New Drug Application Submitted in Japan for INTUNIV® (guanfacine hydrochloride extended release) in Adults with ADHD

New Drug Application Submitted in Japan for INTUNIV^® (guanfacine hydrochloride extended release) in Adults with ADHD

• Shire’s partner, Shionogi, filed application to expand INTUNIV^® indication in Japan to include adults with ADHD
• Phase 3 clinical trial in Japan was first ever to evaluate INTUNIV^® in adult patients with ADHD
• Japan is the world’s third largest ADHD market growing more than 20% annually¹

Dublin, Ireland – August 13, 2018 – Shire plc (LSE: SHP, NASDAQ: SHPG) announces that its partner in Japan, Shionogi & Co., Ltd has submitted a New Drug Application (NDA) for the manufacture and marketing in Japan of INTUNIV^® (guanfacine hydrochloride extended release) for the treatment of attention deficit hyperactivity disorder (ADHD) in adults. The Japanese Phase 3 clinical trial was the first ever to evaluate INTUNIV in adult patients (18 years and over) with ADHD.

"This is a key milestone, taking us a step closer to potentially providing INTUNIV to adults in Japan in addition to the approved pediatric indication,” said Brigitte Robertson, M.D., VP and Head of Global Clinical Development, Neuroscience, Shire. "There remains a significant need for new non-stimulant treatment options for adults being diagnosed with ADHD in Japan,” she said.

INTUNIV, a non-stimulant, selective alpha-2A adrenergic receptor agonist² has been approved as a treatment for child and adolescent patients (6 to 17 years old) with ADHD in Japan since March 2017. INTUNIV is being co-developed and commercialized by Shire and Shionogi under a licensing contract signed in 2011.

ADHD is characterized by 3 core symptoms of inattention, hyperactivity or impulsivity, or a combination of these symptoms,^3,4 and can have substantial impact on major areas of life, including: schooling, work and employment, behaviour, and social functioning.^5,6,7   Non-stimulant medications are an important alternative to stimulants for some patients with ADHD.⁸

Topline results from the Phase 3 efficacy trial in adults in Japan showed INTUNIV (4 to 6mg), administered once daily, met its primary endpoint, demonstrating superiority over placebo in the improvement of ADHD symptoms. Results also showed statistically significant improvement over placebo in patients’ global functioning.

This Phase 3 trial was a 12- week, randomized, double-blind, multi-center, parallel-group, placebo-controlled study in 201 adult patients (18 years old and over) with ADHD. The primary efficacy analysis demonstrated that INTUNIV (4 to 6 mg), administered as a once-daily dose, was superior to placebo with respect to the change from baseline to endpoint on a clinician administered ADHD rating scale (ADHD-RS-IV with adults prompts) total score.  INTUNIV also demonstrated significance over placebo at the end of treatment on the secondary efficacy analysis of the Clinical Global Impression-Improvement scale (CGI-I), a standardized assessment tool that allows clinicians to rate changes in patients’ clinical condition over time. In this study, clinicians rated more than twice as many patients taking INTUNIV as "improved” and nearly half of patients as "much improved” or "very much improved”. 

Treatment-emergent adverse events in the study were generally mild to moderate in severity and similar to those observed in previous INTUNIV studies with no new or unexpected safety findings. Treatment-emergent adverse events reported at more than or equal to 10% for INTUNIV were somnolence, dry mouth, blood pressure decreased, nasopharyngitis, dizziness postural and constipation.

About ADHD

Attention deficit hyperactivity disorder (ADHD) is recognised by the World Health Organization (WHO).³  Although there is no global consensus, a cross-national analysis of WHO World Mental Health (WMH) surveys estimated the mean prevalence of ADHD at 2.8% (range 0.6 to 7.3%) in adults.⁹

Although the exact origin of ADHD is not fully understood, the area of the brain identified as the prefrontal cortex is known to control several cognitive functions including attention and social behaviours,^10,11,12   and has been associated with some structural and functional abnormalities in individuals with ADHD.^13,14

ADHD is a complex disorder and approaches to treatment typically include educational methods, psychotherapy and medication.⁸  When required, either stimulants or non-stimulants are indicated as part of a comprehensive treatment programme for ADHD.⁸ Non-stimulant medications are an important alternative to stimulants for some ADHD patients.⁸

About INTUNIV

INTUNIV (guanfacine hydrochloride extended 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.²

INTUNIV contains the active substance guanfacine, a selective alpha-2A adrenergic receptor agonist.² Studies suggest that guanfacine may exert physiological effects by selectively stimulating the alpha-2A adrenergic receptor in the prefrontal cortex.^15,16

INTUNIV is currently approved in 36 countries around the world including Australia, Canada, Switzerland, the United States, and Europe. INTUNIV should only be used in accordance with locally approved prescribing information. Please refer to the local label for the approved indication.

INTUNIV Safety Information for Japan


Precautions on Indication
1.    The efficacy and safety of INTUNIV in children under 6 years of age or adults over 18 years of age have not been established.
2.    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.
3.    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 (INTUNIV is 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 (INTUNIV should be administered with care in the following patients.)
1) 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.]
2) Patients with a current or previous history of hypertension [Blood pressure may increase when administration of this drug is abruptly discontinued.]
3) 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.]
4) 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.]
5) 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.]
6) Patients with severe hepatic function disorder [The blood concentration of this drug may increase.]
7) Patients with severe renal function disorder [The blood concentration of this drug may increase.]
8) Patients in depressed state [The symptom may get worse because of the sedative effects of this drug.]
2.    Important Precautions
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
1) 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.
2) 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.
3) 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.

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

For further information please contact:

NOTES TO EDITORS

About Shire

Shire is the global biotechnology leader serving patients with rare diseases and specialized conditions. We seek to push boundaries through discovering and delivering new possibilities for patient communities who often have few or no other champions. Relentlessly on the edge of what’s next, we are serial innovators with a diverse pipeline offering fresh thinking and new hope. Serving patients and partnering with healthcare communities in over 100 countries, we strive to be part of the entire patient journey to enable earlier diagnosis, raise standards of care, accelerate access to treatment, and support patients. Our diverse portfolio of therapeutic areas includes Immunology, Hematology, Genetic Diseases, Neuroscience, Internal Medicine, Ophthalmics, and Oncology.
 
Championing patients is our call to action - it brings the opportunity - and responsibility - to change people’s lives.

www.shire.com

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• Shire faces risks relating to the expected exit of the United Kingdom from the European Union;
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• the potential uncertainty among our employees, customers, suppliers, and other business partners resulting from the announcement by Takeda Pharmaceutical Company Limited on May 8, 2018 of a recommended offer for Shire under the UK Takeover Code; 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 "ITEM1A: 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

¹ IQVIA MIDAS data, 2018

² INTUNIV Prescribing Information, Shionogi & Co., Ltd 2017.

³ 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 August 2018.

⁴ American Psychiatric Association. (2013) Diagnostic and statistical manual of mental disorders: DSM-5 (5th ed.). Arlington, VA: American Psychiatric Publishing.

⁵ DIAMANTOPOULOU S, et al. (2007) Impact of Executive Functioning and Symptoms of Attention Deficit Hyperactivity Disorder on Children's Peer Relations and School Performance. Dev Neuropsychol. 32(1):521-542.

⁶ BIEDERMAN J, et al. (2006) Functional Impairments in Adults with Self-reports of Diagnosed ADHD: A Controlled Study of 1001 Adults in the Community. J Clin Psychiatry. 67:524-540.

⁷ SHAW M, et al. (2012) A Systematic Review and Analysis of Long-term Outcomes in Attention Deficit Hyperactivity Disorder: Effects of Treatment and Non-treatment. BMC Medicine. 10:99.

⁸  Kooij SJ, et al. (2010) European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD. BMC Psychiatry. 10: 67.

⁹ FAYFED J, et al. (2017) The descriptive epidemiology of DSM-IV Adult ADHD in the world health organization world mental health surveys. ADHD Attention Deficit and Hyperactivity Disorders. Mar 1;9(1):47-65

¹⁰ WILKINS AJ, et al. (1987). Frontal lesions and sustained attention. Neuropsychologia. 25:359-365.

¹¹ ANDERSON SW, et al. (1999). Impairment of social and moral behavior related to early damage in human prefrontal ?cortex. Nature Neuroscience. 2:1032-1037.

¹² MANES F, et al. (2002). Decision-making processes following damage to the prefrontal cortex. Brain. 125:624-639.

¹³ 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.

¹⁴ 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.

¹⁵ REN WW, et al. (2012). Stimulation of a(2A)-adrenoceptors promotes the maturation of dendritic spines in cultured neurons of the medial prefrontal cortex. Molecular and Cellular Neuroscience. 49:205-216.

¹⁶ WANG M, et al. (2007). Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 129:397-410.