SHIRE RELEASES DATA AT THE WFH CONGRESS 2018 EVALU

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SHIRE RELEASES DATA AT THE WORLD FEDERATION OF HEMOPHILIA CONGRESS 2018 EVALUATING VONVENDI ^® [VON WILLEBRAND FACTOR (RECOMBINANT)] IN ADULTS WITH VON WILLEBRAND DISEASE DURING AND AFTER SURGERY

-       Study evaluated safety, efficacy of recombinant von Willebrand factor with or without recombinant FVIII

-       Findings suggest potential for more tailored treatment

            -       VONVENDI [von Willebrand factor (Recombinant)] is approved only in the U.S.

Zug, Switzerland - May 22, 2018 - Shire plc (LSE: SHP, NASDAQ: SHPG) the global biotech leader in rare diseases, presented clinical data evaluating the capacity of recombinant von Willebrand factor (rVWF) to replenish functional VWF and restore constitutive factor VIII (FVIII) levels when administered before, during and/or after surgery for adult patients (age 18 years or older) affected by von Willebrand disease (VWD), the most common hereditary bleeding disorder. ¹ The results being presented tomorrow at the World Federation of Hemophilia (WFH) Congress in Glasgow, Scotland, show the potential for rVWF to help manage bleeding risks during and post-surgery. rVWF is marketed in the United States as VONVENDI ^® [von Willebrand factor (Recombinant)].

"There is an unmet clinical need for those living with von Willebrand disease, as they face a heightened risk of bleeding during surgery," said Flora Peyvandi, Professor of Internal Medicine at the University of Milan and the Director of the Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy. "People with von Willebrand disease lack proper function or quantity of von Willebrand factor, and some also have a secondary factor VIII deficiency. In this study, recombinant von Willebrand factor was administered to replace the insufficient or dysfunctional von Willebrand factor, allowing the body to naturally replenish FVIII in most patients. These study results demonstrate clinical promise as physicians were able to tailor treatment based on each patient's individual need for one or both factor therapies."

Controlling bleeding with or without recombinant FVIII The study was a Phase 3 prospective, open-label, multicenter trial to evaluate the efficacy and safety of rVWF with or without recombinant FVIII (rFVIII) in adults (age 18 years and older) diagnosed with severe VWD perioperatively including the effect on endogenous FVIII levels by administering rVWF with or without rFVIII in 15 adults with severe VWD undergoing elective surgical procedures. ^2,3

Results from the study showed that all 15 study participants had overall/intraoperative hemostatic efficacy ratings of "excellent" (as good as or better than expected) or "good" (probably as good as expected). ⁴ Ninety percent of VONVENDI infusions were administered alone (without accompanying rFVIII therapy). ² In this and other studies, one study participant tested positive for binding antibodies to VWF. ⁴ No binding antibodies against potential impurities such as rFurin, CHO-protein or mouse IgG developed after treatment with rVWF. ⁴

"Shire has a long heritage in hematology and we are committed to developing innovative solutions for the patients that need them most," said Andreas Busch, Head of Research and Development and Chief Scientific Officer, Shire. "These study results demonstrate potential clinical value as we look to bring a new treatment option to those living with von Willebrand disease, working toward our vision of individualized treatment and addressing unmet needs for people with bleeding disorders."

VONVENDI was first approved in December 2015 in the U.S. where it is the first and only rVWF treatment for VWD that specifically addresses the primary deficiency or dysfunction of VWF while allowing the body to replenish FVIII. In April 2018, it was approved in the U.S. for perioperative management of bleeding in adults with VWD. A Marketing Authorization Application has been submitted to EMA (European Medicines Agency).

About von Willebrand disease (VWD) VWD is the most common inherited bleeding disorder, affecting up to 1 percent of the global population. ⁵ VWD is caused by a deficiency or dysfunction of VWF, one of several types of proteins in the blood that are needed to facilitate proper blood clotting. ¹ Due to this deficiency or dysfunction in VWF, blood is not able to clot effectively in people with VWD, which results in heavy menstrual periods, easy bruising or frequent nose bleeds. ¹ Bleeding caused by VWD is unpredictable and varies greatly among patients with this disease. ⁶

VONVENDI [von Willebrand factor (Recombinant)] Important Information (U.S. only) ³

Indication VONVENDI [von Willebrand factor (recombinant)] is a recombinant von Willebrand factor indicated for use in adults (age 18 and older) diagnosed with von Willebrand disease (VWD) for:

• On-demand treatment and control of bleeding episodes.
• Perioperative management of bleeding.

DETAILED IMPORTANT RISK INFORMATION

CONTRAINDICATIONS Do not use VONVENDI in patients who have had life-threatening hypersensitivity reactions to VONVENDI or its components (tri-sodium citrate-dihydrate, glycine, mannitol, trehalose-dihydrate, polysorbate 80, and hamster or mouse proteins).

WARNINGS AND PRECAUTIONS Embolism and Thrombosis Thromboembolic reactions, including disseminated intravascular coagulation, venous thrombosis, pulmonary embolism, myocardial infarction, and stroke, can occur, particularly in patients with known risk factors for thrombosis, including low ADAMTS13 levels. Monitor for early signs and symptoms of thrombosis such as pain, swelling, discoloration, dyspnea, cough, hemoptysis, and syncope, and institute prophylaxis measures against thromboembolism based on current recommendations.

In patients requiring frequent doses of VONVENDI in combination with recombinant factor VIII, monitor plasma levels for FVIII:C activity because sustained excessive factor VIII plasma levels can increase the risk of thromboembolic events.

One out of 80 VWD subjects treated with VONVENDI in clinical trials developed proximal deep vein thrombosis in perioperative period after undergoing total hip replacement surgery.

Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, may occur. Symptoms can include anaphylactic shock, generalized urticaria, angioedema, chest tightness, hypotension, shock, lethargy, nausea, vomiting, paresthesia, pruritus, restlessness, wheezing and/or acute respiratory distress. Discontinue VONVENDI if hypersensitivity symptoms occur and administer appropriate emergency treatment.

Neutralizing Antibodies (Inhibitors) Inhibitors to von Willebrand factor and/or factor VIII can occur. If the expected plasma levels of VWF activity (VWF:RCo) are not attained, perform an appropriate assay to determine if anti-VWF or anti-factor VIII inhibitors are present. Consider other therapeutic options and direct the patient to a physician with experience in the care of either VWD or hemophilia A.

In patients with high levels of inhibitors to VWF or factor VIII, VONVENDI therapy may not be effective and infusion of this protein may lead to severe hypersensitivity reactions. Since  inhibitor antibodies can occur concomitantly with anaphylactic reactions, evaluate patients experiencing an anaphylactic reaction for the presence of inhibitors.

ADVERSE REACTIONS In clinical trials, the most common adverse reactions observed in greater than or equal to 2% of subjects (n=80) were generalized pruritus, nausea and dizziness.

One subject treated with VONVENDI in perioperative setting developed deep vein thrombosis after undergoing total hip replacement surgery.

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

References

1. National Hemophilia Foundation. Von Willebrand Disease. Available at: https://www.hemophilia.org/Bleeding-Disorders...nd-Disease.
2. Peyvandi F, Mamavev A, Wang JD, et al. Evaluation of the effect on endogenous factor VIII activity (FVIII:C) after recombinant von Willebrand factor (rVWF) administration during the elective surgery study in patients with severe von Willebrand disease (VWD). WFH 2018.
3. Shire. rVWF in Prophylaxis. Available at https://clinicaltrials.gov/ct2/show/NCT02973087 .
4. VONVENDI U.S. Prescribing Information. Available at: http://www.shirecontent.com/PI/PDFs/VONVENDI_USA_ENG.pdf .
5. World Federation of Hemophilia. What is von Willebrand disease (VWD)? Available at: https://www.wfh.org/en/page.aspx?pid=673 .
6. National Hemophilia Foundation. "VWD Summit Highlights." HEMAWARE website. https://hemaware.org/story/vwd-summit-highights .

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 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.