Positive Response from European Regulatory Procedure Supports Approval of Elvanse® (lisdexamfetamine dimesylate) for ADHD

Nyon, Switzerland (ots/PRNewswire) -

Shire plc today announces a positive outcome from the European
Decentralised Procedure (DCP) for Elvanse(R) (to be known as
Tyvense(R) in Ireland). Elvanse is indicated as part of a
comprehensive treatment programme for attention deficit/hyperactivity
disorder (ADHD) in children aged 6 years of age and over when
response to previous methylphenidate treatment is considered
clinically inadequate.[1]

The UK Medicines and Healthcare products Regulatory Agency (MHRA)
acted as the Reference Member State on behalf of seven other European
countries participating in the procedure (Denmark, Finland, Germany,
Ireland, Norway, Spain and Sweden). Product labelling has been agreed
by these countries, which will now issue their national Marketing
Authorisations (approvals); this typically takes a further one to
three months. In some countries, negotiations with national pricing
and reimbursement authorities will now be required before the
medicine is made available to patients, and the timing for this
process varies between countries.

Elvanse was accepted for review by the MHRA in January 2012, with the
application based on two European Phase 3 studies in children and
adolescents with ADHD and further supported by clinical data from the
USA.[2],[3]

Elvanse is a long-acting, once daily medication for the control of
the symptoms of ADHD.[2],[3] Elvanse is the first of a new class of
dopamine modulators approved in Europe that uses pro-drug technology
to release the active drug in the body. It is currently available in
the USA and Canada under the trade name Vyvanse(R), for the treatment
of ADHD in children, adolescents and adults, and in Brazil under the
trade name Venvanse(R), for the treatment of ADHD in children aged 6
to 12 years. It is currently the most prescribed branded ADHD
medicine in the USA. The efficacy and safety of Elvanse has been
studied in many clinical trials and Elvanse has been prescribed to
treat more than 4 million patients in the USA, Brazil and Canada.[4]

"We are delighted that the national approvals of Elvanse in Europe
are now imminent," said Angus Russell, CEO, Shire. "ADHD is one of
the most common psychiatric disorders affecting children and
adolescents. As all ADHD patients are different and will vary in
their responses to the available treatments, we believe introducing
Elvanse will provide physicians with a broader range of options to
help patients with ADHD manage their individual needs effectively. We
will now work closely with the pricing and reimbursement authorities
in the respective countries to ensure that Elvanse is made available
to patients as soon as possible."

About Elvanse

Elvanse (lisdexamfetamine dimesylate) has not yet received national
marketing authorisation in each respective EU country involved in the
DCP, and national licenses are expected to be issued one to three
months after DCP closure. It is already available in the USA and
Canada (brand name Vyvanse) and in Brazil (brand name Venvanse),
where it has been used to treat over 4 million patients.[4] Elvanse's
efficacy and tolerability have been studied in clinical trials both
in the USA and Europe.[2],[3],[5]-[11]

Elvanse is a single daily dose prodrug medication for the treatment
of ADHD. A prodrug is a substance that is ingested in an inactive
form and then activated within the body.[12]

The inactive prodrug is absorbed from the gut into the bloodstream
where it is gradually converted to the active part of the medicine,
d-amfetamine (d-AMF).[12] The active part of Elvanse is thought to
work by increasing the levels of neurotransmitters (chemicals that
are stored in nerve cells in the brain and nervous system, which
transmit messages between the nerve cells) responsible for activity,
attention and concentration.[ 13]

Elvanse was developed with the goal of providing a long duration of
effect to help patients achieve control of their ADHD symptoms
throughout the day.[14]

Indication[1]

Elvanse is indicated as part of a comprehensive treatment programme
for attention deficit/hyperactivity disorder (ADHD) in children aged
6 years and over when response to previous methylphenidate treatment
is considered clinically inadequate.

Treatment must be under the supervision of a specialist in childhood
and/or adolescent behavioural disorders. Diagnosis should be made
according to DSM-IV criteria or the guidelines in ICD-10 and should
be based on a complete history and evaluation of the patient.
Diagnosis cannot be made solely on the presence of one or more
symptom.

The specific aetiology of this syndrome is unknown, and there is no
single diagnostic test. Adequate diagnosis requires the use of
medical and specialised psychological, educational, and social
resources.

A comprehensive treatment programme typically includes psychological,
educational and social measures as well as pharmacotherapy and is
aimed at stabilising children with a behavioural syndrome
characterised by symptoms which may include chronic history of short
attention span, distractibility, emotional lability, impulsivity,
moderate to severe hyperactivity, minor neurological signs and
abnormal EEG. Learning may or may not be impaired.

Elvanse is not indicated in all children with ADHD and the decision
to use the drug must be based on a very thorough assessment of the
severity and chronicity of the child's symptoms in relation to the
child's age and potential for abuse, misuse or diversion.

Appropriate educational placement is essential, and psychosocial
intervention is generally necessary. The use of Elvanse should always
be used in this way according to the licensed indication.

About Elvanse Clinical Trials

The safety and efficacy of Elvanse was studied in two European Phase
3 studies:

Study 325:[2]A randomised, double blind, multicentre, parallel-group,
placebo- and active-controlled, dose-optimisation, safety and
efficacy study in 336 children and adolescents aged 6 to 17 years.
Results of this study have been accepted for publication in European
Neuropsychopharmacology and were also presented on October 21st 2011
at the American Academy of Child and Adolescent Psychiatry (AACAP)
congress in Toronto.

Study 326:[3]A Phase 3, double blind, placebo-controlled, randomized
withdrawal, multicentre, extension, safety and efficacy study of
lisdexamfetamine dimesylate in 276 children and adolescents aged 6-17
with attention-deficit/hyperactivity disorder. Results from this
study were presented on October 13th 2012 at the European College of
Neuropsychopharmacology (ECNP) congress in Vienna.

Misuse and abuse[1]

Stimulants including Elvanse have a potential for abuse, misuse,
dependence, or diversion for non-therapeutic uses that physicians
should consider when prescribing this product. Stimulants should be
prescribed cautiously to patients with a history of substance abuse
or dependence.

Important Safety Information[15]

- Do not take Elvanse 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 Elvanse:
     - 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.
- Mental (psychiatric) problems including:

Children, Teenagers, and Adults

- new or worse behaviour and thought problems
- new or worse bipolar illness
- new or worse aggressive behaviour or hostility

Children and Teenagers

- new psychotic symptoms such as:
- hearing voices
- believing things that are not true
- being suspicious
- new manic symptoms

This is not a complete summary of safety information. For additional
safety information please see the Elvanse patient information leaflet
or discuss with your doctor. Please note that this safety information
reflects the US label which is different from the European
indication.

About ADHD

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most
common psychiatric disorders in children and
adolescents[16],[17],[18] and is recognised by the World Health
Organization (WHO).[19]

Globally, ADHD affects around 5% of children and adolescents.[20]
Based on this prevalence rate, one can estimate that 5 million young
people in the EU are suffering from ADHD.

What causes ADHD?

While the exact origin of ADHD is not known, it is thought that the
disorder may be caused by an imbalance of neurotransmitters (or
chemicals in the brain).[21]

ADHD is thought to result from complex interactions between genetic
and environmental factors,[22] with studies estimating that genetic
factors explain 60 to 75% of the aetiology of ADHD.[22],[23]

Environmental factors which may increase the risk of developing ADHD
include low birth weight/prematurity, maternal smoking during
pregnancy, and severe early psychosocial adversity (e.g. children who
have survived deprived institutional care).[22]

Notes to editors

Shire enables people with life-altering conditions to lead better
lives.

Through our deep understanding of patients' needs, we develop and
provide healthcare in the areas of:

- Behavioral Health and Gastro Intestinal conditions
- Rare Diseases
- Regenerative Medicine

as well as other symptomatic conditions treated by specialist
physicians.

We aspire to imagine and lead the future of healthcare, creating
value for patients, physicians, policymakers, payors and our
shareholders.

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.

References

1) Elvanse European Summary of Product Characteristics
2) 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. Joint Annual Meeting Of The AmericanAcademy Of Child And 
Adolescent Psychiatry
  (AACAP) And The CanadianAcademy Of Child And Adolescent Psychiatry,
2011.
3) 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. Paper
P7. 009. Poster
  presented at the 25th ECNP conference (13-17 October 2012, Vienna)
4) Shire Data on File SPD489-016
5) Biederman J et al. Efficacy and tolerability of lisdexamfetamine 
dimesylate
  (NRP-104) in children with attention-deficit/hyperactivity 
disorder: a phase III,
  multicenter, randomized, double-blind, forced-dose, parallel-group 
study. ClinTher
  2007;29:450-463.
6) Findling RL et al. Long-term effectiveness and safety of 
lisdexamfetamine
  dimesylate in school-aged children with 
attention-deficit/hyperactivity disorder. CNS
  Spectr 2008;13(7):614-620.
7) Findling RL et al. Effectiveness, safety, and tolerability of
  lisdexamfetamine dimesylate in children with 
attention-deficit/hyperactivity disorder:
  an open-label, dose-optimization study. J Child Adolesc 
Psychopharmacol.
  2009;19(6):649-62.
8) Wigal SB et al. A 13-hour laboratory school study of 
lisdexamfetamine
  dimesylate in school-aged children with 
attention-deficit/hyperactivity disorder.
  Child Adolesc Psychiatry Ment Health 2009;3(1):17
9) Coghill DR, Banaschewski T, Lecendreux ML, et al. Efficacy and 
Safety of
  Lisdexamfetamine Dimesylate in children and adolescents with ADHD: 
A phase 3,
  randomized, double-blind, multicenter, parallel-group, placebo and 
active controlled,
  dose-optimized study in Europe. Poster presented at the AACAP/CACAP
Joint Annual
  Meeting, 18-23 October 2011, Toronto, Canada.
  10) Findling RL, Childress AC, Cutler AJ, et al. Efficacy and 
safety of
  lisdexamfetamine dimesylate in adolescents with 
attention-deficit/hyperactivity
  disorder. J Am Acad Child Adolesc Psychiatry. 2011;50(4):395-405.
  11) Childress AC et al. Long-Term Safety and Effectiveness of 
Lisdexamfetamine
  Dimesylate in Adolescents With Attention-Deficit/Hyperactivity 
Disorder. Poster
  presented at the 164th Annual Meeting of the APA, 14-18 May 2011, 
Honolulu, Hawaii.
  12) Pennick M, Absorption Of Lisdexamfetamine Dimesylate And Its 
Enzymatic
  Conversion To D-Amphetamine. Neuropsychiatric Disease and Treatment
2010;6:317-327.
  13) Faraone S, Buitelaar J, Comparing the efficacy of stimulants 
for ADHD in
  children and adolescents using meta-analysis Eur Child Adolesc 
Psychiatry 2009
  14) Jasinski D, Krishnan S. Abuse liability and safety of oral 
lisdexamfetamine
  dimesylate in individuals with a history of stimulant abuse. J 
Psychopharmacol
  2009a;23:419-427.
  15) VYVANSE (R) (lisdexamfetamine dimesylate) capsules, for oral 
use, Initial
  U.S. Approval: 2007. Highlights of Prescribing Information
  16) Pliszka S and the AACAP Work Group on Quality Issues. 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.
  17) Bloom B, Cohen RA, Freeman G. Summary health statistics for 
U.S. children:
  National Health Interview Survey, 2010. Vital Health Stat 10. 
2011;(250):1-80.
  18) McCarthy S, Wilton L, Murray ML, et al. The epidemiology of
  pharmacologically treated attention deficit hyperactivity disorder 
(ADHD) in children,
  adolescents and adults in UK primary care. BMC Pediatr. 2012;12:78.
  19) International Classification of Diseases, 10th ed., (ICD-10). 
World Health
  Organization 2007:Chapter 5,F90. Accessed August 2012 at:
  http://apps.who.int/classifications/icd10/browse/2010/en#/F90-F98.
  20) Polanczyk G, de Lima MS, Horta BL, et al. The worldwide 
prevalence of ADHD:
  a systematic review and metaregression analysis. Am J Psych. 2007; 
164:942-948.
  21) 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.
  22) Cortese S, The neurobiology and genetics of 
Attention-Deficit/Hyperactivity
  Disorder (ADHD): What every clinician should know, European Journal
of Paediatric
  Neurology (2012), doi:10.1016/j.ejpn.2012.01.009
  23) Faraone S, Perlis R, Doyle A et al. Molecular Genetics Of 
Attention Deficit
  Hyperactivity Disorder. Biol Psychiatry 2005; 57:1313-1323.

For further information please contact:

Investor Relations

Eric Rojas: [email protected], +1-781-482-0999

Sarah Elton-Farr: [email protected], +44-1256-894157

Media

Nicole Barraud: [email protected], +41-22-419-4056

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