Shire announces FDA approval of ADYNOVATE® [Antihemophilic Factor (Recombinant), PEGylated] for use in Children and Surgical settings

New FDA-approved indications for ADYNOVATE provides more hemophilia A patients access to proven prophylaxis with a simple, twice-weekly dosing schedule

Lexington, Mass. – December 27, 2016 – Shire plc (LSE: SHP, NASDAQ: SHPG) announced today that the U.S. Food and Drug Administration (FDA) has approved ADYNOVATE [Antihemophilic Factor (Recombinant), PEGylated], an extended circulating half-life recombinant Factor VIII (rFVIII) treatment for hemophilia A, in pediatric patients under 12 years of age. The FDA also approved ADYNOVATE for use in surgical settings for both adult and pediatric patients. ADYNOVATE is built on the full-length ADVATE^® [Antihemophilic Factor (Recombinant)] molecule, a market leading treatment for hemophilia A with more than 13 years of real-world patient experience.

“Physicians need additional treatment options for pediatric patients and those undergoing surgery with hemophilia A,” said lead investigator Eric Mullins, M.D., Research Director, Hemophilia Treatment Center, Cincinnati Children’s Hospital Medical Center. “As someone who has routinely seen the benefits of factor replacement in adult patients with hemophilia A, I am pleased to be able to provide ADYNOVATE to more patients.”

The approval of ADYNOVATE to treat children under the age of 12 was based on data from a prospective, uncontrolled, open-label, multi-center Phase 3 trial designed to assess the immunogenicity along with the safety and efficacy of ADYNOVATE. Results from the study showed that ADYNOVATE met its primary endpoint with no previously treated children having developed inhibitory antibodies to ADYNOVATE. In addition, no treatment-related serious adverse events were reported. More than 70 percent (73 percent) of children had zero joint bleeds (n=48/66) while on prophylactic treatment with ADYNOVATE and nearly 40 percent (38 percent) experienced zero bleeds (n= 25/66). The median overall annualized bleeding rate (ABR) among pediatric patients treated with ADYNOVATE was 2.0 (mean ABR 3.04; range 2.21–4.19), which was similar to the rates seen in the adult study.

“At Shire, we are dedicated to developing innovative therapies for patients living with hemophilia A,” said Philip J. Vickers, Ph.D., Global Head of Research and Development at Shire. “Today’s announcement of the new FDA-approved indications for ADYNOVATE in pediatric patients less than 12 years of age and those undergoing surgery underscores our commitment to provide treatment options with proven efficacy profiles to more patients living with hemophilia A.”

Approval to use ADYNOVATE in surgical settings for both adult and pediatric patients was based on interim results of an ongoing Phase 3 study of perioperative control of hemostasis among 15 patients with severe hemophilia A undergoing surgical procedures.

ADYNOVATE was first approved by the FDA in November 2015. ADYNOVATE provides proven prophylaxis with simple, twice-weekly dosing for children and adult patients with hemophilia A, helping to further individualize options for this patient population. The most common adverse reactions reported in >= 1% of subjects in the clinical studies were headache and nausea. Through a collaboration with Nektar Therapeutics (NASDAQ: NKTR), ADYNOVATE leverages proprietary PEGylation technology designed to extend the amount of FVIII available for use in the body. The technology was selected because it maintains the integrity of the parent molecule (ADVATE) while reducing the time at which the body clears ADYNOVATE, resulting in an extended circulating half-life.

About ADYNOVATE
ADYNOVATE is built on the full-length ADVATE molecule, a market-leading treatment for hemophilia A that has been used by patients worldwide for more than 13 years. ADYNOVATE was first approved by the FDA in November 2015. ADYNOVATE provides proven prophylaxis with simple, twice-weekly dosing for children and adult patients with hemophilia A, helping to further individualize options for this patient population. The PEGylation technology was selected because it maintains the integrity of the parent molecule (ADVATE) and reduces the time at which the body clears ADYNOVATE, resulting in an extended circulating half-life.

ADYNOVATE [Antihemophilic Factor (Recombinant), PEGylated] Important Information

Indications
ADYNOVATE, Antihemophilic Factor (Recombinant), PEGylated, is a human antihemophilic factor indicated in children and adults with hemophilia A (congenital factor VIII deficiency) for:

• On-demand treatment and control of bleeding episodes
• Perioperative management
• Routine prophylaxis to reduce the frequency of bleeding episodes

Limitation of Use
ADYNOVATE is not indicated for the treatment of von Willebrand disease.

ADYNOVATE [Antihemophilic Factor (Recombinant), PEGylated] DETAILED IMPORTANT RISK INFORMATION

CONTRAINDICATIONS
ADYNOVATE is contraindicated in patients who have had prior anaphylactic reaction to ADYNOVATE, to the parent molecule (ADVATE [Antihemophilic Factor (Recombinant)]), mouse or hamster protein, or excipients of ADYNOVATE (e.g. Tris, mannitol, trehalose, glutathione, and/or polysorbate 80).

WARNINGS & PRECAUTIONS
Hypersensitivity Reactions
Hypersensitivity reactions are possible with ADYNOVATE. Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with other recombinant antihemophilic factor VIII products, including the parent molecule, ADVATE. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur.

Neutralizing Antibodies
Formation of neutralizing antibodies (inhibitors) to factor VIII can occur following administration of ADYNOVATE. Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled with expected dose.

ADVERSE REACTIONS
The most common adverse reactions (≥1% of subjects) reported in the clinical studies were headache and nausea.

For ADYNOVATE Full Prescribing Information, visit http://www.shirecontent.com/PI/PDFs/ADYNOVATE_USA_ENG.pdf

ADVATE [Antihemophilic Factor (Recombinant)] Important Information

Indications
ADVATE [Antihemophilic Factor (Recombinant)] is a recombinant antihemophilic factor indicated for use in children and adults with hemophilia A (congenital factor VIII deficiency) for:

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

ADVATE is not indicated for the treatment of von Willebrand disease.

ADVATE [Antihemophilic Factor (Recombinant)] DETAILED IMPORTANT RISK INFORMATION

CONTRAINDICATIONS
ADVATE is contraindicated in patients who have life-threatening hypersensitivity reactions, including anaphylaxis, to mouse or hamster protein or other constituents of the product.

WARNINGS & PRECAUTIONS
Hypersensitivity Reactions
Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. Symptoms include dizziness, paresthesia, rash, flushing, facial swelling, urticaria, dyspnea, pruritus, and vomiting. Discontinue ADVATE if hypersensitivity symptoms occur and administer appropriate emergency treatment.

Neutralizing Antibodies
Neutralizing antibodies (inhibitors) have been reported following administration of ADVATE predominantly in previously untreated patients (PUPs) and previously minimally treated patients (MTPs). Monitor all patients for the development of factor VIII inhibitors by appropriate clinical observation and laboratory testing. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor VIII inhibitor concentration.

ADVERSE REACTIONS
Serious adverse reactions seen with ADVATE are hypersensitivity reactions, including anaphylaxis, and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.
The most common adverse reactions observed in clinical trials (frequency ≥5% of subjects) were pyrexia, headache, cough, nasopharyngitis, arthralgia, vomiting, upper respiratory tract infection, limb injury, nasal congestion, and diarrhea.

For ADVATE Full Prescribing Information, visit http://www.shirecontent.com/PI/PDFs/ADVATE_USA_ENG.pdf

About Hemophilia A
Hemophilia A, the most common type of hemophilia, is a rare bleeding disorder that causes longer-than-normal bleeding due to lack of clotting factor VIII in the blood. The severity of hemophilia A is determined by the amount of factor in the blood, with more severity associated with lower amounts of factor. More than half of patients with hemophilia A have the severe form of the condition. Approximately 25-30% of individuals with severe hemophilia A develop inhibitors. Inhibitors are a rare, but a serious medical problem that can occur when a person with hemophilia has an immune response to treatment with clotting factor concentrates. Hemophilia primarily affects males, with an incidence of one in 5,000 male births.

SHIRE and the Shire Logo are registered trademarks of Shire Pharmaceutical Holdings Ireland Limited or its affiliates. ADYNOVATE and ADVATE are registered trademarks of Baxalta Incorporated, a wholly owned, indirect subsidiary of Shire plc.

FOR FURTHER INFORMATION PLEASE CONTACT:

Investor Relations
Robert Coates	[email protected]	+44 1256 894874
Ian Karp	[email protected]	+1 781 482 9018
Media
Debbi Ford	[email protected]	+1 617 949 9083
Kelly Schlemm	[email protected]	+1 617 588 8358

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.
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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• 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;
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• 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 ended June 30, 2016.

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