Shire Reports on Four Decades of Real-World Safety Experience With FEIBA [Anti-Inhibitor Coagulant Complex]

LEXINGTON, Massachusetts, December 2, 2016 /PRNewswire/ --

Shire plc (LSE: SHP;NASDAQ: SHPG), the leading biotechnology company focused on serving individuals with rare diseases, is presenting an update on its safety database describing 40 years of real-world experience with the bypassing agent FEIBA [Anti-Inhibitor Coagulant Complex]. Shire also revealed new in vitro data showing the potential for excessive thrombin generation when combining an investigational procoagulant bispecific antibody and bypass therapy for breakthrough bleeds. These data are now available online as part of the Proceedings of the 58th American Society of Hematology (ASH) Annual Meeting, to be held December 3-6 in San Diego, California.

Inhibitors are a rare but serious complication impacting about 5-7 percent of patients with hemophilia A. They form when the body's immune system attacks the molecules in factor therapy, causing it to be ineffective.^[1],[2] Bypassing agents help bypass the inhibitor to help the body form a clot and stop bleeding.^[3]

Recently, concerns have emerged related to the use of an investigational non-factor product when combined with marketed bypassing agents for hemophilia patients with inhibitors. Shire conducted an analysis of a sequence analogue biosimilar of one investigational agent, emicizumab, in combination with bypassing agents. Researchers characterized in vitro the rate and level of thrombin generation resulting from combining the bypassing agent and investigational non-factor product. The data found a multi-fold increase in thrombin generation, indicating a potential thrombotic risk for patients who receive the investigational agent combined with an approved bypass agent for breakthrough bleeds. (Synergistic Effects of a Procoagulant Bispecific Antibody and Rescue Therapies on Thrombin Generation- a Potential Safety Risk, http://www.bloodjournal.org/content/128/22/4952.)^[4]

"FEIBA is a widely approved treatment option for people with hemophilia A and B with inhibitors, and has a well-established safety and efficacy profile^[5]," said Leonard Valentino, M.D., Global Head of Hematology Medical Affairs, Shire. "Shire embraces new products with the potential to build on current standards of hemophilia care. As with any new product, rigorous clinical studies and careful review of safety and efficacy data are crucial to inform healthcare providers and patients on the best way to safely and effectively incorporate potential new therapeutic agents into existing management strategies."

Shire continually evaluates the safety profile of its products through ongoing safety surveillance. The risk of thromboembolic events (TEEs) is well characterized in the FEIBA label. FEIBA has a boxed warning for identified thromboembolic risk.^[5] Approximately three TEEs have been reported per 100,000 infusions based upon more than seven billion units (equivalent to about two million infusions) distributed over the past 40 years.^[6]

During ASH, Shire is presenting an update on its safety database describing the real-world experience with FEIBA. The global review of safety databases for AE reports of FEIBA received from 1975 through July 2016 showing the reporting rate of TEEs associated with FEIBA is comparable with previously reported data. (Four Decade Cumulative Review of Thrombo-Embolic Events Reported with the Use of Activated Prothrombin Complex Concentrate in Congenital Haemophilia, http://www.bloodjournal.org/content/128/22/503.)^[6]

Indications for FEIBA [Anti-Inhibitor Coagulant Complex]

FEIBA is an Anti-Inhibitor Coagulant Complex indicated for use in hemophilia A and B patients with inhibitors for:

• Control and prevention of bleeding episodes
• Perioperative management
• Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

FEIBA is not indicated for the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to coagulation factor VIII or coagulation factor IX.

Detailed Important Risk Information for FEIBA [Anti-Inhibitor Coagulant Complex]

WARNING: THROMBOEMBOLIC EVENTS

• Thromboembolic events have been reported during post-marketing surveillance following infusion of FEIBA, particularly following the administration of high doses and/or in patients with thrombotic risk factors.
• Monitor patients receiving FEIBA for signs and symptoms of thromboembolic events.

The use of FEIBA is contraindicated in patients with:

• Known anaphylactic or severe hypersensitivity reactions to FEIBA or any of its components, including factors of the kinin generating system
• Disseminated intravascular coagulation (DIC)
• Acute thrombosis or embolism (including myocardial infarction)

Thromboembolic events (including venous thrombosis, pulmonary embolism, myocardial infarction, and stroke) can occur with FEIBA, particularly following the administration of high doses (above 200 units per kg per day) and/or in patients with thrombotic risk factors.

Infusion of FEIBA should not exceed a dose of 100 units per kg body weight every 6 hours and daily doses of 200 units per kg body weight. Maximum injection or infusion rate must not exceed 2 units per kg of body weight per minute. Monitor patients receiving more than 100 units per kg of body weight of FEIBA for the development of DIC, acute coronary ischemia and signs and symptoms of other thromboembolic events. If clinical signs or symptoms occur, such as chest pain or pressure, shortness of breath, altered consciousness, vision, or speech, limb or abdomen swelling and/or pain, discontinue the infusion and initiate appropriate diagnostic and therapeutic measures.

Hypersensitivity and allergic reactions, including severe anaphylactoid reactions, can occur following the infusion of FEIBA. The symptoms include urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension. These reactions can be severe and systemic (e.g., anaphylaxis with urticaria and angioedema, bronchospasm, and circulatory shock). Other infusion reactions, such as chills, pyrexia, and hypertension have also been reported. If signs and symptoms of severe allergic reactions occur, immediately discontinue administration of FEIBA and provide appropriate supportive care.

Because FEIBA is made from human plasma it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

The most frequently reported adverse reactions observed in >5% of subjects in the prophylaxis trial were anemia, diarrhea, hemarthrosis, hepatitis B surface antibody positive, nausea, and vomiting.

The serious adverse reactions seen with FEIBA are hypersensitivity reactions and thromboembolic events, including stroke, pulmonary embolism and deep vein thrombosis.

Use of antifibrinolytics within approximately 6 to 12 hours after the administration of FEIBA is not recommended.

For FEIBA Full Prescribing Information, visithttp://www.shirecontent.com/PI/PDFs/FEIBA_USA_ENG.pdf

SHIRE and the Shire Logo are registered trademarks of Shire Pharmaceutical Holdings Ireland Limited or its affiliates.

FEIBA is a registered trademark of Baxalta Incorporated, a wholly owned, indirect subsidiary of Shire plc.

References

1. WFH Inhibitors Working Group. "About Bleeding Disorders: What are inhibitors?" World Federation of Hemophilia website. http://www.wfh.org/en/page.aspx?pid=651 Accessed November 7, 2016.
2. Wight J. Paisley S. "The Epidemiology of Inhibitors in Haemophilia A: A Systematic Review." Haemophilia 2003.
3. Center for Disease Control and Prevention. "Inhibitors." CDC website. https://www.cdc.gov/ncbddd/hemophilia/inhibitors.html Accessed November 30, 2016.
4. Knappe S. et al. "Synergistic Effects of a Procoagulant Bispecific Antibody and Rescue Therapies on Thrombin Generation- a Potential Safety Risk." American Society of Hematology. San Diego, California. December 3-6, 2016. Available at: http://www.bloodjournal.org/content/128/22/4952
5. FEIBA Prescribing Information.
6. Crea R. et al. "Four Decade Cumulative Review of Thrombo-Embolic Events Reported with the Use of Activated Prothrombin Complex Concentrate in Congenital Haemophilia." American Society of Hematology. San Diego, California. December 3-6, 2016. Available at: http://www.bloodjournal.org/content/128/22/503

NOTES TO EDITORS

About Shire

Shire is the leading global biotechnology company focused on serving people with rare diseases and other highly specialized conditions. 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.

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 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 with respect to Shire's acquisition of NPS Pharmaceuticals, Inc., Dyax Corp. ("Dyax") or Baxalta Inc. ("Baxalta") 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 the 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;
• difficulties in integrating Dyax or Baxalta into Shire may lead to the combined company not being able to realize the expected operating efficiencies, cost savings, revenue enhancements, synergies or other benefits at the time anticipated or at all; and
• other risks and uncertainties detailed from time to time in Shire's filings with the Securities and Exchange Commission, including those risks outlined in "ITEM 1A: Risk Factors" in Shire's Quarterly Report on Form 10-Q for the quarter endedJune 30, 2016.

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.

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