Shire Receives European Approval for Label Extension of CINRYZE®(C1 inhibitor [human]) to Prevent and Treat Hereditary Angioedema (HAE) Attacks in Paediatric Patients with HAE

Zug, Switzerland (ots/PRNewswire) -

CINRYZE is now the first and only Hereditary angioedema
treatment approved for routine prevention in paediatrics

Shire plc (LSE: SHP, NASDAQ: SHPG) announced that the European
Commission (EC) has approved a label extension granting three new
indications for CINRYZE® (C1 inhibitor [human]), broadening its use
to children with Hereditary angiodema (HAE), a rare, genetic disorder
that results in recurring attacks of edema (swelling).[1] The body
sites most commonly affected are mainly the extremities and
abdomen.[1] CINRYZE is now indicated for routine prevention of
angioedema attacks in children (ages 6 years and above) with severe
and recurrent attacks of HAE who are intolerant to or insufficiently
protected by oral preventions treatments, or patients who are
inadequately managed with repeated acute treatment.[2] It is the
first and only HAE treatment with this indication in paediatric
patients.[2] CINRYZE is also now approved for the treatment and
pre-procedure prevention of angioedema attacks in children (ages 2
years and above) with HAE.[2]

Symptoms of HAE often present in childhood, and while attacks can
occur at any age, early onset may predict a more severe disease
course.[3] Attacks often occur in children without a clear
trigger,[2] and may affect a child's participation in school,
activities, and sports, which can leave them feeling socially
isolated.[3],[4] Less frequently, HAE can cause life-threatening
attacks due to obstruction in the upper airways.[5],[6],[7]

"This paediatric label expansion demonstrates our ongoing
commitment to improving the lives of patients of all ages living with
HAE," said Philip J. Vickers, Ph.D., Head of R&D, Shire. "We believe
the future of HAE means preventing attacks before they happen, and
are proud to now be able to offer the first long-term preventative
treatment for paediatric patients. As we expand our HAE portfolio, we
remain focused on innovative solutions that fulfil unmet needs for
people worldwide living with this rare disease."

CINRYZE has been approved since 2011 for these indications in
adults and adolescents ages 12-17 years with HAE.[2]

Henrik Balle Boysen, Executive Director of HAEi stated, "Over the
years we have encountered many children who suffer from frequent and
severe HAE symptoms that often occur spontaneously and without
warning. Despite improvements in the management of HAE in recent
years, this new long-term prophylaxis indication for alleviating the
frequency of HAE symptoms will be a welcome addition for families
with HAE in Europe."

CINRYZE will be available for use in paediatric patients later in
2017 throughout Member States of the European Union (EU), as well the
European Economic Area (EEA) in which Shire currently has a licence
in the adult and adolescent population.

About HAE

HAE is a rare, genetic disorder that affects an estimated one in
50,000 people worldwide and results in recurring attacks of edema
(swelling).[8]

Long-term prophylaxis refers to the routine use of medication to
prevent episodes of angioedema, and may be considered for severely
symptomatic patients with HAE.[8] Management of HAE also includes
on-demand treatment of swelling attacks (known as acute treatment) to
minimise the consequences of the symptoms, and pre-procedure
prevention, which is often used before certain surgeries and to cover
other periods of high risk of attack (such as stressful times
including school examinations, for example).[8]

Paediatric Study Results[2]

The efficacy of CINRYZE for the treatment and prevention of
angioedema attacks in paediatric patients with HAE has been
demonstrated in two open-label studies (LEVP 2006-1 and LEVP 2006-4)
and two paediatric clinical studies (0624-203 and 0624-301).[2]

Two studies demonstrated the efficacy of CINRYZE for the treatment
of HAE in patients ages 6-11 years. The first study (LEVP 2006-1)
included 22 paediatric patients (of a total of 101 enrolled patients)
who were treated for 121 acute HAE attacks. The proportion of HAE
attacks achieving unequivocal relief of the defining symptom within
four hours after treatment was comparable between the 22 children
(ages 2-17 years) and adults enrolled in the study, with 89% and 86%
of attacks achieving relief, respectively.[2]

The second study (0624-203) enrolled nine paediatric patients who
received a single dose of CINRYZE based on their weight with children
weighing between 10 and 25 kg (n=3) receiving 500 units and those
weighing >25 kg receiving either 1000 units (n=3) or 1500 units
(n=3). All nine (100%) subjects achieved unequivocal beginning of
relief of the defining symptom within four hours following initiation
of treatment with CINRYZE.[2] The 1500-unit dose is not an approved
dosage.

In addition, two studies demonstrated the efficacy of CINRYZE for
the prevention of HAE in paediatric patients. The first study (LEVP
2006-4) included 23 paediatric patients (of a total of 146 enrolled
patients) between the ages of 3 and 17 years. The children received
1000 units of CINRYZE every three to seven days, with the exception
of a 3-year-old child who received 500 units every three to seven
days. Prior to enrolment, the children reported a median of three HAE
attacks each month. While receiving CINRYZE prophylaxis during the
study, 87% of the children reported an average of one or fewer attack
per month, which were comparable to those observed in adults in the
study.[2]

The second study (0624-301) included six paediatric subjects ages
6-11 years who were randomised to twice-weekly CINRYZE dosing for 12
weeks in two treatment sequences (500/1000 units or 1000/500 units).
Both doses resulted in similar reduction of attack-frequency and
showed clinical benefit regarding severity, duration, and requirement
for acute treatment of attacks.[2]

For three subjects under the age of 6 years, administration of
CINRYZE (500 units or 1000 units) was associated with increases in C1
INH levels and clinical efficacy in acute treatment and prevention of
attacks. Overall administration of CINRYZE was well tolerated.[2]

Across clinical studies, there were 61 unique paediatric subjects
enrolled and exposed to over 2,500 infusions of CINRYZE (2-5 years,
n=3; 6-11 years, n=32; 12-17 years, n=26). Among these children,
adverse reactions with CINZYRE included headache, nausea, pyrexia,
and infusion site erythema. None of these adverse reactions were
severe, and none led to discontinuation of medicinal product.[2]
Overall, the safety and tolerability of CINRYZE were similar in
children, adolescents, and adults.[2]

About CINRYZE

CINRYZE is the first and only C1 esterase inhibitor (C1-INH)
therapy approved for routine prevention in children, adolescents, and
adults with HAE. CINRYZE is also approved for acute treatment and
pre-procedure prevention of angioedema attacks.[2]

The active substance in CINRYZE is C1-INH, which can restore
functional C1-INH levels in patients with HAE.[2] Patients with HAE
are prone to swelling due to an underlying deficiency in
C1-INH.[6],[9] C1-INH plays an integral role in the kinin-generating
pathway and controls the production of the protein
bradykinin.[1],[9],[10],[11] During a swelling attack, overproduction
of bradykinin increases the permeability of blood vessels, causing
fluids to "leak" into the surrounding tissue, resulting in
swelling.[1],[13] Treatment with C1-INH raises the plasma level of
C1-INH and helps regulate the production of bradykinin released
during an attack.[2],[12],[13]

CINRYZE is administered intravenously and may be
self-administered.[2] The decision on the use of home-treatment for
an individual patient should be made by the treating physician, who
should ensure that appropriate training is provided and the use
reviewed at intervals.[2] CINRYZE therapy should be initiated under
supervision of a physician experienced in the care of patients with
HAE.[2]

For treatment of angioedema attacks in adolescents (ages 12-17
years) and adults, a dose of 1000 units of CINRYZE is given at the
first sign of the onset of an attack.[2] A second dose of 1000 units
may be administered if the patient has not responded adequately after
60 minutes.[2] For patients experiencing laryngeal attacks, or if the
initiation of treatment is delayed, the second dose can be given
sooner than 60 minutes.[2]

For routine prevention of angioedema attacks in adolescents (ages
12-17 years) and adults, 1000 units of CINRYZE every 3 or 4 days is
the recommended starting dose.[2] The dosing interval may need to be
adjusted according to individual response.[2] The continued need for
regular prophylaxis with CINRYZE should be reviewed on a regular
basis.[2]

For pre-procedure prevention of angioedema attacks in adolescents
(ages 12-17 years) and adults, 1000 units of CINRYZE is given within
24 hours before a medical, dental, or surgical procedure.[2]

For treatment of angioedema attacks in children (ages 2-11 years)
who weigh more than 25 kg, a dose of 1000 units of CINRYZE is given
at the first sign of the onset of an attack.[1] A second dose of 1000
units may be administered if the patient has not responded adequately
after 60 minutes.[1] For children who weigh between 10 to 25 kg, the
starting dose is 500 units with a second dose of 500 units if the
patient has not responded adequately after 60 minutes.[1]

For pre-procedure prevention of angioedema attacks in children
(ages 2-11 years) who weigh more than 25 kg, 1000 units of CINRYZE is
given within 24 hours before a medical, dental, or surgical
procedure.[1] For children weighing between 10 to 25 kg, the dose is
500 units.[1]

For routine prevention of angioedema attacks (ages 6-11 years),
500 units of CINRYZE every three or four days is the recommended
starting dose (regardless of weight).[1] The dosing interval may need
to be adjusted according to individual response. The continued need
for regular prophylaxis with CINRYZE should be reviewed on a regular
basis.[1]

Safety and Tolerability

The only common (i.e., >=1/100 to <1/10) adverse reaction observed
following CINRYZE infusion in clinical studies was rash; descriptions
of rash characteristics were non-specific, but were typically
described as involving the upper extremities, chest, abdomen, or
injection site.[2] None of the rashes were serious, and none led to
discontinuation of medicinal product.[2]

Contraindications

CINRYZE is contraindicated in patients who are hypersensitive to
the active ingredients or any excipients.[2]

Special Warnings and Precautions for Use[2]

- Thrombotic events have been reported in neonatal and infant
subjects undergoing cardiac bypass procedures while receiving
off-label high doses of another C1 inhibitor product (up to 500
units/kg) to prevent capillary leak syndrome. Based upon an animal
study there is a potential thrombogenic threshold at doses greater
than 200 units/kg. Patients with known risk factors for thrombotic
events (including indwelling catheters) should be monitored
closely.
- Thrombotic events have been reported in neonatal and infant
subjects undergoing cardiac bypass procedures while receiving
off-label high doses of another C1 inhibitor product (up to 500
units/kg) to prevent capillary leak syndrome.
- Standard measures to prevent infections resulting from the use of
medicinal products prepared from human blood or plasma include
selection of donors, screening of individual donations and plasma
pools for specific markers of infection, and the inclusion of
effective manufacturing steps for the inactivation/removal of
viruses. Despite this, when medicinal products prepared from human
blood or 4 plasma are administered, the possibility of transmitting
infective agents cannot be totally excluded. This also applies to
unknown or emerging viruses and other pathogens. The measures taken
are considered effective for enveloped viruses such as HIV, HBV,
and HCV, and for the non-enveloped viruses HAV and parvovirus B19.
Appropriate vaccination (hepatitis A and B) should be considered
for patients in regular/repeated receipt of human plasma-derived C1
inhibitor product. It is strongly recommended that every time
CINRYZE is administered to a patient, the name and batch number of
the product are recorded in order to maintain a link between the
patient and the batch of the product.
- As with any biological product hypersensitivity reactions may
occur. Hypersensitivity reactions may have symptoms similar to
angioedema attacks. Patients should be informed of the early signs
of hypersensitivity reactions including hives, generalised
urticaria, tightness of the chest, wheezing, hypotension, and
anaphylaxis. If these symptoms occur after administration, they
should alert their physician. In case of anaphylactic reactions or
shock, emergency medical treatment should be administered.
- There are limited data on the use of this medicinal product in
home- or self-administration. Potential risks associated with
home-treatment are related to the administration itself as well as
the handling of adverse drug reactions, particularly
hypersensitivity. The decision on the use of home-treatment for an
individual patient should be made by the treating physician, who
should ensure that appropriate training is provided and the use
reviewed at intervals.
- Each vial of CINRYZE contains approximately 11.5 mg of sodium. To
be taken into consideration by patients on a controlled sodium
diet.

NOTES TO EDITOR

About Shire

Shire is the leading global biotechnology company focused on
serving people with rare diseases and other highly specialised
conditions. We strive to develop best-in-class products, many of
which are available in more than 100 countries, across core
therapeutic areas including Haematology, 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.

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 combined 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 acquisition of 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 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.

?This medicinal product is subject to additional monitoring. This
will allow quick identification of new safety information. Healthcare
professionals are asked to report any suspected adverse reactions.
See section 4.8 of the Summary of Product Characteristics for how to
report adverse reactions.

References

1. Bork K, Davis-Lorton M. Overview of hereditary angioedema
caused by C1-inhibitor deficiency: assessment and clinical
management. Eur Ann Allergy Clin Immunol 2013; 45(1):7-16.

2. CINRYZE (C1 Inhibitor [human]) Summary of Product
Characteristics. January 2017. Document on File at Shire.

3. Farkas H, et al. International consensus on the diagnosis and
management of paediatric patients with hereditary angioedema with C1
inhibitor deficiency. Allergy. 2017; 72(2):300-13.

4. Read N, et al. Patient hereditary angioedema: a survey of UK
service provision and patient experience. Clin Exp Immunol 2014;
178:473-88.

5. Donaldson V, Evans R. A biochemical abnormality in hereditary
angioneurotic edema: absence of serum inhibitor of C1-esterase. Am J
Med. 1963; 35:37-44.

6. Bork K, et al. Hereditary angioedema: New findings concerning
symptoms, affected organs, and course. Am J Med 2006; 119(3):267-74.

7. Bork K. Fatal laryngeal attacks and mortality in hereditary
angioedema due to C1-INH deficiency. JAACI 2012; DOI:
http://dx.doi.org/10.1016/j.jaci.2012.05.055.

8. Craig T, et al. WAO guideline for the management of hereditary
angioedema. World Allergy Organ Journal 2012; 5(12):182-99.

9. Lung C, et al, Analysis of an exon 1 polymorphism of the B2
bradykinin receptor gene and its transcript in normal subjects and
patients with C1 inhibitor deficiency. Allergy, Asthma Clin Immunol
1997; 99(1):134-146.

10. Nussberger J, et al. Local bradykinin generation in hereditary
angioedema. Allergy Asthma Clin Immunol 1999; 104(6):1321-1322.

11. Bjorkqvist J, et al. Hereditary angioedema: a
bradykinin-mediated swelling disorder. Thromb Haemost 2013;
109:368-374.

12. Nussberger J, et al. Plasma bradykinin in angio-edema. The
Lancet 1998; 351:1693-1697.

13. Kaplan AP, Joseph K. The bradykinin-forming cascade and its
role in hereditary angioedema. Ann Allergy Asthma Immunol 2010;
104:193.

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

Annabel Cowper, annabel.cowper@shire.com, +41-44-878-6638

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