Recombinant ADAMTS13 for Patients with Severe Congenital Thrombotic Thrombocytopenic Purpura: Design of a Phase 3b Open-Label Continuation Study of Prophylactic and on-Demand Treatment

Background Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare and potentially life-threatening autosomal recessive inherited thrombotic microangiopathy with an estimated prevalence of <1 in 1 million people. cTTP is caused by a deficiency of the metalloprotease ADAMTS13. Although patients can receive replacement therapy with infusions of either fresh-frozen or solvent/detergent-treated plasma, the level of ADAMTS13 that can be achieved is restricted by infusion volume, and patients can also experience adverse reactions to plasma infusions. A recombinant ADAMTS13 (rADAMTS13; TAK-755; Takeda Development Center Americas, Inc., Lexington, MA, USA) is being developed for use as a replacement therapy for patients with cTTP. A phase 1 study (NCT02216084) in patients with severe cTTP has shown the pharmacokinetic (PK) parameters of rADAMTS13 to be comparable with those estimated in previous plasma infusion studies. A phase 3 study (NCT03393975) to assess the safety and efficacy of rADAMTS13 in patients with severe cTTP was initiated in October 2017 and is ongoing. Here, we report the design of a continuation study, which follows on from the phase 3 study. Study Design and Methods This is a phase 3b, prospective, open-label, multicenter, single-arm continuation study (NCT04683003) to evaluate the long-term safety and efficacy of rADAMTS13 for prophylactic and on-demand treatment in patients with severe cTTP. The study will enroll approximately 77 patients and include approximately 57 patients who completed the phase 3 study (48 patients from the prophylaxis cohort; 9 patients from the on-demand cohort) and at least 20 patients who are naïve to rADAMTS13. Patients from expanded access programs or who had an allergic reaction to prophylactic standard of care therapy in the phase 3 study are also eligible for enrollment. Patients who were 0 to 70 years of age at screening for either the phase 3 study or the continuation study and were diagnosed with severe congenital ADAMTS13 deficiency (ADAMTS13 activity <10%) are eligible for inclusion. Patients will be excluded if they have a known life-threatening hypersensitivity to any constituents of rADAMTS13 or have functional ADAMTS13 inhibitors at screening. Patients will be enrolled into either the prophylaxis or on-demand cohort depending on their current therapy and physician consultations (Figure). Patients who completed the phase 3 study and those naïve to rADAMTS13 treatment who are enrolled in the prophylaxis cohort will receive 40 IU/kg rADAMTS13 intravenous infusions either once a week (Q1W) or once every 2 weeks (Q2W). Patients in the prophylaxis cohort can opt to receive at-home rADAMTS13 infusions and will be required to attend interval study visits every 12 weeks. Patients experiencing an acute TTP event will be enrolled in the on-demand cohort and receive 40 IU/kg rADAMTS13 on day 1, 20 IU/kg on day 2, and 15-IU/kg infusions daily from day 3 until 2 days after resolution of the acute event; patients can then choose to move into the prophylaxis cohort or discontinue from the study. Patients in the prophylaxis cohort who experience an acute TTP event during the study will also receive rADAMTS13 in the same dosing regimen as the on-demand cohort (Figure). The primary objective is to evaluate the long-term safety and tolerability of rADAMTS13, measured by the incidence of related treatment-emergent adverse events and serious adverse events, as well as clinically significant changes in vital signs, clinical chemistry, and hematology. The efficacy of rADAMTS13 prophylaxis is a secondary objective of the study, as is the incidence of isolated TTP manifestations. Other secondary outcomes include immunogenicity, health-related quality of life, and healthcare resource utilization in both the prophylaxis and on-demand cohorts. PK and pharmacodynamic parameters of rADAMTS13 will also be assessed. Patient participation is estimated to be either up to 3 years in duration or dependent on the commercial availability of rADAMTS13 in the respective country. The study was initiated in April 2021; estimated completion is September 2026. Conclusion Treatment options for cTTP are limited. This study will evaluate the long-term safety and efficacy of rADAMTS13 for the treatment of patients with severe cTTP. Figure 1 Figure 1. Disclosures Jain: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc.,: Current Employment. Marquez: Takeda Development Center Americas, Inc.,: Current Employment; Takeda: Current equity holder in publicly-traded company. Martell: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc.,: Current Employment.