MA-TAKEDA

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK ) (“Takeda”), the global biotechnology leader in rare diseases, will present research covering a broad range of rare bleeding disorders at the 27th Annual International Society on Thrombosis and Haemostasis Congress (ISTH), July 6-10, 2019 in Melbourne, Australia. Showcased in 10 oral presentations and 38 poster presentations, these data underscore Takeda’s pursuit of treatment innovation to achieve optimized and personalized patient care in hematology.

“At Takeda, we are proud of the hematology heritage Shire, Baxalta and Baxter built over 70 years and we plan on expanding on it through continued research and innovation, in pursuit of a world without bleeds,” said Dr. med. Wolfhard Erdlenbruch, Vice President Head of Global Medical Affairs Hematology, Takeda. “We look forward to presenting new data from PROPEL and important updates from our gene therapy and leading factor pipeline at ISTH 2019, showcasing our continued development and commitment in this area.”

Importance of personalized prophylaxis in haemophilia
At ISTH 2019, Takeda will unveil new data from the Phase IIIb/IV PROPEL study – a PRO spective, randomized, multi-center study comparing the safety and efficacy of ADYNOVATE following P K-guided prophylaxis targeting two different Factor E ight (FVIII) trough L evels in subjects with severe hemophilia A.¹ This data will build on results presented at the European Association of Haemophilia and Allied Disorders (EAHAD) 2019,² to provide important insights into the role of personalized prophylaxis for enabling improved patient outcomes and bleed protection, in people living with hemophilia A.¹

• PK-guided rurioctocog alfa pegol prophylaxis in patients with severe hemophilia A targeting two FVIII trough levels: results from the phase 3 PROPEL Study.
  • Hemophilia Optimizing Prophylaxis, ABSTRACT #OC 42.1; Monday, 08 July 2019, 14:45-16:00, Melbourne Room 2

Advancing the Promise of Gene Therapy in Hemophilia
Takeda will also present 14 scientific updates regarding its gene therapy pipeline for both hemophilia A and B. The goal of gene therapy is to enable a hemophilia patient’s body to naturally produce a sufficient amount of the missing factor VIII or IX to alleviate bleeding episodes.³ Therefore, it may be possible to help convert a hemophilia patient’s bleeding phenotype from severe to mild or even normal in some cases.⁴ Takeda’s TAK-754 is our AAV FVIII gene therapy vector currently under investigation in a Phase I/II trial.

Notably, Takeda will showcase the following gene therapy data, in oral presentations:

• Nonclinical pharmacology of TAK-748/SHP648 a novel factor IX (FIX) gene therapy vector in mice and rhesus monkeys.
  • Gene Therapy Basic 1; Oral #OC 22.1 ; Sunday, 07 July 2019, 14:45-16:00, Melbourne Room 1

• Preexisting immunity against AAV8 and other AAV serotypes in healthy individuals and patients with hemophilia B.
  • Gene Therapy Basic 2; Oral #OC31.4; Monday, 08 July, 2019, 10:45-12:00, Melbourne Room 1

• Whole exome sequencing of patients treated with adeno-associated virus serotype 8-factor IX (AAV8-FIX) gene therapy (BAX335) reveals potential determinants of persistent transgene expression.
  • Gene Therapy Basic 2; Oral #31.1; Monday, 08 July, 2019, 10:45-12:00, Melbourne Room 1

• CTLA-4 IgGs - a powerful tool to enable re-administration in AAV8 gene therapy and to suppress anti-AAV8 T cell responses.
  • Gene Therapy Basic 2; Oral #31.2; Monday, 08 July, 2019, 10:45-12:00, Melbourne Room 1

Takeda will also present 33 other scientific data releases on the company’s recently acquired broad portfolio of treatments for bleeding disorders, in oral and poster presentations throughout ISTH. These will include:

6 Hematology Franchise Product Oral Presentations

• FVIII:
  • Development and characterization of an ELISA combined chromogenic assay for selective measurement of human FVIII activity in animal plasma matrix.
  • Development of a formulation for oral delivery of FVIII via a robotic pill.
  • The route of FVIII endocytosis by antigen-presenting cells determines the pattern of FVIII peptide-specific T cells activation.

• TAK-755:
  • Efficacy of recombinant ADAMTS13 (TAK755) in a humanized mouse model for sickle cell disease.

• VEYVONDI:
  • A new transgenic mouse model tolerant to human recombinant von Willebrand factor.

• ADYNOVATE
  • PK-guided rurioctocog alfa pegol prophylaxis in patients with severe hemophilia A targeting two FVIII trough levels: Safety and efficacy results from the phase 3 PROPEL Study

38 Poster Presentations

• ADYNOVATE:
  • A phase 3b , open-label, multicenter, CONTINUATION study of rurioctocog alfa pegol for prophylaxis in previously treated patients with severe hemophilia A: Clinical course and outcomes in patients with target joints.
  • A retrospective, observational study using specialty pharmacy data of rurioctocog alfa pegol in clinical practice in the United States.
  • High concentrations of polyethylene glycol (PEG) mediate vacuolation of human monocyte-derived macrophages in vitro without impairing their functionality.
  • Outcomes with an extended prophylactic treatment schedule of rurioctocog alfa pegol in a phase 3b, open-label, multicenter, CONTINUATION study in previously treated patients with severe hemophilia A.
  • Safety and immunogenicity results from a phase 3b, open-label, multicenter, CONTINUATION study of rurioctocog alfa pegol for prophylaxis in previously treated patients with severe hemophilia A.

• Gene Therapy:
  • Factor VIII clotting and chromogenic activities for TAK-754 / SHP654, a clinical hemophilia A gene therapy candidate, using in vitro and in vivo assays.
  • Biological relevance of low-titer anti-AAV8 neutralizing antibodies.
  • Comparative integration site analysis of two factor IX (fix) gene therapy vectors with different vector design in mice.
  • Evaluation of gene therapy mediated factor IX activity in selected in vivo test systems.
  • Immunogenicity assessment of FVIII variants for 2nd generation gene therapy.
  • Increased immunogenicity of CpG containing Adeno-associated virus serotype 8 (AAV8) constructs might contribute to the drop of transgene expression.
  • Influence of obesity on gene therapy mediated factor IX expression in mice.
  • Modulation of the Liver Immune Microenvironment by an Adeno-Associated Virus Serotype 8 Gene Therapy Vector.
  • Nonclinical efficacy and toxicology evaluation of a human FVIII gene therapy vector (TAK-754/SHP654) in mice.
  • Prevalence of preexisting immunity to adeno-associated virus (AAV) in adults with hemophilia: interim results from an international epidemiology study.

• ADVATE:
  • AHEAD International and German Studies: Subgroup analysis of patients with moderate or severe hemophilia A receiving antihemophilic factor (recombinant) as Immune Tolerance Induction (ITI) therapy.
  • Distinct antibody signatures in patients with FVIII inhibitors undergoing Immune Tolerance Induction (ITI) therapy.
  • Interferon-gamma-inducible protein 10 levels are altered in patients with haemophilia with advanced haemophiliac arthropathy.

• FEIBA:
  • Bispecific antibodies with light chain specificity for factor IXa and X improve thrombin generation in hemophilia A plasma.
  • FVIII knock out mice treated with bypassing agent reveal thrombogenic activity when coadministered with bispecific-FIX/FX antibody.
  • Real-world clinical management of patients with hemophila and inhibitors with aPCC: efficacy and safety data after 6 months in the “FEIBA Global Outcome Study (FEIBA GO)”.
  • Safety of activated Prothrombin Complex Concentrate (aPCC) monotherapy in patients with haemophilia and inhibitors (PwHI): A systematic review.

• Hemophilia A/ FVIII:
  • Characterisation of a new mouse model of haemophilia A developed using CRISPR/CAS9 technology.
  • Pharmacokinetic and pharmacodynamic profiles of PSAylated and PEGylated rFVIII indicate consistent extended half-life potential in rodents and monkey.
  • Adding the patient’s voice to a hemophilia specific goal menu to facilitate Goal Attainment Scaling: a qualitative study.
  • Incidence and prevalence of diagnosed and undiagnosed hemophilia A and hemophilia B in select countries.

• TAK-755:
  • Characterization of von Willebrand factor and ADAMTS13 in the Tim Townes mouse model of sickle cell disease.
  • Cost of Illness (COI ) of congenital Thrombotic Thrombocytopenic Purpura (cTTP) in the United States.
  • Design of the first clinical study of recombinant ADAMTS13 for the acute treatment of patients with acquired thrombotic thrombocytopenic purpura (aTTP).
  • Dose-dependent effects of recombinant ADAMTS13 (TAK755) on recovery in a humanized mouse model of sickle cell disease.
  • Efficacy and PK/PD Relationship of Recombinant ADAMTS13 (TAK755) in a Humanized Mouse Model of Sickle Cell Disease.
  • Extension of non-clinical safety margins for recombinant ADAMTS13 (TAK755)
  • Feasibility study for subcutaneous route of administration of recombinant ADAMTS13 (TAK755).
  • Recombinant ADAMTS13 (TAK755) can override the inhibitory effect of free hemoglobin on VWF multimer cleavage in vitro.
  • Recombinant ADAMTS13 reduces the cell adhesion of blood from sickle cell disease mice under shear stress.

• VEYVONDI/ VONVENDI
  • Determination of large and ultra-large multimers in recombinant human VWF (rVWF) and pharmacokinetic analyses in patients with Type 3 von Willebrand Disease (VWD).
  • Infusion requirements in on demand treatment of bleeding events in von Willebrand Disease (VWD): an indirect treatment comparison between recombinant von Willebrand factor (VWF) and plasma derived VWF concentrates.
  • Bleeding patterns in patients with von Willebrand Disease: An analysis of a US medical claims database.

About Hemophilia
Hemophilia is a challenging chronic disease that causes longer-than-normal bleeding due to absent or deficient clotting factor in the blood.⁵ Hemophilia A is more common than hemophilia B;⁵ hemophilia A affects about 150,000 people, whereas hemophilia B affects about 30,000 people worldwide.⁶

People with hemophilia, working closely with their healthcare professionals, can live healthy lives with proper care and adequate treatment.⁷ Treatment regimens typically include on-demand and/or regular prophylactic infusions of factor replacement therapy to control or prevent the risk of bleeding.^5,8

About Takeda Hematology
Following its recent acquisition of Shire, Takeda is a leader in hemophilia with the longest heritage and market-leading portfolio, backed by established safety and efficacy profiles with decades of real world experience. We have 70+ years driving innovation for patients⁹ and a broad portfolio of 11 products across nine hemophilia indications¹⁰ . Our experience as leaders in hematology means we are well prepared to meet today’s needs as we pursue future developments in the care of bleeding disorders. Together with the hematology community, we are raising expectations for the future, including earlier diagnosis, earlier and full protection against bleeds, and more personalized patient care.

About Takeda Pharmaceutical Company Limited
Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK ) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to bringing Better Health and a Brighter Future to patients by translating science into highly-innovative medicines.

Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Gastroenterology (GI), Neuroscience, and Rare Diseases. We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people's lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries and regions.

For more information, visit https://www.takeda.com

References

1	Klamroth R, Windyga J, Radulescu V, et al., PK-guided rurioctocog alfa pegol prophylaxis in patients with severe hemophilia A targeting two FVIII trough levels: results from the phase 3 PROPEL Study. Presented at ISTH 2019 (International Society on Thrombosis and Haemostasis (ISTH) Biennial Congress. July 6-10, 2019. Abstract #A-1052-0038-01311.
2	Klamroth R, Windyga J, Radulescu V, et al., Results of a phase 3, randomized, multicenter study of RURIOCTOCOG ALFA PEGOL PK-guided prophylaxis targeting 2 FVIII trough levels in patients with severe Hemophilia A (propel study). Presented at European Association of Haematology and Allied Disorders (EAHAD) February 2019. Abstract #255.
3	National Institutes of Health: National Heart, Lung and Blood Institute. “Gene Therapy Helps Patients With Hemophilia B.” National Heart, Lung and Blood Institute website. https://www.nhlbi.nih.gov/news/enewsletter/professional/ProfHemophilia-article Last Accessed April 2019.
4	Nathwani AC, Tuddenham EG, Rangarajan S, et al., Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B. N Engl J Med. 2011;365(25):2357–2365. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265081/ Last Accessed April 2019.
5	World Federation of Hemophilia. “What is hemophilia?” World Federation of Hemophilia website. http://www.wfh.org/en/page.aspx?pid=646 . Last Accessed April 2019.
6	World Federation of Hemophilia. Report on the Annual Global Survey 2017. World Federation of Hemophilia website. http://www1.wfh.org/publications/files/pdf-1714.pdf Last Accessed April 2019.
7	World Federation of Hemophilia. “About Bleeding Disorders: Treatment.” World Federation of Hemophilia website. https://www.wfh.org/en/page.aspx?pid=642 Last Accessed April 2019.
8	National Hemophilia Foundation. “Hemophilia A”. National Hemophilia Foundation website. https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Hemophilia-A . Last Accessed April 2019.
9	Shire Website. Standards of Care for Hemophilia. Website: https://www.shire.com/who-we-are/how-we-operate/policies-and-positions/standards-of-care-for-hemophilia Last Accessed April 2019.
10	Shire Website. Product List. Website: https://www.shire.com/products/product-list?t= Last Accessed June 2019

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