Shire plc Release: EU Study Shows Once-Daily Lisdexamfetamine Dimesylate (LDX) Effective for Symptom Control in Children and Adolescents with ADHD

BASINGSTOKE, England, October 21, 2011 /PRNewswire/ --

Success of pivotal, phase III trial marks long-acting, prodrug stimulant LDX as potential new treatment option for ADHD in Europe

For international medical media only

Shire plc (LSE: SHP, NASDAQ: SHPGY), the global specialty biopharmaceutical company, today presented positive top line results of the first European phase III study of once-daily lisdexamfetamine dimesylate (LDX) in children and adolescents aged 6 to 17 years with Attention-Deficit/Hyperactivity Disorder (ADHD)^[1]. LDX is the first chemically formulated long-acting, prodrug of dexamfetamine for treatment of ADHD, and is currently licensed only in the US, Canada and Brazil.^[1]

The study, conducted at 48 sites across Europe, showed that LDX demonstrated efficacy on the primary and key secondary measures compared to placebo, and a safety profile consistent with the known effects of amfetamine treatment and previous LDX trials.^[1]

"The results of this European study show that a once-daily morning dose of LDX was effective in children and adolescents with at least moderately symptomatic ADHD, and are consistent with those of previous studies conducted outside of Europe," said Dr Jeffrey Jonas, Senior Vice President of Research and Development for Shire's Specialty Pharmaceuticals business. "These results provide important clinical trial data in support of LDX and its potential role as a new option for the treatment of ADHD in children and adolescents in Europe. The study will support the clinical package for European MAA* filing."

Moderately symptomatic ADHD is defined as having a baseline ADHD-RS-IV total score greater than or equal to 28. The ADHD-RS-IV is designed to reflect current symptomatology of ADHD based on criteria set in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Series (DSM-IV), with a total score ranging from 0 (reflecting no symptoms) to 54 (reflecting severe symptoms).^[1]

In the study, 336 patients were randomised to receive LDX, osmotic-controlled extended-release methylphenidate (OROS-MPH**) or placebo, over a period of seven weeks. The OROS-MPH active reference treatment arm was included to provide data on a current standard therapy for ADHD in Europe.^[1] The primary comparison is LDX vs placebo. Formal comparisons between LDX and OROS-MPH were not planned. Study exclusion criteria included, but were not limited to: significant symptoms resulting from comorbid psychiatric diagnosis; symptoms that may have contraindicated LDX and/or OROS-MPH treatment such as a history of drug abuse; history of serious cardiac abnormalities; and hypersensitivity or intolerance to amfetamine and/or methylphenidate.

The primary measure was the change in total score of the ADHD-RS-IV of LDX vs. placebo. At baseline, the ADHD-RS-IV total score was 40.7, 41.0, and 40.5 for subjects receiving LDX, placebo, and OROS-MPH respectively. At endpoint, the ADHD-RS-IV total score was 16.0 for LDX, 34.8 for placebo, and 21.7 for OROS-MPH.^[1] The difference between both active agents and placebo in least-square mean^[] change from baseline in ADHD-RS-IV total score was statistically significant. (p<0.001).

A key secondary efficacy measure was the improvement with LDX vs. placebo with OROS-MPH included as an active control on the Clinical Global Impressions - Global Improvement (CGI-I) scale. Results showed improvement of symptoms from 78% of patients in the LDX group, 14% in the placebo group, and 61% in the OROS-MPH group.^[1]

Serious adverse events occurred across all treatment groups (LDX, 3; placebo, 3; OROS-MPH, 2); most of them were judged to be unrelated to the treatment. The most common (>10%) treatment-emergent adverse events (TEAEs) reported by patients receiving LDX were decreased appetite, headache, insomnia, weight decreased, nausea, and anorexia. The percentage of subjects who had TEAEs leading to discontinuation across all treatment groups were LDX, 5%; placebo, 4%; and OROS-MPH,-2%. The overall nature, pattern, and incidence of TEAEs were consistent with those reported in other LDX studies in ADHD.

Further results on the study will be published soon.

* Marketing Authorisation Application

** Marketed as CONCERTA^® and CONCERTA^®XL by Johnson & Johnson

^[] "Least square mean" is a statistical way of measuring differences between means.

About the clinical trial

The clinical trial was a phase III, randomised, double-blind, multicentre, parallel-group, placebo- and active-controlled, dose-optimisation, safety and efficacy study of lisdexamfetamine dimesylate in 336 children and adolescents aged 6 to17 with Attention-Deficit/Hyperactivity Disorder (ADHD).

Doses were 30, 50, and 70mg/day for LDX and 18, 36, and 54mg for OROS-MPH (54 mg being the highest strength available in Europe). Patients were randomised in a 1:1:1 ratio to a daily morning dose of LDX, OROS-MPH, or placebo.

The study took place in 48 sites across Europe, including Belgium, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, Sweden and the UK. The primary outcome measure was efficacy as measured by the ADHD Rating Scale IV (ADHD-RS-IV).- The secondary outcome measures included Clinical Global Impressions-Improvement scale (CGI-I); Conners' Parent Rating Scale-Revised (CPRS-R); Child Health and Illness Profile, Child Edition: Parent Report Form (CHIP-CE:PRF); the Health Utilities Index-Mark2 (HUI-2); and the Weiss Functional Impairment Rating Scale- Parent (WFIRS-P).- Safety assessments included adverse events, vital signs, electrocardiograms, clinical laboratory parameters, physician examination, Brief Psychiatric Rating Scale for Children (BPRS-C) and the Columbia-Suicide Severity Rating Scale (C-SSRS).^[2]

About lisdexamfetamine dimesylate^{[3; 4]}

LDX is available as a prescription-only medicine in the USA (brand name VYVANSE^®;approved for the treatment of ADHD in children and adolescents aged 6 to 17 and adults), Canada (brand name VYVANSE^®

available for use in children and adolescents aged 6 to 17 and adults) and Brazil (VENVANSE; approved for children aged 6-12 years)

LDX should be used as part of a total treatment program that may include counseling or other therapies.

LDX is a prodrug of dextroamphetamine. After oral administration, LDX is rapidly absorbed from the gastrointestinal tract and hydrolyzed primarily in whole blood to dextroamphetamine, which is responsible for the drug's activity.

The safety and tolerability profiles of LDX are generally consistent with those of other CNS (central nervous system) stimulant medications, the most common side effects being decreased appetite, insomnia, abdominal pain, headache, and irritability.

About VYVANSE

VYVANSE is a stimulant medication and federally controlled substance (CII) because it can be abused or lead to dependence. Keep VYVANSE in a safe place to prevent misuse and abuse. Selling or giving away VYVANSE may harm others, and is against the law. Misuse of stimulants may cause sudden death and serious cardiovascular adverse events.

IMPORTANT SAFETY INFORMATION

VYVANSE is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep in safe place to prevent misuse and abuse. Selling or giving away VYVANSE may harm others, and is illegal. VYVANSE is a stimulant. Misuse of stimulants may cause sudden death and serious heart problems.

• VYVANSE should not be taken by patients who have:

Heart disease or hardening of the arteries, moderate to severe high blood pressure, overactive thyroid gland (hyperthyroidism), glaucoma, agitated states, a history of drug abuse, taken an anti-depression medicine called a monoamine oxidase inhibitor (MAOI) within the last 14 days, or sensitivity to, are allergic to, or had a reaction to other stimulant medicines.

• VYVANSE is a stimulant medicine. The following have been reported with use of stimulant medicines.

Heart-related problems:

• sudden death in patients who have heart problems or heart defects
• stroke and heart attack in adults
• increased blood pressure and heart rate

Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Call your doctor right away if you or your child have any signs of heart problems such as chest pain, shortness of breath, or fainting while taking VYVANSE.

Mental (Psychiatric) problems:

All Patients

• new or worse behavior and thought problems
• new or worse bipolar illness
• new or worse aggressive behavior or hostility

Children and Teenagers

• new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms

Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking VYVANSE, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.

• Serious side effects have been reported with use of stimulant medicines such as VYVANSE, including:
  • seizures, mainly in patients with a history of seizures
  • eyesight changes or blurred vision
  • motion and verbal tics. Patients with tics or Tourette's syndrome may experience a worsening of symptoms while taking VYVANSE.
  • slowing of growth. 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:

    - upper belly pain - nausea             - dry mouth
    - dizziness        - weight loss        - trouble sleeping
    - irritability     - decreased appetite - vomiting

This is not a complete summary of safety information. For additional safety information, please contact Shire's medical information office at medinfoglobal@shire.com.

About ADHD

ADHD is one of the most common psychiatric disorders in children and adolescents.^{[5; 6]} Worldwide prevalence of ADHD is estimated at 5.3 percent.^[7]

ADHD is a psychiatric behavioural 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.^[8;9] The exact origin of ADHD is unknown, but scientists speculate the disorder may be caused, in part, by an imbalance of two neurotransmitters, dopamine (DA) and noradrenaline (NA), which are believed to play an important role in the ability to focus and pay attention to tasks.^[10] Adequate diagnosis requires the use of medical and special psychological, educational and social resources, utilising diagnostic criteria such as Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV-TR) or International Classification of Diseases 10 (ICD-10).^[8;9]

Although there is no "cure" for ADHD, there are accepted treatments that specifically target its symptoms. A multimodal treatment approach that combines medication and behavioural modifications are found to be most effective in managing ADHD.^[11]

• ADHD-RS-IV is a standardized, validated test for assessing symptoms of ADHD and for assessing their response to treatment. The scale, which contains 18 items, is based on the ADHD diagnostic criteria as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision^®, a publication of the American Psychiatric Association.^[12]
• CGI is a standard assessment used to rate the severity of a patient's illness and improvement over time.^[13]
• CPRS-R is a comprehensive parent-rated scale that uses observer and self-report ratings to help assess ADHD and evaluate behavioral issues in children and adolescents.^[14]
• CHIP-CE/PRF is a 76-item questionnaire designed to measure the health of children aged 6 to 11 years from the caregiver's perspective, and consists of five domains (Satisfaction, Comfort, Risk Avoidance, Resilience, and Achievement) that measure structurally distinct, interrelated aspects of health.^[15]
• The Health Utilities Index (HUI) descriptive system focuses on impairment and classifies respondents into either HUI2 or HUI3 health states.- The HUI2 consists of seven attributes (sensation, mobility, emotion, cognition, selfcare, pain and fertility), with three to five levels, leading to 24,000 possible health states.^[16]
• WFIRS-P is a scale to be completed by the parent/guardian of a child and evaluates how an individual is able to function; questions are framed to assess how often an individual's behaviour or emotional problems have impacted various clinically-relevant domains of functioning.^[17]

For further information please contact:

Investor Relations
Eric Rojas (erojas@shire.com), +1-781-482-0999
Sarah Elton-Farr, +44-1256-894-157

Media
Jessica Mann (jmann@shire.com), +44-1256-894-280
Matthew Cabrey (mcabrey@shire.com), +1-484-595-8248
Nicole Barraud (nbarraud@shire.com) + 41-22-419-4056
Emma Overington (emma.overington@porternovelli.co.uk),
+44-7720-277-120
Kim Pickworth (kim.pickworth@porternovellinovelli.co.uk),
+44-7720-277-175

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 attention deficit hyperactivity disorder, human genetic therapies, gastrointestinal diseases and regenerative medicine 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: http://www.shire.com.

"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, 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.

Reference List

(1) Coghill D, Banaschewski T, Lecendreux M et al. Efficacy and safety of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder: a Phase III, randomized, double-blind, multicenter, parallel-group, placebo- and active-controlled, dose-optimized study in Europe. Abstract presented at the Joint Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) and the Canadian Academy of Child and Adolescent Psychiatry, Toronto, Canada, 18-23 October 2011. 2011.

(2) Shire: Data on file. 325. 2011.

(3) Krishnan S, Zhang Y. Relative bioavailability of lisdexamfetamine 70-mg capsules in fasted and fed healthy adult volunteers and in solution: a single-dose, crossover pharmacokinetic study. J Clin Pharmacol 2008; 48(3):293-302.

(4) Shojaei A, Ermer JC, Krishnan S. Lisdexamfetamine dimesylate as a treatment for ADHD: dosage formulation and pH effects. Presented at the Annual Meeting of the American Psychiatric Association, San Diego CA, USA, 19-24 May 2007. 2011.

(5) Novik TS, Hervas A, Ralson SJ et al. Influence of gender on Attention-Deficit/Hyperactivity Disorder in Europe - ADORE. Eur Child Adolesc Psychiatry [Suppl 1] 2006; 15:1/15-1/24.

(6) American Academy of Child and Adolescent Psychiatry. Practice Parameter for the Assessment and Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry 2007; 46(7):894-921.

(7) Polanczyk G, de Lima MS, Horta BL et al. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 2007; 164(6):942-948.

(8) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR Fourth Edition (Text Revision). 2000.

(9) WHO. International Classification of Diseases, 10th ed., (ICD-10). 2007.

(10) Cheon KA, Ryu YH, Kim YK et al. Dopamine transporter density in the basal ganglia assessed with [123I]IPT SPET in children with attention deficit hyperactivity disorder. Eur J Nucl Med Mol Imaging 2003; 30(2):306-311.

(11) National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: changes in effectiveness and growth after the end of treatment. Pediatrics 2004; 113(4):762-769.

(12) Collett BR, Ohan JL, Myers KM. Ten-year review of rating scales. V: scales assessing attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2003; 42(9):1015-1037.

(13) Guy W. Clinical Global Impressions. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education and Welfare, 1976.

(14) Conners CK, Sitarenios G, Parker JD et al. The revised Conners' Parent Rating Scale (CPRS-R): factor structure, reliability, and criterion validity. J Abnorm Child Psychol 1998; 26(4):257-268.

(15) Riley AW, Forrest CB, Starfield B et al. The Parent Report Form of the CHIP-Child Edition: reliability and validity. Med Care 2004; 42(3):210-220.

(16) Grutters JP, Joore MA, van der HF et al. Choosing between measures: comparison of EQ-5D, HUI2 and HUI3 in persons with hearing complaints. Qual Life Res 2007; 16(8):1439-1449.

(17) Weiss MD, Wasdell MB, Bomben MM. Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P). Version 2, November 29, 2004. 2004.

SOURCE Shire plc