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

ots Originaltext: Shire Pharmaceuticals Group Plc
Im Internet recherchierbar: http://www.presseportal.de