Shire Announces EMA Validation of Veyvondi[TM] [Von Willebrand Factor (Recombinant)] Marketing Authorization Application for Treatment of Von Willebrand Disease

ZUG, Switzerland, June 22, 2017 /PRNewswire/ --

VEYVONDI is the first and only recombinant von Willebrand factor treatment for adults with von Willebrand disease, the most common inherited bleeding disorder^[1],[2],[3]

Shire plc (LSE: SHP, NASDAQ: SHPG), the leading biotechnology company focused on serving individuals with rare diseases, today announced that the European Medicines Agency (EMA) validated the Marketing Authorization Application (MAA) for VEYVONDI to prevent and treat bleeding episodes and peri-operative bleeding in adults (age 18 and older) diagnosed with von Willebrand Disease (VWD), the most common inherited bleeding disorder. Currently available in the U.S. as VONVENDI^® [von Willebrand factor (Recombinant)], VEYVONDI is the first and only recombinant von Willebrand factor (rVWF) treatment for adults living with VWD.^[1],[2],[3]

"With its clinical profile and physiology, VEYVONDI is a first-of-its-kind treatment for VWD," said Alice Dietrich, MD, Head of Global Medical Affairs, Shire. "We're deeply committed to advancing standards of care and outcomes for VWD patients worldwide, and today's submission marks an important milestone in our efforts to address needs of patients living with VWD and make VEYVONDI available to more patients who could benefit from its use."

Patients with VWD have a deficiency or dysfunction of VWF, a blood protein required for proper clotting.^[4] Because of this, the blood does not clot properly, which may result in heavy menstrual periods, easy bruising, or frequent nose bleeds.^[4] VEYVONDI is an innovative VWF replacement therapy produced and formulated without the addition of any exogenous raw materials of human or animal origin, resulting in a product that contains only trace amounts of FVIII.^[2] This provides physicians with the flexibility to manage VWF levels.^[3]

VEYVONDI was studied in patients, 18 to 64 years of age, in a multi-center, open label, non-randomized study assessing safety, efficacy and pharmacokinetics, with and without rFVIII.^[2],[3] It was also studied in patients, 18 years and older, in a prospective, uncontrolled, international, multi-center, open label, non-randomized study assessing control of hemostasis before, during or after surgical procedures, with or without rFVIII.^[5] The most common adverse reaction observed was generalized pruritus (itching).^[3],[6] The EMA filing is based on data from these two Phase 3 clinical trials shared publicly in December 2015 and December 2016, respectively.

About von Willebrand disease (VWD) 

VWD is the most common inherited bleeding disorder worldwide, affecting up to 1 percent of the world's population.^[7] VWD is caused by a deficiency or dysfunction of VWF, resulting in impaired blood clotting, and it affects women and men equally.^[4],[8] The disease can manifest through various bleeding events, including heavy menstrual periods, easy bruising or frequent nose bleeds.^[4] Bleeding caused by VWD is unpredictable and varies greatly among patients with the disease.^[8] Many people with VWD may not know that they have it because their symptoms are mild or change over time.^[9] Research shows that as many as 9 out of 10 people with VWD have not been diagnosed.^[9]

About VONVENDI in the United States 

VONVENDI was approved by the U.S. Food and Drug Administration (FDA) in December 2015 and is indicated for on-demand treatment and control of bleeding episodes in adults (18 years and older) with VWD.^[1] VONVENDI is the first and only rVWF treatment developed for people living with VWD.^[1] Shire is also seeking prophylaxis and pediatric indications for VONVENDI, with trials anticipated to conclude in 2019 and 2020, respectively. For more information on VONVENDI, please visit vonvendi.com.

VONVENDI [von Willebrand factor (Recombinant)] Important Information 

Indication
VONVENDI [von Willebrand factor (Recombinant)] is a recombinant von Willebrand factor indicated for on-demand treatment and control of bleeding episodes in adults (age 18 and older) diagnosed with von Willebrand disease.

DETAILED IMPORTANT RISK INFORMATION 

CONTRAINDICATIONS
VONVENDI is contraindicated in patients who have had life-threatening hypersensitivity reactions to VONVENDI or constituents of the product (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 (DIC), venous thrombosis, pulmonary embolism, myocardial infarction, and stroke, can occur, particularly in patients with known risk factors for thrombosis. Monitor for early signs and symptoms of thrombosis such as pain, swelling, discoloration, dyspnea, cough, hemoptysis, and syncope.

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

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. If signs and symptoms of severe allergic reactions occur, immediately discontinue administration of VONVENDI and provide appropriate supportive care.

Neutralizing Antibodies
Neutralizing antibodies (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-FVIII inhibitors are present. Consider other therapeutic options and direct the patient to a physician with experience in the care of either von Willebrand disease 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
The most common adverse reaction observed in ≥2% of subjects in clinical trials (n=66) was generalized pruritus.

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

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

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, 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;
• 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, including expected operating efficiencies, cost savings, revenue enhancements, synergies or other benefits at the time anticipated or at all with respect to Shire's acquisition of 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 may decrease its business flexibility and increase borrowing costs; 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 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. "FDA approved first recombinant von Willebrand factor to treat bleeding episodes." FDA website. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm476065. Accessed June 21, 2017.
2. VONVENDI Prescribing Information.
3. Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 2015;126(17):2038-2046.
4. Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008;14(2):171-232.
5. Baxalta. Recombinant von Willebrand factor in subjects with severe von Willebrand disease undergoing surgery. Available from: https://clinicaltrials.gov/ct2/show/NCT02283268. Accessed June 16, 2017.
6. Shire Data on File.
7. James PD, Goodeve AC. von Willebrand Disease. Genet Med. 2011;13(5):365-76.
8. Leebeek FW, Eikenboom JC. Von Willebrand's Disease. N Engl J Med. 2016;375(21):2067-2080.
9. What is von Willebrand disease (VWD)? World Federation of Hemophilia website. https://www.wfh.org/en/page.aspx?pid=673. Accessed May 3, 2017.

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SOURCE Shire plc