BackgroundAcquired thrombotic thrombocytopenic Purpura (aTTP) is a life-threatening ultra-orphan disease with a reported annual incidence between 1.5 and 6.0 cases per million in Europe and mainly affecting otherwise young and healthy adults aged 40 years on average. The goal of this study was to assess the incidence of aTTP in Germany.MethodsA systematic review was performed to determine the published evidence on the aTTP epidemiology in Germany. To obtain additional evidence on the proportion of aTTP cases within the national Thrombotic Microangiopathy (TMA) population a hospital-level study was performed, using a retrospective data collection approach. Diagnosis of aTTP was confirmed if ADAMTS13 level were < 10% and/or the medical records explicitly mentioned aTTP diagnosis. The aggregated hospital data were then projected to the national level using logistic regression techniques.ResultsThe systematic literature search did not provide incidence estimates of aTTP in Germany. Eight centers (≈27% of the top 30 TMA hospitals) delivered data according to a predefined data collection form. On average (year 2014–2016) a total number of 172 aTTP episodes per year was projected (95% confidence interval [95%CI]: 132–212). The majority were newly diagnosed aTTP cases (n = 121; 95%CI: 105–129), and 51 were recurrent aTTP cases (95%CI: 27–84). The average annual projected incidence (year 2014–2016) of aTTP episodes was 2.10 per million inhabitants in Germany (95%CI: 1.60–2.58).ConclusionsThe determined annual incidence of newly diagnosed aTTP cases and the overall annual incidence of aTTP episodes in Germany confirm the ultra-orphan character of aTTP. An external validation against international registries (France, UK and USA) shows that our findings are quite comparable with those international incidence rates.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare and life-threatening autoimmune thrombotic microangiopathy. Caplacizumab, evaluated in phase II and III studies in adults, shortens the time to platelet count response and reduces aTTP exacerbations, has a favorable safety profile, and can potentially reduce refractoriness and mortality associated with aTTP. Since no children with aTTP were enrolled in these clinical trials, caplacizumab has been initially approved for use only in adult patients with aTTP (10 mg). Pediatric dosing recommendations were developed using model-based simulations. A semimechanistic pharmacokinetic/pharmacodynamic population model has been developed describing the interaction between caplacizumab and von Willebrand factor antigen (vWF:Ag) following intravenous and subcutaneous administration of caplacizumab in different adult populations, at various dose levels, using nonlinear mixed-effects modeling. Based on the allometrically scaled pharmacokinetic/pharmacodynamic model, different dosing regimens were simulated in 8000 children (aged 2-18 years). Simulated caplacizumab exposures and vWF:Ag levels across different age categories were compared to an adult reference group. A simulated daily dose of 5 mg in children weighing <40 kg and of 10 mg in children weighing ≥40 kg resulted in similar exposures and vWF:Ag suppression across age and weight groups. Despite the lack of pediatric clinical data, the results of this modeling and simulation analysis constituted the basis for the European extension of indication for caplacizumab (10 mg) to adolescents aged >12 years and with a body weight ≥40 kg. This represents a rare case in which regulatory authorities have deemed a modeling and simulation study robust enough to approve a variation of indication.

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 immunosuppressiveThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Background Immune‐mediated thrombotic thrombocytopenic purpura (iTTP) is a life‐threatening thrombotic microangiopathy. Due to its rarity, epidemiology and real‐world outcomes data are scarce. Objectives The aim was to assess epidemiology, treatment patterns, clinical outcomes, and disease burden in patients with iTTP in the United States. Methods This longitudinal, retrospective observational study of the Optum‐Humedica database included patients with an iTTP diagnosis (≥1 documented ADAMTS13 activity less than 10% or one or more iTTP episodes) from January 2007 to December 2019. Results Of 666 patients with an iTTP diagnosis between October 2015 and December 2019, 302 (45%) had one or more iTTP episodes. The pooled annual incidence of documented iTTP during this period was 3.43/million, and the annual incidence of one or more iTTP episodes was 1.81/million. Patients with one or more iTTP episodes received a median of six therapeutic plasma exchange (TPE) sessions per episode; 86% received corticosteroids, and 59% received rituximab. Exacerbations occurred in 17% (52/302) and relapse in 11% (34/302); 34% (103/302) had one or more thromboembolic events. Mortality rates during the study period were 25% (167/666) among all patients with iTTP diagnosis, and 14% (41/302) among patients with one or more iTTP episodes. In the assessment of disease burden (January 2007 to September 2019), patients in the iTTP cohort (n = 514) presented with a mean of 14 comorbidities, compared with 3 in a matched non‐iTTP cohort (n = 2570). In a cluster analysis, duration of iTTP episode and mortality rate were greater in older versus younger patients. Conclusions Despite treatment with TPE and immunosuppressants, patients with iTTP have high risk of morbidity and mortality, demonstrating the need for more effective therapies.