Recombinant ADAMTS13 Prophylaxis in Pediatric Patients with Congenital Thrombotic Thrombocytopenic Purpura: Results from the Phase 3 Randomized, Crossover Study and the Phase 3b Continuation Study
Authors: Scully Marie , Berger Claire , Biebuyck Nathalie , Bonanad Boix Santiago , Dossier Claire , Hassenpflug Wolf-Achim , Kentouche Karim , Schaefer Beverly , Trisolini Silvia Maria , Wu Runhui , Xiao Juan , Xue Feng , Mellgård Björn , Patel Munjal , Patwari Parth , Wang Linda T. , Xiao Shan , Zhang Pinghai 
Published: December 2024

Background
Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening thrombotic microangiopathy caused by an inherited deficiency of the enzyme ADAMTS13. Ongoing Phase 3 (NCT03393975) and Phase 3b continuation (NCT04683003) studies are investigating the safety and efficacy of recombinant ADAMTS13 (rADAMTS13; Takeda Pharmaceuticals U.S.A., Inc.) prophylaxis in patients with cTTP.
Aims
To evaluate the efficacy and safety of rADAMTS13 prophylaxis in pediatric patients with cTTP.
Methods
The Phase 3 prospective, randomized, controlled, open-label, multicentre, crossover study enrolled patients 0-70 years old with confirmed cTTP. Patients were randomized 1:1 to receive either 40 IU/kg intravenous rADAMTS13 or standard of care (SoC) prophylaxis, administered weekly or every other week (based on the regimen prior to enrolment). SoC was determined by the investigator and included fresh frozen plasma, pooled solvent/detergent-treated plasma, or plasma-derived factor VIII/von Willebrand factor concentrates. Patients received rADAMTS13 or SoC for 6 months (Period 1) then crossed over to the alternate treatment for 6 months (Period 2); all patients then received rADAMTS13 for 6 months (Period 3). The primary outcome was incidence of acute TTP events. Secondary outcomes included incidence of non-acute TTP manifestations, safety, and immunogenicity. Patients completing the Phase 3 study could enrol into the Phase 3b open-label continuation study and continue 40 IU/kg rADAMTS13 prophylaxis. New patients could also enrol directly in the Phase 3b study. Written informed consent was obtained for all patients. Data are presented for pediatric patients (aged &lt;12 years); NCT03393975 cutoff: Aug 11, 2023; NCT04683003 cutoff: Jun 20, 2023. Descriptive results of mean ± SD are presented.
Results
As of data cutoff, 8 pediatric patients were randomized in the Phase 3 study (&lt;6 years, n=4; ≥6 to &lt;12 years, n=4) and 6 were dosed in the Phase 3b study (&lt;6 years, n=3; ≥6 to &lt;12 years, n=3). Overall, 6 patients were male and 8 were female. In the Phase 3 study, the mean ± SD observation period for rADAMTS13 prophylaxis was 0.54 ± 0.03 years vs 0.53 ± 0.04 years for SoC (Periods 1 and 2), and 0.54 ± 0.03 years for Period 3. The observation period in the Phase 3b study was 0.65 ± 0.30 years. In the Phase 3 study, no acute events were reported. For subacute events, the mean annualized event rate in Periods 1 and 2 was 0.23 ± 0.65 for rADAMTS13 prophylaxis vs 0.51 ± 0.95 for SoC. No subacute events occurred in Period 3. For thrombocytopenia, the mean annualized event rate in Periods 1 and 2 was 2.98 ± 6.32 for rADAMTS13 prophylaxis vs 4.05 ± 7.62 for SoC, and 0.69 ± 1.96 for Period 3. For elevated lactate dehydrogenase (LDH), the mean annualized event rate in Periods 1 and 2 was 3.21 ± 8.37 for rADAMTS13 prophylaxis vs 3.00 ± 8.49 for SoC, and 2.90 ± 8.19 for Period 3. In the Phase 3b study, the mean annualized event rate was 0.21 ± 0.51 for acute events and 0.41 ± 0.64 for subacute events. The mean annualized rate was 1.86 ± 2.04 for thrombocytopenia and 0.63 ± 1.05 for elevated LDH. All acute and subacute events occurred in the context of infections. No neurological manifestations were reported in either study. The pharmacokinetics of ADAMTS13 activity (including parameters such as maximum concentration) were generally similar across age groups. In the Phase 3 study, 39 adverse events (AEs) were reported in 8 patients during rADAMTS13 prophylaxis, and 21 AEs were reported in 7 patients during SoC (Periods 1 and 2). During Period 3, 17 AEs were reported in 4 patients. In the Phase 3b study, 26 AEs were reported in 5 patients. No AEs were considered related to rADAMTS13 in either study. Three AEs (allergic transfusion reaction, pyrexia, and tachycardia) reported in 2 patients were considered related to SoC. No serious AEs were reported in patients receiving rADAMTS13 prophylaxis. Two serious AEs (pyrexia and thrombocytopenia) were reported in 2 patients receiving SoC; the pyrexia event was considered related to SoC. No AEs led to study drug discontinuation or death. No anti-ADAMTS13 neutralizing antibodies were detected.
Conclusions
The efficacy findings for rADAMTS13 prophylaxis in pediatric patients with cTTP were generally consistent with previously reported results in adult and adolescent patients. No dose adjustments were needed for pediatric patients. No new safety concerns with rADAMTS13 prophylaxis were identified.