Congenital Thrombotic Thrombocytopenic Purpura Research Articles

The economic and social burden of congenital thrombotic thrombocytopenic purpura (cTTP) in Italy

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare genetic disorder characterized by an abnormal clotting process leading to serious health complications such as thrombocytopenia and hemolytic anemia. Despite its clinical significance, the estimated broader economic and social impacts in Italy on patients and society remain underexplored. Methods: A detailed questionnaire, developed and validated by a panel of cTTP experts, was distributed to healthcare professionals and patient associations to gather comprehensive data on the economic and social burden of cTTP in Italy. The study was focused on direct and indirect costs associated with the disease management of 15 patients with cTTP, as well as out-of-pocket expenses incurred by patients. Results: The analysis revealed that of the 15 patients diagnosed with cTTP in Italy, 60% were adults aged 40-55 years. Productivity loss and diminished quality of life dominated the economic burden of cTTP, accounting for 81.05% of total costs. Direct medical costs, while substantial, represented a smaller portion of the overall financial impact. Additionally, out-of-pocket expenses, though constituting the smallest fraction, underscored the financial contributions made by patients towards their own care management. Conclusion: The findings underscore the need for a multidisciplinary and holistic approach to cTTP management that extends beyond the clinical treatment. Addressing the economic and social implications of the disease is crucial for improving patient well-being and ensuring the sustainability of healthcare systems. The study advocates for increased awareness, research, and access to care for cTTP patients, highlighting the importance of comprehensive support networks to mitigate the disease’s broader societal impacts, estimated to be around 2 million euro for 15 patients in 10 years.

The Highs and Lows of ADAMTS13 Activity.

Severe deficiency of ADAMTS13 (<10 iu/dL) is diagnostic of thrombotic thrombocytopenic purpura (TTP) and leads to accumulation of ultra-large vWF multimers, platelet aggregation, and widespread microthrombi, which can be life-threatening. However, the clinical implications of a low ADAMTS13 activity level are not only important in an acute episode of TTP. In this article, we discuss the effects of low ADAMTS13 activity in congenital and immune-mediated TTP patients not only at presentation but once in a clinical remission. Evidence is emerging of the clinical effects of low ADAMTS13 activity in other disease areas outside of TTP, and here, we explore the wider impact of low ADAMTS13 activity on the vascular endothelium and the potential for recombinant ADAMTS13 therapy in other thrombotic disease states.

Thrombotic thrombocytopenic purpura: 100 years of research on Moschcowitz syndrome

AbstractIn the 100 years since Eli Moschcowitz reported the first case of thrombotic thrombocytopenic purpura (TTP), there has been remarkable awareness and progress in the diagnosis and management of this rare blood disorder. This progress initially was the result of careful clinical observations followed by well thought-out therapeutic interventions, with dual goals of both improving outcomes and discerning the pathophysiology of TTP. The discovery of the ADAMTS13 protease set in motion the efforts to more accurately define the specific etiologies of thrombotic microangiopathies (TMAs) based on objective, scientific data rather than clinical characterizations alone. This accurate differentiation led to better and more revealing clinical trials and advancements in the treatment of TTP and other TMAs. Further advances followed and included improvements in immune-suppressive therapy and targeted therapies of immune-mediated TTP (iTTP; caplacizumab) and congenital TTP (cTTP; recombinant ADAMTS13). The longitudinal study of patients with TTP revealed the unexpected risk for long-term complications in both patients with iTTP and those with cTTP in remission. Ongoing studies aim to further understand the prevalence, mechanisms, and appropriate screening for these mood disorders, neurocognitive deficits, and cardiovascular complications that develop at remarkably high rates and are associated with a decreased life expectancy. These discoveries are a result of the collaborative efforts of investigators worldwide that have been fostered by the frequent interactions of investigators via the International TTP Working Group meetings and TMA workshops held regularly at international meetings. These efforts will support the rapid pace of discovery and improved understanding of this rare disease.

Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura

BackgroundCongenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known.MethodsIn this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment.ResultsA total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy.ConclusionsDuring prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.)

Apadamtase Alfa: First Approval.

Apadamtase alfa (ADAMTS13, recombinant-krhn; ADZYNMA), a human recombinant form of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13), is being developed by Takeda under license from KM biologics for thrombotic thrombocytopenic purpura (TTP) and sickle cell disease. On 9 November 2023, apadamtase alfa was approved in the USA for prophylactic and on-demand enzyme replacement therapy (ERT) in paediatric and adult patients with congenital TTP. Apadamtase alfa is under regulatory review for congenital TTP in the EU and Japan, and is under clinical development for immune-mediated TTP in several countries worldwide. Clinical development of apadamtase alfa for vaso-occlusive crisis related to sickle cell anaemia is underway in the USA. This article summarizes the milestones in the development of apadamtase alfa leading to this first approval in the USA for congenital TTP.

Congenital thrombotic thrombocytopenic purpura and recombinant ADAMTS13

Congenital thrombotic thrombocytopenic purpura and recombinant ADAMTS13

Advances in the treatment of thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a fatal thrombotic disease caused by a marked decrease in the activity of ADAMTS13, a von Willebrand factor cleaving protease. In congenital TTP, ADAMTS13 activity is decreased by an abnormality in ADAMTS13, and in acquired TTP, by anti-ADAMTS13 autoantibody. Death from thrombosis in the acute phase has been an issue with conventional treatment of acquired TTP by plasma exchange or immunosuppressive therapy. However, the advent of caplacizumab, an anti-VWF nanobody, has made it possible to suppress thrombus formation and is expected to improve survival rates. In addition, some case series have shown the efficacy of caplacizumab without plasma exchange for acquired TTP, and this approach is being investigated in clinical trials. Fresh-frozen plasma is transfused to supply ADAMTS13 for congenital TTP, but frequent transfusions over a long period of time can lead to problems such as infection and allergic reactions. Novel therapies such as recombinant ADAMTS13 products and gene therapy are now under development, and show promise for future clinical use.

Congenital thrombotic thrombocytopenic purpura in children

Introduction. Congenital thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening genetic disorder characterized by recurrent episodes of microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction due to the defi ciency or dysfunction of the ADAMTS13 enzyme. Despite the availability of clinical and laboratory diagnostic criteria the diagnosis remains challenging due to a wide range of diseases with similar appearance.Aim: to analyze the clinical manifestations and treatment results of identifi ed cases of congenital TTP at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology.Methods. This article reviews 11 clinical cases with congenital TTP genetically confi rmed or with typical clinical and laboratory signs.Results. Clinical and laboratory signs of TTP are highly variable and nonspecifi c, which was observed in the described cohort of patients. One of the trigger factors is often an acute respiratory viral infection, and stabilization of the disease can occur after transfusions of blood components. A delay of diagnosis can often lead not only to a delay of correct therapy, but also to the prescription of wrong therapy. The main diagnosis confi rmatory method was a molecular genetic test, which was carried out in 8 cases. All patients diagnosed with congenital TTP were successfully treated with FFP therapy.Conclusion. Early diagnosis of TTP is diffi cult due to the lack of specifi c clinical manifestations and easily accessible laboratory tests

Pregnancy-Related Outcomes in Patients with Congenital Thrombotic Thrombocytopenic Purpura: Post Hoc Analysis of a Retrospective Chart Review Study

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening inherited deficiency of the von Willebrand factor-cleaving metalloprotease, ADAMTS13, leading to consumptive thrombocytopenia due to microvascular thrombosis. Symptoms typically present either in early infancy, in adulthood during pregnancy, or in association with systemic infections, periods and conditions in life that are associated with an increased risk of acute cTTP episodes. Prophylaxis with plasma or plasma-derived therapies to replenish ADAMTS13 are commonly used. Limited evidence is available about the clinical burden of cTTP among female patients during pregnancy. Aims: A chart review was undertaken to gain insight into the natural history of cTTP, short- and long-term clinical outcomes, burden of disease, and treatment patterns. A post hoc analysis aimed to assess the clinical characteristics, treatment patterns and outcomes of patients with cTTP during pregnancy. Methods: An international, multi-center, retrospective chart review collected data from January 01, 2009 to December 31, 2020. Patients with cTTP were included if they were diagnosed with cTTP, received therapeutic intervention for cTTP, or had a cTTP-related clinical event recorded between January 01, 2009 and December 31, 2017 (index identification period). Patients were followed from their study index date until loss to follow-up, enrollment in a clinical trial, death, or the end of the study period. Ethics approval and informed consent were obtained where applicable. Data presented are from a post hoc analysis which assessed clinical characteristics and outcomes during pregnancy in female patients who were &amp;gt;14 years of age at study index. Results:A total of 78 patients with cTTP were identified during the index identification period and included in the analysis, 61 (78%) were female and the median (IQR) age at diagnosis was 26.5 (14.5-37.0) years. Overall, 92 acute episodes were reported by 55 of the 78 patients included in the analysis. Triggers for acute episodes were recorded in 46 of the 92 episodes, with infection (n=21/46) and pregnancy (n=17/46) being the most common. Prophylaxis was administered in 47/78 patients, with pregnancy (n=13/47) and clinical symptomatology (n=13/47) being the most common reasons to initiate prophylaxis. Information regarding pregnancy was collected from 55 female patients who were aged &amp;gt;14 years at study index. Of these 55 patients, 45 reported ≥1 pregnancy and 30 were diagnosed with cTTP during or immediately after pregnancy. One or more pregnancy-related complications were reported by 26/45 patients who were ever pregnant. The most common complication was fetal death or pregnancy loss which was reported in 16/45 patients (Table 1). Of the 55 female patients &amp;gt;14 years of age at study index, 41 had documented acute episodes during the study period, of whom 22 were pregnant at the time an episode occurred. Each of these 22 patients experienced 1 acute episode while pregnant during the study. Twenty-six pregnancy-related complications were reported during 18 of these 22 acute episodes (Table 2). The most frequently reported were fetal death or pregnancy loss (n=8), hemolysis, elevated liver enzymes and low platelet count (n=7; HELLP syndrome), and pre-eclampsia (n=6). A total of 54 treatments (plasma exchange [PEX], fresh frozen plasma [FFP], steroids, red blood cell transfusion, platelet transfusion, caesarean section, intravenous immunoglobulins, rituximab, and hemodialysis) were received by the 22 pregnant patients who experienced an acute episode while pregnant during the study period. Forty-four treatments were administered for acute episodes associated with pregnancy-related complications. Of the 54 treatments administered, PEX (n=15/54) and FFP (n=11/54) were the most common. Conclusions: Data from this chart review show that a high proportion of pregnant patients with cTTP experience pregnancy-related complications which could result in poor fetal and maternal outcomes. Pregnancy is a common trigger for acute cTTP episodes and initiation of prophylaxis. Despite current therapeutic interventions, pregnancy-related complications represent a high clinical burden for cTTP patients. Novel therapies with demonstrated efficacy and safety profiles are needed to address the poor clinical outcomes experienced by pregnant patients with cTTP.

Quantitative System Pharmacology Modeling of the Effect of Recombinant ADAMTS13 on Platelets in Patients with Congenital Thrombotic Thrombocytopenic Purpura

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, thrombotic microangiopathy due to an inherited deficiency of the von Willebrand factor (VWF)-cleaving protease, ADAMTS13.Accumulation of ultra-large VWF multimers increases blood clot formation in small blood vessels, leading to a low platelet count (thrombocytopenia). Treatment of cTTP consists of ADAMTS13 replacement with infusions of plasma-based therapies (PBT). Recombinant ADAMTS13 (rADAMTS13; Takeda Development Center Americas, Inc., Lexington, MA, USA) is in development for patients with cTTP.The ultra-rare nature of cTTP limits the sample size for a formally powered study to assess the impact of ADAMTS13 supplementation on efficacy outcome. This study was a proof-of-principle that model-based clinical trial simulations can be used to supplement clinical trial data in ultra-rare indications. Aims: To calibrate and validate a quantitative system pharmacology (QSP) model describing a mechanistic relationship between ADAMTS13, VWF and platelet numbers in patients with cTTP who received long-term prophylaxis with rADAMTS13 or PBT (fresh frozen or solvent/detergent treated plasma). In addition, to evaluate the treatment benefits of rADAMTS13 versus PBT using clinical trial simulations in virtual patients with cTTP as a supplement to the cTTP phase 3 study (NCT03393975) data. Methods: A QSP model was built using i) in vitro enzyme kinetic data and preclinical experimental data following administration of recombinant VWF and rADAMTS13 in ADAMTS13 knockout (KO) mice, and ii) data from the literature including platelet count and VWF activity from healthy human and untreated patients with cTTP. These data were used to calibrate the parameters corresponding to interactions between ADAMTS13 activity, VWF activity, and platelets. The model was validated against literature data from patients with cTTP treated with PBT and with data from a phase 2 study of patients with immune-mediated TTP treated with rADAMTS13 (NCT03922308). The model was then calibrated to longitudinal platelet data from the cTTP phase 3 study, in which patients with cTTP received prophylaxis for 6 months with PBT (exposure equivalent to ~10 IU/kg ADAMTS13 in the form of 10-20 mL/kg doses) and rADAMTS13 (40 IU/kg) either once every week (Q1W) or once every 2 weeks (Q2W) dosing intervals . The model was used to provide 1-year clinical trial simulations of isolated thrombocytopenia occurrences in a population of 1,000 virtual patients, phenotype-matched to patients in the cTTP phase 3 study. Results:Virtual clinical trial simulations using the QSP model suggested that rADAMTS13 administered over 1 year with a Q1W or Q2W schedule results in significantly fewer patients experiencing occurrences of thrombocytopenia (platelet count threshold of &amp;lt;150 x 10 9/L) compared to patients treated with PBT (hazard ratio [HR] relative to Q2W PBT: Q1W PBT, HR = 0.62; Q2W rADAMTS13, HR = 0.47; Q1W rADAMTS13, HR = 0.18). The treatment difference between rADAMTS13 and PBT was even more pronounced when a thrombocytopenia threshold of &amp;lt;100 x 10 9/L was used (Figure and Table). Simulations also predicted a prophylactic carry-over effect on platelets, with approximately 20 days taken to reach 90% of the long-term average platelet count when switching from rADAMTS13 to PBT or from PBT to rADAMTS13. A correlation analysis for a Q2W dosing of rADAMTS13 demonstrated that ADAMTS13 trough activity (C trough, Spearman ρ = 0.96) and time with ADAMTS13 activity above 10% (Spearman ρ = 0.93) showed stronger correlations with increased platelet count than the maximum plasma ADAMTS13 activity level (C max, Spearman ρ = 0.68). A correlation analysis for a Q1W dosing frequency produced similar results.Mean time above 10% ADAMTS13 activity was higher following rADAMTS13 versus PBT administration (5.2 vs 1.7 days). Conclusions: This model-based virtual clinical trial simulation predicts that dosing with rADAMTS13 would provide &amp;gt;50% reduction in the HR of thrombocytopenia occurrences over PBT. Patients may also have a higher level of protection for 2-3 weeks when switching from rADAMTS13 to PBT. These findings supplement the assessment of clinical benefit of rADAMTS13 in the cTTP phase 3 study and show that increased ADAMTS13 activity following rADAMTS13 administration is likely to reduce occurrences of thrombocytopenia in cTTP.

Clinical Outcomes of Congenital Thrombotic Thrombocytopenic Purpura: A Multinational Chart Review Study

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening genetic disorder. Severe deficiency of the von Willebrand factor-cleaving metalloprotease ADAMTS13 results in the formation of platelet-rich microthrombi, leading to platelet consumption and thrombocytopenia. Current treatment strategies primarily focus on replenishing ADAMTS13 through plasma-derived products. Research into the natural history of cTTP, clinical outcomes, disease burden, and treatment patterns is limited. Aims: The primary objectives of this chart review were to describe the characteristics of cTTP patients, and the prevalence and incidence of clinical manifestations of cTTP and its complications. The secondary objectives were to describe the treatment patterns, treatment-related outcomes, and healthcare resource utilization in patients with cTTP. Methods: This retrospective chart review, conducted across 9 sites in France, Germany, Italy, Spain, Switzerland, the United Kingdom, and the United States, collected patient-level data from medical records between January 1, 2009 and December 31, 2020. Patients with cTTP were included if they experienced any of the following index events between January 1, 2009 and December 31, 2017: diagnosis with cTTP, receipt of prophylactic treatment for cTTP, receipt of treatment on demand for an acute cTTP episode or isolatedthrombotic thrombocytopenic purpura (TTP) manifestation; or another cTTP-related major clinical event (Table 1). The date of the first qualifying index event was defined as the study index date. Patients were followed until loss to follow-up, enrollment in a clinical trial, the end of the study period, or death. All results were summarized using descriptive statistics. Ethics approval and informed consent were obtained where applicable. Results: A total of 78 patients met the criteria for inclusion with a mean (SD) follow-up of 8.1 (3.1) years. The mean (SD) age at initial cTTP diagnosis and study index were 26.2 (17.3) years and 29.5 (15.7) years, respectively. Most patients were female (78.2%). The initial diagnosis was characterized clinically by systemic (n=44, 56.4%), neurological (n=26, 33.3%), gastrointestinal (n=23, 29.5%) and renal (n=22, 28.2%) manifestations (Table 2). A total of 92 acute cTTP episodes were reported by 55/78 (70.5%) patients during the study period, resulting in an event rate of 0.145 episodes per person-year (PPY). Most episodes (n=70/92, 76.1%) resolved without complications, 16/92 (17.4%) resolved but resulted in organ damage, and 2/92 (2.2%) resulted in death. The majority of acute cTTP episodes (n=85/92, 92.4%) required hospitalization, with 32/85 (37.6%) resulting in intensive care unit (ICU) admission. Four isolated TTP manifestations were reported at study index, all required hospitalization, with 1 patient admitted to ICU. A total of 64 isolated TTP manifestations were documented in 29 patients (37.2%) during the study period. The event rate of isolated TTP manifestations was 0.101 events PPY. Thrombocytopenia was the most commonly reported (n=49/64, 76.6%) symptom of isolated TTP manifestations recorded during the study period. Clinical resolution was achieved in most isolated TTP manifestations (n=58/64, 90.6%) and none resulted in death. Organ damage was reported in 22/78 (28.2%) patients during acute episodes during the study period or during isolated TTP manifestations at index, of which neurological (n=15), renal (n=11), and cardiac (n=8) damage were most common. Prophylaxis was initiated in 47/78 patients, with clinical symptoms (n=13/47, 27.7%) and pregnancy (n=13/47, 27.7%) as the most common reasons for initiation. Of the 65 prophylactic treatments administered, 41 (63.1%) were stopped or interrupted with the most common reasons being pregnancy (n=17; childbirth, stillbirth, prophylaxis during pregnancy), failure to achieve normalization of levels (n=6), and normalization of levels achieved (n=3). Conclusions: These findings demonstrate a substantial burden arising from disease-related manifestations in cTTP patients. Managing patients with cTTP is additionally burdensome to healthcare systems as many patients require multiple hospital and ICU stays. Novel, effective therapies with demonstrated efficacy and safety profiles may offer substantial benefits to patients and healthcare systems.

Preferences of Patients with Congenital Thrombotic Thrombocytopenic Purpura and Other Chronic Conditions for in-Home Prophylactic Infusions

Background Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening, thrombotic microangiopathy caused by an inherited deficiency of the von Willebrand factor (VWF)-cleaving enzyme ADAMTS13. Current treatment approaches include replacement therapy with intravenous (IV) infusions of either fresh frozen plasma, solvent/detergent-treated plasma, or factor VIII/VWF concentrates administered in a hospital/clinical setting. There is recent interest in novel treatments for cTTP and other chronic conditions where patients may be able to receive treatment at home with limited risk and a manageable safety profile compared to outpatient treatment. Understanding patient preferences regarding treatment at home vs an outpatient setting could help to inform approaches to patient care for both cTTP and other chronic conditions. Aims The primary objective was to assess stated preferences of patients with either cTTP or another chronic condition requiring treatment with regular IV infusions (listed in Table 1) toward prophylactic infusions administered at home vs in an outpatient setting. Secondary objectives were to estimate the utility and disutility of 7 attributes (listed in Table 2) associated with patient preferences and to assess whether clinical, sociodemographic, or other factors influence patient preferences. Methods This cross-sectional cohort study utilized an online discrete choice experiment survey, in which patients were presented with pairwise choice sets consisting of 7 attributes and their associated levels (listed in Table 2). In the survey, each patient was asked to choose their preferred alternative in a choice set (repeated 16 times) using different combinations of varying attribute levels for all 7 attributes, using an orthogonal experimental design. The survey also included a time trade-off exercise to enable the attribute levels to be adjusted for quality adjusted life years. The survey was conducted in France, Germany, Spain, the UK, and the US. Patients ≥18 years old with either cTTP or another chronic condition (listed in Table 1) who were receiving prophylactic IV infusions for ≥3 months, in either an outpatient setting or a hybrid outpatient and at-home setting, were eligible for inclusion. Treatment frequency ranged from once a week to once every 3 weeks. Data were analyzed using multinomial logit regression models. Results In total, 307 complete patient responses (France, n=18; Germany, n=95; Spain, n=96; UK, n=7; US, n=91) were included in the analyses. Median (range) age was 44.0 (20.0-78.0) years and 25 patients (8.1%) had cTTP ( Table 1). Overall, 137 patients (44.6%) reported an overall preference for receiving infusions at home, 85 patients (27.7%) reported a preference for receiving treatment in a hospital/clinic, and 85 patients (27.7%) reported a preference for receiving treatment via a hybrid outpatient and at-home setting. The majority of patients would prefer either a doctor or a nurse to administer their treatment at home (n=125, 40.7%). Patients placed significantly greater value on certain treatment-setting attributes ( Table 2); being comfortable with the treatment environment was considered the most important attribute. For the ‘convenience and impact on daily life’ attribute, selection of ‘flexibility in scheduling infusions’ was influenced by age (estimate: 0.019, 95% CI: 0.007; 0.032), and whether the patient had been diagnosed &amp;gt;5 years ago vs &amp;lt;1 year ago (estimate: 0.744, 95% CI: 0.255; 1.269). A high proportion of patients (60.9%) were willing to trade 12 months of their lives to receive treatment at home. Also, 59.0% and 56.4% of patients, respectively, were willing to trade 12 months to ensure that complications did not necessitate treatment in a hospital setting and that travelling to a hospital/clinic was not required to receive prophylaxis. Conclusions The majority of patients with cTTP or another chronic condition requiring treatment with regular IV infusions stated that they would prefer to receive treatment at home with support from healthcare providers. A high proportion of patients were also willing to trade 12 months of their lives to receive treatment at home; a limitation of the time trade-off exercise was that the maximum time that could be traded was 12 months. These findings provide insights into the importance of the treatment setting preferences of patients receiving prophylactic infusions.

Recombinant ADAMTS13 for the Treatment of Acute TTP Events in Patients with Congenital Thrombotic Thrombocytopenic Purpura: Results from the Phase 3 Randomized, Controlled, Crossover Study and the Phase 3b Continuation Study

Background Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening thrombotic microangiopathy caused by an inherited deficiency of the enzyme ADAMTS13. An ongoing phase 3 study (NCT03393975) and phase 3b continuation study (NCT04683003) are investigating the safety and efficacy of recombinant ADAMTS13 (rADAMTS13; TAK-755; Takeda Development Center Americas, Inc., Lexington, MA, USA) for prophylaxis and on-demand treatment of acute events in patients with cTTP. Aims To assess the efficacy and safety of rADAMTS13 for the treatment of acute TTP events and long-term prophylaxis in patients with severe cTTP. Methods The phase 3 prospective, randomized, controlled, open-label, multicenter, crossover study (NCT03393975) is open to enroll patients 0-70 years old with severe cTTP (ADAMTS13 activity &amp;lt;10%). Upon completion of the phase 3 study, patients could enroll into the phase 3b prospective, open-label, multicenter, single treatment arm continuation study (NCT04683003). In the phase 3 study, patients were randomized 1:1 at enrollment to receive prophylaxis with either rADAMTS13 or standard of care (SoC). SoC was determined by the treating physician and could include fresh frozen plasma, pooled solvent/detergent-treated plasma, or factor VIII/von Willebrand factor concentrates. Patients in the phase 3b continuation study received open-label rADAMTS13 treatment. In both studies, patients could be enrolled and receive treatment on demand for acute TTP events. Per protocol, rADAMTS13 was to be administered at 40 IU/kg on Day 1, 20 IU/kg on Day 2 and 15 IU/kg daily from Day 3 onwards until 2 days after resolution of the acute event (defined as platelet count either ≥150,000/μL or within 25% of baseline; and elevation of LDH levels ≤1.5× of baseline or ≤1.5× the upper limit of normal). Data are presented from a pre-planned interim analysis (data cutoff: August 12, 2022) and focus on the treatment of acute TTP events in both studies. Results At the time of the data cutoff, 8 acute TTP events were reported in 7 patients ( Table), all of whom were ≥18 years old. None of the events occurred while the patient was receiving rADAMTS13 prophylaxis. Six events occurred in 5 patients (median age: 20.0 years; sex: 3 male, 2 female) who received on-demand treatment in the phase 3 study; 2 of these patients were randomized to receive rADAMTS13 and 3 to receive SoC. One event also occurred in the phase 3 study while the patient was receiving prophylaxis with SoC. One event occurred in the screening period prior to the patient starting rADAMTS13 prophylaxis in the phase 3b continuation study; this event was treated with rADAMTS13. Platelet counts observed during the first 3 days of treatment for all 8 acute TTP events are shown in the Figure. Prior to study treatment, on Day 0, the mean platelet counts were similar between the rADAMTS13 and SoC cohorts. Over the first 3 treatment days, the mean platelet count increased more than ~5-fold with rADAMTS13, and ~3-fold with SoC. All three acute TTP events treated with rADAMTS13 resolved without requiring the administration of any other treatment containing ADAMTS13. Based on pharmacokinetics (PK) data available in 5 patients (3 received treatment with rADAMTS13 and 2 with SoC), the post-infusion ADAMTS13 activity levels ~1 hour after administration were between 80% to 270% of normal with rADAMTS13 and between 10% to 48% with SoC. These observed ADAMTS13 activity levels were as expected based on the linear PK observed following single dose PK assessments in the phase 3 study. Of the 4 patients who received SoC for the treatment of an acute TTP event, 2 experienced a mild treatment-emergent adverse event (TEAE) that was considered related to the SoC (nausea and pruritis). Of the 3 patients who received rADAMTS13, 1 patient experienced 3 mild TEAEs (feeling hot, nausea, and thrombocytosis) that were considered related to rADAMTS13. No serious TEAEs related to rADAMTS13 were reported and no neutralizing antibodies against ADAMTS13 were observed. Conclusions The resolution of acute TTP events and an improvement in platelet count in patients with cTTP following treatment with rADAMTS13 was closely related to higher ADAMTS13 activity exposure. No serious TEAEs related to rADAMTS13 were reported.

Population Pharmacokinetics and Exposure-Response Analyses to Demonstrate the Link of Causality between ADAMTS13 and the Clinical Effects of Recombinant ADAMTS13 Compared to Plasma-Based Therapies

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening deficiency of ADAMTS13. TTP clinical manifestations include thrombocytopenia and microangiopathic hemolytic anemia (MAHA) but incomplete understanding of their relationship to ADAMTS13 exposure is a challenge for assessing the impact of ADAMTS13 supplementation. Integrated population pharmacokinetics (PopPK) analysis and exposure-response modeling were conducted to support the clinical benefit assessment of recombinant ADAMTS13 (rADAMTS13; Takeda Development Center Americas, Inc., Lexington, MA, USA) in patients with cTTP. Aims: To characterize ADAMTS13 activity following intravenous (IV) administration of rADAMTS13 or plasma-based therapies (PBT) in patients with cTTP, to identify sources of variability, and to evaluate the relationship between ADAMTS13 activity and the probability of isolated TTP manifestations. Methods:The PopPK analysis included data from phase 1 (NCT02216084), pivotal phase 3 (NCT03393975), and phase 3b continuation (NCT04683003) studies of rADAMTS13. Exposure-response analyses included data from NCT03393975 where patients received rADAMTS13 or PBT in prophylaxis treatment period 1 and crossed over to the opposite treatment in period 2. PBT consisted of fresh frozen plasma, solvent/detergent-treated plasma or factor VIII/von Willebrand factor concentrates. A covariate analysis was conducted to identify sources and assess the significance of variability on the PK of ADAMTS13 activity. Exposure-response models were developed to assess the relationship between the average ADAMTS13 plasma activity for a given dosing interval (C ave) and the count of isolated TTP manifestations: thrombocytopenia (platelet count decreased ≥25% of baseline or a platelet count &amp;lt;150,000/µL) or MAHA (increased lactate dehydrogenase &amp;gt;1.5 × of baseline or &amp;gt;1.5 × upper limit of normal). Cox proportional hazard modeling using recurring events was performed to demonstrate the treatment effect of rADAMTS13 over PBT, and explain carry-over prophylactic effects. Repeated time to event was performed using longitudinal data from all periods to demonstrate ADAMTS13-dependent reduction in the hazard of thrombocytopenia. Results: A 2-compartment PK model with linear elimination adequately characterized the time profiles of ADAMTS13 activity following body-weight-based IV administration of rADAMTS13 or PBT (N=65 patients). Following body-weight-based dosing, dosing interval (once per week [Q1W] vs every 2 weeks [Q2W]) and treatment type (rADAMTS13 vs PBT) were the only significant extrinsic factors found with an impact on ADAMTS13 PK. ADAMTS13 C ave was associated with a significant reduction of the thrombocytopenia hazard in an activity-dependent manner (Figure). Exposure-response model simulations suggested that &amp;gt;95% of patients treated with rADAMTS13 are predicted to have plasma C ave ADAMTS13 &amp;gt;0.13 IU/mL (equivalent to 13% activity), with high (&amp;gt;70%) protection against thrombocytopenia regardless of dosing intervals (Q2W or Q1W) and age. In contrast, a similar level of protection against thrombocytopenia is expected in only ~10% of patients treated with PBT (Table). Similarly, a significant exposure-response relationship was identified between ADAMTS13 C ave and MAHA.In treatment period 1, rADAMTS13 was associated with a higher probability of zero counts of thrombocytopenia versus PBT from week 2 onwards. Patients switching from rADAMTS13 to PBT in period 2 initially had a slightly higher probability of having zero counts of thrombocytopenia than patients switching from PBT to rADAMTS13, suggesting that treatment with rADAMTS13 led to a carry-over prophylactic effect maintained for some time after treatment cessation. Conclusions: Besides body-weight-based dosing, no additional dose adjustments of rADAMTS13 are needed in the cTTP patient population. A consistent and significant ADAMTS13 activity-response relationship was identified in which rADAMTS13 reduced the hazard of objective laboratory based TTP manifestations (thrombocytopenia and MAHA) in an activity-dependent manner. Overall, these findings suggest that rADAMTS13 at 40 IU/kg Q2W or Q1W offers a favorable prophylactic treatment effect over PBT that is attributable to higher ADAMTS13 activity.

The Use of a Large Electronic Health Records System to Define and Characterize a Thrombotic Thrombocytopenic Purpura Population

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening microangiopathy due to a deficiency of the von Willebrand factor (VWF)-cleaving protease ADAMTS13. Microangiopathic hemolytic anemia, severe thrombocytopenia and ischemic end organ injury due to microvascular thrombi are the defining features of TTP. TTP can be caused by auto-antibodies against ADAMTS13 enzyme (immune TTP [ITTP]) or by inherited mutations of the ADAMTS13 gene (congenital TTP [CTTP]). Therapeutic plasma exchange (TPE) to replenish ADAMTS13, with or without steroids, has been the mainstay of treatment. Due to the auto-immune nature of ITTP the International Society on Thrombosis and Hemostasis (ISTH) made a strong recommendation in 2020 to add corticosteroids to TPE for ITTP and a conditional recommendation to add the CD20 inhibitor rituximab as well the VWF monoclonal antibody caplacizumab. Objective: To define and characterize TTP in a living population from a large electronic health record (EHR) database in terms of disease prevalence, demographic characteristics and therapeutic interventions and procedures in light of recent ISTH guidelines. Methods: We conducted a study of data from TriNetX Analytics Network, which contains EHRs from &amp;gt;140 million individuals from 79 Health Care Organizations in the US. We used ICD-10-CM diagnosis codes, ATC and CPT codes applied in the last 10 years to evaluate TTP disease prevalence, therapeutic interventions and procedural interventions respectively. Eligibility criteria applied to define the TTP cohort were as follows: Inclusion criteria: ICD-10 M31.1 diagnosis of thrombotic microangiopathy (TMA)History of thrombocytopenia (platelet volume ≤150,000 per microliter)ICD-10-PCS code for pheresis of plasma or a CPT code for therapeutic apheresis, for plasma pheresis Exclusion criteria: ICD-10-CM codes linked to etiologies of TMA other than TTP (hemopoietic stem cell-associated TMA [M31.11], hemolytic uremic syndrome [D59.3], disseminated intravascular coagulation [D65], antiphospholipid syndrome [D68.61], malignant hypertension [I10, I15])Deceased Results: As of July 31, 2023, there were a total of 142,046,930 living individuals registered in the database in the last 10 years. Of these, 560 individuals met eligibility criteria to define the TTP population (prevalence 0.0004% or 4 cases per million). Demographic characteristics included mean age at diagnosis (39.3 years [SD=14.3]), gender (73% female, 27% male), race (White = 44%, Black or African American = 33%, Asian = 3%, Other or unknown = 20%) and ethnicity (Not Hispanic or Latino = 73%, Unknown = 16%, Hispanic or Latino = 12%). Therapeutic interventions included systemic glucocorticoids (93% [prednisone 84%, methylprednisolone 68%, hydrocortisone 46%, dexamethasone 38%, triamcinolone 14%, betamethasone 9%, prednisolone 5%]), antithrombotics (86% [heparin group 79%, platelet aggregation inhibitors {excluding heparin} 29%, enzymes 27%, other antithrombotic agents {including caplacizumab} 18%, vitamin K antagonists 7%, direct factor Xa inhibitors 7%, direct thrombin inhibitors 2%]) and CD20 inhibitors (including rituximab) (40%). Conclusion: This this is the first report to define and characterize a TTP population from a large US EHR database using a combination administrative codes and laboratory data. The study found a very low prevalence rate; that closely aligns with previously published estimates from registries of 4-5 cases per million for ITTP and 1-2 cases per million for CTTP. It was not possible to differentiate between CTTP and ITTP cases in this study due to a lack of ADAMTS13 genomic data. Demographic findings were consistent with previous registry data (median age of acute TTP presentation in the third to fourth decade of life, typically affecting females more than males). We found a high level of systemic glucocorticoid use as expected, but also high percentage of patients treated with rituximab in line with recent ISTH guidance. The authors are aware of other potential treatments in early development including gene therapy candidates for CTTP and cell therapy candidates for ITTP. This represents a tantalizing prospect for this population; however, to demonstrate efficacy and safety, these new therapies will require scientifically rigorous and well planned clinical studies including robust long-term follow-up.

Novel ADAMTS13 mutations in a patient with congenital thrombotic thrombocytopenic purpura

ABSTRACTCongenital thrombotic thrombocytopenic purpura (TTP) is a rare autosomal recessive genetic disorder caused by mutations in the ADAMTS13 gene. Approximately 200 mutations of the ADAMTS-13 gene have been identified, although only a few have been characterized through in vitro expression studies. We conducted an investigation on a male congenital TTP patient with reduced plasma levels of ADAMTS13 activity. DNA sequence analysis revealed two mutations on chromosome 9 (1.9q34.2) in the patient’s ADAMTS13 gene. One mutation was a non-synonymous mutation (exon 5: c.A530G: p.Y177C), while the other was a nonsense mutation (exon 21: c.G2651A: p.W884X). Both mutations were found to be heterozygous. The patient’s parents had no history of thrombocytopenia or neurological symptoms. DNA sequence analysis showed the patient’s father was a heterozygote for the nonsense mutation of the ADAMTS13 gene (exon 21: c.G2651A: p.W884X), while the mother was a heterozygote for the non-synonymous mutation of the ADAMTS13 gene (exon 5: c.A530G: p.Y177C). To investigate the mechanism behind ADAMTS13 deficiency in this patient, wild type (WT), ADAMTS13 p.Y177C, and ADAMTS13 p.W884X were transiently expressed in 293-6E cells. Expression studies revealed a significant reduction in enzyme activity and secretion, although the protease was detected within the cells. The 3D structures of the natural and mutated ADAMTS-13 proteins were partially reconstructed using the Phyre2 web server. The mutation that replaces the tyrosine residue at amino acid position 177 with cysteine may result in decreased steric hindrance and a looser structure. This mutation affects the binding of calcium ions and the secretion of the enzyme from intracellular to extracellular compartments.

PB0322 Burden of Illness Associated with Congenital Thrombotic Thrombocytopenic Purpura: A Systematic Review

PB0322 Burden of Illness Associated with Congenital Thrombotic Thrombocytopenic Purpura: A Systematic Review

OC 14.2 Pharmacokinetic Characteristics of ADAMTS13 in Patients with Congenital Thrombotic Thrombocytopenic Purpura: Interim Results from a Phase 3 Randomized, Controlled, Open-Label, Crossover Study

OC 14.2 Pharmacokinetic Characteristics of ADAMTS13 in Patients with Congenital Thrombotic Thrombocytopenic Purpura: Interim Results from a Phase 3 Randomized, Controlled, Open-Label, Crossover Study

PB0335 Medical Education in Congenital Thrombotic Thrombocytopenic Purpura Significantly Improves Competence in Making Appropriate Management Choices

PB0335 Medical Education in Congenital Thrombotic Thrombocytopenic Purpura Significantly Improves Competence in Making Appropriate Management Choices

PB1117 Congenital Thrombotic Thrombocytopenic Purpura: Identification of Two Heterozygous Mutations in Splice Sites through NGS Sequencing

PB1117 Congenital Thrombotic Thrombocytopenic Purpura: Identification of Two Heterozygous Mutations in Splice Sites through NGS Sequencing