The efficacy and safety of caplacizumab in Japanese patients with immune-mediated thrombotic thrombocytopenic purpura: an open-label phase 2/3 study

Abstract

Caplacizumab is an anti-von Willebrand factor humanized single-variable-domain immunoglobulin fragment whose efficacy and safety in immune-mediated thrombotic thrombocytopenia purpura (iTTP) have been demonstrated in international studies. This prospective, open-label phase 2/3 study evaluated caplacizumab 10 mg administered daily during plasma exchange and for 30 days afterward, in combination with immunosuppressive treatment, in Japanese adults with a clinical diagnosis of iTTP (new or recurrent). The primary endpoint was prevention of iTTP recurrence; key secondary endpoints included time to platelet count response, time to organ damage normalization, and safety. Among 21 treated patients, 1 of 15 (6.7%) evaluable patients developed iTTP recurrence. Median time to normalization was 2.79 days for platelet count and 2.65 days for organ damage markers (n = 15). Treatment-emergent adverse events (TEAEs) were mostly mild to moderate in severity; the most frequently reported caplacizumab-related TEAEs were increased alanine aminotransferase, epistaxis, and gastrointestinal hemorrhage (all in 9.5% of patients). At least one bleeding event was reported in 7 of 21 patients (33%). Caplacizumab was effective in Japanese patients with iTTP, with a low rate of iTTP recurrence, rapid normalization of platelet counts and organ damage markers, and no unexpected TEAEs. Trial registration: ClinicalTrials.gov identifier, NCT04074187.

Keywords: ADAMTS13; Caplacizumab; Single-domain antibody; Thrombotic thrombocytopenic purpura; Von Willebrand factor inhibitor.

Fig. 1

Study design. Ctd continued, FU follow-up, ICF informed consent form, max maximum, PE plasma exchange, TPE therapeutic plasma exchange

Fig. 2

a Kaplan–Meier plot of time to platelet count response (per-protocol population) and b mean platelet count during daily therapeutic plasma exchange (TPE) period (per-protocol population). In b, error bars represent the standard error of the mean. BL baseline

Fig. 3

Kaplan–Meier plot of time to normalization of all three markers of organ damage (lactate dehydrogenase, cardiac troponin I, and serum creatinine) in the per-protocol population. The x indicates a censored event

Fig. 4

Mean (standard error) standardized Mini-Mental State Examination scores in the per-protocol population. SE standard error, SMMSE Standardized Mini-Mental State Examination

Fig. 5

Mean plasma levels of von Willebrand factor ristocetin cofactor (VWF:RCo) in the safety population. Error bars represent standard error of the mean; D2–3 is the daily TPE period, W1–W10 is the post-daily TPE period; VWF:RCo values of < 20% represent the threshold for pharmacologic activity of caplacizumab. The mean VWF:RCo of 29.2% at Week 4 (slightly above the 20% threshold) was caused by an aberrant data point of 279.6% from one participant who stopped caplacizumab due to physician decision, BL baseline, D day, FU follow-up, TPE therapeutic plasma exchange, W week

Fig. 6

Kaplan–Meier curve of recovery of A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity level to ≥ 10%. The x indicates a censored event