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

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

  PR Newswire

  NYON, Switzerland, December 18, 2012

NYON, Switzerland, December 18, 2012 /PRNewswire/ --

Shire plc (LSE: SHP, NASDAQ: SHPG) today announces a positive outcome from the
European Decentralised Procedure (DCP) for Elvanse ^® (to be known as Tyvense
^® 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 ^® , for the treatment of ADHD in
children, adolescents and adults, and in Brazil under the trade name Venvanse
^® , 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 inEuropeare now
imminent," saidAngus 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.Wewill 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 21 ^st 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 13 ^th 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  American Academy
               Of Child And Adolescent Psychiatry (AACAP) And The  Canadian
              Academy  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 ® (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: erojas@shire.com , +1-781-482-0999

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

         Media     

         Nicole Barraud: nbarraud@shire.com , +41-22-419-4056

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