YASTEST
Shire and Shionogi
Announce Positive Topline Results for INTUNIV® (guanfacine
hydrochloride prolonged release) Evaluated in Phase 3 Clinical
Trial
in Adults with ADHD
-
Topline results revealed the
study met its primary endpoint for INTUNIV® (4
to 6 mg) administered once daily, indicating superiority over
placebo in ADHD symptom improvement
-
Results also showed improvement
over placebo in patients' global functioning
Zug, Switzerland -
September 20, 2017 - Shire plc (LSE: SHP, NASDAQ: SHPG) and its
partner in Japan, Shionogi & Co., Ltd, announced that a Phase 3
study evaluating INTUNIV® (guanfacine hydrochloride prolonged
release) in adult patients with attention deficit hyperactivity
disorder (ADHD) in Japan has positive topline results, and the
study met the primary endpoint. This is the first clinical trial
evaluating INTUNIV in adult patients (18 years old and over) with
ADHD.
"The positive topline results of this Phase 3
study provide us with important data and insights regarding the
clinical profile of INTUNIV in adult patients with ADHD," said
Brigitte Robertson, VP and Head of Global Clinical Development,
Neuropsychiatry, Shire. "We are evaluating the full data set, and
excited to advance the development of INTUNIV as a non-stimulant
treatment option for adults with ADHD in Japan, building on the
established efficacy and safety data for ADHD in child and
adolescent patients."
INTUNIV, a non-stimulant and selective alpha-2A
adrenergic receptor agonist1 is currently
approved as a treatment for child and adolescent patients (6 to 17
years old) in Japan. INTUNIV is being evaluated in Japan as a
potential treatment option for ADHD in adults, a therapeutic area
with significant need. Japan is the third largest ADHD market,
growing at more than 20% annually.
ADHD causes inattention, hyperactivity or
impulsivity, or a combination of these symptoms,2,3 and
can have substantial impact on all major areas of life, including:
schooling, work and employment, behaviour, and social
functioning.4-7
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
6mg), administered as a once-daily dose, was superior to placebo
with respect to the change from baseline on a clinically
administered ADHD rating scale (ADHD-RS-IV with adults prompts)
total score. INTUNIV also demonstrated nominal significance
over placebo at the end of treatment on the clinically
important secondary efficacy analysis of the clinical global
impression improvement scale (CGI-I), suggesting more patients
achieved a marked clinical improvement in global
functioning.
The CGI-I is a standardized assessment tool that
allows clinicians to rate the severity of an illness, change over
time and response to treatment.
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 decrease, nasopharyngitis, dizziness postural and
constipation.
Shire Japan and Shionogi will evaluate the full
data, and will communicate plans for publication or presentation of
the data, as well as potential milestones for the continued
development of INTUNIV in adults with ADHD.
About
ADHD
Attention deficit hyperactivity disorder (ADHD) is recognised by
the World Health Organization (WHO).2 Although
there is no global consensus, a cross-national analysis of WHO
World Mental Health (WMH) surveys estimated the prevalence of ADHD
at 3.4% (range 1.2 to 7.3%) in adults.17
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,7,9,10 and has
been associated with some structural and functional abnormalities
in individuals with ADHD.11-13
ADHD is a complex condition and approaches to
treatment typically include educational methods, psychotherapy and
medication.18 When
required, either stimulants or non-stimulants are indicated as part
of a comprehensive treatment programme for ADHD. Non-stimulant
medications are an important alternative to stimulants for some
ADHD patients.18
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 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.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
- 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 (INTUNIV is
contraindicated in the following patients.)
- Patients with a history of hypersensitivity to
any of the ingredients of this drug.
- Pregnant women or women who may possibly be
pregnant.
- Patients with atrioventricular block second
degree and third degree. [The condition may get worse because of
the central bradycardia effect of this drug.]
Precautions
- 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.]
- 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%).
- Clinically significant adverse
reactions
1) Hypotension (greater than or equal to
5%), bradycardia (greater than or
equal to 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 unknownNote
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.
- Other adverse
reactions
If the following adverse reactions occur, appropriate measures such
as dose reduction, interruption, or discontinuation should be taken
as necessary.
Type/ Incidence |
Greater than or equal
to 5% |
<5%, greater than
or equal to 1% |
<1% |
Incidence
unknownNote 1 |
Hypersensitivity |
|
|
|
Hypersensitivity,
rash, pruritus |
Cardiovascular |
|
Orthostatic
hypotension |
Increased blood
pressure |
Tachycardia, sinus
arrhythmia, pallor, hypertensive encephalopathy |
Psychoneurologic |
Somnolence, headache,
insomnia, dizziness |
Irritability |
Nightmare, affect
lability, agitation, sedation, asthenia |
Anxiety, depression,
lethargy, convulsion, hypersomnia |
Gastrointestinal |
Abdominal pain |
Decreased appetite,
nausea, constipation, diarrhea, thirst, vomiting |
|
Abdominal discomfort,
dyspepsia |
Others |
Malaise |
Enuresis, increased
weight |
Pollakiuria, increased
ALT (GPT) |
Asthma, chest pain,
dehydration |
Note 1: The incidence of adverse reactions on the
basis of overseas clinical studies and spontaneous reports is
unknown.
For further information please
contact:
Investor Relations |
|
|
Ian Karp |
ikarp@shire.com |
+1 781 482 9018 |
Robert Coates |
rcoates@shire.com |
+44 1256 894874 |
Media |
|
|
Gwen Fisher |
gfisher@shire.com |
+1 781 482 9649 |
Clotilde Houzé |
chouze0@shire.com |
+1 781 266 3567 |
SHIRE and the Shire Logo are
registered trademarks of Shire Pharmaceutical Holdings Ireland
Limited or its affiliates.
NOTES TO EDITORS
About Shire
Shire is the leading global biotechnology company
focused on serving people with rare diseases. 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 every day 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.
www.shire.com
©2017 Shire. All rights reserved.
SHIRE and the Shire logo are registered trademarks of Shire
Pharmaceutical Holdings Ireland Limited or its affiliates.
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References
- INTUNIV Prescribing Information, Shionogi &
Co., Ltd 2017.
- International Classification of Diseases (ICD-10
Version). Chapter 5, F90. http://www.icd10data.com. Last accessed
September 2017.
- 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.
- POLANCZYK, G. et al. (2007). The Worldwide
Prevalence of ADHD: A Systematic Review and Metaregression
Analysis. Am J Psych. 164:942-948.
- 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. European
Neuropsychopharmacology. 24:1861-1872.
- REN, WW. et al. (2012). Stimulation of
Alpha(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.
- FAYYAD J, et al. (2007). Cross-national
prevalence and correlates of adult attention-deficit hyperactivity
disorder. Br J Psychiatry. 190: 402-409.
- TAYLOR, E. et al. (2004). European clinical
guidelines for hyperkinetic disorder - first upgrade. European
Child and Adolescent Psychiatry. 13 Suppl 1:i7-i30.
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