Objective: To characterize the durability of platelet count responses in the HERCULES trial.

Methodology: In this post hoc analysis of the HERCULES (NCT02553317) intent-to-treat population (caplacizumab, n=72; placebo, n=73), we identified patients with a fast platelet count response (i.e., ≤3 days vs. >3 days) and described the exacerbation rate by treatment group. Time to durable platelet count response (defined as time to last daily TPE during the overall treatment period), time to complete remission (defined as platelet count >150×109/L and lactate dehydrogenase <1.5×the upper limit of normal for >30 days after cessation of daily TPE), and recurrence-free survival (absence of exacerbation or relapse during the overall study period) were calculated.

Results: More than half of the patients in the HERCULES trial achieved an initial platelet count normalization within 3 days (caplacizumab, 56/72 [78%]; placebo, 43/73 [59%]). In patients with a fast platelet count response (ie, ≤3 days), the exacerbation rate was 3.6% (2/56) with caplacizumab and 44.2% (19/43) with placebo, suggesting that the rapid platelet count response was sustained with caplacizumab, whereas almost half of the fast responders in the placebo group subsequently exacerbated. In patients with time to platelet count response >3 days, the exacerbation rate was 6.7% (1/15) with caplacizumab and 30.0% (9/30) with placebo, confirming the durable response with caplacizumab. The exacerbation rate among placebo patients with platelet response >3 days remained high but was numerically lower compared with fast responders. Of the patients who experienced exacerbations, 90% (2/3 in the caplacizumab group and 26/28 in the placebo group) switched to open-label caplacizumab, which may have favored the outcomes of placebo patients. Despite this bias, the median (95% CI) time to durable response was 4.5 (4.4–4.6) days with caplacizumab and 10.5 (6.5–14.5) days with placebo; accordingly, the median (95% CI) time to complete remission was shorter in the caplacizumab group (40.0 [37.7–41.1] days) compared with placebo (44.2 [42.0–48.2] days). The analysis of overall recurrence-free survival during the entire study period demonstrated an early and sustained benefit for caplacizumab over placebo, mainly driven by significant reduction in exacerbations during the study drug treatment period. The effect was sustained, despite six relapses in the caplacizumab group in the follow-up period in patients with unresolved underlying autoimmune disease activity.

Conclusion: Caplacizumab demonstrated a faster and sustained platelet count response compared with the placebo group, in which many fast responders subsequently had an exacerbation. Fast platelet count responses with caplacizumab were maintained and translated into clinically relevant improvements in time to complete remission and overall recurrence-free survival. Data first presented at EHA 2020 virtual meeting, June 11–21st. Study sponsored by Sanofi.