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Shire Receives European Approval for Label Extension of FIRAZYR® (icatibant injection) for the Symptomatic Treatment of Acute Hereditary Angioedema (HAE) Attacks in Paediatric Patients

FIRAZYR is the first and only subcutaneous treatment in Europe for acute HAE attacks approved for children aged 2 years and older

Zug, Switzerland – October 26, 2017 – Shire plc (LSE: SHP, NASDAQ: SHPG), the global leader in serving patients with rare diseases, announced today that the European Commission (EC) has approved a label extension granting a new indication for FIRAZYR® (icatibant injection), broadening its use to adolescents and children aged 2 years and older, with hereditary angioedema (HAE) caused by C1-esterase-inhibitor (C1-INH) deficiency. FIRAZYR has been approved in the European Union (EU) since 2008 for symptomatic treatment of acute attacks of HAE in adults with C1-INH deficiency.1

HAE is a rare genetic disease characterized by recurrent attacks of localized oedema (swelling).2, 3 The areas of the body most commonly affected are the extremities, gastrointestinal tract and, less frequently, HAE can cause life-threatening attacks due to obstruction in the upper airways.2, 3, 4 Symptoms of HAE often present in childhood, and while attacks can occur at any age, early onset may predict a more severe disease course.5

“As a long-term partner to the HAE community, we understand the unique burden this disease places on children living with HAE and their caregivers,” said Jennifer Schranz, Global Development Lead, HAE, Shire. “This approval in Europe demonstrates our unwavering commitment to helping patients and represents a significant advance for paediatric patients, who now have a subcutaneous treatment option for acute HAE attacks.”

The use of FIRAZYR in paediatric patients was studied in an open label, non-randomised single-arm study, involving 32 paediatric patients with HAE.6 The efficacy population consisted of 11 children and 11 adolescents with attacks. The primary efficacy endpoint was time to onset of symptom relief (TOSR) based on the investigator-assessed composite post-treatment symptom score, defined as earliest time post-treatment when 20% or more improvement in the composite symptom score was achieved, without worsening of any single component score.6

Overall, median TOSR was 1.0 hour, with no differences between children and adolescents. More than 70% of patients experienced symptom relief at 1.1 hours, and more than 90% by 2 hours post-treatment.6

The majority of paediatric patients who were treated with subcutaneous FIRAZYR experienced injection site reactions such as erythema, swelling, burning sensation, skin pain and itching/pruritus; these were found to be mild to moderate in severity and consistent with reactions that have been reported in adults.6

The study showed FIRAZYR was well tolerated and demonstrated rapid resolution of symptoms during an HAE attack through a single injection.6 The study that led to this approval is the first and only trial investigating a subcutaneous therapy in the HAE paediatric population.

“Due to the unpredictable and debilitating nature of HAE attacks, children living with the condition can benefit from having a new treatment option that can provide symptomatic relief of acute HAE attacks with a subcutaneous injection,” said Henrik Balle Boysen, Executive Director of HAEi. “Clinical work to bring treatment options to younger patients is vitally important and greatly appreciated by the global HAE community.”

FIRAZYR will be available for use in paediatric patients in Europe beginning in Q4.

About Hereditary Angioedema
HAE is a rare, genetic disorder estimated to affect about one in 10,000 to one in 50,000 people worldwide and results in recurring attacks of oedema (swelling).7, 8

Management of HAE includes on-demand treatment of swelling attacks 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). Long-term prophylaxis (the routine use of medication to prevent episodes of angioedema) may be considered for severely symptomatic patients with HAE.7

FIRAZYR Paediatric Study Results6
The use of FIRAZYR in paediatric patients was studied in an open label, non-randomised single-arm study (HGT-FIR-086). A total of 32 paediatric patients with HAE (11 children with an attack, 11 adolescents with an attack and 10 adolescents without an attack) were treated with FIRAZYR during the study. FIRAZYR was administered by subcutaneous injection at a dose of 0.4 mg/kg based on body weight to a maximum dose of 30 mg. The majority of patients were followed up for a minimum of 6 months.

The primary efficacy endpoint was time to onset of symptom relief (TOSR) based on the investigator-assessed composite post-treatment symptom score, defined as earliest time post-treatment when 20% or more improvement in the composite symptom score was achieved, without worsening of any single component score. An additional efficacy endpoint was time to minimum symptoms (TTMS), defined as earliest time post-treatment when all symptoms were mild or absent (clinical remission).

Overall, median TOSR was 1.0 hour. More than 70% of patients experienced symptom relief at 1.1 hours, and more than 90% by 2 hours post-treatment. Overall, the median TTMS was 1.1 hours. Approximately 50% of patients reached minimum symptoms at 1 hour, and 80% at 2 hours post-treatment.

The majority of paediatric patients who were treated with subcutaneous FIRAZYR experienced injection site reactions such as erythema, swelling, burning sensation, skin pain and itching/pruritus; these were found to be mild to moderate in severity and consistent with reactions that have been reported in adults. Two paediatric patients experienced injection site reactions which were assessed as severe and which were completely resolved within 6 hours. These reactions were erythema, swelling, burning and warm sensation. There is limited data on the treatment of more than one HAE attack with FIRAZYR in the paediatric population.

Shire’s Commitment to Hereditary Angioedema
Shire is a dedicated, long-term partner to the HAE community with nearly a decade of experience supporting patients. We believe each patient deserves a right-fit approach to treatment and are committed to serial innovation. Our existing portfolio of products includes distinct therapy options to help meet the needs of our patients with HAE. Beyond our focus on developing novel treatments, we provide specialized services and support offerings tailored to the HAE community. Learn more at shire.com.

About FIRAZYR
FIRAZYR is indicated in Europe for symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults, adolescents and children aged 2 years and older, with C1-esterase-inhibitor deficiency.

The active substance, icatibant, is a specific bradykinin B2 receptor antagonist. It represents a novel, targeted, subcutaneously-administered approach to the treatment of HAE attacks designed to block the effects of bradykinin, the key mediator of oedema formation. FIRAZYR is a synthetic decapeptide (a peptide containing ten amino acids).

For patients who have never previously received FIRAZYR, the first treatment should be given in a medical institution or under the guidance of a physician. In cases of insufficient relief or recurrence of symptoms after treatment with FIRAZYR, patients should seek medical advice, and subsequent doses should be given in a medical institution. The decision to initiate self-administration should only be taken by a physician experienced in the diagnosis and treatment of HAE.

Patients with laryngeal attacks should always seek medical advice and be managed in an appropriate medical institution after self-administration of FIRAZYR, until the physician considers discharge to be safe.

Icatibant has an orphan drug designation status in the EU for treatment of hereditary angioedema. Where commercially available, the drug is supplied in a pre-filled 3 ml syringe. FIRAZYR can be stored at up to 25 degrees Celsius without refrigeration.

FIRAZYR is not available in all countries and prescribing information may differ between countries. Please consult your local prescribing information.

Important Safety Information in Europe

Contraindications
Hypersensitivity to the active substance or to any of the excipients.

Warnings and Precautions
Laryngeal attacks: Patients with laryngeal attacks should be managed in an appropriate medical institution after injection until the physician considers discharge to be safe.

Ischemic heart disease: Under ischemic conditions, a deterioration of cardiac function and a decrease in coronary blood flow could theoretically arise from antagonism of bradykinin receptor type 2. Caution should therefore be observed in the administration of FIRAZYR to patients with acute ischemic heart disease or unstable angina pectoris.

Stroke: Although there is evidence to support a beneficial effect of B2 receptor blockade immediately following a stroke, there is a theoretical possibility that icatibant may attenuate the positive late phase neuroprotective effects of bradykinin. Accordingly, caution should be observed in the administration of icatibant to patients in the weeks following a stroke.

Caregiver/Self-administration: For patients who have never received FIRAZYR previously, the first treatment should be given in a medical institution or under the guidance of a physician. In case of insufficient relief or recurrence of symptoms after self- treatment or administration by a caregiver, it is recommended that the patient or caregiver should seek medical advice. For adults, subsequent doses given for the same attack should be administered within a medical institution. There are no data on administering subsequent doses for the same attack in adolescents and children. Patients experiencing a laryngeal attack should always seek medical advice and be observed in a medical institution also after having taken the injection at home.

Adverse Reactions
Almost all subjects who were treated with subcutaneous icatibant in clinical trials developed reactions at the site of injection (characterised by skin irritation, swelling, pain, itchiness, erythema, burning sensation). These reactions were generally mild to moderate in severity, transient, and resolved without further intervention.

Very common
(frequency ≥1/10): Injection site reaction*.

Common
(≥1/100 to <1/10): Dizziness, headache, nausea, rash, erythema, pruritus, pyrexia, increased transaminases.

* Injection site bruising, Injection site hematoma, Injection site burning, Injection site erythema, Injection site hypoesthesia, Injection site irritation, Injection site numbness, Injection site edema, Injection site pain, Injection site pressure sensation, Injection site pruritus, Injection site swelling, Injection site urticaria, and Injection site warmth.

Paediatric Population: The majority of paediatric patients (8 children aged 2 to 11 and 24 adolescents aged 12 to 17 years) who were treated with subcutaneous icatibant experienced injection site reactions such as erythema, swelling, burning sensation, skin pain and itching/pruritus; these were found to be mild to moderate in severity and consistent with reactions that have been reported in adults. Two paediatric patients experienced injection site reactions which were assessed as severe and which were completely resolved within 6 hours. These reactions were erythema, swelling, burning and warm sensation.

No clinically significant changes in reproductive hormones were observed during clinical studies.

For further information please contact:

Investor Relations  
Ian Karpikarp@shire.com+1 781 482 9018
Robert Coatesrcoates@shire.com+44 203 549 0874
Media  
Elizabeth Kalinaekalina@shire.com+1 781 482 2713
Gwen Fishergfisher@shire.com+1 781 482 9649

NOTES TO EDITORS

About Shire
Shire is the global leader in serving patients with rare diseases. We strive to develop best-in-class therapies across a core of rare disease areas including hematology, immunology, genetic diseases, neuroscience, and internal medicine with growing therapeutic areas in ophthalmics and oncology. Our diversified capabilities enable us to reach patients in more than 100 countries who are struggling to live their lives to the fullest.

We feel a strong sense of urgency to address unmet medical needs and work tirelessly to improve people’s lives with medicines that have a meaningful impact on patients and all who support them on their journey.

www.shire.com

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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;
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  • 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 has increased its borrowing costs may decrease its business flexibility; 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

  1. [FIRAZYR® Summary of Product Characteristics]
  2. Circardi M, Bork K, Caballero T, et al, on behalf of HAWK (Hereditary Angioedema International Working Group). Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy. 2012; 67(2):147-157.
  3. Zuraw BL. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-1036.
  4. Banerji A. The burden of illness in patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2013;111(5):329-336.
  5. 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.
  6. Farkas H, et al. Treatment Effect and Safety of Icatibant in Pediatric Patients with Hereditary Angioedema. Journal of Allergy and Clinical Immunology: In Practice. 2017; 1-8.
  7. Craig T, et al. WAO guideline for the management of hereditary angioedema. World Allergy Organ Journal 2012; 5(12):182-99.
  8. Longhurst HJ, Bork K. Hereditary angioedema: causes, manifestations, and treatment. Br J Hosp Med. 2006;67(12):654-657.

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