Takeda Announces Results from First-of-Its-Kind Phase IIIb/IV Trial PROPEL – a Randomized PK-Guided Prophylaxis Study Evaluating Higher Factor VIII Levels in Hemophilia A– at EAHAD 2019

• The PROPEL study compared the safety and efficacy of ADYNOVATE^® [Antihemophilic Factor [Recombinant], PEGylated] following pharmacokinetic (PK)-guided prophylaxis
• The novel design of the study was built upon preliminary data indicating that FVIII exposure associated with higher trough levels may be able to help enhance bleed protection and help more patients reach zero bleeds
• Takeda’s strong inaugural presence at EAHAD underscores its commitment to the hemophilia community following recent completion of Shire acquisition

CAMBRIDGE, Mass. & OSAKA, Japan--(BUSINESS WIRE/AETOSWire)-- Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”), the global biotechnology leader in rare diseases, has today announced results from its phase IIIb/IV clinical trial for ADYNOVATE at the 12^th Annual Congress of the European Association of Haemophilia and Allied Disorders (EAHAD), taking place 6-9 February, in Prague, Czech Republic. The PROPEL study is a PROspective, randomized, multi-center study comparing the safety and efficacy of ADYNOVATE following PK-guided prophylaxis targeting two different Factor Eight (FVIII) trough Levels in subjects with severe hemophilia A.

The study showed that ADYNOVATE prophylaxis targeting 8–12% (HIGH) vs 1–3 % (LOW) trough levels was associated with a trend toward a higher proportion of patients with a total annualized all bleed rate (ABR)=0 (66% HIGH vs 39% LOW; p=0.075). The HIGH group was also associated with a trend toward a lower total ABR, as well as a higher proportion of patients with all annualized joint bleed rate (AJBR)=0 (90% HIGH vs 68% LOW) and all spontaneous ABR=0 (84% HIGH vs 61% LOW). The data suggests that optimizing FVIII profiles through PK-driven dosing that targets trough levels 8-12% was consistently achievable and further treatment personalization for patients with hemophilia A should be considered. Safety profiles were comparable and consistent with previous ADYNOVATE trials. Ongoing analyses will characterize the relationship between PK-tailored dosing of ADYNOVATE FVIII levels and bleeding events.

“The study reiterates the importance of personalized prophylaxis for those living with hemophilia,” said Dr. med. Robert Klamroth, Head of the Department of Internal Medicine Angiology and Coagulation Disorders and Director of the Comprehensive Care Haemophilia Treatment Center and the Haemostasis and Thrombosis Unit at the Vivantes Klinikum in Berlin, Germany. “The findings suggest the need to measure actual FVIII levels and show a clear trend that if we’re able to keep FVIII levels in a higher range, there may be better patient outcomes, including enhanced bleed protection that could help more patients reach zero bleeds.”

“At Takeda, we are proud of the hematology heritage Shire and Baxalta built over 60 years and we plan on expanding on it through continued research and innovation, including continued focus on direct factor replacement,” said Dr. med. Wolfhard Erdlenbruch, Vice President Head of Global Medical Affairs Hematology, Takeda. “We are excited to be at EAHAD and share the results of PROPEL study. The zero all bleed rates and zero all spontaneous joint bleeds in this study have not been reported previously with people living with hemophilia A. This supports that factor levels matter and brings us a step closer to achieving our goal of optimized and personalized patient care, because every bleed matters.”

In addition to PROPEL, Takeda will present a dozen scientific data releases on the company’s recently acquired broad portfolio of treatments for bleeding disorders throughout EAHAD, including:

• AHEAD international and German studies: Effectiveness, safety, and quality of life outcomes in hemophilia A patients treated with antihemophilic factor (recombinant) in a real world setting over 5 years.
• Insights into the evolution of haemophiliac arthropathy: The Irish personalised approach to the treatment of haemophilia (iPATH) study.
• Physical activity and haemophilic joint arthropathy amongst adults with severe haemophilia in Ireland: The Irish personalised approach to the treatment of haemophilia (iPATH) study.
• Barriers to physical activity amongst adults with moderate and severe haemophilia in Ireland: The Irish personalised approach to the treatment of haemophilia (iPATH) study.
• Results from a phase 3B, open-label, multicenter, continuation study of rurioctocog alfa pegol for prophylaxis in previously treated patients with severe hemophilia A: Analysis by age group.
• Design of a phase 3, prospective, multicenter, open-label study of safety and hemostatic efficacy of rurioctocog alfa pegol in previously untreated patients <6 years of age with severe hemophilia A.
• Demographic and baseline data from patients with hemophilia and inhibitors enrolled in the FEIBA global outcomes (“FEIBA GO”) study.
• Analysis of joint bleeding events from a phase 3, multicenter, open-label study of on-demand recombinant von Willebrand factor (VWF) treatment in patients with severe von Willebrand disease (VWD).
• Evaluation of laboratory safety data from patients with severe von Willebrand disease (VWD) in association with infusion of recombinant von Willebrand factor (VWF) in a phase 3, multicenter, open-label study.
• Efficacy and safety of prophylaxis with recombinant von Willebrand factor (VWF) in severe von Willebrand disease (VWD): Design of a prospective, phase 3, open-label, international multicenter study.
• Nonclinical safety evaluation of a next generation factor IX (FIX) gene therapy construct (SHP648) in mice.

About the PROPEL Study

The PROPEL study evaluated the safety and efficacy of ADYNOVATE in PK-guided prophylaxis targeting two different FVIII trough levels in previously treated patients.

Methods: Eligible subjects had FVIII activity <1%, annualized bleed rate (ABR) ≥2, and transitioned from a previous SHP660 (ADYNOVATE) study or were 12–65 years old with ≥150 exposure days to plasma-derived or recombinant FVIII. After initial PK assessments, subjects received 12 months of PK-guided prophylaxis targeting FVIII trough levels of 1–3% (LOW) or 8–12% (HIGH) (1^st 6 months: dose adjustment period). Primary outcome was the % of subjects with a total ABR=0 (all bleeds) during the 2^nd 6-month study period. Secondary outcomes included total ABR, spontaneous ABR and joint ABR (AJBR) (all bleeds), and adverse events (AEs).

Results: Overall, 115 male subjects (57 LOW, 58 HIGH) received ≥1 SHP660 dose. Median (range) age was 28 (12–61) years; 106 subjects (56 LOW, 50 HIGH) completed the study. During the 2^nd 6 months, total ABR=0 was achieved by 22/57 (39%) LOW, 38/58 (66%; P=0.075) HIGH, spontaneous ABR=0 by 35/57 (61%) and 49/58 (84%; P=0.141), respectively, and AJBR=0 by 39/57 (68%) and 52/58 (90%; P=0.179). Mean (SD), median (IQR) total ABRs for the 2^nd 6-month period: 3.6 (7.3), 2.0 (4.0) LOW; 1.6 (3.3), 0 (2.0) HIGH. Overall AEs and SAEs occurred in 63% and 9% of subjects, with 1 HIGH subject (0.9%) SAE considered related to SHP660: a transient 0.6 BU inhibitor without evidence of anti-FVIII binding, which resolved by study end. AE profiles were comparable and consistent with previous SHP660 trials.

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 Japan, Canada, and Colombia, and is approved as ADYNOVI® in the 28 Member States of the European Union (EU) as well as Iceland, Liechtenstein, Norway and Switzerland. In Europe ADYNOVI is approved for the treatment and prophylaxis of bleeding in patients 12 years and above with hemophilia A.

ADYNOVI SAFETY INFORMATION FOR EUROPE

Please consult the ADYNOVI Summary of Product Characteristics (SmPC) 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.

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

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 60+ years driving innovation for patients and a broad portfolio of 11 products across 9 hemophilia indications. 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

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