Pivotal Phase 3 Data Presented at ISTH 2023 Congress Spotlight TAK-755 Prophylaxis for Patients with Congenital Thrombotic Thrombocytopenic Purpura (cTTP)

• Data from First and Only Phase 3 Controlled Trial in cTTP Demonstrate Strong Efficacy and Favorable Safety Profile with TAK-755 (recombinant ADAMTS13), Compared to Plasma-Based Therapies
• Patients Receiving TAK-755 Achieved an Increase in Plasma ADAMTS13 Enzyme Activity Levels, Which Are Deficient in Patients with cTTP, Compared to Plasma-Based Therapies

Takeda (TSE: 4502/NYSE:TAK) today presented favorable interim results from a global pivotal Phase 3 randomized, controlled, open-label, crossover trial evaluating the safety and efficacy of TAK-755 (recombinant ADAMTS13) replacement therapy for the prophylactic treatment of congenital thrombotic thrombocytopenic purpura (cTTP), and pharmacokinetics (PK) characteristics of TAK-755, as well as long-term data on TAK-755 prophylaxis from a Phase 3b continuation study.

cTTP is an ultra-rare, chronic and debilitating blood clotting disorder caused by a deficiency in ADAMTS13 enzyme. Clinical presentation of cTTP lies on a spectrum of severity ranging from severe acute TTP events to chronic, recurring TTP manifestations (e.g., thrombocytopenia, hemolytic activity, headache, abdominal pain). Acute TTP events have a mortality rate of >90%, if left untreated.¹ These studies were designed to evaluate the clinical benefit of TAK-755 in patients with cTTP across multiple clinically relevant endpoints and based on the totality of the evidence provided by efficacy, PK, safety and tolerability data. Both acute and subacute TTP events, including TTP-related organ-specific signs and symptoms were evaluated.

In the pivotal trial, no patient had an acute TTP event while receiving TAK-755 prophylactic treatment. TAK-755 also reduced the incidence of thrombocytopenia by 60%, as compared to plasma-based therapy (for the rate ratio = 0.40 TAK-755/plasma-based therapy with 95% Confidence Interval 0.3 to 0.7). Thrombocytopenia, an important marker of disease activity, was the most frequently observed TTP manifestation. In addition, the results show that TAK-755 demonstrated a favorable safety and tolerability profile, with a potential safety advantage over plasma-based therapies. In the pivotal trial, treatment-emergent adverse events (TEAEs) were reported in 10.3% of patients ages 12-68 receiving TAK-755 compared to 50% of patients receiving plasma-based therapy. (Presentation Number: OC 14.1)

“These findings suggest that recombinant ADAMTS13 is a promising innovative investigational treatment for patients with cTTP,” said Marie Scully, M.D., Department of Haematology, University College London Hospitals, London, United Kingdom. “Given the high burden of illness these patients experience, complicated by unpredictable acute episodes and multiple disease-related complications, this is a much-needed option, supported through a first-of-its-kind clinical trial.”

PK characteristics of ADAMTS13 after a single infusion (0-168 hours) were evaluated and compared to plasma-based therapy in 36 cTTP patients aged 12 and older. Patients receiving TAK-755 achieved a five-fold increase in their ADAMTS13 activity levels compared to those receiving plasma-based therapy (C_max 100% activity for TAK-755 vs. 19% activity for plasma-based therapy) and lower variability (23.8% vs. 56% coefficient of variation [CV], respectively). (Presentation Number: OC 14.2)

“People with cTTP face life-threatening events and debilitating symptoms, and have no approved treatment for the disease,” said Daniel Curran, M.D., Head, Rare Genetics & Hematology Therapeutic Area Unit at Takeda. “We are encouraged by what these positive results mean for people living with this rare disorder, and we look forward to continuing to advance this program for patients who may benefit from treatment with TAK-755.”

Takeda also presented an interim analysis of the Phase 3b continuation study, evaluating the safety and efficacy of long-term TAK-755 prophylaxis in 29 patients with cTTP (mean ± SD age: 40.4 ± 12.1; 62% female; median [range] duration of treatment 0.7 [0-1.4] years). Results demonstrated a consistently favorable safety profile with TAK-755 prophylaxis and no development of neutralizing antibodies. Zero acute TTP events occurred during TAK-755 prophylaxis, and the incidence rates of subacute TTP events and TTP manifestations were comparable to those with TAK-755 prophylaxis in the pivotal study. (Presentation Number: OC 14.4)

Results were presented today in three oral presentations delivered at the International Society on Thrombosis and Haemostasis (ISTH) 2023 Congress. The full text of Takeda abstracts at ISTH can be found here: https://www.isth2023.org/program

TAK-755 is an investigational therapy that has not been approved by the U.S. Food & Drug Administration (FDA), European Medicines Agency (EMA) or other Regulatory authorities. The FDA has accepted and granted Priority Review for Takeda’s Biologics License Application (BLA) for TAK-755 for the treatment of cTTP.

ABOUT TAK-755

TAK-755 is the first and only recombinant ADAMTS13 protein in development. It provides targeted therapy to address an unmet medical need in patients with thrombotic thrombocytopenic purpura (TTP), by replacing the missing or deficient ADAMTS13 enzyme.²

The TAK-755 cTTP clinical development program includes one first-in-human, Phase 1 study, 281101 (NCT02216084),³ and two ongoing Phase 3 studies: a pivotal Phase 3 study, Study 281102 (NCT03393975), and one Phase 3b continuation study, Study TAK-755-3002 (NCT04683003).^4,5 TAK-755 is also being investigated in immune-mediated TTP (iTTP) and sickle cell disease, with Phase 2b (NCT05714969) and Phase 1 (NCT03997760) trials ongoing, respectively, with the Phase 1 trial due to provide data in 2023.^6,7

TAK-755 was granted Orphan Drug Designation (ODD) by the U.S. Food and Drug Administration (FDA) for the treatment (ODA-08-2622) and prevention (ODA-08-2652) of TTP including its congenital, acquired idiopathic and secondary forms; and by the European Medicines Agency (EMA) and Japan’s Ministry of Health, Labour and Welfare (MHLW) for the treatment of TTP (EU/3/08/588). The FDA has also granted TAK-755 Fast Track Designation (FTD) for the treatment, prevention and routine prophylaxis of acute episodes of TTP in patients with congenital ADAMTS13 deficiency and granted its Biologics License Application (BLA) Priority Review.

ABOUT cTTP

cTTP is an ultra-rare, chronic and debilitating blood clotting disorder associated with life-threatening acute episodes and long-term chronic symptoms.^8,9 cTTP is a sub-type of TTP that has an estimated prevalence of <1 cases/million,⁹ with cTTP accounting for ≤5% of patients with TTP.^10,11 It develops due to deficiency in ADAMTS13 enzyme, a von Willebrand factor (VWF) cleaving protease, which results in the accumulation of ultra-large VWF multimers in the blood.⁸ The accumulation of ultra-large VWF multimers leads to uncontrolled platelet aggregation and adhesion.^9,12 This can lead to abnormal clotting in the small blood vessels of the body and is associated with hemolytic anemia and low platelet levels (thrombocytopenia).¹²

cTTP has both acute and chronic manifestations (including stroke and cardiovascular disease) and is associated with a significant disease burden. Patients’ quality of life and lifespan are significantly reduced compared to the general population, due to serious, ongoing widespread organ damage and other co-morbidities resulting from an ADAMTS13-deficient state.^9,10,13,14 TAK-755 (recombinant ADAMTS13) is a novel investigational therapeutic approach for cTTP.¹⁵

There are no medications specifically approved by regulatory authorities for routine prophylactic treatment of cTTP. Current treatment centers around plasma-based therapy, either by infusion or plasma exchange.¹⁶ Plasma-based therapy is time consuming and can be associated with severe treatment complications.^14,16,17 These can include treatment-limiting volume overload and allergic reactions.^16,17

ABOUT TAKEDA

Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit www.takeda.com.

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References

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¹ Van Dorland H et al. Haematologica. 2019;104:2107-16

² Scully M et al. Blood. 2017;130:2055 -63

³ ClinicalTrials.gov Phase 1 Dose Escalation, Single Dose Study to Assess Safety and Pharmacokinetics of BAX930 in Hereditary Thrombotic Thrombocytopenic Purpura (TTP) Available at: https://clinicaltrials.gov/ct2/show/NCT02216084 Last accessed March 2023

⁴ ClinicalTrials.gov A Study of BAX 930 in Children, Teenagers, and Adults Born With Thrombotic Thrombocytopenic Purpura (TTP). Available at: https://clinicaltrials.gov/ct2/show/NCT03393975. Last accessed: March 2023

⁵ ClinicalTrials.gov A Study of TAK-755 in Participants With Congenital Thrombotic Thrombocytopenic Purpura Available at: https://clinicaltrials.gov/ct2/show/NCT04683003 Last accessed March 2023

⁶ ClinicalTrials.gov A Study of TAK-755 (rADAMTS13) With Little to No Plasma Exchange (PEX) Treatment in Adults With Immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP)) Available at: https://clinicaltrials.gov/ct2/show/NCT05714969 Last accessed June 2023

⁷ ClinicalTrials.gov A Study of SHP655 (rADAMTS13) in Sickle Cell Disease (RAISE) Available at: https://clinicaltrials.gov/ct2/show/NCT03997760 Last accessed March 2023

⁸ Alwan F, et al., Blood. 2019;133:1644-51

⁹ Kremer Hovinga JA, et al., Nat Rev Dis Primers. 2017;3:17020

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¹⁵ Royal College of Pathologists Bulletin 200 October 2022. Available at: https://www.rcpath.org/profession/publications/college-bulletin/october-2022/thrombotic-thrombocytopenic-purpura-past-present-and-future.html Last accessed March 2023

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¹⁷ McGuckin S et al. Vox Sanguinis 2014;106:161-66

C-APROM/INT/TAK-755/0003 June 2023

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