Top-line Results from Phase 3 Studies for Vyvanse in MDD

Shire Reports Top-line Results from Two Phase 3 Studies for Vyvanse®(lisdexamfetamine dimesylate) Capsules (CII) as an Adjunctive Treatment forAdults with Major Depressive Disorder February 7, 2014 - Shire plc (LSE: SHP, NASDAQ: SHPG) announces top-lineresults from two pivotal Phase 3 investigational studies evaluating theefficacy and safety of Vyvanse® (lisdexamfetamine dimesylate) Capsules (CII)versus placebo as an adjunctive treatment for major depressive disorder (MDD)in adults who inadequately responded to antidepressant monotherapy with a SSRIor SNRI. Vyvanse did not meet the primary efficacy endpoint versus placebo foreither study. The safety profile for Vyvanse in these two studies appears to begenerally consistent with the known profile established in studies in adultswith Attention-Deficit/Hyperactivity Disorder (ADHD). Based on these clinicaltrial results, Shire will no longer pursue this clinical development program. "While this news in major depressive disorder is disappointing for patients andShire, we will later in the year be filing with the FDA for a new indicationfor Vyvanse in Binge Eating Disorder in adults, and Vyvanse is an effective andleading treatment for ADHD," said Flemming Ornskov, M.D., Shire's ChiefExecutive Officer. "We remain committed to serving patients with ADHD and willinvest in solutions to meet their treatment needs accordingly. Shire'sportfolio of treatments in rare diseases is also growing, strengthened recentlywith the acquisition of ViroPharma. Rare Diseases is an area of great unmetpatient need and it's where we will increasingly focus our strategicdevelopment and investment." Vyvanse is a prescription medicine currently only approved for the treatment ofADHD in the United States, Canada, Australia, several European countries (tradename: Elvanse®/Tyvense®) and Brazil (trade name: Venvanse™). Vyvanse shouldonly be used in accordance with locally approved prescribing information. CNS stimulants (amphetamines and methylphenidate-containing products) have ahigh potential for abuse and dependence. Assess the risk of abuse prior toprescribing and monitor for signs of abuse and dependence while on therapy. ABOUT THE MDD STUDIES Each of the two identically designed Phase 3, multi-center, randomized,double-blind, parallel-group, placebo-controlled, dose-optimized studies wasdesigned to assess the efficacy, safety, and tolerability of Vyvanse inpatients aged 18 to 65 who met DSM-IV-TR® criteria for a diagnosis of MDD. Thefirst study randomized (404 adults), and the second study randomized (426adults). The primary efficacy endpoint for the studies was defined as thechange from augmentation baseline (Week 8) to Week 16 in Montgomery-ǺsbergDepression Rating Scale (MADRS) total score. Vyvanse did not meet the primaryefficacy endpoint versus placebo for either study (p=0.883, p=0.583). In thefirst study, subjects experienced a mean reduction of 6.1 in MADRS total scorefor Vyvanse compared with 6.3 for placebo. Augmentation baseline MADRS scoresfor Vyvanse and placebo groups were 25.4 and 25.2 respectively. In the secondstudy, subjects experienced a mean reduction of 7.3 in MADRS total score forVyvanse compared with 6.8 for placebo. Augmentation baseline MADRS scores forVyvanse and placebo groups were 26.0 and 25.7 respectively. Safety and tolerability of Vyvanse were evaluated based on treatment-emergentadverse events (TEAEs), vital signs, weight, clinical laboratory results, andelectrocardiogram (ECG) results. Study SPD489-322 In study SPD489-322, 3 patients treated with Vyvanse and 5 patients treatedwith placebo experienced serious adverse events (SAEs). Eight (8) patients onVyvanse and 7 patients on placebo had TEAEs that led to studydiscontinuation. The most commonly reported (>5% of subjects) TEAEs in subjectstaking Vyvanse included insomnia, dry mouth, decreased appetite, headache,nausea, nasopharyngitis, and dizziness. Study SPD489-323 In study SPD489-323 1 patient treated with Vyvanse and 1 patient treated withplacebo experienced serious adverse events (SAE). Two (2) patients on Vyvanseand 1 patient on placebo had treatment-emergent adverse events (TEAEs) that ledto study discontinuation. The most commonly reported (>5% of subjects) TEAEs insubjects taking Vyvanse included headache, dry mouth, nasopharyngitis,decreased appetite, insomnia, hyperhidrosis and restlessness. Further evaluation of the safety information related to vital signs, ECG, andclinical laboratory results and other safety assessments is currently underway. The 16-week studies consisted of an 8-week single blind lead-in phase with anantidepressant (selective serotonin reuptake inhibitors (SSRI) or serotonin andnorepinephrine reuptake inhibitors (SNRI)), and an 8-week double-blindadjunctive treatment phase. Subjects who demonstrated an inadequate response tothe antidepressant treatment at Week 8, defined in the study protocol as havinga MADRS total score ≥ 18 and a 5% and at least twice the rate of placebo) reported in clinical trials were: * Children aged 6 to 12: decreased appetite, insomnia, upper abdominal pain, irritability, vomiting, decreased weight, nausea, dry mouth and dizziness; * Adolescents aged 13 to 17: decreased appetite, insomnia, and decreased weight; * Adults: decreased appetite, insomnia, dry mouth, diarrhea, nausea, anxiety and anorexia. Please click here for Full Prescribing Information http://pi.shirecontent.com/PI/PDFs/Vyvanse_USA_ENG.pdf . For further information please contact: Investor Relations Eric Rojas [email protected] +1 781 482 0999 Sarah Elton-Farr [email protected] +44 1256 894157 Media Jessica Mann [email protected] +44 1256 894 280 Gwen Fisher [email protected] +1 484 595 9836 NOTES TO EDITORS Shire enables people with life-altering conditions to lead better lives. Our strategy is to focus on developing and marketing innovative specialtymedicines to meet significant unmet patient needs. We provide treatments in Neuroscience, Rare Diseases, Gastrointestinal andInternal Medicine, and we are developing treatments for symptomatic conditionstreated by specialist physicians in other targeted therapeutic areas. www.shire.com The Vyvanse®, Elvanse®, Tyvense®, and Venvanse™ marks used in this release aretrademarks of Shire plc or companies within the Shire group. FORWARD - LOOKING STATEMENTS - "SAFE HARBOR" STATEMENT UNDER THE PRIVATESECURITIES LITIGATION REFORM ACT OF 1995 Statements included in this announcement that are not historical facts areforward-looking statements. Forward-looking statements involve a number ofrisks and uncertainties and are subject to change at any time. In the eventsuch risks or uncertainties materialize, Shire's results could be materiallyadversely affected. The risks and uncertainties include, but are not limitedto, 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 business, could have a material adverse effect on Shire's revenues, financial condition or results of operations; * any failure to achieve Shire's strategic objectives with respect to the acquisition of ViroPharma Inc., including a failure to achieve targeted sales of CINRYZE, may adversely affect Shire's financial condition and results of operations; and other risks and uncertainties detailed from time to time in Shire's filingswith the U.S. Securities and Exchange Commission, including its most recentAnnual Report on Form 10-K.

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