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, March 16, 2017 /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. 

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