Population Pharmacokinetics and Exposure-Response Analyses to Demonstrate the Link of Causality between ADAMTS13 and the Clinical Effects of Recombinant ADAMTS13 Compared to Plasma-Based Therapies

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening deficiency of ADAMTS13. TTP clinical manifestations include thrombocytopenia and microangiopathic hemolytic anemia (MAHA) but incomplete understanding of their relationship to ADAMTS13 exposure is a challenge for assessing the impact of ADAMTS13 supplementation. Integrated population pharmacokinetics (PopPK) analysis and exposure-response modeling were conducted to support the clinical benefit assessment of recombinant ADAMTS13 (rADAMTS13; Takeda Development Center Americas, Inc., Lexington, MA, USA) in patients with cTTP.

Aims: To characterize ADAMTS13 activity following intravenous (IV) administration of rADAMTS13 or plasma-based therapies (PBT) in patients with cTTP, to identify sources of variability, and to evaluate the relationship between ADAMTS13 activity and the probability of isolated TTP manifestations.

Methods: The PopPK analysis included data from phase 1 (NCT02216084), pivotal phase 3 (NCT03393975), and phase 3b continuation (NCT04683003) studies of rADAMTS13. Exposure-response analyses included data from NCT03393975 where patients received rADAMTS13 or PBT in prophylaxis treatment period 1 and crossed over to the opposite treatment in period 2. PBT consisted of fresh frozen plasma, solvent/detergent-treated plasma or factor VIII/von Willebrand factor concentrates. A covariate analysis was conducted to identify sources and assess the significance of variability on the PK of ADAMTS13 activity. Exposure-response models were developed to assess the relationship between the average ADAMTS13 plasma activity for a given dosing interval (C_ave) and the count of isolated TTP manifestations: thrombocytopenia (platelet count decreased ≥25% of baseline or a platelet count <150,000/µL) or MAHA (increased lactate dehydrogenase >1.5 × of baseline or >1.5 × upper limit of normal). Cox proportional hazard modeling using recurring events was performed to demonstrate the treatment effect of rADAMTS13 over PBT, and explain carry-over prophylactic effects. Repeated time to event was performed using longitudinal data from all periods to demonstrate ADAMTS13-dependent reduction in the hazard of thrombocytopenia.

Results: A 2-compartment PK model with linear elimination adequately characterized the time profiles of ADAMTS13 activity following body-weight–based IV administration of rADAMTS13 or PBT (N=65 patients). Following body-weight–based dosing, dosing interval (once per week [Q1W] vs every 2 weeks [Q2W]) and treatment type (rADAMTS13 vs PBT) were the only significant extrinsic factors found with an impact on ADAMTS13 PK. ADAMTS13 C_ave was associated with a significant reduction of the thrombocytopenia hazard in an activity-dependent manner (Figure). Exposure-response model simulations suggested that >95% of patients treated with rADAMTS13 are predicted to have plasma C_ave ADAMTS13 >0.13 IU/mL (equivalent to 13% activity), with high (>70%) protection against thrombocytopenia regardless of dosing intervals (Q2W or Q1W) and age. In contrast, a similar level of protection against thrombocytopenia is expected in only ~10% of patients treated with PBT (Table). Similarly, a significant exposure-response relationship was identified between ADAMTS13 C_ave and MAHA. In treatment period 1, rADAMTS13 was associated with a higher probability of zero counts of thrombocytopenia versus PBT from week 2 onwards. Patients switching from rADAMTS13 to PBT in period 2 initially had a slightly higher probability of having zero counts of thrombocytopenia than patients switching from PBT to rADAMTS13, suggesting that treatment with rADAMTS13 led to a carry-over prophylactic effect maintained for some time after treatment cessation.

Conclusions: Besides body-weight–based dosing, no additional dose adjustments of rADAMTS13 are needed in the cTTP patient population. A consistent and significant ADAMTS13 activity-response relationship was identified in which rADAMTS13 reduced the hazard of objective laboratory based TTP manifestations (thrombocytopenia and MAHA) in an activity-dependent manner. Overall, these findings suggest that rADAMTS13 at 40 IU/kg Q2W or Q1W offers a favorable prophylactic treatment effect over PBT that is attributable to higher ADAMTS13 activity.