Shire Reports Results From Two Head-To-Head Studies Comparing Vyvanse® With Concerta® In ADHD Study

Top-Line Results From Two Head-to-Head Studies Comparing Vyvanse® (lisdexamfetamine dimesylate), CII, With Concerta® (methylphenidate HCl), CII, in Adolescents with ADHD

July 17, 2014 – Shire plc (LSE: SHP, NASDAQ: SHPG) today announced top-line results from two Phase 4 efficacy and safety studies of Vyvanse® (lisdexamfetamine dimesylate) compared with Concerta (methylphenidate HCl) with a placebo reference arm in adolescents aged 13-17 diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD).

In SPD489-406, the forced-dose titration study, Vyvanse was found to be statistically superior to Concerta on the primary efficacy analysis (p = 0.0013) with mean reductions on the ADHD RS-IV total score of 25.4 and 22.1 points, respectively. In SPD489-405, the dose optimization study, neither Vyvanse nor Concerta was found to be statistically superior to the other on the primary efficacy analysis (p = 0.0717), with a larger mean improvement found for Vyvanse than Concerta (mean reductions on the ADHD-RS-IV total score of 25.6 and 23.5 points, respectively). The primary efficacy endpoint for both studies was defined as the change from baseline in ADHD-RS-IV total score at Week 6 and Week 8, respectively.

In both studies, the types of adverse events appear to be generally consistent with the known safety profile for Vyvanse established in studies of adolescents with ADHD.

“Treatment decisions for adolescents are complex as they are in a state of transition into adulthood and they experience greater challenges in school, home, and social settings. Our investment in this program underscores our continued commitment to improving ADHD patient care,” said Phil Vickers, Global Head of Research and Development for Shire. “Prospectively designed head-to-head clinical trials provide important information to physicians, patients, caregivers, and payors to make informed choices.”

Vyvanse is a prescription medicine approved for the treatment of ADHD in the United States, Canada, Australia, Mexico, several European countries (trade name: Elvanse®/Tyvense®) and Brazil (trade name: Venvanse™).

CNS stimulants (amphetamines and methylphenidate-containing products) have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy.
Shire plans to submit the efficacy and safety data from the two studies for presentation at a future scientific congress.

ABOUT THE STUDIES

Study SPD489-406

The Phase 4, randomized, double-blind, multicenter, parallel-group, active-controlled, forced-dose titration efficacy and safety study with a placebo reference arm was designed to evaluate the efficacy of Vyvanse compared with Concerta in adolescents (13-17 years of age) with ADHD based on DSM-IV-TR criteria (N=547 treated patients). The primary efficacy outcome was defined as the change from baseline at Week 6 (Visit 6) in the ADHD-RS-IV total score. Patients were randomized to Vyvanse, Concerta, or placebo, respectively, and treated for 6 weeks to evaluate safety and efficacy, followed by a 1-week safety follow-up period. The doses evaluated in this study were Vyvanse 70mg and Concerta 72mg daily. Baseline ADHD-RS-IV total scores were 37.3, 37.0, and 36.1 for Vyvanse, Concerta, and placebo, respectively. At the end of the study [Week 6 (Visit 6)], patients treated with Vyvanse experienced a mean 25.4 point reduction in ADHD-RS-IV total score compared with a 22.1 point reduction for Concerta, and a 17.0 point reduction for placebo. Vyvanse was found to be statistically superior to Concerta (p = 0.0013) on the primary efficacy analysis, with an improvement of 3.4 points compared to Concerta on the ADHD-RS-IV total score.

Safety and tolerability evaluations of Vyvanse and Concerta included treatment-emergent adverse events (TEAEs), vital signs, and weight. Exclusion criteria included a known history of cardiovascular disease, clinically significant ECG, blood pressure exceeding the 90th percentile for age, sex and height, current psychiatric diagnosis and a history of substance abuse or dependence.

In this study, 1 patient treated with Vyvanse, 1 patient treated with Concerta, and 1 patient treated with placebo experienced serious adverse events (SAEs). Sixteen (16) patients on Vyvanse, 15 patients on Concerta, and 1 patient on placebo had TEAEs that led to study discontinuation. The most commonly reported (>=5% of patients) TEAEs in patients taking Vyvanse included decreased appetite, headache, weight decreased, insomnia, dry mouth, dizziness, irritability, nausea, and upper abdominal pain. The most commonly reported (>=5% of patients) TEAEs in patients taking Concerta included decreased appetite, headache, insomnia, irritability, weight decreased, dizziness, nausea, and nasopharyngitis. There were no deaths in this study.

Further evaluation of the efficacy and safety information is currently under way.

Study SPD489-405

The Phase 4, randomized, double-blind, multicenter, parallel-group, active-controlled, dose-optimization efficacy and safety study with a placebo reference arm was designed to evaluate the efficacy of Vyvanse compared with Concerta in adolescents (13-17 years of age) with ADHD based on DSM-IV-TR criteria (N=459 treated patients). The primary efficacy outcome was defined as the change from baseline at Week 8 (Visit 8) in the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) total score. Patients were randomized to Vyvanse, Concerta, or placebo, respectively, and treated for 8 weeks to evaluate safety and efficacy, followed by a 1-week safety follow-up period. At the end of the dose optimization period, 8.2%, 27.2%, and 52.2% of treated patients were receiving Vyvanse doses of 30, 50, and 70mg, respectively. At the end of the dose optimization period, 5.4%, 18.5%, 22.3%, and 46.2% of treated patients were receiving Concerta doses of 18, 36, 54, and 72mg, respectively. Baseline ADHD-RS-IV total scores were 36.6, 37.8, and 38.2 for Vyvanse, Concerta, and placebo, respectively. At the end of the study [Week 8 (Visit 8)], patients treated with Vyvanse experienced a mean 25.6 point reduction in ADHD-RS-IV total score compared with a 23.5 point reduction for Concerta, and a 13.4 point reduction for placebo. While not statistically significant (p = 0.0717), Vyvanse was found to have a larger mean reduction (improvement) of 2.1 points compared to Concerta on the primary efficacy analysis.

Safety and tolerability evaluations of Vyvanse and Concerta included treatment-emergent adverse events (TEAEs), vital signs, and weight. Exclusion criteria included a known history of cardiovascular disease, clinically significant ECG, blood pressure exceeding the 90th percentile for age, sex and height, current psychiatric diagnosis and a history of substance abuse or dependence.

In this study, 1 patient treated with Vyvanse, 1 patient treated with Concerta, and no patients treated with placebo experienced serious adverse events (SAEs). Fourteen (14) patients on Vyvanse, 3 patients on Concerta, and 3 patients on placebo had TEAEs that led to study discontinuation. The most commonly reported (>=5% of patients) TEAEs in patients taking Vyvanse included decreased appetite, weight decreased, irritability, headache, insomnia, initial insomnia, dry mouth, nausea, upper abdominal pain, dizziness, nasopharyngitis, somnolence, fatigue, anxiety, and upper respiratory tract infection. The most commonly reported (>=5% of patients) TEAEs in patients taking Concerta included decreased appetite, weight decreased, headache, insomnia, nausea, irritability, nasopharyngitis, initial insomnia, dry mouth, heart rate increased, and upper abdominal pain. There were no deaths in this study.

Further evaluation of the efficacy and safety information is currently under way.

ABOUT Vyvanse® (lisdexamfetamine dimesylate)
Information about Vyvanse

Vyvanse is indicated for the treatment Attention-Deficit/Hyperactivity Disorder (ADHD) in patients 6 years and above. Vyvanse capsules are currently available in six once-daily dosage strengths of 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg.

ADDITIONAL IMPORTANT SAFETY INFORMATION

• Do not take Vyvanse if you or your child:
  • is taking or has taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI
  • is sensitive to, allergic to, or had a reaction to other stimulant medicines
• Some people have had the following problems when taking stimulant medicines, such as Vyvanse:
  
  1. Heart-related problems including:
  • sudden death in people who have heart problems or heart defects
  • sudden death, stroke and heart attack in adult
  • increased blood pressure and heart rate

Tell your doctor if you or your child has any heart problems, heart defects, high blood pressure, or a family history of these problems. The doctor should check your or your child’s blood pressure and heart rate regularly during treatment.
Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking Vyvanse.

2. Mental (psychiatric) problems including:
• new or worse behavior and thought problems
• new or worse bipolar illness
In Children and Teenagers
• new psychotic symptoms such as:
• seeing things or hearing voices that are not real
• believing things that are not true
• being suspicious
• new manic symptoms

Tell your doctor about any drug abuse, alcohol abuse or mental problems that you or your child has had, or about a family history of suicide, bipolar illness, or depression.
Call your doctor right away if you or your child has any new or worsening mental symptoms or problems while taking Vyvanse.

3. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]:
• Fingers or toes may feel numb, cool, painful, sensitive to temperature and/or change color from pale, to blue, to red

Call your doctor right away if you have or your child has any of these signs or symptoms or develops unexplained wounds on fingers or toes while taking Vyvanse.

• Tell the doctor if you or your child is pregnant, breast-feeding, or plans to become pregnant or breast-feed.

• Vyvanse may cause serious side effects, including:

• slowing of growth (height and weight) in children. Your child should have his or her height and weight checked often while taking Vyvanse. The doctor may stop treatment if a problem is found during these check-ups.

• The most common side effects reported in studies of Vyvanse were:

• anxiety
• decreased appetite
• diarrhea
• dizziness
• dry mouth
• irritability
• loss of appetite
• nausea
• trouble sleeping
• upper stomach pain
• vomiting
• weight loss

For additional safety information, click here for Prescribing Information and Medication Guide and discuss with your doctor.

ABOUT ADHD

Attention-Deficit/Hyperactivity Disorder is a neurobehavioral disorder that manifests as a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development and is inconsistent with developmental level.

ADHD is one of the most common childhood psychiatric disorders. Although many people tend to think of ADHD as a childhood problem, 60% to 85% of children with ADHD may continue to meet the criteria for the disorder during their teenage years. An estimated 11% (6.4 million) of US school-aged children have been diagnosed with ADHD in their lifetime.

The specific etiology of ADHD is unknown. The diagnosis is made utilizing criteria specified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5®) or International Classification of Diseases, 10th revision (ICD-10). Only a trained health care professional can evaluate and diagnose ADHD.

Although there is no cure for ADHD, there are accepted treatments that have been demonstrated to improve symptoms. Standard treatments include educational approaches, psychological therapies which may include behavioral modification, and/or medication. Ongoing assessment and treatment may be necessary.

For further information please contact:

Investor Relations
Jeff Poulton
jpoulton@shire.com
+1 781 482 0945

Sarah Elton-Farr
seltonfarr@shire.com
+44 1256 894157

Media
Audrey Abernathy
aabernathy@shire.com
+1 484-595-2389

Gwen Fisher
gfisher@shire.com
+1 484 595 9836

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 provide treatments in Neuroscience, Rare Diseases, Gastrointestinal, and Internal Medicine and we are developing treatments for symptomatic conditions treated by specialist physicians in other targeted therapeutic areas, such as Ophthalmology.

www.shire.com

FORWARD - LOOKING STATEMENTS - “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. 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;
• revenues from ADDERALL XR are subject to generic erosion and revenues from INTUNIV will become subject to generic competition starting in December 2014;
• the failure to obtain and maintain reimbursement, or an adequate level of reimbursement, by third-party payors in a timely manner for Shire’s products may impact future revenues, financial condition and results of operations;
• Shire conducts its own manufacturing operations for certain of its Rare Diseases products and is reliant on third party contractors 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 the 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 development, approval and manufacturing of Shire’s products is subject to extensive oversight by various regulatory agencies. Submission of an application for regulatory approval of any of our product candidates, such as our planned submission of a New Drug Application to the FDA for Lifitegrast may be delayed for any number of reasons and, once submitted, may be subjected to lengthy review and ultimately rejected. Moreover, regulatory approvals or interventions associated with changes to manufacturing sites, ingredients or manufacturing processes could lead to significant delays, increase in operating costs, lost product sales, an interruption of research activities or the delay of new product launches;
• 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 impact Shire’s revenues, financial conditions 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 the distraction of senior management, 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, academic institutions, government entities and other organizations. Shire is undergoing a corporate reorganization and the consequent uncertainty could adversely impact 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 ViroPharma Incorporated 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.

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