Shire Pharmaceuticals Group Plc

Phase 3 Study Shows Efficacy is Maintained With lisdexamfetamine dimesylate (LDX) in Children and Adolescents With ADHD After at Least 6 Months of Treatment

Nyon, Switzerland (ots/PRNewswire) - Significantly lower proportion of subjects experiencing treatment failure whilst receiving LDX in the randomised withdrawal period, compared to those subjects receiving placebo.[1]

Today, at the EUNETHYDIS 2nd International ADHD Conference, Shire AG , the global specialty biopharmaceutical company, presented results of the phase 3 study which demonstrated the long-term maintenance of efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents aged 6 to 17 years with Attention-Deficit/Hyperactivity Disorder (ADHD).[1]

Children and adolescents diagnosed with ADHD were treated with LDX (30, 50 or 70mg/day)[1] during an open-label period (comprising dose optimisation, maintenance, and fixed dose periods) of at least 26 weeks before entering a 6-week[1] double-blind randomised withdrawal period, where subjects received either LDX or placebo.[1] Results showed maintenance of efficacy in children and adolescents who continued to receive LDX, as demonstrated by a significantly lower proportion of ADHD treatment failures (13.5%) in this group, compared with placebo (65.8%); and the majority of placebo-treated subjects who met protocol-defined ADHD symptom relapse criteria did so within 2 weeks following randomisation.[1] The overall nature, pattern, and incidence of treatment-emergent adverse events (TEAEs) were also consistent with those reported in other LDX studies in ADHD.[1]

"These are important results which demonstrate the maintenance of efficacy in children and adolescents. Long-term maintenance therapy plays an important role in the treatment of ADHD. There are however, few long-term controlled studies in children and adolescents assessing the maintenance of efficacy and long-term safety of stimulant medication versus placebo," said Dr Jeffrey Jonas, Senior Vice President of Research and Development for Shire's Specialty Pharmaceuticals and Regenerative Medicine businesses. "The positive results presented today complement existing data and we look forward to making LDX available as a treatment option for ADHD in children and adolescents in Europe."

This study is a critical element of the European submission package. A European MAA (Marketing Authorisation Application) for LDX was accepted for review in January 2012.

Relapse or treatment failure in this International study was determined to have occurred when a subject has both a greater than or equal to50% increase (or worsening) in ADHD-Rating Scale-IV (ADHD-RS-IV) total score, and a greater than or equal to2-point increase (or worsening) in Clinical Global Impressions-Severity of Illness (CGI-S) rating scale score, at any double-blind visit relative to the respective scores at randomisation.[1]

The study was conducted at 37 sites in Europe (n=236, or 85% of subjects) and 4 sites in the US (n=40, or 15% of subjects).[2] The results are consistent with a similar randomised withdrawal design (RWD) study in adults in the US.[3]

This study was originally designed to evaluate the long-term efficacy and safety of LDX for the treatment of ADHD in children and adolescents aged 6 to 17, and as an extension to the European phase 3 study of the efficacy and safety of LDX in this population.[2]

Further results on the study will be published soon.

About the clinical trial

The clinical trial was a phase 3, double-blind, placebo-controlled, randomised withdrawal, multicentre, extension study to evaluate the long-term maintenance of efficacy, as well as safety, of lisdexamfetamine dimesylate (LDX) in children and adolescents aged 6 to 17 diagnosed with moderately symptomatic Attention-Deficit/Hyperactivity Disorder (ADHD) (Study SPD489-326).[1]

        - Subjects satisfied all entry criteria to the European phase 3 study of the
          efficacy and safety of LDX (Study SPD489-325).[1] 
        - Moderately symptomatic ADHD is defined as having a baseline ADHD-Rating
          Scale-IV (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).[4] [Generic ] 

The study took place in 37 sites across Europe, including Belgium, France, Germany, Hungary, Italy, Poland, Sweden and the UK; and 4 sites in the US.[2] To ensure that the sample size necessary to assess the primary efficacy measure was met, US children and adolescents (n = 40) were evaluated for direct entry into the study.[1]

The primary objective of this study was to evaluate the long-term maintenance of efficacy of LDX, using a composite endpoint based on the ADHD-RS-IV and Clinical Global Impressions - Severity of Illness (CGI-S) rating scale, via a randomised withdrawal design (RWD) in children and adolescents diagnosed with moderately symptomatic ADHD.[1] Children and adolescents were treated with LDX (30, 50, or 70mg/day) for at least 26 weeks prior to entering a 6-week double-blind randomised (LDX at the subject's open-label fixed dose, or placebo) withdrawal period.[1] Subjects' response status must be confirmed in order to be eligible for enrolment into the RWD period.[1]

The secondary objectives of this study were to:[1]

        1) Assess secondary efficacy outcomes, including the efficacy of LDX through
          the open-label maintenance period, using the clinician-administered ADHD-RS-IV and a
          global clinical measure of improvement, the CGI-I.
        2) Assess the impact of LDX on the perception of health state preferences,
          health-related quality of life (HRQoL), and the relationship between changes in the
          core symptoms of ADHD and changes in functional outcomes, using the Health Utilities
          Index - Mark 2 (HUI-2), the Child Health and Illness Profile, Child Edition: Parent
          Report Form (CHIP-CE:PRF), and the Weiss Functional Impairment Rating Scale - Parent
          (WFIRS-P), respectively.
        3) Evaluate the long-term safety of LDX based on the occurrence of
          treatment-emergent adverse events (TEAEs), specific evaluation of blood pressure and
          pulse, electrocardiogram (ECG) results, clinical laboratory test results, and physical
          examination findings.
        4) Monitor subject safety based on responses to the Brief Psychiatric Rating
          Scale for Children (BPRS-C) and the Columbia-Suicide Severity Rating Scale (C-SSRS). 

The primary efficacy endpoint for each subject was treatment failure at the end of the randomised withdrawal period.[1]

Secondary endpoints of the study were:[1]

- The change from baseline of the ADHD-RS-IV at each visit

- The CGI-I at each applicable visit

- The HUI-2, CHIP-CE:PRF, and WFIRS-P at each applicable visit

About lisdexamfetamine dimesylate[5;6]

LDX is available as a prescription-only medicine in the USA (brand name VYVANSE(R) ; approved for the treatment of ADHD in children and adolescents aged 6 to 17 and adults), Canada (brand name VYVANSE(R) available for use in children and adolescents aged 6 to 17 and adults) and Brazil (VENVANSE(TM); 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 dextroamfetamine. 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.

Indication

Vyvanse is a prescription medicine for the treatment of ADHD in children ages 6 to 17 and adults. Vyvanse should be used as part of a total treatment program that may include counseling or other therapies.

IMPORTANT SAFETY INFORMATION

Vyvanse has a risk of abuse or dependence. Keep in a safe place to prevent misuse and abuse. Selling or sharing Vyvanse may harm others and is illegal. Vyvanse is a stimulant.

Misuse of stimulants may cause sudden death and serious heart problems.

- 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:

Heart-related problems including:

        - sudden death in people 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 has 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 has any sign of heart problems such as chest pain, shortness of breath, or fainting while taking Vyvanse.

Mental (psychiatric) problems including:

Children, Teenagers, and Adults

- 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 - being suspicious - new manic symptoms

Tell your doctor about any mental problems you or your child has, 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, especially:

- seeing or hearing things that are not real - believing things that are not real - being suspicious

- 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.
        - seizures, mainly in people with a history of seizures
        - eyesight changes or blurred vision
        - worsening of sudden, repeated movements or sounds (tics) and Tourette's
          syndrome in people who already have these problems 

- 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

This is not a complete summary of safety information. For additional safety information, please see accompanying Full Prescribing Information and Medication Guide, including Warning about Potential for Abuse, and discuss with your doctor.

This is not a complete summary of safety information. For additional safety information, please click here for Full Prescribing Information and Medication Guide, including Warning about Potential for Abuse, and discuss with your doctor.

About ADHD

ADHD is one of the most common psychiatric disorders in children and adolescents.[7;8] Worldwide prevalence of ADHD is estimated at 5.3 percent.[9]

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.[10;11] 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.[12] 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).[10;11]

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.[13]

        - 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(R), a
          publication of the American Psychiatric Association.[14]
        - CGI is a standard assessment used to rate the severity of a patient's illness
          and improvement over time.[15]
        - 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.[16]
        - 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.[17]
        - 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.[18]
        - 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.[19] 

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 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 Pharmaceuticals, Human Genetic Therapies and Regenerative Medicine products, as well as the ability to secure 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. Maintenance of efficacy of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder: randomized-withdrawal design. Poster presented at the EUNETHYDIS 2nd International ADHD conference 23 - 25 May 2012, Barcelona, Spain. 2012.

(2) Shire. Data on File SPD489-326. A Phase III, Double-Blind, Placebo-Controlled, Randomised Withdrawal, Multicentre, Extension, Safety and Efficacy Study of Lisdexamfetamine Dimesylate (LDX) in Children and Adolescents Aged 6-17 with Attention-Deficit/Hyperactivity Disorder. Final Clinical Study Report, 6 Mar 2012. Report Number: SPD489-326.

(3) Brams M, Weisler R, Findling R et al. Maintenance of Efficacy of Lisdexamfetaimine Dimesylate in Adults With Attention Deficit/Hyperactivity Disorder: Randomized Withdrawal Design. Poster presented at the 164th Annual Meeting of the American Psychiatric Association. 2011.

(4) 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. Poster 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. 2011.

(5) 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.

(6) 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.

(7) 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.

(8) 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.

(9) 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.

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

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

(12) 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.

(13) National Institute of Mental Health. National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: 24-month outcomes of treatment strategies for attention-deficit/hyperactivity disorder. Pediatrics 2004; 113(4):754-761.

(14) 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.

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

(16) 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.

(17) 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.

(18) 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.

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

For further information please contact:

Investor Relations Eric Rojas erojas@shire.com +1-781-482-0999 Sarah Elton-Farr seltonfarr@shire.com +44-1256-894157 Media Jessica Mann (Corporate) jmann@shire.com +44-1256-894-280 Gwen Fisher (Specialty Pharma) gfisher@shire.com +1-484-595-9836 Nicole Barraud nbarraud@shire.com +41-22-419-4056 Emma Overington emma.overington@porternovelli.co.uk +44-7720-277-120

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