S305: PHASE 2 RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, MULTICENTER STUDY OF RECOMBINANT ADAMTS13 IN PATIENTS WITH IMMUNE-MEDIATED THROMBOTIC THROMBOCYTOPENIC PURPURA

Topic: 32. Platelet disorders Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare disorder caused by a severe ADAMTS13 deficiency, due to anti-ADAMTS13 autoantibodies. iTTP treatment includes plasma exchange (PEX) and immunosuppressive therapy. A recombinant ADAMTS13 (rADAMTS13; TAK-755; Takeda Development Center Americas, Inc., Lexington, MA, USA) is under investigation as a therapeutic option for patients with iTTP. Aims: To assess the pharmacokinetic (PK) characteristics of ADAMTS13 in patients with iTTP receiving treatment for an acute TTP episode, the PK/pharmacodynamic (PD) relationship between ADAMTS13 activity levels and biomarkers, and safety. Methods: This phase 2, randomized, placebo-controlled, double-blind, multicenter study (NCT03922308) enrolled patients aged 18–75 years experiencing an acute TTP episode. Patients received up to 1 pre-study PEX. Eligible patients were randomized 1:1:1 into three treatment arms, all with daily PEX and immunosuppressants. Arm 1: placebo given post-PEX and 12 hours post-PEX; Arm 2: rADAMTS13 40 IU/kg intravenous (IV) given post-PEX and placebo 12 hours post-PEX; Arm 3: rADAMTS13 40 IU/kg IV given post-PEX and 12 hours post-PEX. Patients received treatment until clinical remission (platelet normalization [≥150 ×109/L] and lactate dehydrogenase levels <2 × upper limit of normal for ≥48 hours following initial platelet normalization). Post-remission follow-up was 3 months and included ADAMTS13 activity-driven supplementation with placebo or rADAMTS13. Primary endpoints included ADAMTS13 activity levels and PK/PD relationships. Secondary endpoints included incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs, and changes in antibody levels. Results: Twenty-eight patients were enrolled (68% female; median [range] age, 48.5 [24–73] years): Arm 1, n=10; Arm 2, n=9; Arm 3, n=9. At baseline, mean (SD) platelet count ×109/L was 35.8 (32.1), 27.7 (17.6) and 15.4 (7.5) in Arm 1 (n=10), Arm 2 (n=9) and Arm 3 (n=8), respectively. Mean (SD) neutralizing antibody (NAb) levels BU/ml at baseline were 1.6 (1.0), 1.3 (0.3) and 2.0 (1.1) in Arm 1 (n=10), Arm 2 (n=9) and Arm 3 (n=9), respectively. Figure shows pre-remission ADAMTS13 activity time profiles. Higher plasma ADAMTS13 activity exposures were achieved in Arm 2 vs Arm 1 (up to 11.7-fold higher geometric mean [GM] for maximum concentration [Cmax] and 7.7-fold higher for area under the concentration-time curve from time zero [pre-PEX] to 0.5–3 hours after second infusion [AUC(overall)]), and Arm 3 vs Arm 1 (up to 5.4-fold and 5.8-fold higher GM for Cmax and AUC(overall) respectively). Patients positive vs negative for anti-rADAMTS13 antibodies had lower ADAMTS13 GM Cmax and AUC(overall) across all three arms. Post-remission, rADAMTS13 improved platelet counts regardless of NAb levels. While ADAMTS13 activity tracked with platelet recovery, relationship precision was low. Overall, 135 TEAEs in 10 patients and 6 serious TEAEs in 4 patients were reported in Arm 1, 67 TEAEs in 9 patients and 2 serious TEAEs in 1 patient in Arm 2, and 28 TEAEs in 8 patients and 3 serious TEAEs in 3 patients in Arm 3. No serious TEAEs were related to bleeding events or rADAMTS13. No TEAEs led to study discontinuation or death. Summary/Conclusion: rADAMTS13 plus PEX showed favorable tolerability and increased ADAMTS13 exposures compared with placebo plus PEX, leading to increasing ADAMTS13 activity levels over time in patients with iTTP. Post-remission, rADAMTS13 alone improved platelet levels. The data support a therapeutic effect of rADAMTS13 in patients with iTTP and further investigation is warranted.Keywords: ADAMTS13, Pharmacokinetic, Clinical trial, Thrombotic thrombocytopenic purpura (TTP)