INTRODUCTION: Caplacizumab demonstrated efficacy and safety in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in the phase 3 HERCULES trial. However, data on long-term outcomes following caplacizumab treatment are limited. OBJECTIVES: The post-HERCULES trial (NCT02878603) evaluated long-term outcomes of patients with iTTP treated with caplacizumab in HERCULES and safety and efficacy of repeated caplacizumab use. PATIENTS/METHODS: Over 3 years of follow-up, patients could receive open-label caplacizumab with therapeutic plasma exchange (TPE) and immunosuppressive therapy (IST) in case of recurrence. Adverse events (AEs) were assessed during the overall study period (intention-to-observe [ITO] population) and during recurrences (recurrence population). TTP-related events (TTP-related death, recurrence, major thromboembolic events) were assessed in the efficacy ITO population (patients without recurrence during HERCULES or before post-HERCULES). RESULTS: Among 104 enrolled patients, incidences of AEs and serious AEs were similar between patients who had received caplacizumab + TPE + IST during HERCULES (n = 75) and those treated with placebo + TPE + IST (placebo; n = 29). TTP-related events occurred in 8% of patients (4/49) randomized to caplacizumab during HERCULES versus 38% (11/29) randomized to placebo. Nineteen patients had ≥1 recurrence; 13 of these were treated with caplacizumab. The first recurrence episode was resolved or resolving for all patients treated with caplacizumab, including nine patients with repeat caplacizumab use. All second recurrences (6/6) were resolved. Safety profile of caplacizumab for treatment of recurrence was consistent with HERCULES; most bleeding events were nonserious. No major cases of organ dysfunction were observed. CONCLUSIONS: Long-term follow-up supports the safety and efficacy of caplacizumab for iTTP and its repeated use for recurrences.

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.).

The objective of this national, prospective, multi-centre observational study is to describe the prescription rational and practice in Germany, confirm the efficacy of caplacizumab in a real-world setting, and identify predicting factors in iTTP-patients with regard to persistent autoimmune activity, therapy guidance and risk of complications. The rational is to develop new treatment algorithms that optimize overall patient outcome and reduce treatment cost.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disease that causes systemic platelet-rich microthrombi with multiorgan damage. The historical treatment is based on therapeutic plasma exchange (TPE) and immunosuppression. Despite survival rates exceeding 85%, unfavorable outcomes including refractoriness, death and exacerbations of the disease during treatment still calls for a better management strategy. Caplacizumab (Cablivi) appeared recently as a new treatment in iTTP. By inhibiting binding of von Willebrand Factor to platelets, caplacizumab prevents platelets aggregation and the formation of microthrombi. Two pivotal randomized controlled trials have provided positive results where the use of caplacizumab is associated with faster platelet count recovery and less unfavorable outcomes. The other strength of this agent is an impressive alleviation in the burden of care, consisting in less TPE sessions and lower volumes of plasma to achieve remission, as well as substantial shortening in the length of hospitalization. However, since the recent approval of caplacizumab for the treatment of iTTP on the basis of these studies, debates remain regarding its systematic use in this indication. Should all patients be benefited from caplacizumab? Should we reserve caplacizumab only to the more severe patients? Should caplacizumab be initiated frontline or as a salvage therapy? If applicable, how should we select patients for caplacizumab? Lastly, is caplacizumab treatment cost-effective? This review aims at addressing these specific questions at a time when iTTP is entering the area of targeted therapies.

BACKGROUND: In acquired thrombotic thrombocytopenic purpura (TTP), an immune-mediated deficiency of the von Willebrand factor-cleaving protease ADAMTS13 allows unrestrained adhesion of von Willebrand factor multimers to platelets and microthrombosis, which result in thrombocytopenia, hemolytic anemia, and tissue ischemia. Caplacizumab, an anti-von Willebrand factor humanized, bivalent variable-domain-only immunoglobulin fragment, inhibits interaction between von Willebrand factor multimers and platelets. METHODS: In this double-blind, controlled trial, we randomly assigned 145 patients with TTP to receive caplacizumab (10-mg intravenous loading bolus, followed by 10 mg daily subcutaneously) or placebo during plasma exchange and for 30 days thereafter. The primary outcome was the time to normalization of the platelet count, with discontinuation of daily plasma exchange within 5 days thereafter. Key secondary outcomes included a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the trial treatment period; recurrence of TTP at any time during the trial; refractory TTP; and normalization of organ-damage markers. RESULTS: The median time to normalization of the platelet count was shorter with caplacizumab than with placebo (2.69 days [95% confidence interval {CI}, 1.89 to 2.83] vs. 2.88 days [95% CI, 2.68 to 3.56], P=0.01), and patients who received caplacizumab were 1.55 times as likely to have a normalization of the platelet count as those who received placebo. The percentage of patients with a composite outcome event was 74% lower with caplacizumab than with placebo (12% vs. 49%, P<0.001). The percentage of patients who had a recurrence of TTP at any time during the trial was 67% lower with caplacizumab than with placebo (12% vs. 38%, P<0.001). Refractory disease developed in no patients in the caplacizumab group and in three patients in the placebo group. Patients who received caplacizumab needed less plasma exchange and had a shorter hospitalization than those who received placebo. The most common adverse event was mucocutaneous bleeding, which was reported in 65% of the patients in the caplacizumab group and in 48% in the placebo group. During the trial treatment period, three patients in the placebo group died. One patient in the caplacizumab group died from cerebral ischemia after the end of the treatment period. CONCLUSIONS: Among patients with TTP, treatment with caplacizumab was associated with faster normalization of the platelet count; a lower incidence of a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the treatment period; and a lower rate of recurrence of TTP during the trial than placebo. (Funded by Ablynx; HERCULES ClinicalTrials.gov number, NCT02553317 .).

The primary objective of the study is to evaluate the pharmacokinetic characteristics and demonstrate bioequivalence of a reconstituted new lyophilized formulation of caplacizumab for subcutaneous (s.c.) injection as compared to an equal nominal s.c. dose of the reference liquid formulation of caplacizumab. The secondary objective of the study is to compare the safety and tolerability, and the pharmacodynamic parameters of the new formulation with those of the reference formulation.

Introduction Immune thrombotic thrombocytopenic purpura (iTTP) is an acquired, fatal microangiopathy if untreated. Randomized controlled trials (RCT's) demonstrated faster time-to-response with adding caplacizumab to standard of care (SOC). However, concerns about RCT selection bias and the high cost of caplacizumab warrant examination of all evidence, including real-world observational studies. Methods In this systematic review and meta-analysis, we searched the literature for comparative studies evaluating SOC with or without caplacizumab for the treatment of iTTP. We assessed risk-of-bias using the Cochrane RoB-2 tool (RCT's) and Newcastle-Ottawa Scale (observational studies). The primary efficacy outcome was all-cause mortality, and the primary safety outcome was treatment-emergent bleeding. Secondary outcomes included exacerbation and relapse, refractory iTTP, and time-to-response. Results We included two high-quality RCT's and three observational studies at high-risk-of-bias comprising 632 participants. Compared with SOC, caplacizumab was associated with a non-significant reduction in the RR (0.21 [CI 0.05-1.74]) of death in RCT's and observational studies (RR 0.62 [CI 0.07, 4.41]). Compared with SOC, caplacizumab was associated with an increased risk of bleeding in RCT's (RR 1.37 [CI 1.06, 1.77]). In observational studies, the risk of bleeding was not significantly increased (RR 7.10 [CI 0.90, 56.14]). Addition of caplacizumab was also associated with a significant reduction in refractory iTTP and exacerbation, increased risk of relapse, and shortened response time. Conclusion Frontline addition of caplacizumab does not significantly reduce all-cause mortality compared with SOC alone, although it reduces refractory disease risk, shortens time-to-response, and improves exacerbation rates, at the expense of increased relapse and bleeding risk.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy. Several studies have demonstrated the efficy of caplacizumab in iTTP. However, the effect on different populations remains controversial. Therefore, we performed a systematic review and meta-analysis to assess the effectiveness and safety of caplacizumab for treating iTTP. MATERIALS AND METHODS: We searched PubMed, Embase, and the Cochrane Library for studies until March 24, 2023. Participants were hospitalized patients with iTTP. Interventions included caplacizumab versus placebo or standard of care (SOC). Outcomes assessed included all-cause mortality, exacerbation, relapse, refractory, time-to-platelet-count-recovery, length of TPE and hospital stay, bleeding, and thrombosis. RESULTS: A total of 1119 patients from eight studies were subjected to meta-analysis. The results of the meta-analysis showed that iTTP patients treated with caplacizumab achieved a reduction in mortality (RR 0.38, 95% CI: 0.19-0.75), exacerbation (RR 0.29, 95% CI: 0.14-0.61) and refractory (RR 0.50, 95% CI: 0.31-0.81). Besides, adding caplacizumab to SOC was associated with a shorten time-to-platelet-count-recovery (MD -2.31, 95% CI: -3.86 to -0.77) and the length of TPE (MD -4.61, 95% CI: -6.20 to -3.02). In terms of safety, the bleeding rate was higher in the caplacizumab group (RR 1.57, 95% CI: 1.21-2.02), while there was no significant difference in hospital stay and thrombosis between the two groups. CONCLUSIONS: Caplacizumab is an effective treatment for patients with iTTP, especially in reducing all-cause mortality, exacerbations, refractoriness, and the time-to-platelet-count-recovery. Although the risk of bleeding may be increased, it is generally modest and manageable.

The interpretation of platelet counts has to be revaluated in the light of caplacizumab. By effectively blocking platelet binding sites on VWF-multimers, the nanobody leads to a rapid normalization of the platelet count within 3 to 4 days. Most importantly, caplacizumab uncouples platelet counts from ADAMTS13 activity and thereby launches unprecedented thrombocyte dynamics, with potential pitfalls for over- and undertreatment. A relevant number of patients responds to caplacizumab with a brisk increase in platelet count, followed by a marked dip of platelets (patient on the left). This may mislead treating physicians into re-intensifying therapy, with a respective risk for adverse side-effects and complications. Taken together, these observations call for reliable descriptions and the identification of predictive parameters to predict the platelet response upon administration of caplacizumab in a large patient cohort. Here, PREDICT-2020 is designed as a retrospective study to specifically address the following aspects: * Identifying and describing clusters of platelet responses to caplacizumab * Identifying potential pitfalls for treating physicians * Predicting the individual thrombocyte response * Correlating platelet responses with individual patient outcome

CLINICAL QUESTION: In people with acquired thrombotic thrombocytopenic purpura (TTP), does caplacizumab decrease the time to normalisation of the platelet count and the risk of death and complications caused by thrombotic events and organ damage? EVIDENCE FROM TRIAL: In adults with acquired TTP, caplacizumab decreased the time to normalisation of the platelet count and decreased the risk of TTP-related death and recurrence of TTP.