FDA Issues Complete Response Letter for INTUNIV(TM) (guanfacine) Extended Release for the Treatment of ADHD in Children and Adolescents

Friday, September 18, 2009 General News
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PHILADELPHIA, July 28 Shire plc (LSE: SHP,NASDAQ: SHPGY), the global specialty biopharmaceutical company, announcesthat it has received a Complete Response letter today for INTUNIV(TM)(guanfacine) Extended Release from the Food and Drug Administration (FDA).This decision comes following labeling discussions with the FDA that did notresult in agreement in time to meet the PDUFA date.

The FDA did not identify safety concerns regarding INTUNIV in theComplete Response letter or request new clinical studies. Shire and the FDAwill continue to work together to resolve the remaining labeling languageover the next 4 to 8 weeks.

"Shire is confident that we will quickly come to agreement on the finalproduct label and anticipates a launch in the fourth quarter as planned,"said Mike Cola, President of Shire Specialty Pharmaceuticals. "When approved,INTUNIV will be the first selective alpha-2A receptor agonist for thetreatment of ADHD, and will provide patients with an important new treatmentoption."


INTUNIV is being studied for the treatment of ADHD in children andadolescents aged 6 to 17 years. INTUNIV is a once-daily, extended releaseformulation of guanfacine, designed to provide steady delivery of drugthroughout the day. INTUNIV is not a controlled substance and has no knownpotential for abuse or dependence.

Guanfacine, the active ingredient in INTUNIV, is thought to work directlyby binding selectively to alpha-2A adrenergic receptors located in theprefrontal cortex - an area of the brain that has been linked to ADHD.(4-6)Stimulation of the postsynaptic alpha-2A receptors is thought to strengthenworking memory, reduce susceptibility to distraction, improve attentionregulation, improve behavioral inhibition and enhance impulse control.(6-10)Although the mechanism of action of guanfacine in the treatment of ADHD isnot fully understood, preclinical research suggests this selective alpha-2Aagonist strengthens working memory and prefrontal cortex neuronal firing.(6)This research supports the use of guanfacine for the treatment of ADHD.(6)

Safety was also evaluated during these pivotal trials and safety datashowed that adverse events reported by participants using INTUNIV weregenerally mild to moderate in severity, with the most common side effectsbeing sedative in nature.(1,2) Sedation-related, treatment-emergent adverseevents were among the most common and were usually transient and mild tomoderate in severity.(1,2) Treatment-related adverse events greater than 10percent included somnolence (32 percent), headache (26 percent), fatigue (18percent), upper abdominal pain (14 percent), and sedation (13 percent).(11)Small to modest changes in blood pressure, pulse rate, and ECG parameterswere observed.(11)

About ADHD

ADHD is one of the most common psychiatric disorders in children andadolescents.(12) Worldwide prevalence of ADHD is estimated at 5.3 percent(with large variability), according to a comprehensive systematic review ofthis topic published in 2007 in the American Journal of Psychiatry.(13) Inthe United States, approximately 7.8 percent of all school-aged children, orabout 4.4 million children aged 4 to 17 years, have been diagnosed with ADHDat some point in their lives, according to the Centers for Disease Controland Prevention (CDC).(14) The disorder is also estimated to affect 4.4percent of US adults aged 18 to 44 based on results from the NationalComorbidity Survey Replication.(15) When this percentage is extrapolated tothe full US population aged 18 and over, approximately 9.8 million adults arebelieved to have ADHD.(16)

ADHD is a psychiatric behavioral disorder that manifests as a persistentpattern of inattention and/or hyperactivity-impulsivity that is more frequentand severe than is typically observed in individuals at a comparable level ofdevelopment.(17,18) The specific etiology of ADHD is unknown and there is nosingle diagnostic test for this syndrome.(12) Adequate diagnosis requires theuse of medical and special psychological, educational, and social resources,utilizing diagnostic criteria such as Diagnostic and Statistical Manual ofMental Disorders-IV (DSM-IV(R)) or International Classification of Diseases10 (ICD-10).(12,17,18)

Although there is no cure for ADHD, there are accepted treatments thatspecifically target its symptoms. Standard treatments include educationalapproaches, psychological or behavioral modification, and medication.(12)

Notes to editors


Shire's strategic goal is to become the leading specialtybiopharmaceutical company that focuses on meeting the needs of the specialistphysician. Shire focuses its business on attention deficit hyperactivitydisorder (ADHD), human genetic therapies (HGT) and gastrointestinal (GI)diseases as well as opportunities in other therapeutic areas to the extentthey arise through acquisitions. Shire's in-licensing, merger and acquisitionefforts are focused on products in specialist markets with strongintellectual property protection and global rights. Shire believes that acarefully selected and balanced portfolio of products with strategicallyaligned 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.


Statements included herein that are not historical facts areforward-looking statements. Such forward-looking statements involve a numberof risks and uncertainties and are subject to change at any time. In theevent such risks or uncertainties materialize, the Company's results could bematerially adversely affected. The risks and uncertainties include, but arenot limited to, risks associated with: the inherent uncertainty of research,development, approval, reimbursement, manufacturing and commercialization ofthe Company's Specialty Pharmaceutical and Human Genetic Therapies products,as well as the ability to secure and integrate new products forcommercialization and/or development; government regulation of the Company'sproducts; the Company's ability to manufacture its products in sufficientquantities to meet demand; the impact of competitive therapies on theCompany's products; the Company's ability to register, maintain and enforcepatents and other intellectual property rights relating to its products; theCompany's ability to obtain and maintain government and other third-partyreimbursement for its products; and other risks and uncertainties detailedfrom time to time in the Company's filings with the Securities and ExchangeCommission.

1. Biederman J, Melmed R, Patel A, et al. A randomized, double-blind,placebo-controlled study of guanfacine extended release in children andadolescents with attention-deficit/hyperactivity disorder. Pediatrics.2008;121(1):e73-e84.

2. Sallee F, McGough J, Wigal T, et al. Guanfacine extended release inchildren and adolescents with ADHD: a placebo-controlled trial. J Am AcadChild and Adolesc Psychiatry. 2009;48(2):1-11.

3. Connor D, Spencer T, Kratochvil C, et al. Effects of guanfacineextended release on secondary measures in children withattention-deficit/hyperactivity disorder and oppositional symptoms. Presentedat the American Psychiatric Association Annual Meeting; May 18, 2009; SanFrancisco, CA.

4. Arnsten AF, Scahill L, Findling R. Alpha-2 adrenergic receptoragonists for the treatment of attention-deficit/hyperactivity disorder:emerging concepts from new data.

J of Child and Adolesc Psychopharmacology. 2007;17:4:393-406.

5. MacDonald E, Kobilka BK, Scheinin M. Gene targeting-homing in onalpha-2-adrenoceptor subtype function. Trends in Pharmacol Sci.1997;18:211-219.

6. Wang M, Arnsten AF, Brennan A, et al. α2A-adrenoceptors strengthenworking memory networks by inhibiting cAMP-HCN channel signaling inprefrontal cortex. Cell. 2007;129:397-410.

7. Arnsten AF, Li BM. Neurobiology of executive functions: catecholamineinfluences on prefrontal cortical functions. Biol Psychiatry. 2005;57:1377-1385.

8. Steere JC, Arnsten AFT. The alpha-2A noradrenergic agonist,guanfacine, improves visual object discrimination reversal performance inrhesus monkeys. Behav Neurosci. 1997;111:1-9.

9. Mao Z-M, Arnsten AFT, Li B-M. Local infusion of alpha-1 adrenergicagonist into the prefrontal cortex impairs spatial working memory performancein monkeys. Biol Psychiatry. 1999;46:1259-1265.

10. Jakala P, Riekkinen M, Sirvio, J, et al. Guanfacine, but notclonidine, improves planning and working memory performance in humans.Neuropsychopharmacology. 1999;2[5]:460-470.

11. INTUNIV Data on File SPD503005; Shire plc. ISS Summary of ClinicalSafety 2006; -: 1-190.

12. Pliszka S and the AACAP Work Group on Quality Issues. Practiceparameter for the assessment and treatment of children and adolescents withattention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry.2007;46(7):894-921.

13. Polanczyk G, de Lima MS, Horta BL, et al. The worldwide prevalence ofADHD: a systematic review and metaregression analysis. Am J Psych. 2007;164:942-948.

14. Mental health in the United States: Prevalence of diagnosis andmedication treatment for attention-deficit/hyperactivity disorder, UnitedStates, 2003. MMWR. 2005;54(34):842-847.

15. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlatesof adult ADHD in the United States: results from the national comorbiditysurvey replication. Am J Psychiatry. 2006; 163:716-723.

16. Annual Estimates of the Population by Selected Age Groups and Sex forthe United States: April 1, 2000 to July 1, 2005 (NC-EST2005-02). U.S. CensusBureau. http://www.census.gov/popest/national/asrh/NC-EST2005-sa.html.Accessed July 13, 2009.

17. Diagnostic and Statistical Manual of Mental Disorders. 4th ed., TextRevision (DSM-IV-TR(R)). Arlington, VA: American Psychiatric Publishing;2000:85-93.

18. International Classification of Diseases, 10th ed., (ICD-10). WorldHealth Organization; 2007: Chapter 5,F90.http://www.who.int/classifications/apps/icd/icd10online/. Accessed July 13,2009.For further information please contact: Investor Relations Clea Rosenfeld (Rest of the World) +44-1256-894-160 Eric Rojas (North America) +1-617-551-9715 Media Jessica Mann (Rest of the World) +44-1256-894-280 Matthew Cabrey (North America) +1-484-595-8248

SOURCE Shire Plc

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