Takeda Provides Updates on Its Pharmacokinetic-guided Prophylaxis Studies at ISTH 2020, Reinforcing Its Commitment to Advancing Personalized Care for People with Bleeding Disorders

− The Data Demonstrating Benefits of Pharmacokinetic-Guided Prophylaxis Therapy in Hemophilia and von Willebrand Disease are Among 13 Presentations from Takeda’s Hematology Portfolio and Pipeline

OSAKA, Japan--(BUSINESS WIRE)--Takeda Pharmaceutical Company Limited (“Takeda”) (TSE: 4502/NYSE:TAK) today announced that 13 abstracts are being presented from the company’s Hematology portfolio and pipeline at the International Society on Thrombosis and Haemostasis 2020 Virtual Congress (ISTH 2020). Among the data, Takeda spotlighted four abstracts to highlight its commitment to advancing personalized care through pharmacokinetic (PK)-guided prophylaxis in people living with hemophilia or von Willebrand Disease (VWD) – including scientific updates in patients with hemophilia A from the Phase 3 PROPEL and Phase 3b CONTINUATION studies investigating potential benefits of personalized TAK-660 (rurioctocog alfa pegol) prophylaxis. Two population studies into the PK/pharmacodynamic (PD) profiles of recombinant von Willebrand factor (rVWF), which provide data to assist in the optimization of rVWF personalized dosing strategies, were also presented.

Takeda addresses the unique needs of each patient with personalized care
Takeda presented a total of 13 abstracts at ISTH 2020, available on the ISTH Congress Abstracts Site. Among them, Takeda spotlighted four abstracts which support its personalized care approach for patients with bleeding disorders, especially hemophilia and VWD.

Prophylaxis for hemophilia A can help prevent spontaneous bleeds because even a single bleed may be life-threatening or contribute to permanent joint damage.^i,ii Factor VIII (FVIII) prophylaxis can be tailored to the individual’s PK profile using multiple parameters of the PK curve, enabling adjusted dosing to achieve predictable FVIII levels to minimize bleeding risk. Personalized treatment in hemophilia A aiming for higher trough levels by PK-guided dosing may help to optimize some outcomes by tailoring treatment for individual patient needs. Supporting data presented at ISTH 2020 include:

• Target joint resolution analysis from the PROPEL trial in hemophilia Aⁱⁱⁱ [Abstract PB0921]
  Data from a post-hoc analysis of the Phase III PROPEL trial evaluating the efficacy and target joint (TJ) resolution with PK-guided TAK-660 prophylaxis in patients with hemophilia A show that targeting 8–12% versus 1–3% FVIII trough levels was associated with reduced bleeding into TJs, reduced annualized bleed rate (ABR) irrespective of baseline TJ status, and TJ resolution within the first 6 months.

• Personalizing prophylaxis with TAK-660 in Hemophilia A^iv [Abstract PB0920]
  An analysis exploring the potential benefits of personalized TAK-660 prophylaxis evaluated data on extended fixed dose or PK-tailored dosing from two respective studies – the Phase IIIb CONTINUATION and the Phase III PROPEL studies. Results from the two studies support the feasibility and efficacy of personalized TAK-660 prophylaxis by extending the fixed dose interval or by targeting elevated FVIII levels with PK-tailored dosing.

“Because every patient is unique, there is no ‘one-size-fits-all’ approach to hemophilia care. We are committed to improving outcomes and quality of life for each person living with a bleeding disorder,” commented Dr Carmen Escuriola-Ettingshausen, Co-director, Haemophilia Centre Rhein-Main - HZRM, Frankfurt-Mörfelden, Germany, one of the researchers leading the CONTINUATION and PROPEL studies. “The data presented at ISTH 2020 demonstrate the value that innovative, personalized approaches provide to the management of hemophilia.”

On the other hand, for patients with VWD, rVWF replacement therapy corrects VWF activity, as measured mostly by VWF:Ristocetin Cofactor (RCo), and leads consecutively to an endogenous increase of FVIII activity to hemostatically effective levels. The goals of Takeda’s PK studies in VWD are to understand the effects of rVWF dosing on VWF:RCo and FVIII activities and thus help patients living with VWD and their physicians achieve agreed treatment goals.

• Population PK and PD models for rVWF in VWD^v [Abstract PB1541]
  Results from the modelling supported the feasibility of this PK/PD population model for describing VWF:RCo and FVIII activity in rVWF-treated patients with different VWD types, which could assist in the optimization of rVWF personalized dosing strategies. The population PK/PD models aimed to characterize VWF:RCo and endogenous FVIII activity-time curves following administration of rVWF, based on data from Phase I and Phase III studies.

• Exploring the relationship between multimeric pattern and VWF:RCo activity^vi [Abstract PB1544]
  Results from the modelling supported the feasibility of this PK population model for describing activity-time profiles of small, medium and large multimers following rVWF dosing on VWF:RCo. The findings increase understanding of the effects of rVWF dosing on VWF:RCo and FVIII activities which could potentially optimize treatment regimens for individual patient needs.

Takeda is committed to creating a world without bleeds
“Findings presented at ISTH 2020 reaffirm Takeda’s commitment to support personalized care as the optimal treatment approach for patients with bleeding disorders,” added Dr. med. Wolfhard Erdlenbruch, M.D., Vice President Head of Global Medical Affairs Hematology, Takeda. “Some of our data may be especially informative when considering the treatment of patients with hemophilia A requiring higher FVIII activity trough levels because of their active lifestyles and increased risk of injury-related bleeds. What we have presented at ISTH 2020 support the rationale for a personalized approach to prophylaxis for the management of both hemophilia and VWD, and have the potential to help the medical community change their patients’ lives for the better.”

In addition to data from the four aforementioned studies, Takeda presented real-world evidence (RWE) of extended half-life (EHL) prophylaxis with TAK-660 [Abstract PB0919], which showed that switching from standard half-life (SHL) FVIII to TAK-660 given at lower frequency and with weekly consumption resulted in reduced ABRs.^vii Results were also presented from the American Thrombosis and Hemostasis Network ATHN 2: Factor Switching Study [Abstract PB1049], which show that for the 52 participants in the study who switched from any FVIII concentrate to TAK-660, no new inhibitors were detected after 50 exposure days or 12 months.^viii

A further seven studies presented included a retrospective chart review of gastrointestinal bleeding in VWD [Abstract PB1555], and pre-clinical and post-marketing updates on susoctocog alfa for the treatment of acquired hemophilia [Abstract PB0779].

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 EUROPE^ix
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 VEYVONDI/VONVENDI
In Europe, 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.^x

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

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 EUROPE^x
Please consult the VEYVONDI Summary Product Characteristics (SmPC) here 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) have occurred. 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. Any FVIII that would be administered along with VEYVONDI should be a pure FVIII product.

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
During treatment with VEYVONDI, the following adverse reactions may occur: hypersensitivity or allergic reactions, thromboembolic events, inhibitor formation against VWF.

The following adverse reactions, grouped by MedDRA SOC and frequency, were reported in clinical trials, post-authorisation safety studies, or post-marketing reporting: 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 (common ≥ 1/100 to < 1/10), infusion-related reaction, anaphylactic reaction (frequency not known).

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.

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 OBIZUR
In Europe, OBIZUR is indicated for the treatment of bleeding episodes in adults with acquired haemophilia caused by antibodies to Factor VIII.^xi

OBIZUR SAFTEY INFORMATION FOR EUROPE^xi
Please consult the OBIZUR Summary of Product Characteristics (SmPC) here before prescribing, particularly in relation to dosing and treatment monitoring.

Contraindications
Known anaphylactic reactions to the active substance, hamster protein, or to any of the excipients listed in the SmPC.

Special warnings and precautions for use
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.

Inhibitory antibodies against porcine Factor VIII (measured using a modification of the Nijmegen variation of the Bethesda assay) were detected before and after exposure to OBIZUR.

Each vial contains 4.4 mg (198 mM) sodium per ml of reconstituted solution.

Monitor Factor VIII activity and clinical condition 30 minutes after the first injection and 3 hours after administering OBIZUR.

Monitor Factor VIII activity immediately prior to and 30 minutes after subsequent doses and refer to the table in the SmPC for recommended target Factor VIII trough levels.

Adverse Reactions
Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the injection site, chills, flushing, generalized urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) are possible and may progress to severe anaphylaxis (including shock).

Positive test for inhibitory antibodies against porcine Factor VIII has been rated as common (≥1/100 to <1/10) in the 29 adult subjects evaluable for safety in the clinical trial.

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

For US specific safety information, please refer to the OBIZUR 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.^xii Hemophilia A is more common than hemophilia B; in 2018, hemophilia A affects about 173,711 people, whereas hemophilia B affects about 34,289 people worldwide.^xiii

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

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 patients^xvi and a broad portfolio of 11 products across multiple bleeding disorders.^xvii 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, 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.

Important Notice
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The companies in which Takeda directly and indirectly owns investments are separate entities. In this press release, “Takeda” is sometimes used for convenience where references are made to Takeda and its subsidiaries in general. Likewise, the words “we”, “us” and “our” are also used to refer to subsidiaries in general or to those who work for them. These expressions are also used where no useful purpose is served by identifying the particular company or companies.

Forward-Looking Statements
This press release and any materials distributed in connection with this press release may contain forward-looking statements, beliefs or opinions regarding Takeda’s future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements often include words such as “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “aims”, “intends”, “ensures”, “will”, “may”, “should”, “would”, “could” “anticipates”, “estimates”, “projects” or similar expressions or the negative thereof. Forward-looking statements in this document are based on Takeda’s estimates and assumptions only as of the date hereof. Such forward-looking statements do not represent any guarantee by Takeda or its management of future performance and involve known and unknown risks, uncertainties and other factors, including but not limited to: the economic circumstances surrounding Takeda’s global business, including general economic conditions in Japan and the United States; competitive pressures and developments; changes to applicable laws and regulations; the success of or failure of product development programs; decisions of regulatory authorities and the timing thereof; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the timing and impact of post-merger integration efforts with acquired companies; and the ability to divest assets that are not core to Takeda’s operations and the timing of any such divestment(s), any of which may cause Takeda’s actual results, performance, achievements or financial position to be materially different from any future results, performance, achievements or financial position expressed or implied by such forward-looking statements. For more information on these and other factors which may affect Takeda’s results, performance, achievements, or financial position, see “Item 3. Key Information—D. Risk Factors” in Takeda’s most recent Annual Report on Form 20-F and Takeda’s other reports filed with the U.S. Securities and Exchange Commission, available on Takeda’s website at: https://www.takeda.com/investors/reports/sec-filings/ or at www.sec.gov. Future results, performance, achievements or financial position of Takeda could differ materially from those expressed in or implied by the forward-looking statements. Persons receiving this press release should not rely unduly on any forward-looking statements. Takeda undertakes no obligation to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results of Takeda in this press release may not be indicative of, and are not an estimate, forecast or projection of Takeda’s future results.

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References

^i Gringeri, A., Ewenstein, B. & Reininger, A. The burden of bleeding in haemophilia: is one bleed too many? Haemophilia. 2014;20:459-463.

^ii Carcao, M. & Srivastava, A. Factor VIII/factor IX prophylaxis for severe hemophilia. Semin Hematol. 2016;53:3-9.

^iiiISTH 2020. Abstract PB0921. Efficacy and Target Joint Resolution With Pharmacokinetic-Guided Rurioctocog Alfa Pegol Prophylaxis Targeting Two Factor VIII Trough Levels in Patients With Severe Hemophilia A: Posthoc Analysis of the Phase 3 PROPEL Trial.

^ivISTH 2020. Abstract PB0920. Personalizing Prophylaxis With Rurioctocog Alfa Pegol in Previously Treated Patients With Severe Hemophilia A: Outcomes From the Phase 3b CONTINUATION and Phase 3 PROPEL Studies.

^vISTH 2020. Abstract PB1541. Population Pharmacokinetics and Pharmacodynamics of Recombinant von Willebrand Factor.

^viISTH 2020. Abstract PB1544. Investigating the Relationship Between VWF Multimeric Pattern and VWF:RCo Activity Through Population PK Modeling in Patients with Severe VWD Treated with Recombinant VWF.

^vii ISTH 2020. Abstract PB0919. Real-world Outcomes Before and After Switching From Standard Half-life Factor VIII to Rurioctocog Alfa Pegol in the United States.

^viiiISTH 2020. Abstract PB1049. Lack of Inhibitor Development After Switching to Rurioctocog Alfa Pegol in the American Thrombosis and Hemostasis Network ATHN 2: Factor Switching Study.

^ix European Medicines Agency. Adynovi Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/adynovi-epar-product-information_en.pdf. Last accessed June 2020.

^x European Medicines Agency. Veyvondi Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/veyvondi-epar-product-information_en.pdf. Last accessed June 2020.

^xi European Medicines Agency. OBIZUR Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/obizur-epar-product-information_en.pdf. Last accessed June 2020.

^xiiWorld Federation of Hemophilia. Introduction to hemophilia: what is hemophilia?. World Federation of Hemophilia website. Available at: https://elearning.wfh.org/elearning-centres/introduction-to-hemophilia/#what_is_hemophilia. Last accessed June 2020.

^xiii20^th Anniversary Report on the Annual Global Survey 2018. World Federation of Hemophilia. Available at: http://www1.wfh.org/publications/files/pdf-1731.pdf. Last accessed June 2020.

^xiv World Federation of Hemophilia. “Introduction to hemophilia: treatment.” Available here: https://elearning.wfh.org/elearning-centres/introduction-to-hemophilia/#hemophilia_treatment. Last accessed June 2020.

^xv NHS. Haemophilia: treatment. Available here: https://www.nhs.uk/conditions/haemophilia/treatment/. Last accessed June 2020.

^xviTakeda Website. Rare Diseases. Available at: https://www.takeda.at/what-we-do/areas-of-focus/rare-diseases/. Last accessed June 2020.

^xviiTakeda Website. U.S. Product List. Available at: https://www.takeda.com/en-us/what-we-do/product-portfolio/. Last accessed June 2020.