INTUNIV® (Guanfacine Hydrochloride Prolonged Release), a Non-stimulant for the Treatment of ADHD, Receives Approval in Japan

ZUG, Switzerland, March 30, 2017 /PRNewswire/ --

A NewNon-stimulantClinicalOption forChildren andAdolescentsFrom 6 to 17Years oldWith ADHD 

Shire plc (LSE: SHP, NASDAQ: SHPG) today announced that its partner in Japan, Shionogi & Co., Ltd, has received the approval of the Japanese Ministry of Health, Labor and Welfare to manufacture and market INTUNIV. INTUNIV is a new, once-daily non-stimulant indicated for the treatment of attention deficit hyperactivity disorder (ADHD),^[1] a common psychiatric disorder in children and adolescents.^[2],[3]

ADHD causes inattention, hyperactivity or impulsivity, or a combination of these symptoms,^[4],[5] and can have substantial impact on all major areas of life, including: schooling, work and employment, behaviour, social functioning, self-esteem and health.^[6]-[9]

INTUNIV is a selective alpha-2A adrenergic receptor agonist.^[1] With a unique mechanism of action, INTUNIV represents an additional treatment option in the management of ADHD.

"Shire is committed to ensuring that every person with ADHD is able to benefit from a treatment most suited to their needs," said Philip J Vickers, PhD, Global Head of Shire Research and Development. "The approval of INTUNIV marks a significant advance in the treatment of ADHD in children and adolescents in Japan, who may benefit from a new treatment option."

As part of the partnership, a Phase 3 placebo-controlled clinical study and long-term extension study evaluating the efficacy and safety of INTUNIV in 254 patients was conducted in Japan. In the trial, INTUNIV administered once daily, showed significant improvements over placebo, as measured by ADHD-RS-IV total score, in all core symptoms of ADHD: hyperactivity/impulsivity, and inattention. The most common adverse events were somnolence in 146 patients (57.5%), decreased blood pressure in 39 patients (15.4%), and headache in 31 patients (12.2%).^[1]

ADHD is a complex condition and approaches to treatment typically include educational methods, psychotherapy and medication.^[10] When required, either stimulants or non-stimulants are indicated as part of a comprehensive treatment programme for ADHD. Children and adolescents have a wide spectrum of individual needs as patients, so it is important that a range of treatment options are available. Non-stimulant medications are an important alternative to stimulants for some ADHD patients.^[10]

About ADHD 

Attention deficit hyperactivity disorder (ADHD) is recognised by the World Health Organization (WHO).^[2] Worldwide prevalence of ADHD is estimated to vary between 5.9% and 7.1%.^[3]

Whilst the exact origin of ADHD is not fully understood, the area of the brain known as the prefrontal cortex is known to control several cognitive functions including attention and social behaviours,^{[9],[11],[12]} and has been associated with some structural and functional abnormalities in individuals with ADHD.^[13]-[15]

About INTUNIV 

INTUNIV (guanfacine hydrochloride prolonged release) is a once-daily non-stimulant indicated for the treatment of attention deficit/hyperactivity disorder (ADHD) in children and adolescents from 6 to 17 years old.^[1]

INTUNIV provides significantly improved ADHD symptom control vs. placebo^[1],[16] and has a well-documented safety profile across the dose range.^[1]

INTUNIV contains the active substance guanfacine, a selective alpha-2A adrenergic receptor agonist.^[1] Studies suggest that guanfacine may exert physiological effects by selectively stimulating the alpha-2A adrenergic receptor in the prefrontal cortex.^[17]-[18]

INTUNIV is currently approved by Shire in the US, Canada, and Europe. Please refer to the local label for the approved indication.

INTUNIV Safety Information for Japan^[1]

Precautions on indication 

The efficacy and safety of INTUNIV in children under 6 years of age or adults over 18 years of age have not been established.

If INTUNIV is continued after age 18 in patients who started pharmacological treatment with this drug before the age of 18 years, it should be administered with caution after the therapeutic benefits are weighed against the possible risks. The efficacy and safety of INTUNIV should regularly be evaluated, and if INTUNIV is of no value, it should be considered for discontinuation and must not be administered without purpose.

A diagnosis of ADHD must be made with caution, according to standard, established diagnostic criteria, including DSM* published by the American Psychiatric Association. INTUNIV must be used only in patients who meet such criteria.

*Diagnostic and Statistical Manual of Mental Disorders

Contraindication (INTUNIVis contraindicated in the following patients.) 

  1. Patients with a history of hypersensitivity to any of the ingredients of this drug.
  2. Pregnant women or women who may possibly be pregnant.
  3. Patients with atrioventricular block second-degree and third-degree. [The condition may get worse because of the central bradycardia effect of this drug.]

Precautions 

1. Careful Administration (INTUNIVshould be administered with care in the following patients.) 

Patients with a current or previous history of hypotension, orthostatic hypotension, bradycardia, or cardiovascular disease, or patients treating with drugs which can reduce blood pressure or pulse rate [INTUNIV may decrease blood pressure and heart rate.]

Patients with a current or previous history of hypertension [Blood pressure may increase when administration of this drug is abruptly discontinued.]

Patients with a current or previous history of arrhythmia, patients with congenital long QT syndrome or patients treating with drugs that are known to cause QT prolongation [QT prolongation may occur because of this drug.]

Patients with a current or previous history of ischaemic heart disease such as angina pectoris and myocardial infarction [If the acute reduction of blood pressure occurs, ischaemic heart disease may get worse because of the decreased coronary flow.]

Patients with cerebrovascular disorder such as cerebral infarction etc. [If the acute reduction of blood pressure occurs, the symptoms may be aggravated due to the decrease in cerebral blood flow.]

Patients with severe hepatic function disorder [The blood concentration of this drug may increase.]

Patients with severe renal function disorder [The blood concentration of this drug may increase.]

Patients in depressed state [The symptom may get worse because of the sedative effects of this drug.]

2. Importantprecautions 

  1.  Before prescribing INTUNIV, the physician or healthcare professional should fully inform the patient and his/her parent or other appropriate representative of its therapeutic position and potential risks, including adverse reactions to the drug, and instruct the patient on the proper administration method.  
  2.  During long-term use of INTUNIV, the value of ongoing treatment should be periodically assessed and patients should not be administered without purpose. ~ 
  3.  Since syncope may occur when advanced decreases in blood pressure or pulse rate are observed, blood pressure and pulse rate should be measured prior to initiation of treatment of INTUNIV and 1-2 weeks after changing the dosage. Blood pressure and pulse rate should also be measured at intervals of once in 4 weeks after setting an optimal dose. Also, dehydration along with the administration of INTUNIV should be fully cautioned. If any dehydration symptoms are observed, proper care such as fluid replacement should be taken.  
  4.  Since the effects on cardiovascular system (advanced bradycardia, hypotension, QT prolongation etc.) may appear, the following points should be cautioned before and during treatment with INTUNIV.

     i)  The presence or absence of abnormality in ECG should be confirmed before treatment with INTUNIV. If any abnormality in ECG is observed, the initiation of administration should be carefully judged.
     ii) When INTUNIV is administered to patients with cardiovascular disease or with a medical history of cardiovascular disease, or any abnormality in ECG is observed before treatment with INTUNIV, patients' condition should be carefully observed by conducting routine ECG and so on.
     iii) Patients' cardiovascular condition should be cautioned during treatment with INTUNIV. If any symptoms suggesting the effects on cardiovascular system (bradycardia, syncope, dizziness, palpitations, etc.) appear, proper care should be taken by conducting ECG and so on.

  5. Since suicidal ideation or behavior may occur, patient's condition should be carefully observed. Also, patients, the parents or other appropriate representative should be instructed to contact a medical institution immediately, if any suicidal symptoms occur.
  6. While hostility and aggression are frequently observed in AD/HD patients, occurrence of these events during treatment has been also reported. The occurrence or worsening of these events should be carefully monitored during treatment.
  7.  Since INTUNIV may cause weight increase, body weight should be monitored regularly. If any symptom of obesity appears, proper care should be taken such as food therapy, movement therapy, etc.
  8.  Since sleepiness, sedation, etc. may occur, patients should be cautioned not to engage in operating potentially hazardous machinery, including automobiles during treatment.

Drug interactions 

This drug is primarily metabolized by the hepatic metabolizing enzymes CYP3A4 and CYP3A5.

Adverse reactions 

Out of 254 patients evaluated for safety before NDA approval, adverse reactions (including abnormal changes in laboratory values) were observed in 190 patients (74.8%). Main adverse reactions were somnolence in 146 patients (57.5%), decreased blood pressure in 39 patients (15.4%), and headache in 31 patients (12.2%).

1.Clinically significant adverse reactions 

Hypotension (≧5%), bradycardia (≧5%): Since advanced hypotension or/and bradycardia may occur and lead to syncope, patients' condition should be carefully monitored, measuring blood pressure and pulse rate regularly. If any of these symptoms appears, proper care such as dose reduction, interruption, or discontinuation should be taken.

Syncope (Incidence unknown^{[Note 1]}): Since syncope may occur, patients should be fully observed. If any abnormality is observed, proper care such as discontinuation of administration should be taken.

Atrioventricular block (<0.5%): Since atrioventricular block may occur, proper care such as dose reduction, interruption, or discontinuation should be taken if any abnormality is observed.

2. Other adverse reactions 

If the following adverse reactions occur, appropriate measures such as dose reduction, interruption, or discontinuation should be taken as necessary.

greater than <5%, greater or equal than or Incidence Type/ Incidence to 5% equal to 1% <1% unknown[Note 1] Hypersensitivity, Hypersensitivity rash, pruritus Tachycardia, sinus arrhythmia, pallor, Orthostatic Increased hypertensive Cardiovascular hypotension blood pressure encephalopathy Nightmare, affect Somnolence, lability, headache, agitation, Anxiety, depression, insomnia, sedation, lethargy, convulsion, Psychoneurologic dizziness Irritability asthenia hypersomnia Decreased appetite, nausea, constipation, diarrhea, Abdominal thirst, Abdominal discomfort, Gastrointestinal pain vomiting dyspepsia Enuresis, Pollakiuria, increased increased ALT Asthma, chest pain, Others Malaise weight (GPT) dehydration

Note 1: The incidence of adverse reactions on the basis of overseas clinical studies and spontaneous reports is unknown.

NOTES TO EDITORS 

About Shire 

Shire is the leading global biotechnology company focused on serving people with rare diseases and other highly specialized conditions. We strive to develop best-in-class products, many of which are available in more than 100 countries, across core therapeutic areas including Hematology, Immunology, Neuroscience, Ophthalmics, Lysosomal Storage Disorders, Gastrointestinal / Internal Medicine / Endocrine and Hereditary Angioedema; and a growing franchise in Oncology.

Our employees come to work everyday with a shared mission: to develop and deliver breakthrough therapies for the hundreds of millions of people in the world affected by rare diseases and other high-need conditions, and who lack effective therapies to live their lives to the fullest.

http://www.shire.com

Forward-Looking Statements 

Statements included herein that are not historical facts, including without limitation statements concerning future strategy, plans, objectives, expectations and intentions, the anticipated timing of clinical trials and approvals for, and the commercial potential of, inline or pipeline products, 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, Shire's results could be materially adversely affected. The risks and uncertainties include, but are not limited to, the following:

• Shire's products may not be a commercial success;
• increased pricing pressures and limits on patient access as a result of governmental regulations and market developments may affect Shire's future revenues, financial condition and results of operations;
• Shire conducts its own manufacturing operations for certain of its products and is reliant on third party contract manufacturers to manufacture other products and to provide goods and services. Some of Shire's products or ingredients are only available from a single approved source for manufacture. Any disruption to the supply chain for any of Shire's 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 for some period of time;
• the manufacture of Shire's products is subject to extensive oversight by various regulatory agencies. Regulatory approvals or interventions associated with changes to manufacturing sites, ingredients or manufacturing processes could lead to, among other things, significant delays, an increase in operating costs, lost product sales, an interruption of research activities or the delay of new product launches;
• certain of Shire's therapies involve lengthy and complex processes, which may prevent Shire from timely responding to market forces and effectively managing its production capacity;
• Shire has a portfolio of products in various stages of research and development. The successful development of these products is highly uncertain and requires significant expenditures and time, and there is no guarantee that these products will receive regulatory approval;
• the actions of certain customers could affect Shire's ability to sell or market products profitably. Fluctuations in buying or distribution patterns by such customers can adversely affect Shire's revenues, financial conditions or results of operations;
• Shire's products and product candidates face substantial competition in the product markets in which it operates, including competition from generics;
• adverse outcomes in legal matters, tax audits and other disputes, including Shire's ability to enforce and defend patents and other intellectual property rights required for its business, could have a material adverse effect on the Company's revenues, financial condition or results of operations;
• inability to successfully compete for highly qualified personnel from other companies and organizations;
• failure to achieve the strategic objectives, including expected operating efficiencies, cost savings, revenue enhancements, synergies or other benefits at the time anticipated or at all with respect to Shire's acquisitions, including NPS Pharmaceuticals Inc., Dyax Corp. or Baxalta Incorporated may adversely affect Shire's financial condition and results of operations;
• Shire's growth strategy depends in part upon its ability to expand its product portfolio through external collaborations, which, if unsuccessful, may adversely affect the development and sale of its products;
• a slowdown of global economic growth, or economic instability of countries in which Shire does business, as well as changes in foreign currency exchange rates and interest rates, that adversely impact the availability and cost of credit and customer purchasing and payment patterns, including the collectability of customer accounts receivable;
• failure of a marketed product to work effectively or if such a product is the cause of adverse side effects could result in damage to Shire's reputation, the withdrawal of the product and legal action against Shire;
• 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 significant legal costs and the payment of substantial compensation or fines;
• Shire is dependent on information technology and its systems and infrastructure face certain risks, including from service disruptions, the loss of sensitive or confidential information, cyber-attacks and other security breaches or data leakages that could have a material adverse effect on Shire's revenues, financial condition or results of operations;
• Shire incurred substantial additional indebtedness to finance the Baxalta acquisition, which may decrease its business flexibility and increase borrowing costs; and

A further list and description of risks, uncertainties and other matters can be found in Shire's most recent Annual Report on Form 10-K and in Shire's subsequent Quarterly Reports on Form 10-Q, in each case including those risks outlined in "ITEM 1A: Risk Factors", and in Shire's subsequent reports on Form 8-K and other Securities and Exchange Commission filings, all of which are available on Shire's website.

All forward-looking statements attributable to us or any person acting on our behalf are expressly qualified in their entirety by this cautionary statement. Readers are cautioned not to place undue reliance on these forward-looking statements that speak only as of the date hereof. Except to the extent otherwise required by applicable law, we do not undertake any obligation to update or revise forward-looking statements, whether as a result of new information, future events or otherwise.

References 

INTUNIV Prescribing Information, Shionogi & Co., Ltd 2017.

POLANCZYK, G. et al. (2007). The Worldwide Prevalence of ADHD: A Systematic Review and Metaregression Analysis. Am J Psych. 164:942-948.

WILLCUTT, EG. (2012). The Prevalence of DSM-IV Attention-deficit/Hyperactivity Disorder: A Meta-analytic Review. Neurotherapeutics. 9:490-499.

International Classification of Diseases, 10th ed., (ICD-10). World Health Organization 2007. Chapter 5,F90. http://apps.who.int/classifications/icd10/browse/2010/en#/F90-F98. Last accessed June 2014.

American Psychiatric Association. (2013) Diagnostic and statistical manual of mental disorders: DSM-5 (5th ed.). Arlington, VA: American Psychiatric Publishing.

DIAMANTOPOULOU S, et al. Impact of Executive Functioning and Symptoms of Attention Deficit Hyperactivity Disorder on Children's Peer Relations and School Performance. Dev Neuropsychol 2007; 32(1):521-542.

BIEDERMAN J, et al. Functional Impairments in Adults with Self-reports of Diagnosed ADHD: A Controlled Study of 1001 Adults in the Community. J Clin Psychiatry 2006; 67:524-540.

SHAW M, et al. A Systematic Review and Analysis of Long-term Outcomes in Attention Deficit Hyperactivity Disorder: Effects of Treatment and Non-treatment. BMC Medicine 2012; 10:99.

MANES, F. et al. (2002). Decision-making processes following damage to the prefrontal cortex. Brain. 125:624-639.

TAYLOR, E. et al. (2004). European clinical guidelines for hyperkinetic disorder - first upgrade. European Child and Adolescent Psychiatry. 13 Suppl 1:i7-i30.

WILKINS, AJ. et al. (1987). Frontal lesions and sustained attention. Neuropsychologia. 25:359-365.

ANDERSON, SW. et al. (1999). Impairment of social and moral behavior related to early damage in human prefrontal 
cortex. Nature Neuroscience. 2:1032-1037.

FARAONE S, et al. (2005) Molecular Genetics of Attention Deficit Hyperactivity Disorder. BioPsych 57:1313-1323.

RUBIA, K. et al. (1999). Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: a study with functional MRI. American Journal of Psychiatry. 156:891-896.

HOEKZEMA, E. et al. (2014). An independent components and functional connectivity analysis of resting state FMRI data points to neural network dysregulation in adult ADHD. Human Brain Mapping. 35:1261-1272.

HERVAS, A. et al. (2014). Efficacy and safety of extended-release guanfacine hydrochloride in children and
adolescents with attention-deficit/hyperactivity disorder: A randomized, controlled, Phase III trial. EuropeanNeuropsychopharmacology. 24:1861-1872.

REN, WW. et al. (2012). Stimulation of α(2A)-adrenoceptors promotes the maturation of dendritic spines in cultured neurons of the medial prefrontal cortex. Molecular and Cellular Neuroscience. 49:205-216.

WANG, M. et al. (2007). Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN 
channel signaling in prefrontal cortex. Cell 129:397-410.

For further information please contact:
Media
Lauren Starr
lauren.starr@shire.com
+41-41-288-4443

SOURCE Shire plc