Caplacizumab, Anti-Vwf Nanobody Potentially Changing the Treatment Paradigm in Thrombotic Thrombocytopenic Purpura: Results of the TITAN Trial

INTRODUCTION: The TITAN trial achieved its primary endpoint in the ITT analysis of 75 subjects treated either with caplacizumab or placebo added to daily plasma exchange (PE).

METHODS: Caplacizumab is a Nanobody which binds the A1 domain of vWF and thereby blocks the interaction of multimeric vWF with the GPIb-IX-V platelet receptor, preventing platelet aggregation typical of TTP. TITAN was a randomized, placebo controlled, single-blind, parallel design study. The primary endpoint was time to confirmed platelet response defined as platelet count normalization confirmed 48 hours later. Analysis was prospectively stratified according to whether or not subjects received a single PE prior to randomization. Treatment consisted of one IV bolus injection of caplacizumab 10mg (CAP) or placebo (PLC) prior to first on-study PE, followed by daily SC administration after PE. Once PE was stopped, CAP or PLC SC administration continued, daily for 30 days.

RESULTS: The ITT population consisted of 36 and 39 subjects randomized 1:1 to CAP or PLC, respectively. Treatment arms were well balanced for age, race, body mass index. Presentation of TTP as an initial TTP episode or recurrent TTP was similar for both groups with 2/3 first episode and 1/3 recurrent. Platelet count and LDH were similar as summarized in table 1.

Time to reach platelet response was almost 2 days shorter for CAP versus PLC, with a 39% reduction in time to response in the stratum with no prior PE, and 43% reduction in time to response in the stratum with a single prior PE. The overall hazard ratio was 2.197 for obtaining the confirmed platelet response with CAP over PLC, with a significance of p=0.013. The distribution of time to response was narrower for CAP in comparison to the distribution of subjects receiving PLC which was skewed towards longer confirmed platelet response time in table 2.

Exacerbation of TTP occurred in 3 (8%) subjects receiving CAP versus 11 (28%) in the PLC arm. Complete remission defined as confirmed platelet response and absence of exacerbation up to 30 days after end of daily PE was achieved in 29 (81%) subjects of the CAP arm versus 18 (46%) subjects receiving PLC. The greater proportion of complete remission, coupled with the faster and narrower distribution of time to confirmed platelet response supports a greater predictability of patient response to PE in the CAP arm, and is reflected in number of days of PE. The number of consecutive days of PE was (mean ± st dev) 6.6 ± 3.4 days for CAP versus 8.1 ± 6.5 days for PLC with a total plasma volume administered including tapering of 22.5 ± 15.9 liters for CAP versus 28.4 ± 21.3 liters for PLC. The proportion of subjects with exacerbation and/or relapse up to the 1 month follow-up was even for both groups: 13 (36.1%) and 13 (33.3%) for both arms. Higher number of early relapses in the CAP arm substantiates a protective effect and warrants longer CAP treatment in some patients.

Treatment emergent adverse events (TEAE) and deaths are summarized in table 3.

CONCLUSIONS: Caplacizumab, as a novel treatment, improved standard of care of patients affected with acquired TTP by a more rapid achievement of platelet normalization and lower number of exacerbations with manageable side effects and bleeding episodes. The TEAEs were consistent with the serious and potentially life-threatening condition of TTP. Further reducing PE and optimizing duration of caplacizumab should be investigated in future clinical trials.