Shire submits investigational New Drug Application to FDA

Shire submits investigational New Drug Application to FDA for Gene Therapy candidate SHP654 for treatment of Hemophilia A

SHP654 aims to deliver sustained protection against bleeds for patients with hemophilia A

Lexington, Mass.   -   July 6, 2017   - Shire plc (LSE: SHP, NASDAQ: SHPG), the leading biotechnology company focused on serving people with rare diseases, today announced the submission of an investigational new drug (IND) application to the U.S. Food and Drug Administration (FDA) for SHP654, also designated as BAX 888, an investigational factor VIII (FVIII) gene therapy for the treatment of hemophilia A. SHP654 aims to protect hemophilia A patients against bleeds through the delivery of a long-term, constant level of factor expression. ¹ The IND filing for SHP654 represents the latest step forward for Shire's gene therapy program, which shows promise for both hemophilia A and B populations.

"Shire is leveraging decades of scientific leadership in hemophilia to advance research in gene therapy for this community," said Paul Monahan, M.D., Senior Medical Director, Gene Therapy, Shire. "Drawing from our rich heritage, Shire is well equipped to sustainably support the development of gene therapies that aim to advance current standards of care and minimize the burden of this disease. SHP654 uses a proprietary technology platform designed to produce sustained levels of factor similar to the natural mechanisms of the body. Our goal with gene therapy for hemophilia is to uphold the highest standards for safety and efficacy."

Shire's gene therapy program for hemophilia A uses a recombinant adeno-associated virus serotype 8 (rAAV8) vector, which selectively targets the liver. ^1,2 It involves the delivery of a functional copy of FVIII to the body's liver to enable its own production of FVIII, rather than relying on a factor-based treatment. ¹ SHP654 uses the rAAV8 vector to deliver a codon-optimized, B-domain deleted FVIII (BDD-FVIII) specifically to a patient's liver, where FVIII would then be produced and used to manage bleeds. ¹ The FVIII expression is further controlled in patients by incorporating the liver-specific transthyretin (TTR) promoter/enhancer. ¹

The IND filing for SHP654 was based on the results of pre-clinical and phase 1 studies demonstrating the potential utility of this candidate, including the following that will be presented at the International Society on Thrombosis and Haemostasis (ISTH) 26th Biennial Congress in Berlin, Germany, from July 8 - 13, 2017:

• Development of SHP654, a highly efficient AAV8-based BDD-FVIII gene therapy vector for treatment of hemophilia A . Session Title: Gene Therapy for Hemophilia: Clinical. Oral # OC 13.6.10th July, 17:45-19:00 CEST; Hall B ¹
• Integration site analysis in mice demonstrates excellent biosafety profile of a recombinant (r) FVIII adeno-associated virus (AAV8) gene therapy product. Session Title: Poster Session. Poster # PB 1094. 11th July, 12:00-13:15 CEST; Exhibition Hall 4.2 ³
• Dose response and long-term expression of a human FVIII gene therapy construct in hemophilia A mice. Session Title: Poster Session. Poster # PB 1101. 11th July, 12:00-13:15 CEST; Exhibition Hall 4.2 ²
• Nonclinical safety evaluation of a human FVIII gene therapy construct in mice. Session Title: Poster Session. Poster # PB 1099. 11th July, 12:00-13:15 CEST; Exhibition Hall 4.2 ⁴

An IND is a request for FDA authorization to administer an investigational drug to humans. ⁵ Following the FDA's acceptance of the IND for SHP654, Shire will study SHP654 in a global multi-center study evaluating safety and examining the SHP654 doses required to boost factor VIII activity levels and affect hemophilic bleeding and will pursue bringing this innovation to markets worldwide.

About SHP654 Shire is developing SHP654 (BAX 888), which includes technology acquired from Chatham Therapeutics, LLC, a spin-out of Asklepios Biopharmaceutical, Inc . SHP654 is an investigational factor VIII (FVIII) gene therapy intended to treat hemophilia A using a recombinant adeno-associated virus serotype 8 (rAAV8) vector to deliver a codon-optimized, B-domain deleted FVIII (BDD-FVIII) specifically to a patient's liver, where FVIII would then be produced and used to manage bleeds. ^1,2

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. ⁶ The severity of hemophilia A is determined by the amount of factor in the blood, with more severity associated with lower amounts of factor. ⁷ More than half of patients with hemophilia A have the severe form of the condition. ⁷ Approximately 25-30% of individuals with severe hemophilia A develop inhibitors. ⁸ Inhibitors are a serious medical problem that can occur when a person with hemophilia has an immune response to treatment with clotting factor concentrates. ⁹ Hemophilia primarily affects males, with an incidence of one in 5,000 male births. ^7,10

References

1. Falkner et al. "Development of SHP654 a highly efficient AAV8-based BDD-FVIII gene therapy vector for treatment of hemophilia A." International Society on Thrombosis and Haemostasis Congress. Berlin, Germany July 8-13, 2017. Available at: http://onlinelibrary.wiley.com/doi/10.1111/rt...1/issuetoc
2. Hoellriegl et al. "Dose response and long-term expression of a human FVIII gene therapy construct in hemophilia A mice." International Society on Thrombosis and Haemostasis Congress. Berlin, Germany July 8-13, 2017. Available at: http://onlinelibrary.wiley.com/doi/10.1111/rt...1/issuetoc
3. Hoellriegl et al. "Integration site analysis in mice demonstrates excellent biosafety profile of a recombinant ® FVIII adeno-associated virus (AAV8) gene therapy product." International Society on Thrombosis and Haemostasis Congress. Berlin, Germany July 8-13, 2017. Available at: http://onlinelibrary.wiley.com/doi/10.1111/rt...1/issuetoc
4. Hoellriegl et al. "Nonclinical safety evaluation of a human FVIII gene therapy construct in mice." International Society on Thrombosis and Haemostasis Congress. Berlin, Germany July 8-13, 2017. Available at: http://onlinelibrary.wiley.com/doi/10.1111/rt...1/issuetoc
5. U.S Food and Drug Administration. "Investigational New Drug (IND) or Device Exemption (IDE) Process (CBER)." U.S Food and Drug Administration website. https://www.fda.gov/biologicsbloodvaccines/de...efault.htm . Accessed June 28, 2017.
6. World Federation of Hemophilia. "What is hemophilia?" World Federation of Hemophilia website. http://www.wfh.org/en/page.aspx?pid=646 . Accessed June 23, 2017. 
7. National Hemophilia Foundation. "Hemophilia A." National Hemophilia Foundation website. https://www.hemophilia.org/Bleeding-Disorders...mophilia-A .  Accessed June 23, 2017.
8. World Federation of Hemophilia. "Who is at risk of developing inhibitors?" World Federation of Hemophilia website. http://www.wfh.org/en/page.aspx?pid=653 . Accessed June 23, 2017.
9. World Federation of Hemophilia. "What are inhibitors?" World Federation of Hemophilia website. http://www.wfh.org/en/page.aspx?pid=651 . Accessed June 23, 2017.
10. Centers for Disease Control and Prevention. "Hemophilia." Centers for Disease Control and Prevention website. http://www.cdc.gov/ncbddd/hemophilia/facts.html . Accessed June 29, 2017.

NOTES TO EDITORS

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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.

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