Discussion
ADAMTS13, exacerbations, cognitive impairment, initiation of caplacizumab., TTP
RECURRENCE, DISEASE, ITTP, SECONDARY, TTP
This study, the first to evaluate caplacizumab treatment in Japanese individuals with iTTP, indicates that adding caplacizumab to the standard protocol of TPE and immunosuppressive treatment results in a low rate of iTTP recurrence, and rapid normalization of platelet count and organ function parameters. It is notable that the participants in our study were generally older than those seen in US and European studies of individuals with iTTP (median 59 years versus 33–41 years) and included a lower proportion of females (48% vs. 77–82%) [Only one participant in the current study had an iTTP recurrence after caplacizumab had been interrupted, so the primary endpoint occurred at a rate of 6.7%, well below the 20% rate used as a predefined criterion of success. This criterion corresponds to the number of participants fewer than three out of 15 patients (below 20%), which is set based on the expected number of participants with recurrence in our study would be 2.25 (the expected recurrence rate of 15%), assuming that capalacizumab treatment reduces relative risk (an estimated recurrence rate without capalacizumab treatment of 30%, which is based on a systematic review of past studies [The favorable efficacy of caplacizumab treatment was also observed with regard to the secondary endpoints in our study. All 15 participants (100%) in the PP population and 17/21 participants (81.0%) in the mITT population experienced a rapid platelet count response, and the median times to platelet count normalization in our study (median 2.79 days in the PP population and 3.49 days in the mITT population), were similar to those observed in the TITAN and HERCULES studies [Fourteen of 15 participants (93.3%) in the PP population and 18 of 21 participants (85.7%) in the mITT population had normalization of all three organ damage marker levels within a median of 2.65 days and 3.57 days, respectively. The normalization of organ damage marker levels was almost as rapid as the platelet response, suggesting that suppression of microthrombus formation during caplacizumab treatment leads to a rapid recovery from iTTP-related organ damage. In addition, rapid improvement from baseline in SMMSE scores indicated that cognitive impairment due to iTTP, present prior to the start of caplacizumab treatment, rapidly reversed after initiation of caplacizumab.In line with data from the HERCULES and TITAN studies, none of the individuals who received caplacizumab in our study developed refractory disease. In the HERCULES study, none of the 65 caplacizumab recipients had refractory disease, but 3 of the 64 placebo recipients (4.7%) had refractory acquired TTP [The type and incidence of caplacizumab-related TEAEs in the current study were similar to those reported in the TITAN and HERCULES studies [VWF is the target molecule of caplacizumab and is also known to contribute to stabilization of FVIII. In this study, pharmacodynamic parameters, including VWF:RCo, VWF:Ag, and FVIII:C, showed a similar trend to that observed in the TITAN study [Our data support previous findings that ADAMTS13 activity is a predictor of exacerbation or recurrence. In our study, the only participant who had an iTTP recurrence had an ADAMTS13 level of < 1%. Similarly, almost all exacerbations and relapses in caplacizumab recipients in the TITAN and HERCULES studies occurred in participants with an ADMATS13 activity of < 10% at the end of treatment [Our study has some limitations, specifically the small sample size arising from the rarity of iTTP in clinical practice, and the lack of a control group. Given these limitations, results should be considered preliminary; however, it is important to note that they are internally consistent across endpoints, as well as being externally consistent with previously published data in mostly European individuals with TTP.In conclusion, in Japanese individuals with iTTP, caplacizumab in combination with TPE and immunosuppressive treatment was associated with a low rate of iTTP recurrence (6.7%), which met the criterion for success, and rapid normalization of platelet counts and organ damage markers. No unexpected TEAEs were identified in the Japanese study population.