OC 14.2 - Pharmacokinetic characteristics of ADAMTS13 in patients with congenital thrombotic thrombocytopenic purpura: Interim results from a phase 3 randomized, controlled, open-label, crossover study

Sunday, June 25, 2023

11:00 – 11:15 ET

Room: 520

Session Available As: On-Demand

Presenting Author(s)

Spero Cataland, MD (he/him/his)

Professor
Department of Internal Medicine, Ohio State University, Columbus, OH, USA
Westerville, Ohio, United States

Co-Author(s)

MP

Munjal Patel

Associate Scientific Director, Quantitative Clinical Pharmacology
Takeda Development Center Americas, Inc., Cambridge, MA, USA
Cambridge, Massachusetts, United States
BM

Björn Mellgård

Vice President, Global Program Lead, Rare Genetics and Hematology
Takeda Development Center Americas, Inc., Cambridge, MA, USA
Cambridge, Massachusetts, United States
TO

Thomas L Ortel

Professor of Medicine & Pathology
Duke University, Durham, NC, USA
Durham, North Carolina, United States
Marie Scully, MD

Professor of Haemostasis and Thrombosis
Department of Haematology, University College London Hospitals, London, UK
London, England, United Kingdom
LW

Linda T Wang

Executive Medical Director, Clinical Sciences, Rare Diseases and Hematology
Takeda Development Center Americas, Inc., Cambridge, MA, USA
Cambridge, Massachusetts, United States
Jerzy Windyga, Prof. dr med. (he/him/his)

Head Department of Hemostasis Disorders and Internal Medicine
Institute of Hematology and Transfusion Medicine
Warsaw, Mazowieckie, Poland
IB

Indranil Bhattacharya

Section Head, Rare Genetics and Hematology, Quantitative Clinical Pharmacology
Takeda Development Center Americas, Inc., Cambridge, MA, USA
Cambridge, Massachusetts, United States

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombotic microangiopathy caused by an inherited deficiency of the enzyme ADAMTS13. Replacement therapy with recombinant ADAMTS13 (rADAMTS13; TAK-755; Takeda Development Center Americas, Inc., Lexington, MA, USA) is currently under investigation as a potential therapeutic option for patients with cTTP.

Aims: To evaluate the pharmacokinetic (PK) characteristics of ADAMTS13 following intravenous (IV) administration of rADAMTS13 and standard of care (SoC) in patients with cTTP.

Methods: This phase 3 study (NCT03393975) was open to enroll patients aged 0–70 years with severe cTTP (ADAMTS13 activity < 10%), and included three 6-month prophylaxis treatment periods, two crossover PK assessments (PK-I and PK-II), and one end-of-study PK assessment (PK-III). The start-of-study PK-I assessment (1:1 randomized crossover design) characterized the ADAMTS13 activity pharmacokinetics following administration of a single 40 IU/kg IV infusion of rADAMTS13 and SoC, with a 14 (±2) day washout period between each treatment. After completion of PK-I, patients entered prophylaxis Period 1. SoC was determined by the treating physician and could include fresh frozen plasma, factor VIII/von Willebrand factor concentrates, or solvent/detergent-treated plasma. A non-compartmental PK analysis approach was utilized. Data presented are from a pre-planned interim analysis (data cutoff: August 12, 2022) and focus on PK-I.

Results: Evaluable data from 36 adult/adolescent patients (≥12 years old) were analyzed. Mean average ADAMTS13 activity (0–168h) and maximum ADAMTS13 activity following a single rADAMTS13 IV infusion were 0.26 IU/ml and 1.0 IU/ml, respectively, compared with 0.07 IU/ml and 0.19 IU/ml, respectively, following SoC (Table). rADAMTS13 exhibited lower interindividual variability compared with SoC (Figure). Mean time ≥10% ADAMTS13 activity was 5.2 days following a single rADAMTS13 infusion compared with 1.7 days following SoC (Table).

Conclusion(s): rADAMTS13 achieved consistently higher ADAMTS13 activity exposures compared with SoC.

Learning Objectives:

Gain an understanding of the PK characteristics of ADAMTS13 from the first randomized, controlled trial comparing rADAMTS13 prophylaxis with SoC in patients with cTTP.
Understand and compare the source ADAMTS13 content between rADAMTS13 and SoC.
Recognize unmet needs in patients with cTTP receiving SoC.