Recombinant ADAMTS13 prophylaxis in patients with congenital thrombotic thrombocytopenic purpura: Final analysis from A phase 3 randomized, controlled study

Abstract Introduction Data from the final analysis of a phase 3 study (NCT03393975) that investigated the efficacy and safety of recombinant ADAMTS13 (rADAMTS13; Takeda Pharmaceuticals U.S.A., Inc.) and plasma-based therapy (PBT) prophylaxis in patients with congenital thrombotic thrombocytopenic purpura (cTTP) are presented. Treatment satisfaction was also investigated in the study. Methods In this prospective, randomized, controlled, open-label phase 3 study, patients 0–70 years old with confirmed cTTP were randomized 1:1 to receive either 40 IU/kg rADAMTS13 or PBT prophylaxis every 1–2 weeks as dictated by the participant's usual PBT prophylaxis schedule. Choice of PBT product and dosing schedule were determined by the investigator, with the same dosing frequency as rADAMTS13. Participants received treatment for 6 months (Period 1) and then crossed over to the alternate treatment for an additional 6 months (Period 2); all participants then received rADAMTS13 prophylaxis for 6 months (Period 3). All participants provided written informed consent. The primary endpoint was the incidence of acute TTP events. Secondary endpoints included the incidence of TTP manifestations, safety, and immunogenicity. The incidence of subacute TTP events was an exploratory endpoint. For adult participants, treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM-9) which incorporates three domains (treatment effectiveness, convenience, and global satisfaction) scored using a 0–100 scale, with higher scores indicating higher treatment satisfaction. Results In total, 48 participants were enrolled in the prophylactic cohort: median (range) age 32.5 (3–68) years; 58.3% (28/48) were female. For Periods 1 and 2, the mean ±SD observation period was 0.55 ±0.04 years for rADAMTS13 (n=45) and 0.53 ±0.08 years for PBT (n=46), and 0.57 ±0.18 years for Period 3 (n=45). No participants experienced an acute TTP event while receiving rADAMTS13 prophylaxis. One participant experienced an acute TTP event due to a viral infection while receiving PBT; the mean ±SD annualized event rate (AER) was 0.04 ±0.25. The mean ±SD AER of thrombocytopenia was 2.09 ±4.56 for rADAMTS13 prophylaxis and 4.02 ±6.05 for PBT in Periods 1 and 2, and 0.98 ±2.63 in Period 3. For elevated LDH, the mean ±SD AER was 0.99 ±3.70 for rADAMTS13 and 1.60 ±4.34 for PBT (Periods 1 and 2), and 0.85 ±2.67 for Period 3. The mean ±SD AER of neurological symptoms was 0.72 ±2.91 for rADAMTS13 and 1.11 ±3.94 for PBT in Periods 1 and 2, and 0.87 ±2.32 in Period 3. During rADAMTS13 prophylaxis (Periods 1 and 2), 1 participant experienced a subacute TTP event (mean ±SD AER, 0.04 ±0.28), and 3 participants each experienced a subacute TTP event during Period 3 (AER 0.10 ±0.41). During PBT, 7 subacute TTP events occurred in 6 participants (AER 0.30 ±0.81). During Periods 1 and 2, 83.0% (39/47) of participants experienced 273 adverse events (AEs) while receiving rADAMTS13 prophylaxis, and 91.7% (44/48) experienced 300 AEs while receiving PBT. During rADAMTS13 prophylaxis in Period 3, 76.1% (35/46) of participants experienced 237 AEs. During Periods 1 and 2, 1 serious AE (SAE) occurred in 1 participant receiving rADAMTS13 and 7 SAEs occurred in 7 participants receiving PBT. In Period 3, 6 SAEs occurred in 5 participants. During rADAMTS13 prophylaxis (Periods 1, 2, and 3), no SAEs were treatment related, and no AEs led to treatment interruption/discontinuation. During PBT, 1 SAE (pyrexia) was considered treatment related, 18 AEs in 13 participants led to treatment interruption and 1 AE (rash) led to treatment discontinuation. No AEs led to study discontinuation or death. No neutralizing antibodies were detected. Regardless of treatment sequence, participants receiving rADAMTS13 reported large increases in all TSQM-9 domain scores relative to baseline (range of mean change: 21.4–36.1) at each end of period visit compared with PBT (1.5–14.8). Conclusions Consistent with the preplanned interim analysis, no acute TTP events occurred during rADAMTS13 prophylaxis and lower AERs of TTP manifestations and subacute TTP events were observed versus PBT in patients (adult and pediatric) with cTTP. No new safety concerns were identified and, despite a small sample size owing to the rarity of cTTP, participants reported greater treatment satisfaction during rADAMTS13 prophylaxis compared with PBT. These findings support the clinical benefit of rADAMTS13 prophylaxis in patients with cTTP.