Shire Announces FDA Approval for Label Expansion of CINRYZE® for Prevention of Attacks in Pediatric HAE

Shire Announces FDA Approval for Label Expansion of CINRYZE^® (C1 esterase inhibitor [human]) for Prevention of Attacks in Pediatric Hereditary Angioedema Patients

• CINRYZE is the first and only therapy indicated in the U.S. to help prevent angioedema attacks in pediatric patients with hereditary angioedema (HAE) as young as 6
• Shire is the only drug developer to complete a pediatric study for the prophylactic treatment of HAE
• HAE is a rare, genetic disorder that causes debilitating, painful and sometimes life-threatening swelling in the body

Dublin, Ireland - Thursday, June 21, 2018 - Shire plc (LSE: SHP, NASDAQ: SHPG), the leading global biotechnology company focused on rare diseases, today announced that the U.S. Food and Drug Administration (FDA) has approved a label expansion for CINRYZE^® (C1 esterase inhibitor [human]), making it available to help prevent angioedema attacks in children aged 6 years and older with hereditary angioedema (HAE). CINRYZE has been approved in the U.S. since October 2008 for routine prophylaxis against attacks in adolescents and adults living with HAE.^[1]  

HAE is a rare, genetic disorder estimated to affect about 1 in 10,000 to 1 in 50,000 people worldwide.^[2],[3] The condition results in recurring attacks of edema (swelling) in various parts of the body, including the abdomen, face, feet, genitals, hands and throat that can be can debilitating and painful.^2,[4],[5] Attacks that obstruct the airways (laryngeal attacks) are potentially life-threatening due to the risk of asphyxiation.^2,4,5

Andreas Busch, Ph.D., Executive Vice President, Head of Research and Development at Shire said: "Symptoms of HAE often present in childhood with the average child experiencing their first HAE attack around the age of 10.^[6] With the FDA label expansion of CINRYZE, children as young as 6 years old living with HAE now have the first FDA approved treatment option available to help prevent attacks."

The approval was based on data from a dedicated Phase 3 multicenter single-blind study (0624-301) that evaluated the use of CINRYZE in 12 patients living with HAE aged 7 to 11. Compared to the baseline observational period, the mean reduction in the normalized number of attacks for CINRYZE 500 U and CINRYZE 1,000 U was 71.1% and 84.5%, respectively. Both doses lessened the severity of attacks and reduced the use of acute treatment compared to baseline. The adverse reactions were headache, nausea, pyrexia (fever), and infusion site erythema (redness of the skin). None of these adverse reactions were severe, and none led to discontinuation (n=12, ages 7-11).¹

"This news is exciting for the HAE community because those living with HAE who are as young as 6 have a new option to help prevent attacks," said Anthony Castaldo, President of the U.S. Hereditary Angioedema Association.

In March 2017, CINRYZE was granted European Commission (EC) approval for the label expansion granting three new indications, including routine prevention of angioedema attacks in children (ages 6 years and above) with severe and recurrent attacks of HAE.^[7]

About the CINRYZE Pediatric Study
Study 0624-301 was a Phase 3 multicenter, single-blind study that enrolled 12 patients aged 7 to 11 with HAE who were required to have an average of greater than or equal to1.0 angioedema attacks per month that were moderate, severe, or required acute treatment during the 12-week baseline observation period. Patients received 500 U and 1000 U of CINRYZE every 3-4 days for 12 weeks. The primary efficacy endpoint was the monthly-normalized number of attacks.

Overall the safety and tolerability of CINRYZE has been shown to be similar in clinical studies of pediatric, adolescent and adult patients with HAE.

About CINRYZE
CINRYZE is currently approved for routine prophylaxis against angioedema attacks in children aged 6 years and older, adolescent and adult patients with HAE. The active substance in CINRYZE is C1-Esterase Inhibitor (C1-INH), which raises plasma levels of C1-INH in patients with HAE, who are prone to swelling due to an underlying deficiency in C1-INH. Treatment with C1-INH addresses the underlying cause of HAE by replacing the deficient protein and helps regulate the production of bradykinin released during an attack. CINRYZE was the first C1-INH proven to help prevent swelling attacks in those living with HAE.¹

In Europe, 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.

IMPORTANT SAFETY INFORMATION (U.S. ONLY)

Contraindications: CINRYZE is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product.

Hypersensitivity Reactions: Severe hypersensitivity reactions may occur during or after administration of CINRYZE. Consider treatment methods carefully, because hypersensitivity reactions may have symptoms similar to HAE attacks. In case of hypersensitivity, discontinue CINRYZE infusion and institute appropriate treatment. Have epinephrine immediately available for treatment of an acute severe hypersensitivity reaction.

Thromboembolic Events: Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of C1 Esterase Inhibitor (Human) products, including CINRYZE, following administration in patients with HAE. Risk factors may include presence of an indwelling venous catheter/access device, prior history of thrombosis, underlying atherosclerosis, use of oral contraceptives, certain androgens, morbid obesity, and immobility. Benefits of CINRYZE for routine prophylaxis of HAE attacks should be weighed against the risks of TE events in patients with underlying risk factors. Monitor patients with known risk factors for TE events during and after CINRYZE administration.

Transmissible Infectious Agents: Because CINRYZE is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. ALL infections thought by a physician possibly to have been transmitted by CINRYZE should be reported to Shire Medical Information at
1-800-828-2088.

Adverse Reactions:  The only serious adverse reaction observed in clinical studies of CINRYZE was cerebrovascular accident. The most common adverse reactions (greater than or equal to 5%) observed were headache, nausea, rash, vomiting, and fever. Post marketing adverse reactions include local infusion site reactions and hypersensitivity.  Post marketing thromboembolic events have been reported, including catheter-related and deep venous thromboses, transient ischemic attack, and stroke.

Please click here for Full Prescribing Information

To report SUSPECTED ADVERSE REACTIONS, contact Shire Medical Information at 1-800-828-2088 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Shire's Commitment to Hereditary Angioedema
HAE is a rare, genetic disorder estimated to affect about 1 in 10,000 to 1 in 50,000 people worldwide.^2,3 The condition results in recurring attacks of edema (swelling) in various parts of the body, including the abdomen, face, feet, genitals, hands and throat that can be debilitating and painful. Attacks that obstruct the airways (asphyxiation) are potentially life-threatening.^2,4,5 Shire is a dedicated, long-term partner to the HAE community with a decade of experience supporting patients. We are committed to serial innovation in HAE and our portfolio of products includes a number of therapy options to help meet the individual needs of those living with the disease. Beyond our focus on developing novel treatments, we provide specialized services and support offerings tailored to the HAE community. Learn more at shire.com.       

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 Rare Disease and Neuroscience divisions support our diverse portfolio of therapeutic areas, including Immunology, Hematology, Genetic Diseases, Internal Medicine, Ophthalmics, Oncology, and neuropsychiatry disorders.


Championing patients is our call to action - it brings the opportunity - and responsibility - to change people's lives.

www.shire.com

Stephen Williams. Deputy Company Secretary, is responsible for arranging the release of this announcement.

Insider Information

This announcement contains inside information.

Forward-Looking Statements


Statements included herein that are not historical facts, including without limitation statements concerning future strategy, plans, objectives, expectations and intentions, projected revenues, 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 depends on third parties to supply certain inputs and services critical to its operations including certain inputs, services and ingredients critical to its manufacturing processes. 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;
• the nature of producing plasma-based therapies 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;
• failure to comply with laws and regulations governing the sales and marketing of its products could materially impact Shire's revenues and profitability;
• Shire's products and product candidates face substantial competition in the product markets in which it operates, including competition from generics;
• Shire's patented products are subject to significant 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 Shire's revenues, financial condition or results of operations;
• Shire may fail to obtain, maintain, enforce or defend the intellectual property rights required to conduct its business;
• Shire faces intense competition for highly qualified personnel from other companies and organizations;
• failure to successfully execute or attain strategic objectives from Shire's acquisitions and growth strategy may adversely affect the 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, could have negative consequences for Shire's business and increase the risk of non-payment by Shire's customers;
• changes in foreign currency exchange rates and interest rates could have a material adverse effect on Shire's operating results and liquidity;
• Shire is subject to evolving and complex tax laws, which may result in additional liabilities that may adversely affect the Shire's financial condition or results of operations;
• if a marketed product fails to work effectively or causes adverse side effects, this could result in damage to Shire's reputation, the withdrawal of the product and legal action against Shire;
• 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 faces risks relating to the expected exit of the United Kingdom from the European Union;
• Shire incurred substantial additional indebtedness to finance the Baxalta acquisition, which has increased its borrowing costs and may decrease its business flexibility;
• Shire's ongoing strategic review of its Neuroscience franchise may distract management and employees and may not lead to improved operating performance or financial results; there can be no guarantee that, once completed, Shire's strategic review will result in any additional strategic changes beyond those that have already been announced;
• the potential uncertainty resulting from the announcement by Takeda Pharmaceutical Company Limited on 8 May 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.