Takeda Demonstrates Ongoing Commitment in Rare Hematology By Continuing to Gather Real-World Evidence and Advance Personalized Treatment

Takeda continues to gather and apply real-world evidence to improve the diagnosis of hemophilia and
advance personalized treatment in its ongoing commitment to ensuring people living with bleeding disorders receive the most effective care possible

Osaka, Japan, February 5, 2020 – Takeda Pharmaceutical Company Limited (TSE: 4502/NYSE:TAK) (“Takeda”) today announced that nine hematology abstracts are being presented at the 13^th Annual Congress of the European Association for Haemophilia and Allied Disorders, EAHAD 2020. The data being presented demonstrate Takeda’s ongoing commitment in rare hematology by continuing to gather important real-world evidence, beyond its product portfolio, and advance personalized treatment for those living with bleeding disorders. 

Gathering Real-World Evidence and Identifying Unmet Needs in Bleeding Disorders
The real-world evidence being presented by Takeda goes beyond its product portfolio and shines a spotlight on the important unmet needs faced by the wider bleeding disorders community. Specifically, literature review findings in the abstract “Incidence and Prevalence of Diagnosed and Undiagnosed Hemophilia A and Hemophilia B in the United Kingdom, Germany, France, Italy, and Spain” (abstract P050) reveal that the estimated percentage of undiagnosed cases in EU5 countries ranged from 16–47% for hemophilia A and 34–65% for hemophilia B. The diagnosis rates varied with disease severity, and the highest rates were typically observed for severe disease.

“Many of us are aware that hemophilia is underdiagnosed, but we don’t necessarily have access to data that show a comprehensive picture of the overall rate of undiagnosed cases in a certain region,” says Dan Curran, M.D., Head of the Rare Diseases Therapeutic Area Unit, Takeda. “Our study, which looks at the incidence and prevalence of diagnosed and undiagnosed Hemophilia A and Hemophilia B in EU5 countries, provides more clarity, and the findings continue to motivate our work with the bleeding disorders community to improve diagnosis.”

Takeda is also working tirelessly to better understand the efficacy and safety of its portfolio in a real-world setting, by continuously collecting data from clinics as well as patients who are being treated with its products. Some of the insights being presented at EAHAD 2020 include:

• VEYVONDI® [Recombinant von Willebrand factor (rVWF), vonicog alfa]: Menorrhagia is the most common symptom affecting females with von Willebrand disease (VWD). The abstract “Management of Menorrhagia in a Phase 3, Post-Hoc, Open-Label Study of rVWF in patients with severe VWD” (abstract P218) shows the hemostatic efficacy rating of vWVF in patients being treated with it.
  
  
• ADVATE® [Recombinant Antihemophilic Factor (rAHF), octocog alfa]: The abstract “AHEAD International and German studies: 6-year interim effectiveness and safety outcomes in patients with hemophilia A receiving antihemophilic factor (recombinant) in a real-world setting” (abstract P115) focuses on the long-term effectiveness and tolerability of rAHF, regardless of disease severity, in two study populations. AHEAD is one of the largest long-term real-world studies on hemophilia, conducted in 22 countries around the world.
  
  
• ADYNOVATE® [Recombinant Antihemophilic Factor, PEGylated, TAK-660]:In the abstract “Immunogenicity Profile of Rurioctocog Alfa Pegol in Previously Treated Patients with Severe Congenital Hemophilia A: Findings from 6 Clinical Trials” (abstract P187), researchers analyzed the association of PEGylated TAK-660 and the risk of developing FVIII inhibitors and persistent antibody response.
  
  
• FEIBA® [Anti-Inhibitor Coagulant Complex]: The abstract “Safety and Effectiveness of Activated Prothrombin Complex Concentrate (aPCC) Monotherapy in Patients with Hemophilia and Inhibitors (PwHI) Undergoing Surgery: A Systematic Review and Meta-Analysis” (abstract P114) shows the rate of adverse events in patients treated with aPCC monotherapy in a surgical setting, as well as its hemostatic effectiveness in different surgical procedures.

“Getting a treatment to market is just the beginning,” Curran adds. “We want to ensure our treatments benefit patients and their care team in the real world. Gathering evidence on an ongoing basis from day-to-day medical practice, outside of rigorous clinical studies, is critical. These data will continue to help define our R&D strategies and clinical trial designs.”

Advancing Personalized Treatment in Rare Hematology
In addition to a suite of real-world evidence, Takeda is showcasing its commitment to advancing individualized treatment in hematology, by highlighting the importance of tailoring dosing regimen of hemophilia treatment based on patients’ different pharmacokinetic (PK) profiles.

In the abstract “Rurioctocog Alfa Pegol PK-guided prophylaxis targeting two FVIII Trough Levels in Severe Hemophilia A Patients (PROPEL Phase 3 Study): Impact of Patient FVIII Half-Life on Consumption and Efficacy Outcomes” (abstract OR09), researchers carried out a post hoc analysis to evaluate the relationship between patient FVIII half-life and efficacy and consumption of prophylactic rurioctocog alfa pegol (TAK-660). The abstract describes the impact of  FVIII half-life on the amount and frequency of TAK-660 doses needed to achieve target FVIII troughs.

“Healthcare is changing, and patients are expecting more from their care team,” comments Dr. med. Wolfhard Erdlenbruch, M.D., Vice President Head of Global Medical Affairs Hematology, Takeda. “As technology advances, we are able to tailor everything around us to suit our needs and that should include medical treatments. We cannot assume that one regimen or one dosing strategy is going to be suitable for all patients – that’s because although these patients may be living with the same condition, the variation in their individual pharmacokinetics, for example, may mean they respond to the same treatment differently. With this in mind, Takeda is always finding new ways to make sure treatments for our patients are as tailored to their individual needs as possible.”


ABOUT VEYVONDI/VONVENDI
VEYVONDI is indicated in adults (age 18 and older) with von Willebrand disease (VWD), when desmopressin (DDAVP) treatment alone is ineffective or not indicated for the treatment of hemorrhage and treatment/prevention of surgical bleeding. VEYVONDI should not be used in the treatment of hemophilia A.¹

For full EU Summary of Product Characteristics, including approved indication(s) and important safety information, please visit here.¹

In the US the product has been approved under the trade name VONVENDI^® [von Willebrand factor (Recombinant)] and is indicated for use in adults (age 18 and older) diagnosed with VWD for on-demand treatment and control of bleeding episodes or perioperative management of bleeding.


VEYVONDI SAFETY INFORMATION FOR EUROPE¹
Please consult the Vevondi Summary Product Characteristics (SmPC) before prescribing.

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the SmPC.
Known allergic reaction to mouse or hamster proteins.

Warnings and Precautions
In actively bleeding patients it is recommended to co-administer a FVIII product with VEYVONDI as a first line treatment and depending on the FVIII activity levels (see 4.2 of the SmPC).

Hypersensitivity reactions (including anaphylaxis) may occur. Patients and/or their caregivers should be informed of the early signs of hypersensitivity reactions, which may include but are not limited to tachycardia, tightness of the chest, wheezing and/or acute respiratory distress, hypotension, generalised urticaria, pruritus, rhinoconjunctivitis, angioedema, lethargy, nausea, vomiting, paresthesia, restlessness, and may progress to anaphylactic shock.

VEYVONDI contains trace amounts of mouse immunoglobulin G (MuIgG) and hamster proteins (less than or equal to 2 ng/IU VEYVONDI). VEYVONDI contains trace amounts of recombinant coagulation factor VIII.

There is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors for thrombosis including low ADAMTS13 levels.

In patients requiring frequent doses of VEYVONDI in combination with recombinant factor VIII, plasma levels for FVIII:C activity should be monitored to avoid sustained excessive FVIII:C plasma levels, which may increase the risk of thrombotic events.

Patients with VWD, especially Type 3, may develop neutralising antibodies (inhibitors) to von Willebrand factor. If the expected plasma levels of (VWF:RCo) are not attained, or if bleeding is not controlled with an appropriate dose, an appropriate assay should be performed to determine if a von Willebrand factor inhibitor is present.

This medicinal product contains 5.2 mg sodium in each 650 IU vial or 10.4 mg sodium in each 1300 IU vial. This is equivalent to 2.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult, assuming a body weight of 70 kg and a dose of 80 IU/kg body weight. This is to be taken into consideration by patients on a controlled sodium diet.

Adverse Reactions
The adverse reaction reported in clinical trials were all common (≥ 1/100 to < 1/10) in frequency. The following list is grouped by MedDRA SOC and frequency:

Dizziness, Vertigo, Dysgeusia, Tremor, Tachycardia, Deep venous thrombosis, Hypertension, Hot flush, Vomiting, Nausea, Pruritus generalized, Chest discomfort, Infusion site paraesthesia, Electrocardiogram T wave inversion, Heart rate increased.

Description of selected adverse reactions
In clinical trials, one case of clinically asymptomatic deep vein thrombosis (DVT) was reported for a subject in the surgery study who had total hip replacement.

In addition, one post-marketing case of DVT has been reported spontaneously for an elderly patient.

ADRs from Post-Marketing Experience
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The most common post-marketing ADRs reported in association with rVWF/vonicog alfa treatment include “infusion-related reactions” (IRR) clinically manifested by the following symptoms: tachycardia, flushing, rash, dyspnea, and blurred vision. In the 2 spontaneous post-marketing cases reported, the symptoms resolved and the patients fully recovered in approximately 20 minutes to 4 hours upon stopping the infusion.

For more information, please refer to the VEYVONDI Summary of Product Characteristics here.

For US specific safety information, please refer to the VONVENDI US Prescribing Information here.


About ADYNOVATE/ADYNOVI
ADYNOVATE [Antihemophilic Factor (Recombinant), PEGylated] was first approved by the Food and Drug Administration (FDA) in the U.S. followed by approval in a number of countries including, but not limited to, Japan, Canada, and Colombia. In Europe, ADYNOVATE is approved as ADYNOVI^® for the treatment and prophylaxis of bleeding in patients 12 years and above with hemophilia A.  

ADYNOVI SAFETY INFORMATION FOR EUROPE²
Please consult the ADYNOVI Summary of Product Characteristics (SmPC) here before prescribing, particularly in relation to dosing and treatment monitoring.

Contraindications
Hypersensitivity to the active substance, to the parent molecule octocog alfa or to any of the excipients listed in the SmPC. Known allergic reaction to mouse or hamster protein.

Special warnings and precautions for use
The medicinal product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis.

The formation of neutralising antibodies (inhibitors) against factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per ml of plasma using the modified assay.

In general, all patients treated with coagulation factor VIII should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for factor VIII inhibitor presence should be performed.

After reconstitution this medicinal product contains 0.45 mmol sodium (10 mg) per vial.

Adverse Reactions

Common (Greater-than or equal to 1/100 to <1/10)	Headache, Diarrhea, Nausea, Rash
Uncommon (Greater-than or equal to 1/1000 to <1/100)	Factor VIII inhibition in previously-treated patients (PTPs), Hypersensitivity, Flushing

For more information, please refer to the ADYNOVI Summary of Product Characteristics here.

For US specific safety information, please refer to the ADYNOVATE US Prescribing Information here.


ABOUT FEIBA (FACTOR VIII INHIBITOR BYPASSING ACTIVITY)
FEIBA^® (factor VIII inhibitor bypassing activity) is indicated for the treatment of spontaneous bleeding and cover of surgical interventions in haemophilia A patients with factor VIII inhibitors and in non-haemophiliacs with acquired factor VIII inhibitors as well as for prophylaxis in haemophilia A patients with high responding inhibitors and frequent joint bleeding.

FEIBA SAFETY INFORMATION
Please consult the FEIBA Summary of Product Characteristics (SmPC) here before prescribing, particularly in relation to dosing and treatment monitoring.

Contraindications are hypersensitivity to the product, disseminated intravascular coagulation (DIC) and acute thrombosis or embolism (including myocardial infarction).

The Adverse Drug Reactions (ADRs) occurring in the highest frequency (common, greater than or equal to 1/100 to <1/10) were hypersensitivity, headache, dizziness, hypotension, rash, hepatitis B surface antibody positive.

Other symptoms of hypersensitivity reactions to plasma-derived products include lethargy and restlessness.

For more information, please refer to the FEIBA UK Summary of Product Characteristics here.

For US specific safety information, please refer to the FEIBA US Prescribing Information here.


ABOUT ADVATE
ADVATE is a full-length (derived from the complete FVIII gene) recombinant FVIII product that is processed without any blood-based additives. ADVATE is approved in the EU for the treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency) in all age group.

ADVATE is currently approved in over 70 countries worldwide, including the United States, Canada, 28 countries in the European Union, Algeria, Argentina, Australia, Bahrain, Brazil, Brunei, Chile, China, Colombia, Ecuador, GCC, Hong Kong, Iceland, India, Iraq, Israel, Japan, Kazakhstan, Kuwait, Macau, Malaysia, Mexico, Morocco, New Zealand, Norway, Panama, Puerto Rico, Qatar, Russia, Saudi Arabia, Serbia, Singapore, South Korea, Suriname, Switzerland, Taiwan, Thailand, Tunisia, Turkey, UAE, Ukraine, Uruguay, Venezuela, Vietnam.

ADVATE SAFETY INFORMATION FOR EUROPE³
Please consult the ADVATE Summary of Product Characteristics (SmPC) before prescribing, particularly in relation to dosing and treatment monitoring.

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in the SmPC or to mouse or hamster proteins.

Special warnings and precautions for use
The product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the product immediately and contact their physician.

Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis.

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per mL of plasma using the modified assay.

In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for factor VIII inhibitor presence should be performed.

After reconstitution this medicinal product contains 0.45 mmol sodium (10 mg) per vial.

Adverse Reactions

Very common (≥1/10)	Factor VIII inhibition in previously untreated patients (PUPs)
Common (≥1/100 to <1/10)	Headache, Pyrexia
Uncommon (≥1/1000 to <1/100)	Influenza, Laryngitis, Factor VIII inhibition in previously treated patients (PTPs), Lymphangitis, Dizziness, Dysgeusia, Memory impairment, Migraine, Syncope, Tremor, Eye inflammation, Palpitations, Haematoma, Hot flush, Pallor, Dyspnoea, Abdominal pain upper, Diarrhoea, Nausea, Vomiting, Hyperhidrosis, Pruritus, Rash, Urticaria, Chest discomfort, Chest pain, Chills, Feeling abnormal, Peripheral oedema, Vessel puncture site haematoma, Coagulation factor VIII level decreased, Haematocrit decreased, Laboratory test abnormal, Monocyte Count increased, Post procedural complication, Post procedural haemorrhage, Procedural site reaction
Not known	Anaphylactic reaction, Hypersensitivity, Fatigue, Injection site reaction, Malaise

For more information, please refer to the ADVATE Summary of Product Characteristics here.

For US specific safety information, please refer to the ADVATE US Prescribing Information here.


About Hemophilia  
Hemophilia is a chronic disease that causes longer-than-normal bleeding due to absent or deficient clotting factor in the blood.⁴ Hemophilia A is more common than hemophilia B;⁴ in 2017, hemophilia A affects about 158,225 people, whereas hemophilia B affects about 31,247 people worldwide.⁵

People with hemophilia, working closely with their healthcare professionals, can live healthy lives with proper care and adequate treatment.⁶ Treatment regimens typically include on-demand and/or regular prophylactic infusions of factor replacement therapy to control or prevent the risk of bleeding.⁷  


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 patients⁸ and a broad portfolio of 11 products across multiple bleeding disorders.⁹ 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
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, Rare Diseases, Neuroscience, and Gastroenterology (GI). 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.

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


References

1. European Medicines Agency. Veyvondi Summary of Product Characteristics. Available here: https://www.ema.europa.eu/en/documents/product-information/veyvondi-epar-product-information_en.pdf. Last accessed January 2020.
2. European Medicines Agency. Adynovi Summary of Product Characteristics. Available here: https://www.ema.europa.eu/en/documents/product-information/adynovi-epar-product-information_en.pdf. Last accessed January 2020.
3. European Medicines Agency. Advate Summary of Product Characteristics. Available here: https://www.ema.europa.eu/en/documents/product-information/advate-epar-product-information_en.pdf. Last accessed January 2020.
4. World Federation of Hemophilia. “Introduction to hemophilia: what is hemophilia?” World Federation of Hemophilia website. Available here: https://elearning.wfh.org/elearning-centres/introduction-to-hemophilia/#what_is_hemophilia. Last accessed January 2020.
5. World Federation of Hemophilia. Report on the Annual Global Survey 2017. World Federation of Hemophilia website. Available here: http://www1.wfh.org/publications/files/pdf-1714.pdf. Last accessed January 2020.
6. World Federation of Hemophilia. “Introduction to hemophilia: treatment.” Available here: https://elearning.wfh.org/elearning-centres/introduction-to-hemophilia/#hemophilia_treatment. Last accessed January 2020.
7. NHS. “Haemophilia: treatment.” Available here: https://www.nhs.uk/conditions/haemophilia/treatment/. Last accessed January 2020.
8. Takeda Website. Rare Diseases. Available here: https://www.takeda.at/what-we-do/areas-of-focus/rare-diseases/. Last accessed January 2020.
9. Takeda Website. U.S. Product List. Available here: https://www.takeda.com/en-us/what-we-do/product-portfolio/. Last accessed January 2020.

 

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