S305: PHASE 2 RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, MULTICENTER STUDY OF RECOMBINANT ADAMTS13 IN PATIENTS WITH IMMUNE-MEDIATED THROMBOTIC THROMBOCYTOPENIC PURPURA
Bibliographic record
Abstract
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)
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; both teacher heads agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".