Shire plc : FDA APPROVES VONVENDI® FOR PERIOPERATIVE MANAGEMENT OF BLEEDING IN ADULT PATIENTS WITH VON WILLEBRAND DISEASE

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| Source: Shire Pharmaceuticals Group

FDA APPROVES VONVENDI® [VON WILLEBRAND FACTOR (RECOMBINANT)] FOR PERIOPERATIVE MANAGEMENT OF BLEEDING IN ADULT PATIENTS WITH VON WILLEBRAND DISEASE1

  • Expanded use for VONVENDI - the first and only purified recombinant von Willebrand factor - builds on previously approved on-demand treatment indication1 
  • VONVENDI now offers an individualized approach to bleed control in appropriate patients undergoing surgery1
  • von Willebrand disease is the most common inherited bleeding disorder, affecting up to one percent of the U.S. population2

Cambridge, Ma. - April 17, 2018 - Shire plc (LSE: SHP, NASDAQ: SHPG), the global  biotechnology leader in rare disease, today announced the U.S. Food and Drug Administration (FDA) has approved VONVENDI [von Willebrand factor (recombinant)], a recombinant von Willebrand factor (rVWF) treatment for perioperative management of bleeding in adults (age 18 and older) with von Willebrand disease (VWD).1 VONVENDI is also indicated for on-demand treatment and control of bleeding episodes, and it is the first and only recombinant treatment for adults living with VWD, the most common inherited bleeding disorder.1,3-4

"The expanded approval of VONVENDI represents a new treatment option for the surgical setting that can be tailored to each patient's individual needs,"1,3-5 said Andreas Busch, Global Head of Research and Development, Shire. "It's an important milestone in support of our vision of personalizing treatment and helping to address unmet needs for people with bleeding disorders."1,3-5

People with VWD lack proper quantities of VWF or functioning VWF, and they may or may not have a secondary factor VIII (FVIII) deficiency.5 Since not every person with VWD or every bleed requires FVIII replacement, VONVENDI allows healthcare providers to dose recombinant VWF independent of recombinant FVIII based on clinical judgement for each patient, taking into account severity, site of bleeding, the patient's medical history and monitoring of appropriate clinical and laboratory measures.1 Independent dosing with VONVENDI offers an individualized approach to bleed control in appropriate patients undergoing surgery.1

"Persons with von Willebrand disease face a heightened risk of bleeding during surgery and may require factor treatment before, during or after surgery," said Michael Tarantino, M.D., Professor of Pediatrics and Medicine, University of Illinois College of Medicine, and Medical Director and President, The Bleeding and Clotting Disorders Institute. "For surgeries requiring repeated, frequent infusions with combined von Willebrand factor and factor VIII concentrates, an excessive rise in factor VIII levels may increase the risk of thromboembolic complications, such as blood clots.1,7 The expanded use for VONVENDI in surgical settings gives healthcare professionals flexibility in treating von Willebrand disease with an appropriate dose of von Willebrand factor, with or without recombinant factor VIII, based on each patient's unique needs."1,5

The approval of VONVENDI in surgical settings was based on results from a Phase 3 prospective, open-label, multicenter trial to evaluate the efficacy and safety of VONVENDI with or without recombinant FVIII treatment in elective surgical procedures in adults (age 18 years and older) diagnosed with severe VWD.1 Results from the study showed VONVENDI met its primary endpoint, demonstrating overall hemostatic efficacy assessed 24 hours after the last perioperative VONVENDI infusion or at completion of study visit, whichever occurred earlier.1 The overall median dosing frequency of once-daily was demonstrated to normalize hemostasis in appropriate patients.1 One study participant developed deep vein thrombosis three days after undergoing hip replacement surgery while receiving VONVENDI.1

In addition to the expanded use of VONVENDI, the updated Prescribing Information includes new information about pharmacokinetics and storage of VONVENDI. VONVENDI can be stored at refrigerated temperature 2°C to 8°C (36°F to 46°F) or room temperature not to exceed 30°C (86°F). Do not freeze. Store VONVENDI in the original box and protect it from extreme exposure to light.

VONVENDI was first approved by the FDA in December 2015.

Additional Study Details
Intra- and postoperative hemostasis achieved with recombinant VWF with or without recombinant FVIII was rated as "excellent" (as good as or better than expected) or "good" (probably as good as expected) for all 15 study participants treated with VONVENDI.1 To declare the outcome a success, a rating of excellent or good was required.1 Study participants received a dose of 40 to 60 International Units (IU) per kg body weight of VONVENDI 12 to 24 hours before surgery.1 Within 3 hours prior to surgery, each study participant's factor VIII level (FVIII:C) was assessed with a target of 30 IU/dL for minor surgeries and 60 IU/dL for major surgeries.1 Within 1 hour prior to surgery, study participants received a dose of VONVENDI with or without recombinant FVIII (depending on the target FVIII:C levels at the 3 hour assessment).1 One study participant tested positive for binding antibodies to VWF.1 No binding antibodies against potential impurities such as rFurin, CHO-protein or mouse IgG developed after treatment with VONVENDI.1

About von Willebrand disease (VWD)
VWD is the most common inherited bleeding disorder, affecting up to one percent of the U.S. population.2 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.2 Due to this defect or deficiency 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.2 Bleeding caused by VWD varies greatly among patients with this disease.8

VONVENDI [von Willebrand factor (recombinant)] Important Information

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 to2% 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

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

References:

  1. VONVENDI [von Willebrand factor (recombinant)] Prescribing Information.
  2. National Hemophilia Foundation. "Von Willebrand Disease." National Hemophilia Foundation website. https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Von-Willebrand-Disease.
  3. Shire. "Introducing VONVENDI [von Willebrand factor (recombinant)]." VONVENDI website. http://www.vonvendi.com/about/why-vonvendi/.
  4. Shire. "It's a complex disease." VONVENDI website. http://www.vonvendi.com/von-willebrand-disease/.
  5. Favaloro E. "Towards personalised therapy for von Willebrand disease: a future role for recombinant products." Blood Transfusion. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918558/.
  6. Shire. "2016: The year recombinant VWF treatment became available." VONVENDI website. http://www.vonvendi.com/about/why-recombinant/.
  7. 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.
  8. National Hemophilia Foundation. "VWD Summit Highlights." HEMAWARE website. https://hemaware.org/story/vwd-summit-highights.

For further information please contact:

Investor Relations    
Christoph Brackmann christoph.brackmann@shire.com +41 795 432 359
Sun Kim sun.kim@shire.com +1 617 588 8175
Robert Coates rcoates@shire.com +44 203 549 0874
     
Media    
Linda Calandra

 
linda.calandra@shire.com +1 917 697 7543

NOTES TO EDITORS

About Shire

Shire is the global leader in serving patients with rare diseases. We strive to develop best-in-class therapies across a core of rare disease areas including hematology, immunology, genetic diseases, neuroscience, and internal medicine with growing therapeutic areas in ophthalmics and oncology. Our diversified capabilities enable us to reach patients in more than 100 countries who are struggling to live their lives to the fullest.

We feel a strong sense of urgency to address unmet medical needs and work tirelessly to improve people's lives with medicines that have a meaningful impact on patients and all who support them on their journey.

www.shire.com

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  • the potential uncertainty resulting from the announcement by Takeda Pharmaceutical Company Limited that it is considering making an approach to Shire regarding a possible offer for Shire; 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.

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