Real-world data confirm the effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura.
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ABSTRACT:
SUBMITTER: Volker LA
PROVIDER: S-EPMC7362370 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by thrombotic microangiopathy leading to end-organ damage. The standard of care (SOC) treatment is therapeutic plasma exchange (TPE) alongside immunomodulation with steroids, with increasing use of rituximab ± other immunomodulatory agents. The addition of caplacizumab, a nanobody targeting von Willebrand factor, was shown to accelerate platelet count recovery and reduce TPE treatments and hospital length of stay in TTP patients treated in 2 major randomized clinical trials. The addition of caplacizumab to SOC also led to increased bleeding from transient reductions in von Willebrand factor and increased relapse rates. Using data from the 2 clinical trials of caplacizumab, we performed the first-ever cost-effectiveness analysis in TTP. Over a 5-year period, the projected incremental cost-effectiveness ratio (ICER) in our Markov model was $1 482 260, significantly above the accepted 2019 US willingness-to-pay threshold of $195 300. One-way sensitivity analyses showed the utility of the well state and the cost of caplacizumab to have the largest effects on ICER, with a reduction in caplacizumab cost demonstrating the single greatest impact on lowering the ICER. In a probabilistic sensitivity analysis, SOC was favored over caplacizumab in 100% of 10 000 iterations. Our data indicate that the addition of caplacizumab to SOC in treatment of acquired TTP is not cost effective because of the high cost of the medication and its failure to improve relapse rates. The potential impact of caplacizumab on health system cost using longer term follow-up data merits further study.
| S-EPMC7918179 | biostudies-literature
Project description:Thrombotic thrombocytopenic purpura (TTP) is a rare disease with a mortality rate of over 90% if left untreated. Therapeutic plasma exchange (PEX) is the mainstay of treatment of acquired TTP (aTTP), and with the introduction of PEX, the mortality rate declined dramatically below 20%. Although PEX together with corticosteroids are the backbone of the upfront management of patients with aTTP with successful outcomes, patients may remain refractory and/or relapse following an initial response to this treatment. There are some therapeutic options, which can be used among these patients, helping in improving outcomes of aTTP. Caplacizumab (formerly ALX-0081 or ALX-0681) is a humanized single-variable domain immunoglobulin that recognizes the human von Willebrand factor (vWF) A1 domain and inhibits the vWF-platelet glycoprotein 1b-alpha (GP1b-α) interaction. The drug was first developed for the prevention of thrombosis in high-risk patients with acute coronary syndrome undergoing percutaneous coronary intervention; however, drug development for this indication has been discontinued. Recently, caplacizumab received its first approval following Phase II TITAN and Phase III HERCULES trials in the European Union (EU) for the treatment of acute episode of aTTP in adult patients, in addition to PEX and immunosuppression. This review focuses on the use of caplacizumab as an emerging treatment option in patients with aTTP.
| S-EPMC6475094 | biostudies-literature
Project description:The efficacy and safety of caplacizumab in individuals with acquired thrombotic thrombocytopenic purpura (aTTP) have been established in the phase 2 TITAN and phase 3 HERCULES trials. Integrated analysis of data from both trials was conducted to increase statistical power for assessing treatment differences in efficacy and safety outcomes. Caplacizumab was associated with a significant reduction in the number of deaths (0 vs 4; P < .05) and a significantly lower incidence of refractory TTP (0 vs 8; P < .05) vs placebo during the treatment period. Consistent with the individual trials, treatment with caplacizumab resulted in a faster time to platelet count response (hazard ratio, 1.65; P < .001), a 72.6% reduction in the proportion of patients with the composite end point of TTP-related death, TTP exacerbation, or occurrence of at least 1 treatment-emergent major thromboembolic event during the treatment period (13.0% vs 47.3%; P < .001), and a 33.3% reduction in the median number of therapeutic plasma exchange days (5.0 vs 7.5 days) vs placebo. No new safety signals were identified; mild mucocutaneous bleeding was the main safety finding. This integrated analysis provided new evidence that caplacizumab prevents mortality and refractory disease in acquired TTP and strengthened individual trial findings, with a confirmed favorable safety and tolerability profile. These trials were registered at www.clinicaltrials.gov as #NCT01151423 and #NCT02553317.
| S-EPMC8095153 | biostudies-literature
Project description:BACKGROUND:Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening autoimmune thrombotic microangiopathy. Caplacizumab, an anti-von Willebrand Factor Nanobody® , is effective for treating aTTP episodes and is well tolerated. OBJECTIVES AND METHODS:In the phase 3 HERCULES trial (NCT02553317), patients with aTTP received double-blind caplacizumab or placebo during daily therapeutic plasma exchange (TPE) and for ?30 days thereafter. Patients who experienced an exacerbation while on blinded study drug treatment switched to receive open-label caplacizumab plus re-initiation of daily TPE. Exacerbations were defined as recurrence of disease occurring within 30 days after cessation of daily TPE. RESULTS:Thirty-one patients (placebo, n = 28; caplacizumab, n = 3) had an exacerbation during double-blind treatment. Twenty-eight patients switched to open-label caplacizumab (placebo, n = 26; caplacizumab, n = 2); the three others discontinued upon exacerbation. Median time to platelet count response (?150 × 109 /L) was 3.49 days upon receiving caplacizumab. There were no deaths. During open-label treatment, further exacerbation or a major thromboembolic event (vena cava thrombosis) was experienced by one patient (3.6%) each. Consistent with the double-blind phase, the most frequent treatment-emergent adverse events were catheter site hemorrhage (28.6%), headache (21.4%), and epistaxis (17.9%). CONCLUSIONS:These results suggest that caplacizumab was efficacious and well tolerated in patients with aTTP who experienced a disease exacerbation during double-blind treatment in HERCULES.
| S-EPMC7027866 | biostudies-literature
Project description:Thrombotic thrombocytopenic purpura (TTP) is a clearly defined entity of the thrombotic microangiopathies (TMA), a heterogeneous group of disorders characterized by microangiopathic hemolytic anemia with red cell fragmentation, thrombocytopenia and organ dysfunction due to disturbed microcirculation. TTP is characterized by a severe deficiency of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), an enzyme responsible for physiological cleavage of von Willebrand factor (VWF). Organ dysfunction can be severe and life-threatening, and immediate start of appropriate therapy is necessary to avoid permanent damage or death. Until recently, therapeutic options were limited to symptomatic measures, which were not standardized or based on high scientific evidence. In recent years, not only considerable progress has been made in better diagnosis of TTP, but also new therapeutic strategies have been established. Initial treatment is still based on plasma exchange and symptomatic measures to protect organ function, but new concepts (immunosuppression, targeted anti-VWF or anti-complement therapy, replacement with recombinant enzymes) have recently demonstrated impressive advantages.
| S-EPMC6132833 | biostudies-literature
Project description:BackgroundAcquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease in which anti-ADAMTS13 autoantibodies cause severe enzyme deficiency. ADAMTS13 deficiency causes the loss of regulation of von Willebrand factor multimeric size and platelet-tethering function, which results in the formation of disseminated microvascular platelet microthrombi. Precisely how anti-ADAMTS13 autoantibodies, or antibody subsets, cause ADAMTS13 deficiency (ADAMTS13 activity generally < 10%) has not been formally investigated.MethodsWe analysed 92 acquired TTP episodes at presentation, through treatment and remission/relapse using epitope mapping and functional analyses to understand the pathogenic mechanisms of anti-ADAMTS13 IgG.Results89/92 of TTP episodes had IgG recognising the ADAMTS13 N-terminal domains. The central spacer domain was the only N-terminal antigenic target detected. 38/92 TTP episodes had autoantibodies recognising the N-terminal domains alone; 54/92 TTP episodes also had antibodies against the ADAMTS13 C-terminal domains (TSP2-8 and/or CUB domains). Changes in autoantibody specificity were detected in 9/16 patients at relapse, suggesting a continued development of the disease. Functional analyses on IgG from 43 patients revealed inhibitory IgG were limited to anti-spacer domain antibodies. However, 15/43 patients had autoantibodies with no detectable inhibitory action and as many as 32/43 patients had autoantibodies with inhibitory function that was insufficient to account for the severe deficiency state, suggesting that in many patients there is an alternative pathogenic mechanism. We therefore analysed plasma ADAMTS13 antigen levels in 91 acquired TTP presentation samples. We demonstrated markedly reduced ADAMTS13 antigen levels in all presentation samples, median 6% normal (range 0-47%), with 84/91 patients having < 25% ADAMTS13 antigen. ADAMTS13 antigen in the lowest quartile at first presentation was associated with increased mortality (odds ratio 5.7).ConclusionsAnti-spacer domain autoantibodies are the major inhibitory antibodies in acquired TTP. However, depletion of ADAMTS13 antigen (rather than enzyme inhibition) is a dominant pathogenic mechanism. ADAMTS13 antigen levels at presentation have prognostic significance. Taken together, our results provide new insights into the pathophysiology of acquired TTP.
| S-EPMC4563118 | biostudies-literature
Project description:Immune thrombotic thrombocytopenic purpura (iTTP) is an acquired, fatal microangiopathy if untreated. Randomized controlled trials (RCTs) demonstrated faster time to response with addition of 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. In this systematic review and meta-analysis, we searched for comparative studies evaluating SOC with or without caplacizumab for the treatment of iTTP. We assessed risk of bias using the Cochrane risk-of-bias-2 tool (RCTs) and the Newcastle-Ottawa Scale (observational studies). The primary efficacy and safety outcomes were all-cause mortality and treatment-emergent bleeding, respectively. Secondary outcomes included exacerbation and relapse, refractory iTTP, and time to response. We included 2 high-quality RCTs and 3 observational studies at high risk of bias comprising 632 total participants. Compared with SOC, caplacizumab was associated with a nonsignificant reduction in the relative risk [RR] of death in RCTs (RR, 0.21; 95% confidence interval [CI], 0.05-1.74) and observational studies (RR, 0.62; 95% CI, 0.07-4.41). Compared with SOC, caplacizumab was associated with an increased bleeding risk in RCTs (RR, 1.37; 95% CI, 1.06-1.77). In observational studies, bleeding risk was not significantly increased (RR, 7.10; 95% CI, 0.90-56.14). Addition of caplacizumab was associated with a significant reduction in refractory iTTP and exacerbation risks and shortened response time but increased relapse risk. 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.
| S-EPMC10196763 | biostudies-literature
Project description:Introduction:Severe acute kidney injury (AKI) and chronic kidney disease (CKD) are considered to be uncommon in patients with acquired thrombotic thrombocytopenic purpura. However, a recent case series from a tertiary care hospital indicated that 54 (59%) of 92 patients with thrombotic thrombocytopenic purpura presented with AKI; 14 (15%) required dialysis; and 12 (22%) of the 54 patients had CKD at follow-up. Methods:In this prospective analysis of 78 patients diagnosed with their first episode of thrombotic thrombocytopenic purpura and enrolled in the Oklahoma Thrombotic Thrombocytopenic Purpura Registry from 1995 to 2015, we assessed AKI at diagnosis using Kidney Disease: Improving Global Outcomes criteria, and CKD at follow-up as defined by estimated glomerular filtration rate <60 ml/min per 1.73 m2 determined by the Chronic Kidney Disease-Epidemiology Collaboration equation. Results:Forty-five (58%) patients had AKI; 8 (10%) had stage 3 AKI, and 3 (4%) required dialysis. AKI was not associated with the patients' demographic or presenting clinical features. Three of the 8 patients with stage 3 AKI died; among the 5 survivors, estimated glomerular filtration rate was 77 to 107 ml/min per 1.73 m2 (median, 92) with median follow-up of 8.1 years. Among all 62 surviving patients who have had follow-up serum creatinine measurements, 4 (6%) had CKD with median follow-up of 6.4 years. AKI was not associated with the occurrence of CKD (P = 0.74). No patients have required continuing renal replacement therapy. Discussion:In this population-based prospective cohort of consecutive patients with thrombotic thrombocytopenic purpura, without selection or referral bias, severe AKI and CKD are uncommon.
| S-EPMC5733749 | biostudies-literature
Project description:The discovery of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) revolutionized our approach to thrombotic thrombocytopenic purpura (TTP). Inherited or acquired ADAMTS13 deficiency allows the unrestrained growth of microthrombi that are composed of von Willebrand factor and platelets, which account for the thrombocytopenia, hemolytic anemia, schistocytes, and tissue injury that characterize TTP. Most patients with acquired TTP respond to a combination of plasma exchange and rituximab, but some die or acquire irreversible neurological deficits before they can respond, and relapses can occur unpredictably. However, knowledge of the pathophysiology of TTP has inspired new ways to prevent early deaths by targeting autoantibody production, replenishing ADAMTS13, and blocking microvascular thrombosis despite persistent ADAMTS13 deficiency. In addition, monitoring ADAMTS13 has the potential to identify patients who are at risk of relapse in time for preventive therapy.
| S-EPMC5606001 | biostudies-literature
Project description:BACKGROUND:Acquired 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. METHODS:A 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. RESULTS:The 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). CONCLUSIONS:The 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.
| S-EPMC6858672 | biostudies-literature