Press Release www.shire.com For immediate release Elvanse (lisdexamfetamine dimesylate) Receives UK Marketing Authorisation, Providing a New Option for the Treatment of ADHD in Children and Adolescents in the UK The Medicines and Healthcare products Regulatory Agency (MHRA) grants Elvanse licence for use in attention deficit/hyperactivity disorder (ADHD) In the UK ADHD is thought to affect around 3.62% of boys and 0.85% of girls 1 Basingstoke UK February 12th, 2013 Shire plc (LSE: SHP, NASDAQ: SHPG) today announced that its single-daily dose long-acting prodrug stimulant, Elvanse, has been authorised by the MHRA for the treatment of ADHD in children aged 6 years and over when response to previous methylphenidate treatment is considered clinically inadequate. 2 Elvanse is the first stimulant prodrug to be launched in Europe for the treatment of ADHD. It is ingested in an inactive form and subsequently activated within the body, meaning that the active part of Elvanse is gradually released over time. 3 Elvanse provides a long duration of effect to help patients achieve control of their ADHD symptoms. 2 ADHD is one of the most common behavioural psychiatric disorders in children and adolescents, and is recognised by the World Health Organisation, 4,5,6,7 yet treatment options to help manage the symptoms of ADHD remain limited in Europe. In the UK ADHD is thought to affect 3.62% of boys and 0.85% of girls aged between five and 15 years old. 1 Every person with ADHD is different and will vary in his or her response to the available treatments. A new treatment is welcomed as it will provide a broader range of options to help people with ADHD manage their individual needs effectively, said Dr Val Harpin, Consultant Neurodevelopmental Paediatrician, Sheffield Children s NHS Foundation Trust. Commenting on the authorisation, Dr David Williams, Medical Director at Shire UK said, We are delighted that Elvanse is now licensed for use in children and adolescents with ADHD in the UK. Shire is committed to improving the understanding and treatment of ADHD and to ensuring that patients diagnosed with ADHD continue to benefit from these advances. ADHD is a complex disorder and every patient has specific needs. 8 While there is no cure for ADHD, treatment generally includes educational approaches, behavioural or other psychotherapies, and medication (depending on patient age and ADHD severity), or a combination of all of these. 8 Treatments such as Elvanse are believed to work by enhancing the availability of two neurotransmitters (chemical messengers in the brain), noradrenaline and dopamine, helping to correct a presumed chemical imbalance and reduce symptoms such as inattention, impulsivity and hyperactivity. 2,9 Elvanse was accepted for review by the MHRA in January 2012, with the application based on two European Phase 3 safety and efficacy studies in children and adolescents with ADHD and further supported by clinical data from the USA. 10,11,12,13,14,15 Elvanse has been available in the Registered in Jersey, No. 99854, 22 Grenville Street, St Helier, Jersey JE4 8PX
USA since 2007, Canada since 2010 (brand name Vyvanse ) and in Brazil since 2011 (brand name Venvanse ), where it has been used to treat over four million patients. 16 Elvanse has been reviewed via the European Decentralised Procedure, in which the UK MHRA has acted as the Reference Member State. Elvanse is expected to be available in the UK in the first half of 2013. Product labelling has been agreed by the UK and the other seven countries participating in the procedure (Denmark, Finland, Germany, Ireland, Norway, Spain and Sweden) who will issue their own local Marketing Authorisations. About the data 2 As described in the Summary of Product Characteristics (SmPC), the effects of Elvanse in the treatment of ADHD have been demonstrated in international controlled trials (including European patients) in children and adolescents (6 to 17 years). Study 325 2 As described in the SmPC, 336 patients aged 6-17 years were evaluated in the pivotal Phase 3 European Study SPD489-325. In this seven-week randomised double-blind, dosetitrated, placebo- and active-controlled study, Elvanse showed significantly greater efficacy than placebo. The placebo-adjusted mean reduction from baseline at endpoint in patients treated with Elvanse on the ADHD-RS-IV Total Score was 18.6 (p<0.001). In addition to a reduction in symptoms, clinical studies have demonstrated that Elvanse significantly improves functional outcomes, 75% of subjects on Elvanse showed Improvement (defined as very much improved or much improved ) on the Clinical Global Impression-Improvement (CGI-I) rating scale compared to 14.2% on placebo (p<0.001). Elvanse showed significant improvement in child achievement in academic performance, as measured by the Health Related Quality of life instrument, Parent Report Form of the Child Health and Illness Profile- Child Edition (CHIP-CE:PRF) Achievement Domain. Elvanse demonstrated a significant improvement from baseline compared to placebo (Elvanse: 9.4 versus Placebo: -1.1) with a mean difference between the two treatment groups of 10.5 (p<0.001). Results of this study have recently been published in European Neuropsychopharmacology. Study 326 2 Maintenance of effect was demonstrated in a double-blind, placebo-controlled, randomised withdrawal study conducted in children and adolescents ages 6 to 17 (n=157) who met the diagnosis of ADHD (DSM-IV criteria). Patients were optimised to open-label Elvanse for an extended period (at least 26 weeks) prior to entry into the 6-week randomised withdrawal period. Eligible patients were randomised to continue receiving their optimised dose of Elvanse or to switch to placebo. Patients were observed for relapse (treatment failure) during the 6-week double-blind phase. Treatment failure was defined as a 50% increase (worsening) in the ADHD-RS Total Score and a 2-point increase in the CGI-S score compared to scores at entry into the double-blind randomised withdrawal phase. Treatment failure was significantly lower (p<0.001) for the Elvanse subjects (15.8%) compared to placebo (67.5%). For the majority of subjects (70.3%) who were treatment failures regardless of treatment, ADHD symptoms worsened at or before the week 2 visit following randomisation. Results from this study were presented on 13th October 2012 at the European College of Neuropsychopharmacology (ECNP) congress in Vienna. Details of all clinical trials can be found at clinicaltrials.gov. Indication and Important Safety Information 2 Elvanse is indicated as part of a comprehensive treatment programme for ADHD in children aged 6 years of age and over when response to previous methylphenidate treatment is considered clinically inadequate. 2
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. Please consult the Elvanse SmPC before prescribing, particularly in relation to abuse and dependence, pre-treatment evaluation and ongoing monitoring, cardiovascular adverse events, psychiatric adverse events, tics, long-term suppression of growth (height and weight), seizures, visual disturbance, prescribing and dispensing, and use with other sympathomimetic drugs. Adverse reactions observed with Elvanse treatment mainly reflect side effects commonly associated with stimulant use. Very common adverse reactions include decreased appetite, insomnia, dry mouth, headache, decreased weight and upper abdominal pain. Misuse and abuse 2 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. About ADHD ADHD is one of the most common behavioural psychiatric disorders in children and adolescents and is recognised by the World Health Organisation. 4,5,6,7 In the UK, ADHD is thought to affect around 3.62% of boys and 0.85% of girls. 1 While the exact causes of ADHD are not fully understood, it is thought to result from complex interactions between genetic and environmental factors, with studies estimating that genetic factors explain 60 75% of the aetiology of ADHD. 17,18 Environmental factors which may increase the risk of developing ADHD include low birth weight/prematurity, and maternal smoking during pregnancy. 17 For further information please contact: Media Gwen Fisher gfisher@shire.com +1 484 595 9836 Nicole Barraud nbarraud@shire.com + 41 22 419 4056 Just:: Health PR Gemma Taylor gemma@justhealthpr.com +44 208 877 8434 Harriet Smith harriet@justhealthpr.com +44 208 877 8430 3
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. www.shire.com FORWARD - LOOKING STATEMENTS - "SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995 Statements included in this announcement that are not historical facts are forward-looking statements. 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, Shire s results could be materially adversely affected. The risks and uncertainties include, but are not limited to, that: Shire s products may not be a commercial success; revenues from ADDERALL XR are subject to generic erosion; the failure to obtain and maintain reimbursement, or an adequate level of reimbursement, by third-party payors in a timely manner for Shire's products may impact future revenues and earnings; Shire relies on a single source for manufacture of certain of its products and a disruption to the supply chain for those products may result in Shire being unable to continue marketing or developing a product or may result in Shire being unable to do so on a commercially viable basis; Shire uses third party manufacturers to manufacture many of its products and is reliant upon third party contractors for certain goods and services, and any inability of these third party manufacturers to manufacture products, or any failure of these third party contractors to provide these goods and services, in each case in accordance with its respective contractual obligations, could adversely affect Shire s ability to manage its manufacturing processes or to operate its business; the development, approval and manufacturing of Shire s products is subject to extensive oversight by various regulatory agencies and regulatory approvals or interventions associated with changes to manufacturing sites, ingredients or manufacturing processes could lead to significant delays, increase in operating costs, lost product sales, an interruption of research activities or the delay of new product launches; the actions of certain customers could affect Shire 's ability to sell or market products profitably and fluctuations in buying or distribution patterns by such customers could adversely impact Shire s revenues, financial conditions or results of operations; investigations or enforcement action by regulatory authorities or law enforcement agencies relating to Shire s activities in the highly regulated markets in which it operates may result in the distraction of senior management, significant legal costs and the payment of substantial compensation or fines; adverse outcomes in legal matters and other disputes, including Shire s ability to obtain, maintain, enforce and defend patents and other intellectual property rights required for its 4
business, could have a material adverse effect on Shire s revenues, financial condition or results of operations; and other risks and uncertainties detailed from time to time in Shire s filings with the U.S. Securities and Exchange Commission, including its most recent Annual Report on Form 10-K. References 1. Ford, T., Goodman, R. & Meltzer, H. (2003) The British Child and Adolescent Mental Health Survey 1999: the prevalence of DSM-IV disorders. Journal of the American Academy of Child and Adolescent Psychiatry, 42, 1203 1211. 2. Elvanse, UK Summary of Product Characteristics (SmPC) 2013. 3. Pennick M, Absorption Of Lisdexamfetamine Dimesylate And Its Enzymatic Conversion To D- Amphetamine. Neuropsychiatric Disease and Treatment 2010;6:317-327. 4. 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. 5. 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. 6. 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. 7. 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. 8. NICE guideline on diagnosis and management of ADHD in children, young people and adults, National Clinical Practice Guideline Number 72 2009; 1 664. 9. Faraone S, Buitelaar J, Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis Eur Child Adolesc Psychiatry 2009; 19(4):353-64. 10. Coghill D, Banaschewski T, Lecendreaux M et al. European, randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder. European Neuropsychopharmacology 2013; Online publication: http://dx.doi.org/10.1016/j.euroneuro.2012.11.012. 11. 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. 12. 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. Clin Ther 2007;29:450-463. 13. 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. 14. Findling R, Childress A, Krishnan S et al. Long-Term Effectiveness And Safety Of Lisdexamfetamine Dimesylate In School-Aged Children With Attention Deficit/ Hyperactivity Disorder. CNS Spectr 2008;13(7):614-20. 15. Findling R, Childress A, Cutler A 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. 16. Shire Data on File SPD489-016. 17. Cortese, S. The neurobiology of genetics of Attention-Deficit/Hyperactivity Disorder (ADHD): What every clinician should know. Eur J Paediatr Neurol. 2012; 16)5):422-33. 18. Faraone S, Perlis R, Doyle A et al. Molecular Genetics Of Attention Deficit Hyperactivity Disorder. Biol Psychiatry 2005; 57:1313-1323. 5