Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura
Flora Peyvandi, Marie Scully, Johanna A Kremer Hovinga, Spero Cataland, Paul Knöbl, Haifeng Wu, Andrea Artoni, John-Paul Westwood, Magnus Mansouri Taleghani, Bernd Jilma, Filip Callewaert, Hans Ulrichts, Christian Duby, Dominique Tersago, TITAN Investigators, Simon He, Robert Bird, Philip Crispin, Daniel Hsu, Paul Knoebl, Werner Linkesch, Daan Dierickx, Anne Sonet, Dimitri Anthonius Breems, André Efira, Dontcho Peytchev, Sylvain Chantepie, Inge Scharrer, Jens Chemnitz, Gernot Beutel, Bernhard Krämer, Fedai Özcan, Anja Mühlfeld, Achim Jörres, Michael Fischereder, Martin Bommer, Aida Inbal, Deborah Rund, Netanel Horowitz, Flora Peyvandi, Luana Fianchi, Luca Facchini, Silvana Franca Capalbo, Gaetano Giuffrida, Mariana Vasilica, Marius Balea, Susana Vives, Javier de la Rubia, Cristina Arbona, Magdalena Carmona, Hovinga Kremer, Johanna Strebel, Jan-Dirk Studt, Anne Angelillo-Scherrer, Marie Scully, Beverly Hunt, Steven Austin, Vanessa Martlew, Robert Lerner, Morey Blinder, Haifeng Wu, Ilene Weitz, Ana Antun, Ara Metjian, Maria DeSancho, Joseph Kiss, Robert Kaplan, George Rodgers, Craig Kessler, Mary Ann Knovich, Ravindra Sarode, Majed Refaai, Flora Peyvandi, Marie Scully, Johanna A Kremer Hovinga, Spero Cataland, Paul Knöbl, Haifeng Wu, Andrea Artoni, John-Paul Westwood, Magnus Mansouri Taleghani, Bernd Jilma, Filip Callewaert, Hans Ulrichts, Christian Duby, Dominique Tersago, TITAN Investigators, Simon He, Robert Bird, Philip Crispin, Daniel Hsu, Paul Knoebl, Werner Linkesch, Daan Dierickx, Anne Sonet, Dimitri Anthonius Breems, André Efira, Dontcho Peytchev, Sylvain Chantepie, Inge Scharrer, Jens Chemnitz, Gernot Beutel, Bernhard Krämer, Fedai Özcan, Anja Mühlfeld, Achim Jörres, Michael Fischereder, Martin Bommer, Aida Inbal, Deborah Rund, Netanel Horowitz, Flora Peyvandi, Luana Fianchi, Luca Facchini, Silvana Franca Capalbo, Gaetano Giuffrida, Mariana Vasilica, Marius Balea, Susana Vives, Javier de la Rubia, Cristina Arbona, Magdalena Carmona, Hovinga Kremer, Johanna Strebel, Jan-Dirk Studt, Anne Angelillo-Scherrer, Marie Scully, Beverly Hunt, Steven Austin, Vanessa Martlew, Robert Lerner, Morey Blinder, Haifeng Wu, Ilene Weitz, Ana Antun, Ara Metjian, Maria DeSancho, Joseph Kiss, Robert Kaplan, George Rodgers, Craig Kessler, Mary Ann Knovich, Ravindra Sarode, Majed Refaai
Abstract
Background: Acquired thrombotic thrombocytopenic purpura (TTP) is caused by aggregation of platelets on ultralarge von Willebrand factor multimers. This microvascular thrombosis causes multiorgan ischemia with potentially life-threatening complications. Daily plasma exchange and immunosuppressive therapies induce remission, but mortality and morbidity due to microthrombosis remain high.
Methods: Caplacizumab, an anti-von Willebrand factor humanized single-variable-domain immunoglobulin (Nanobody), inhibits the interaction between ultralarge von Willebrand factor multimers and platelets. In this phase 2, controlled study, we randomly assigned patients with acquired TTP to subcutaneous caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 days afterward. The primary end point was the time to a response, defined as confirmed normalization of the platelet count. Major secondary end points included exacerbations and relapses.
Results: Seventy-five patients underwent randomization (36 were assigned to receive caplacizumab, and 39 to receive placebo). The time to a response was significantly reduced with caplacizumab as compared with placebo (39% reduction in median time, P=0.005). Three patients in the caplacizumab group had an exacerbation, as compared with 11 patients in the placebo group. Eight patients in the caplacizumab group had a relapse in the first month after stopping the study drug, of whom 7 had ADAMTS13 activity that remained below 10%, suggesting unresolved autoimmune activity. Bleeding-related adverse events, most of which were mild to moderate in severity, were more common with caplacizumab than with placebo (54% of patients vs. 38%). The frequencies of other adverse events were similar in the two groups. Two patients in the placebo group died, as compared with none in the caplacizumab group.
Conclusions: Caplacizumab induced a faster resolution of the acute TTP episode than did placebo. The platelet-protective effect of caplacizumab was maintained during the treatment period. Caplacizumab was associated with an increased tendency toward bleeding, as compared with placebo. (Funded by Ablynx; ClinicalTrials.gov number, NCT01151423.).
Source: PubMed