptom Improvement Over Stimulant Alone When Dosed Either in the Morning or Evening
This multicenter, double-blind, randomized, placebo-controlled study took place over 9 weeks in 455 patients aged 6 to 17 years with ADHD who had suboptimal response* to treatment with a stimulant. 

Throughout this dose-optimized study, patients continued to take their prescribed dose of a stimulant, with the addition of a morning or evening dose of INTUNIV (1 mg, 2 mg, 3 mg, or 4 mg) or placebo.  The primary efficacy measure for the study was the ADHD-RS-IV.  ADHD-RS-IV is a standardized tool for evaluating symptoms of ADHD and assessing response to treatment, in which clinicians can rate patients within a scoring range of 0 to 54, depending on the severity of symptoms.  At end point, a significantly greater percentage of patients in the morning and evening administration of INTUNIV and stimulant groups compared with those taking placebo with a stimulant met criteria for symptomatic remission (ADHD-RS-IV ≤ 18).  Data from the primary efficacy analysis of the study were previously presented at a national meeting of psychiatry in May 2010. 

Secondary efficacy measures were based on scores from the Conners’ Global Index – Parent (CGI-P) morning and evening assessment, and the exploratory Before-School Functioning Questionnaire (BSFQ).  On a weekly basis, parents completed 2 assessments of the CGI-P, each composed of 10 questions.  The first assessment evaluated patient behaviors in the morning before school, and during the week before the study visit.  The second assessment evaluated patient behaviors in the evening, before bedtime.  The groups that received INTUNIV coadministered with a stimulant showed greater improvement compared with those taking placebo and a stimulant on the CGI-P at both morning and evening assessments.  Additionally, at end point, patients receiving INTUNIV coadministered with a stimulant showed greater improvement on the BSFQ compared with subjects who received placebo and a stimulant. 

In this investigational study, INTUNIV given in the morning or evening when coadministered with a stimulant resulted in significant improvement in ADHD symptoms overall and at morning and evening time points. 

In this study, the most commonly reported treatment-emergent adverse events (TEAEs) among patients treated with INTUNIV and a stimulant (greater than or equal to 5 percent) were headache, somnolence, upper respiratory tract infection, fatigue, insomnia, upper abdominal pain, dizziness, decreased appetite, cough, irritability, and nausea.  The most commonly reported TEAEs among patients in the placebo/stimulant group (greater than or equal to 5 percent) were headache, upper respiratory tract infection, and irritability.  The majority of TEAEs were mild or moderate in severity.  No unique TEAEs were observed with INTUNIV given with a stimulant compared with those reported historically for either treatment alone.

Serious adverse events (SAEs) were reported in 3 patients taking INTUNIV and 1 sibling of a study participant (including one event of syncope).  All SAEs were considered unrelated to INTUNIV.

"We are currently awaiting FDA review of these data and our application for a change in the product labeling for INTUNIV to include coadministration with a stimulant for the treatment of ADHD,” said Michael Yasick, Senior Vice President of Shire’s ADHD Business Unit.  “Shire is pleased with the results of this trial and will continue to research and develop new treatments for ADHD as part of our commitment to patients and their families.”

This study was supported by funding from Shire Development Inc.  Dr Timothy Wilens was a speaker for, received grant support from, and is a consultant for Shire.  

*Suboptimal response was defined as treatment with a stable dose of stimulant for at least four weeks with improvement, yet persistence of mild to moderate ADHD symptoms in the opinion of the investigator (defined as an ADHD-RS-IV total score of at least 24, Clinical Global Impressions-Severity of illness scale score of at least three).  Patients with no response to stimulants prior to study enrollment were excluded from participating in this study.

INTUNIV™ (guanfacine) Extended-Release Tablets is a nonstimulant approved for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents ages 6 to 17.  INTUNIV was approved by the US Food and Drug Administration (FDA) in September 2009 and comes in 4 doses—1 mg, 2 mg, 3 mg, and 4 mg.  INTUNIV should be taken once a day. 

The active ingredient in INTUNIV is guanfacine.  INTUNIV is not a central nervous system (CNS) stimulant or a controlled substance.  It is not likely to cause dependence or be abused.

Additional information about INTUNIV and Full Prescribing Information are available at www.intunivpro.com.

INTUNIV is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents ages 6 to 17.  Efficacy was established in two controlled clinical trials (8 and 9 weeks in duration).  The physician electing to use INTUNIV for extended periods should periodically reevaluate its long-term usefulness for the individual patient.

INTUNIV is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social).

Important Safety Information
INTUNIV should not be used in patients with a history of hypersensitivity to guanfacine or any of its inactive ingredients or by patients taking other products containing guanfacine.

Hypotension, bradycardia, and syncope were observed in clinical trials. Use INTUNIV with caution in treating patients who have experienced hypotension, bradycardia, heart block, or syncope, or who may have a condition that predisposes them to syncope; are treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Heart rate and blood pressure should be measured prior to initiation of therapy, following dose increases, and periodically while on therapy. Patients should be advised to avoid becoming dehydrated or overheated.

Sedation and somnolence were commonly observed in clinical trials. The potential for additive sedative effects with CNS depressant drugs should be considered. Patients should be cautioned against operating heavy equipment or driving until they know how they respond to INTUNIV. Advise patients to avoid use with alcohol.

Common adverse reactions in patients taking INTUNIV that may be dose related over the range of 1 to 4 mg/day include somnolence, sedation, abdominal pain, dizziness, hypotension/decreased blood pressure, dry mouth, and constipation.

Please see INTUNIV Full Prescribing Information at http://pi.shirecontent.com/PI/PDFs/Intuniv_USA_ENG.pdf

About ADHD
Attention Deficit Hyperactivity Disorder (ADHD) is a psychiatric behavioral disorder in which patients exhibit symptoms of hyperactivity, impulsivity, and/or inattention.  ADHD is one of the most common psychiatric disorders in children and adolescents.  The prevalence of ADHD is approximately 3 to 7 percent in school-age children.  Worldwide prevalence of ADHD is estimated at 5.3 percent (with large variability), according to a review of this topic published in 2007.

There is no single test to determine if someone has ADHD; instead, a comprehensive evaluation is required.  This evaluation may include a physical examination, psychological testing, review of school and medical records, as well as parent- and teacher-related behavior scales and family interviews.

Although there is no cure for ADHD, there are accepted treatments that help reduce symptoms.  Treatments include educational approaches, behavioral modification, and/or stimulant or nonstimulant medication.

For further information please contact:

Media Matthew Cabrey (Shire North America) +1 484 595 8248
  Cori Blair (Porter Novelli for Shire)
[email protected]
+1 212 601 8248
+1 917 470 8698

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 attention deficit hyperactivity disorder (ADHD), human genetic therapies (HGT) and gastrointestinal (GI) diseases as well as opportunities in other therapeutic areas to the extent they arise through acquisitions. Shire’s in-licensing, merger and acquisition efforts are focused on products in specialist markets with strong intellectual property protection and global rights. Shire believes that a carefully selected and balanced portfolio of products with strategically aligned and relatively small-scale sales forces will deliver strong results.
For further information on Shire, please visit the Company’s website: www.shire.com.

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, the Company’s results could be materially adversely affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of research, development, approval, reimbursement, manufacturing and commercialization of the Company’s Specialty Pharmaceutical and Human Genetic Therapies products, as well as the ability to secure and integrate new products for commercialization and/or development; government regulation of the Company’s products; the Company’s ability to manufacture its products in sufficient quantities to meet demand; the impact of competitive therapies on the Company’s products; the Company’s ability to register, maintain and enforce patents and other intellectual property rights relating to its products; the Company’s ability to obtain and maintain government and other third-party reimbursement for its products; and other risks and uncertainties detailed from time to time in the Company’s filings with the Securities and Exchange Commission.