The most commonly reported serious adverse event of bleeding was epistaxis, which occurred in 4 patients in the caplacizumab group. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Data was collected retrospectively from 2018-2020 for 85 patients receiving caplacizumab, including 4 children, from 22 UK hospitals. You can find your saved items on your dashboard, in the "saved" tab. PARIS - January 9, 2019 - The New England Journal of Medicine (NEJM) today published positive results of the Phase 3 trial of Cablivi ® (caplacizumab) in adults with acquired thrombotic thrombocytopenic purpura (aTTP). The number of days in intensive care unit (ICU) during the overall study drug treatment period, including the number of days in ICU during the open-label study drug treatment period. Data were analyzed according to the initial treatment allocation (both before and after switch to open-label caplacizumab). Although in the 2 trials caplacizumab treatment was associated with increased TTP relapses and fewer exacerbations compared with SOC, in our models, we used a total recurrence rate representing the sum of relapses and exacerbations despite the former being more likely to incur greater costs as a result of hospital readmissions. J Thromb Haemost 2017;15:1448-1452. Demographic and baseline disease characteristics were generally similar in the two trial groups (Table 1). However, there are considerable risks associated with the use of caplacizumab and they must be weighed against the benefits of the … Outcomes that were not part of the hierarchy included the number of days of plasma exchange and the volume of plasma exchanged, the duration of stay in an intensive care unit and in the hospital, mortality rate, pharmacodynamic and pharmacokinetic variables, and immunogenicity. might be biased towards less complicated disease courses. 1. × You've saved your first item. Blood 2016;128:2175-2178. ); the Department of Hematology, Saint-Antoine University Hospital, Paris (P.C. * There were no significant differences between the groups in the characteristics listed in this table, except as noted. Address reprint requests to Dr. De Winter at Clinical Development, Ablynx, Technologiepark 21, B-9052 Zwijnaarde, Belgium, or at [email protected]. Coppo P, Schwarzinger M, Buffet M, et al. The most common reasons for discontinuation were adverse events, withdrawal of consent, and physician decision (Fig. ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is a von Willebrand factor–cleaving protease that leads to platelet consumption in von Willebrand factor–platelet aggregates and microvascular thrombosis. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK … (A) Utility of well state. On December 16, 2020, the National Institute for Health and Care Excellence (NICE) published guidance 1 recommending caplacizumab combined with plasma exchange and immunosuppressive therapy as an option for treating acute episodes of acquired thrombotic thrombocytopenic purpura in adults and young patients aged 12 years and over. ), and by the Luick Family Fund of Massachusetts General Hospital. To be sure, because of the high price of many orphan drugs, in CEAs of different RDs, the calculated ICERs for orphan drugs vary widely. Among these 29 patients, 9 had a relapse during the follow-up period (Figure 2B). You must be a member to content. An improvement in QALYs with the addition of caplacizumab was noted as compared with SOC (3.19 for caplacizumab vs 2.92 for SOC). × You've saved your first item. These events were mild or moderate in severity in a majority of patients and were severe in 3 patients in the caplacizumab group (epistaxis, gingival bleeding, and upper gastrointestinal hemorrhage in 1 patient each) and in 1 patient in the placebo group (hemorrhagic transformation stroke). The guidance states … J Thromb Haemost 2013;11:481-490. aTTP. During the overall trial period, including the 28-day follow-up period in which patients were no longer receiving caplacizumab or placebo, 9 patients (12%) in the caplacizumab group, as compared with 28 patients (38%) in the placebo group, had a recurrence of TTP, which represented a 67% lower incidence of recurrence with caplacizumab than with placebo (P<0.001) (Table 2). Patients may die or have irreversible neurologic deficits before a response to treatment occurs. 21. (C) Cost of SOC arm. Caplacizumab, a ‘nanobody’ (described in the following) that inhibits the vWF-platelet glycoprotein-Ib interaction, blocks the adhesion of platelets to vWF multimers preventing the for-mation of the pathological microthrombi, and thus preventing end-organ ischemic damage. 18. 5 Caplacizumab is the first targeted therapy that blocks the formation of blood clots, 6 and this therapy has been demonstrated to reduce time to resolution of thrombocytopenia in … Log in Now. 32. If it is shown that the increasingly recognized long-term cognitive effects of TTP can be improved with the use of caplacizumab during a TTP flare, then caplacizumab would harbor an important disease-modifying property that would also help to decrease the ICER compared with SOC over the course of decades. Leebeek FWG, Eikenboom JCJ. Limitations of this study include short follow-up time for the 2 clinical trials upon which our decision tree models are based, the assumption that TTP exacerbations and relapses are of equal monetary cost, lack of established utilities in TTP for the healthy and disease states, unequal distribution of rituximab treatment in the TITAN trial, and exclusion of bleeding costs in our models. Bleeding-related adverse events were reported in 46 patients (65%) in the caplacizumab group and in 35 patients (48%) in the placebo group (Table S3 in the. DOI: 10.1056/NEJMoa1806311, Tap into groundbreaking research and clinically relevant insights. An imbalance between the groups was observed in the percentage of patients with initial as compared with recurrent TTP episodes at presentation; this finding was consistent with somewhat more severe disease in the caplacizumab group, given that initial TTP episodes tend to be more severe at presentation than recurrent episodes. ); Fondazione Istituti di Ricovero e Cura a Carattere Scientifico Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, and the Department of Pathophysiology and Transplantation, University of Milan, Milan (F.P. Serious adverse events (excluding serious adverse events of TTP, which were considered to be secondary efficacy outcomes) were reported in 23 patients (32%) in the caplacizumab group and in 12 patients (16%) in the placebo group during the overall trial period (Table S2 in the Supplementary Appendix). Methods: A semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) population model has been developed describing the interaction between caplacizumab and von Willebrand factor antigen (vWF:Ag) … Information on the ADAMTS13 activity level at the time that administration of caplacizumab or placebo was stopped was available for 120 patients (60 at the end of the period of double-blind administration of caplacizumab, 34 at the end of the period of double-blind administration of placebo, and 26 at the end of the period of open-label administration of caplacizumab). Callewaert, Biswas, De Winter, and Zeldin, being employed by Ablynx. 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. Save Recommend Share . The authors stated that the use of caplacizumab results in a more rapid resolution of TTP episodes as indicated by faster platelet-count normalization. Panel B shows individual-patient data on relapse status during the follow-up period (i.e., after the end of the treatment period). Join PracticeUpdate Now. Learn more about services at Mayo Clinic. 6. Blood. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Additional analyses of upcoming 36-month follow-up data from the HERCULES trial as well as real-world experience with caplacizumab will be important in further understanding the longer term cost implications of this medication. In patients who had a recurrence of TTP while receiving caplacizumab or placebo, ADAMTS13 activity was measured at the time of the recurrence and then weekly beginning with the first day after plasma exchange during treatment with open-label caplacizumab. In the TITAN trial, rituximab use was higher in the SOC arm than in caplacizumab-treated patients. This finding suggests that monitoring of ADAMTS13 activity could be useful in guiding not only immunosuppressive treatment18-22 but also the continuation of caplacizumab treatment beyond 30 days after stopping plasma exchange. Cardiac troponin-I on diagnosis predicts early death and refractoriness in acquired thrombotic thrombocytopenic purpura: experience of the French Thrombotic Microangiopathies Reference Center. Caplacizumab (anti-vWF) Vobarilizumab (anti-IL-6R) • First-in-class treatment for acquired thrombotic thrombocytopenic purpura • Acute, life threatening, ultra-rare blood clotting disorder • No indicated therapeutic drug currently available • Filed for approval in Europe in H1 2017 • Phase III results expected in H2 2017; potential BLA No one who is not an author contributed to the writing of the manuscript. One patient in the caplacizumab group died from cerebral ischemia after the end of the treatment period. Specific circumstances in which the addition of caplacizumab could potentially have a lower ICER would be in patients with severe (including cardiac and neurologic involvement) or refractory disease who are unable to leave the hospital because of a requirement for continued daily TPE. Caplacizumab is an anti-von Willebrand factor humanised single-variable-domain immunoglobulin. The time to normalization of the platelet count was compared between the trial groups with the use of a two-sided stratified log-rank test on the basis of a Kaplan–Meier analysis; the stratification factor was the severity of neurologic involvement at baseline (i.e., Glasgow Coma Scale score of ≤12 vs. >13). Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. We built decision tree models to evaluate the cost effectiveness of SOC plus caplacizumab vs SOC in acquired TTP based on the results of each of the phase 2 TITAN trial at 12-month follow-up and the phase 3 HERCULES trial at 1-month follow-up. the life years gained by decreased mortality). correctly reflect the natural course of iTTP. An exacerbation was defined as a recurrence that occurred within 30 days after the last plasma exchange. (D) Cost of caplacizumab. 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. Clinical importance of ADAMTS13 activity during remission in patients with acquired thrombotic thrombocytopenic purpura. Patients in the well state who have a recurrence will return back to the disease state, at which point the cycle starts again. “Refractory TTP” will become obsolete with this approach, but caplacizumab … Recurrences are termed exacerbations if they occur within 30 days after the last plasma exchange (PE) and relapses if they occur more than 30 days after the last PE. Br J Haematol 2008;141:651-658. Callewaert F, Roodt J, Ulrichts H, et al. † The body-mass index is the weight in kilograms divided by the square of the height in meters. Refractory disease developed in no patients in the caplacizumab group and in 3 patients in the placebo group (P=0.06) (Table 2). One-way sensitivity analyses for TITAN Markov. Baseline was defined as the period before the first administration of caplacizumab or placebo; all the patients were to have received a single plasma-exchange treatment before randomization to caplacizumab or placebo. Most recurrences occur during the first year or two, but they can occur as late as 10 or 20 years after an episode of TTP. Risk factors and manageability of the mainly mild mucocutaneous bleeding profile observed in aTTP patients treated with caplacizumab during the phase III hercules study. Caplacizumab, a bivalent Nb construct against von Willebrand factor, is the first EMEA and FDA-approved therapeutic that is life-saving in acquired thrombotic thrombocytopenic purpura patients []. Baseline cost-effectiveness analysis and probabilistic sensitivity analysis. Therefore, for our analyses patients who underwent successful treatment with resolution of TTP regardless of treatment modality were assumed to have a utility of 1, whereas those suffering relapse at any point were assigned a utility of 0.1. N Engl J Med 2016;374:2497-2498. Already Have An Account? Haematologica 2008;93:232-239. (B) Utility of disease state. Caplacizumab for acquired thrombotic thrombocytopenic purpura. In a PSA of our Markov model for the TITAN trial, SOC was favored over SOC plus caplacizumab at a WTP of $195 330 in 100% of 10 000 iterations in a Monte Carlo simulation. All 4 deaths were adjudicated as TTP-related. To convert the values for creatinine to milligrams per deciliter, divide by 88.4. Additional studies using longer term follow-up data are warranted to assess the full impact of caplacizumab on the cost of treating TTP. No patient in either the phase 2 trial or the current trial died while receiving treatment with caplacizumab. The rare blood disorder can be treated by plasma exchange and immunosuppressive therapy, but acute episodes are still associated with significant mortality (10–20%) and relapses are common. Exacerbations occurred up to 25 days after the end of plasma exchange, which supports the need for treatment with caplacizumab during the period in which a patient is at risk (i.e., for at least 30 days after normalization of the platelet count is achieved). At any given time point, patients who received caplacizumab were 1.55 times as likely to have a normalization of the platelet count as patients who received placebo (rate ratio for normalization of platelet count, 1.55; 95% confidence interval [CI], 1.09 to 2.19; P=0.01). One-way sensitivity analyses of HERCULES trial with model parameters varied across ranges as shown. This indicates that the addition of caplacizumab at its current list price is not cost effective compared with SOC in treating acquired TTP at a WTP of $195 330. 5. Volume 137, Issue 13, 1 April 2021, Pages 1731-1740. Topics: adrenal corticosteroids, caplacizumab, glucocorticoids, mineralocorticoids, rituximab. Using data from the 2 clinical trials of caplacizumab, we performed the first-ever cost-effectiveness analysis in TTP. Copyright ©2020 by American Society of Hematology, http://healtheconomicsdev.tuftsmedicalcenter.org/cear2/search/search.aspx, https://icer-review.org/wp-content/uploads/2017/02/ICER_Assessing-the-Value-of-Drugs-for-Rare-Conditions_051017.pdf, Probability of total recurrence, caplacizumab arm. N Engl J Med 1991;325:393-397. Background Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening autoimmune thrombotic microangiopathy. Adding caplacizumab to standard of care for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) shortened the time to the normalization of platelet counts compared with standard care alone, according to a study published in the New England Journal of Medicine. Additionally, ADAMTS13 tailored approaches to define treatment duration or alternate day regimens and their cost-saving potentials have not been considered.5 In conclusion, the present CEA is based on preliminary assumptions and does not allow to draw any definitive conclusions regarding the cost effectiveness of caplacizumab in iTTP. This added value was associated with a higher incidence of low-grade mucosal bleeding than that with placebo. PLoS One 2010;5(4):e10208-e10208. †† The Glasgow Coma Scale score is a measure of neurologic involvement; scores range from 3 to 15, with lower scores indicating worse mental status. Caplacizumab-yhdp (Cablivi®) is the first Food and Drug Administration-approved treatment indicated for adult patients with acquired thrombotic thrombocytopenic purpura, in combination with plasma exchange and immunosuppressive therapy. Blood 2010;115:1500-1511. Accordingly, the average volume of plasma exchanged was 21.3 liters for patients who received caplacizumab as compared with 35.9 liters for patients in the placebo group, which represented a 41% lower volume with caplacizumab than with placebo. The primary outcome was the time to a response, which was defined as the time from the first intravenous administration of caplacizumab or placebo to normalization of the platelet count (i.e., a platelet count of at least 150,000 per cubic millimeter), with discontinuation of daily plasma exchange within 5 days thereafter. N Engl J Med. Moreover, a 65% shorter duration of care in an intensive care unit (mean, 3.4 days vs. 9.7 days) and a 31% shorter duration of hospitalization (mean, 9.9 days vs. 14.4 days) were also noted (Table 2). Patients received an intravenous loading dose of caplacizumab (10 mg) or placebo before the start of the first plasma exchange after randomization. S4 in the Supplementary Appendix). Normalization of the three organ-damage markers (lactate dehydrogenase, cardiac troponin I, and serum creatinine) occurred somewhat sooner in patients who received caplacizumab than in those who received placebo (Table 2, and Fig. Von Willebrand’s disease. For cost of SOC, as previously published, we used the US average wholesale price for rituximab accounting for 4 inpatient doses ($7724 for each dose of 375 mg/m2 for a 170-cm, 70-kg individual) and our institution’s costs for number of TPE sessions ($6000 per TPE session), intensive care unit (ICU) length of stay (LOS) ($1043 per day for an ICU bed), and total hospital LOS ($490 per day for an inpatient general medicine bed).21  Because both clinical trials reported numerical ranges for number of TPE sessions and LOS, in our models we used the extremes of these ranges in order to maximize such costs in the SOC group and minimize costs in the caplacizumab group (supplemental Table, available on the Blood Web site). In this study, using data obtained from the TITAN and HERCULES trials including medication costs, TPE days, ICU and total hospital LOS, TTP recurrence rates, and deaths, we demonstrate that the addition of caplacizumab to SOC treatment in acquired TTP yields ICERs of ~$1 million to $4 million based on data obtained from the TITAN and HERCULES trials. During the overall trial period, including the 28-day follow-up period in which patients were no longer receiving caplacizumab or placebo, 9 patients (12%) in the caplacizumab group, as compared with 28 patients (38%) in the placebo group, had a recurrence of TTP, which represented a 67% lower incidence of recurrence with caplacizumab than with placebo (P<0.001) (, Refractory disease developed in no patients in the caplacizumab group and in 3 patients in the placebo group (P=0.06) (. ); and Clinical Development, Ablynx, Zwijnaarde, Belgium (F.C., D.B., H.D.W., R.K.Z.). We calculated that this sample size would also provide 83% power to detect a rate of the first key secondary outcome (i.e., a composite of TTP-related death, recurrence of TTP, or a major thromboembolic event during the trial treatment period) that was 20% lower in the caplacizumab group than in the placebo group, using a chi-square test with a large sample approximation and a 5% significance level. Acquired thrombotic thrombocytopenic purpura (TTP) is a rare disease (RD) and hematologic emergency characterized by end-organ damage in the setting of a thrombotic microangiopathy. De Winter and Zeldin contributed equally to this article. We assessed costs from the health system perspective. 2018;132:373. Variations in other parameters, such as changes in SOC arm costs, hospital or ICU LOS, TPE days, or rituximab use, have far less of an impact than caplacizumab cost on overall cost effectiveness of adding caplacizumab to SOC in both decision trees and in our Markov model, whereas a decrease in the utility of the well state significantly increases the ICER. ADAMTS13 activity was measured at a central laboratory at baseline, every week during the treatment period beginning with the first day after the end of daily plasma exchange, and twice during the follow-up period. In 29 of the 120 patients (24%), ADAMTS13 was still severely deficient at the time that the caplacizumab or placebo was stopped. Am J Hematol 2016;91:623-630. Several additional Nb constructs directed against a broad range of autoimmune … For our study, we used 3 times the US GDP, amounting to a WTP of $195 330. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. Sadler JE. Because only HERCULES reported details on hospital LOS and ICU stay, we used these parameters for TITAN. From the Department of Haematology, University College London Hospitals, Cardiometabolic Program, National Institute for Health Research UCLH–UCL Biomedical Research Center, London (M.S. The current treatments — plasma exchange and immunosuppression — replenish functional ADAMTS13 enzyme and control the underlying autoimmune disease but do not directly address the microvascular thrombosis. 23. 2019. In a set of 1-way sensitivity analyses of the Markov model for the TITAN trial, the cost of caplacizumab itself again exerted a greater impact on the ICER of adding caplacizumab to SOC than any other factor analyzed, including number and cost of rituximab treatments, number of TPE days, and ICU and hospital LOS (Figure 4). The time to normalization of the platelet count was also analyzed with the use of a Cox proportional-hazards regression model, with the time to normalization of platelet count as a dependent variable and treatment group and Glasgow Coma Scale category as independent variables (details on the Glasgow Coma Scale categories can be found in the protocol). Continuation of caplacizumab or placebo was to be accompanied by adjustment of immunosuppressive therapy. Purple dashed line represents baseline estimate. (B) Utility of disease state. Rituximab was begun on day 6, when her platelet count … ¶ These outcomes were assessed during the trial treatment period. However, the analysis is a hypothetical best-case scenario in favor of caplacizumab (e.g., providing a cost-utility analysis without having any data on utility for patients with disease progression). Cost-effectiveness analysis of brentuximab vedotin with chemotherapy in newly diagnosed stage III and IV Hodgkin lymphoma, Reforming the orphan drug act for the 21st century, Cost effectiveness of nusinersen in the treatment of patients with infantile-onset and later-onset spinal muscular atrophy in Sweden, Cost-effectiveness of enzyme replacement therapy for Fabry disease, Cost-effectiveness of enzyme replacement therapy with alglucosidase alfa in adult patients with Pompe disease, © 2021 by The American Society of Hematology, Response to Goshua et al (2020) "Cost effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura", Laurence Pollissard (1) Sean D. Sullivan (2), (1) Sanofi, Chilly Mazarin, France; (2) CHOICE Institute, School of Pharmacy, University of Washington, Seattle, WA, USA. To analyze the cost effectiveness of adding caplacizumab to SOC in acquired TTP, we first performed decision tree analyses using data from the TITAN and HERCULES trials, which incorporated the total costs of caplacizumab and rituximab, total days of TPE, number of ICU days, total hospital LOS, TTP recurrence rates, and deaths in the caplacizumab and SOC treatment arms of both trials. They suggest that caplacizumab immediately inhibits the pathophysiological mediator of microthrombosis leading to improvement in organ-damage markers as well as the numbers of exacerbations. Deford CC, Reese JA, Schwartz LH, et al. The authors vouch for the accuracy and completeness of the data and analyses and for the fidelity of the trial to the protocol. Overall, 108 patients completed the trial (i.e., completed all scheduled treatment visits and had their final follow-up visit), and 36 patients who had received at least one dose of caplacizumab or placebo discontinued the trial regimen (13 in the caplacizumab group and 23 in the placebo group). × You've saved your first item. With regard to the model structure we have reason to doubt that the Markov-model developed by Goshua et al. 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. We also assumed that TTP exacerbation (defined in the clinical trials as recurrence of TTP occurring within 30 days after completion of TPE) and relapse (defined as recurrence of thrombocytopenia arising after 30 days of completing daily TPE during a TTP episode) would be equally costly. Peyvandi F, Callewaert F. Caplacizumab for acquired thrombotic thrombocytopenic purpura. We did not include costs associated with bleeding, which were seen at higher rates in the caplacizumab arms of both trials. Time to Confirmed Normalization of the Platelet Count in the Intention-to-Treat Population. 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.
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