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Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening thrombotic microangiopathy, with an untreated mortality rate of >90%. Prompt treatment with therapeutic plasma exchange (TPE) and immunosuppression improves outcomes in patients with aTTP, but 10-20% of patients still die acutely from this disease. The aim of this analysis was to describe in more detail the characteristics and disease courses of the patients who died during the caplacizumab clinical development program. Methods: Patient narratives on all deaths occurring during the phase 2 TITAN and phase 3 HERCULES studies were extracted. Results: In the overall study periods, a total of 6 patients died, 2 patients enrolled in TITAN (Patients 1 and 2) and 4 patients enrolled in HERCULES (Patients 3-6). Five patients received placebo, while 1 (Patient 6) received caplacizumab. Demographics and baseline disease characteristics are summarized in Table 1. The patient narratives are provided below. Patient 1 (placebo) was a 57-year-old male, with a recurrent episode of aTTP. Baseline platelet count was 25 x109/L and ADAMTS13 activity Patient 2 (placebo) was a 49-year-old female, with an initial presumed aTTP episode. Baseline platelet count was 7 x109/L and baseline ADAMTS13 activity was 75%. The patient did not respond to therapy (TPE and corticosteroids), with platelet counts remaining below 35 x109/L over the whole period. On Day 10 of the study, the patient experienced a cerebral hemorrhage, for which study drug treatment was permanently discontinued. The patient was intubated and died the next day of cerebral hemorrhage. Patient 3 (placebo) was a 62-year-old female with an initial aTTP episode. Baseline platelet count was 18 x109/L and ADAMTS13 activity Patient 4 (placebo) was a 72-year-old female with an initial aTTP episode. Baseline platelet count was 21 x109/L and baseline ADAMTS13 activity was Patient 5 (placebo) was a 30-year-old female enrolled with her third aTTP episode. Baseline platelet count was 21 x109/L and ADAMTS13 activity Patient 6 (caplacizumab) was a 77-year-old female with her initial aTTP episode. Baseline platelet count was 38 x109/L and ADAMTS13 activity Conclusion: Although the use of TPE and immunosuppression reduces mortality in patients with aTTP, the disease is still associated with a substantial risk of mortality. The fact that all 5 immediate deaths occurred in the placebo arm suggests that the use of caplacizumab has the potential to reduce acute mortality in patients with aTTP. Table 1. Baseline demographics and disease characteristics. Table 1 Disclosures Cataland: Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Scully:Alexion: Consultancy; Ablynx/Sanofi: Consultancy; Novartis: Consultancy; Shire/Takeda: Consultancy; Shire: Research Funding. Peyvandi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria; Kedrion: Honoraria; Alnylam: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Octapharma: Research Funding. Knoebl:Roche: Consultancy; Shire/Takeda: Consultancy; Novo-Nordisk: Consultancy, Research Funding; CSL-Behring: Consultancy; Ablynx/Sanofi: Consultancy. Kremer Hovinga:Ablynx/Sanofi: Consultancy, Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Shire: Consultancy, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology), Research Funding; CSL-Behring: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Roche: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Siemens: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology). Coppo:Ablynx/Sanofi: Consultancy; Alexion: Consultancy; Shire: Consultancy. Metjian:Genentech: Consultancy, Research Funding; AblynxNV/Sanofi: Consultancy, Research Funding. De La Rubia:Takeda: Consultancy; AMGEN: Consultancy; Janssen: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy. Pavenski:Ablynx: Honoraria, Research Funding; Bioverativ: Research Funding; Shire: Honoraria; Octapharma: Research Funding; Alexion: Honoraria, Research Funding. De Winter:Ablynx, a Sanofi company: Employment. Callewaert:Sanofi (formerly employed by Ablynx, a Sanofi company): Employment.

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is an acute, life-threatening thrombotic microangiopathy that requires urgent and specialized treatment. Prior to the introduction of caplacizumab, the treatment for aTTP was based on daily therapeutic plasma exchange (TPE; to replenish functional ADAMTS13 enzyme) plus immunosuppression (mainly corticosteroids and rituximab; to suppress anti-ADAMTS13 autoantibody production). TPE combined with immunosuppressive therapy improved outcomes in patients; however, episodes of aTTP are still associated with an acute mortality of up to 20% as these therapies do not have an immediate effect on the pathologic microvascular thrombosis. The primary results of the randomized, double-blind, placebo-controlled phase 3 HERCULES study showed that, in combination with TPE and corticosteroids, caplacizumab shortened the time to platelet count response and reduced the incidence of a composite outcome of TTP-related death, exacerbation, or major thromboembolic events, by inhibiting vWF-platelet interaction and, thereby, stopping the formation of microthrombi. As additional immunosuppression per local practice was permitted in HERCULES, the present analysis aimed to determine whether there was any difference in the efficacy of caplacizumab according to the initial immunosuppression regimen. Methods: Data of patients participating in HERCULES were stratified based on the type of first-line immunosuppression regimen (i.e. therapy started up to Day 3 of the treatment period) and analyzed descriptively. The main 2 groups analyzed were those receiving corticosteroids only and those receiving a combined regimen of corticosteroids and rituximab. Differences in dose or dosing frequency were not taken into consideration in this descriptive analysis. Results: Of the 145 randomized patients in the HERCULES study, 112 (77.2%) patients received only corticosteroids as first-line immunosuppressive therapy, while 24 (16.6%) patients received corticosteroids and rituximab (initiated within the first 3 days of the study). Three patients (2.1%) received another type of initial immunosuppression (cyclophosphamide + corticosteroids [n=1], hydroxychloroquine [n=1], and mycophenolate mofetil + corticosteroids [n=1]), 1 patient (0.7%) started immunosuppression later in the study (cyclophosphamide + corticosteroids), while 5 patients (3.4%) did not receive any immunosuppressive treatment during the study. Baseline characteristics between the main 2 subgroups were well balanced (Table 1). Immunosuppressive therapy intensification occurred in 38 patients (33.9%) initiated on corticosteroids alone (most often addition of rituximab [n=37], others included splenectomy [n=2], bortezomib [n=1], mycophenolate mofetil [n=1]), and in 3 patients (12.5%) initiated on corticosteroids with rituximab (bortezomib [n=1] and mycophenolate mofetil [n=3]). Caplacizumab treatment improved outcomes in patients with aTTP irrespective of the type of initial immunosuppression. Data on time to platelet count response and clinical outcomes are summarized in Table 2. Caplacizumab reduced the rate of the composite endpoint of TTP-related death, exacerbation, and major thromboembolic events during the double-blind treatment period irrespective of baseline immunosuppression regimen. Notably, in the placebo arm, exacerbations occurred in both subgroups to a similar extent, indicating that corticosteroids, with or without rituximab, are not immediately effective. Overall, recurrences (exacerbations or relapses) during the study were also reduced by caplacizumab in both subgroups (Table 2). Two placebo patients died during the treatment period in the corticosteroid only subgroup versus none in the corticosteroid plus rituximab subgroup (one other placebo patient died during the study drug treatment period while receiving another type of immunosuppression). Conclusion: Immunosuppressive therapy in aTTP aims to control the underlying autoimmune disease, but requires time to take effect; this exposes patients to thrombotic complications and death. Caplacizumab treatment prevents disease exacerbations and death, irrespective of the type of initial immunosuppression used, allowing time for immunosuppressive therapy to take effect. Disclosures Pavenski: Ablynx: Honoraria, Research Funding; Shire: Honoraria; Alexion: Honoraria, Research Funding; Octapharma: Research Funding; Bioverativ: Research Funding. Knoebl:Novo-Nordisk: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy; CSL-Behring: Consultancy; Shire/Takeda: Consultancy; Roche: Consultancy. Scully:Shire: Research Funding; Alexion: Consultancy; Ablynx/Sanofi: Consultancy; Shire/Takeda: Consultancy; Novartis: Consultancy. Kremer Hovinga:Siemens: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Shire: Consultancy, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology), Research Funding; CSL-Behring: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Ablynx/Sanofi: Consultancy, Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Roche: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology). Coppo:Shire: Consultancy; Ablynx/Sanofi: Consultancy; Alexion: Consultancy. Peyvandi:Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria; Kedrion: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Alnylam: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Research Funding. Cataland:Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Metjian:Genentech: Consultancy, Research Funding; AblynxNV/Sanofi: Consultancy, Research Funding. De La Rubia:Celgene Corporation: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; AMGEN: Consultancy; Janssen: Consultancy. De Winter:Ablynx, a Sanofi company: Employment. de Passos Sousa:Sanofi: Employment. Callewaert:Sanofi (formerly employed by Ablynx, a Sanofi company): Employment.

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening autoimmune thrombotic microangiopathy that involves abnormal processing of von-Willebrand factor (vWF) and results in multiple organ dysfunction. Although aTTP remains a very unpredictable disease, risk factors for death include older age, lactate dehydrogenase (LDH) levels >10x the upper limit of normal (ULN), and cerebral involvement (i.e., the French severity score) (Benhamou et al. Haematologica 2012;97:1181-1186). In addition, raised cardiac troponin-I (cTnI) levels of >2.5 µg/L have also been linked with a higher risk of mortality or refractoriness (Benhamou et al. J Thromb Haemost 2015;13:293-302). In the randomized, double-blind, placebo-controlled phase 3 HERCULES study, patients with aTTP were randomized to placebo or caplacizumab, plus daily therapeutic plasma exchange and immunosuppression. This analysis aimed to determine the efficacy of caplacizumab in patients participating in HERCULES according to baseline disease severity. Methods: In the HERCULES study, very severe disease was defined as: a French severity score ≥3, orsevere neurological involvement (i.e. coma, seizures, focal deficit), orcardiac involvement (cTnI >2.5xULN) All of these factors have independently been associated with worse outcomes and higher mortality. The French severity score is a discrete score from 0 to 4, involving evaluation of 3 parameters: Cerebral involvement: yes=1; no=0LDH: >10xULN=1; ≤10xULN=0Age: >60 years=2; >40 and ≤60 years=1; ≤40 years=0 Scores ≥3 indicate very severe disease. Data from patients participating in HERCULES were extracted and analyzed according to less severe/very severe disease and are presented descriptively. Results: Overall efficacy outcomes according to baseline disease severity are presented in Table 1. Patients who presented with less severe disease at baseline had a similar risk of mortality compared with patients who presented with very severe disease. Similar trends were observed for other clinically relevant outcomes, such as exacerbations of aTTP and refractoriness. Treatment with caplacizumab improved outcomes in both patient subgroups. Irrespective of disease severity, caplacizumab treatment resulted in faster platelet count normalization and a lower proportion of patients experiencing the composite endpoint of TTP-related death, exacerbation of TTP, or treatment-emergent major thromboembolic event during the double-blind treatment period. No patients who received caplacizumab died, while deaths occurred in 1 (2.1%) and 2 patients (8.0%) in the less severe and very severe subgroups of patients who received placebo, respectively. No patients receiving caplacizumab developed refractory disease, whereas 1 (2.1%) and 2 placebo-treated patients (8.0%) with less severe and very severe disease, respectively, developed refractory disease. Conclusions: aTTP can be unpredictable, and, although this analysis included a small patient population, our results suggest that patients with less severe disease at baseline are equally at risk of death, refractoriness and exacerbations as patients with very severe disease. A clear treatment benefit was observed in all patients who received caplacizumab irrespective of disease severity at baseline, which highlights the importance of starting therapy early in all patients with aTTP. Table 1. Overall efficacy outcomes according to baseline disease severity in the HERCULES study, during the double-blind treatment period. Table 1 Disclosures Coppo: Shire: Consultancy; Alexion: Consultancy; Ablynx/Sanofi: Consultancy. Cataland:Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Peyvandi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Honoraria; Grifols: Honoraria; Alnylam: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Octapharma: Research Funding. Knoebl:Ablynx/Sanofi: Consultancy; Novo-Nordisk: Consultancy, Research Funding; Shire/Takeda: Consultancy; CSL-Behring: Consultancy; Roche: Consultancy. Scully:Novartis: Consultancy; Shire: Research Funding; Alexion: Consultancy; Shire/Takeda: Consultancy; Ablynx/Sanofi: Consultancy. Kremer Hovinga:Ablynx/Sanofi: Consultancy, Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Roche: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Shire: Consultancy, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology), Research Funding; CSL-Behring: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Siemens: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology). Metjian:AblynxNV/Sanofi: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. De La Rubia:Takeda: Consultancy; AMGEN: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Celgene Corporation: Consultancy. Pavenski:Shire: Honoraria; Alexion: Honoraria, Research Funding; Octapharma: Research Funding; Bioverativ: Research Funding; Ablynx: Honoraria, Research Funding. De Winter:Ablynx, a Sanofi company: Employment. de Passos Sousa:Sanofi: Employment. Callewaert:Sanofi (formerly employed by Ablynx, a Sanofi company): Employment.

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening autoimmune thrombotic microangiopathy caused by a deficiency in the activity of ADAMTS13 leading to the formation of ultra-large multimers of von Willebrand factor (vWF) and abnormal platelet adhesion in the microvasculature. aTTP requires prompt diagnosis and rapid initiation of treatment to limit the risk of negative or fatal outcomes. The clinical diagnosis of aTTP is based on thrombocytopenia and microangiopathic hemolytic anemia and is confirmed by ADAMTS13 Methods: In HERCULES, ADAMTS13 was measured at study baseline (following initial TPE), weekly following cessation of daily TPE during the treatment period, and twice during the follow-up period. Data from patients for whom the diagnosis of aTTP was not confirmed based on documented ADAMTS13 levels Results: Overall, 7 patients in the placebo group (9.6%) and 13 patients in the caplacizumab group (18.1%) had a baseline ADAMTS13 ≥10%; of these, 4 and 9 patients, respectively, had a prior medical history of aTTP and/or ADAMTS13 values 60% for all patients and remained well above 10% throughout the study period. Possible alternative diagnoses included pancreatitis-induced TTP in 2 patients. One patient was reported as having 'thrombotic microangiopathy' and discontinued study drug treatment after 4 days (but continued daily TPE). The fourth patient had a report of 'megaloblastic anemia' and 'general adenopathies' and was withdrawn from the study due to a 'non-TTP diagnosis' after 2 days. The patients who continued daily TPE achieved a platelet count of >150 x109/L. Two patients experienced a moderate bleeding-related serious adverse event (SAE), 1 case of 'gastric ulcer hemorrhage' (considered unlikely related to study drug and recovered without intervention) and 1 case of epistaxis that led to study drug discontinuation (considered possibly related to study drug and recovered without intervention). Other mild bleeding-related non-serious adverse events (AEs) were reported in 1 patient: gingival bleeding (possibly related), ecchymosis (possibly related), and rectal hemorrhage (not/unlikely related). All events recovered spontaneously without intervention. Two other non-bleeding related SAEs were reported in 2 patients, both considered unrelated to study drug: 1 case of bacteremia and 1 case of cardiac tamponade. Conclusion: The experience of caplacizumab in patients with a suspected non-aTTP diagnosis to date is limited, and so no definite conclusion can be drawn. Bleeding-related AEs were reported in 3 of the 4 patients; however, the type, nature and manageability of these events appear similar to those reported in the other patients in the study. Table 1. Baseline characteristics and outcomes during the study period for patients with baseline ADAMTS13 ≥10% treated with caplacizumab in the HERCULES study. Table 1 Disclosures De La Rubia: Celgene Corporation: Consultancy; Janssen: Consultancy; AMGEN: Consultancy; Takeda: Consultancy; AbbVie: Consultancy. Peyvandi:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylam: Honoraria; Grifols: Honoraria; Kedrion: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Octapharma: Research Funding. Scully:Shire/Takeda: Consultancy; Novartis: Consultancy; Shire: Research Funding; Alexion: Consultancy; Ablynx/Sanofi: Consultancy. Cataland:Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Coppo:Shire: Consultancy; Ablynx/Sanofi: Consultancy; Alexion: Consultancy. Kremer Hovinga:Shire: Consultancy, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology), Research Funding; Siemens: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Roche: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); CSL-Behring: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Ablynx/Sanofi: Consultancy, Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology). Knoebl:Novo-Nordisk: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy; Shire/Takeda: Consultancy; CSL-Behring: Consultancy; Roche: Consultancy. Metjian:AblynxNV/Sanofi: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Pavenski:Alexion: Honoraria, Research Funding; Shire: Honoraria; Bioverativ: Research Funding; Octapharma: Research Funding; Ablynx: Honoraria, Research Funding. De Winter:Ablynx, a Sanofi company: Employment. de Passos Sousa:Sanofi: Employment. Callewaert:Sanofi (formerly employed by Ablynx, a Sanofi company): Employment.

Introduction : During the clinical development of caplacizumab, safety and tolerability data have been accrued from Phase I, Phase II, and Phase III studies in 3 discrete populations, comprising patients with acquired thrombotic thrombocytopenic purpura (aTTP), patients undergoing percutaneous coronary intervention (PCI; indication is not being pursued), and healthy patients. Given that caplacizumab blocks the interaction of the Willebrand factor (vWF) A1 domain with the GPIb-IX-V platelet receptor, the main expected safety risk is bleeding. Methods : The objective of this integrated analysis is to characterize the safety and tolerability of caplacizumab based on summaries of data from the pooled Phase I, Phase II, and Phase III studies, with a main focus on the safety data from the Phase II and Phase III studies in the aTTP Population, (i.e., the TITAN and HERCULES studies). Treatment-emergent adverse events (TEAEs) and clinical laboratory evaluations (hematology, biochemistry, and coagulation markers) were evaluated and summarized. Treatment-emergent bleeding was specified as an event of special interest. Data were analyzed during the double-blind (DB)/single-blind (SB) treatment period, and during the overall study period (including the follow-up period) for the aTTP population. R esults : Safety data for caplacizumab have been accrued in 790 patients within the 3 populations (220 aTTP patients, 410 PCI patients, and 160 healthy patients). In the pooled aTTP population, 216 (98.2%) patients received at least one dose of study drug (i.e., Safety Population), 106 patients in the caplacizumab group and 110 patients in the placebo group. The median duration of exposure to study drug was 35.0 days in the caplacizumab group and 32.5 days in the placebo group. Similar percentages of patients were reported with TEAEs in the caplacizumab (96.2%) and placebo (95.5%) groups. Events that occurred more frequently (≥5% difference) in the caplacizumab group vs. placebo were epistaxis (29.2% vs. 5.5%), headache (20.8% vs 13.6%) and gingival bleeding (16.0% vs 2.7%). The majority of these events were mild in intensity. Events that occurred more frequently in the placebo group were TTP (35.5% vs 5.7%), hypokalaemia (20.0% vs 12.3%), and hypertension (12.7% vs 4.7%). Relative risks were calculated for the most frequent TEAEs (Figure 1). Patients in the caplacizumab group had a significantly higher risk of experiencing gingival bleeding and epistaxis. Patients in the placebo group had a significantly higher risk of TTP recurrence and hypertension. Study drug discontinuation due to TEAEs occurred with similar frequencies in the caplacizumab (6.6%) and placebo (10.0%) groups, and were mostly individual events with the exception of TTP and myocardial infarction. A lower percentage of patients experienced SAEs in the caplacizumab group (29.2%) vs. placebo (49.1%). The most frequently reported SAE was TTP in both the caplacizumab (5.7%) and placebo (34.5%) groups. All other SAEs were reported in less than 5% of the patients. A higher percentage of patients experienced bleeding TEAEs in the caplacizumab group (60.4%) than in the placebo group (42.7%). Bleeding TEAEs were mainly mucocutaneous, most were self-limited and the majority resolved. Results from laboratory tests showed a general normalization of key hematology and chemistry parameters over time. Both treatment groups were similar with respect to clinically notable laboratory values, with very few abnormalities reported as TEAEs. The safety profile of caplacizumab observed in other populations was similar to that observed in the aTTP population, with no new safety signals identified. Bleeding TEAEs were the most commonly reported events in healthy patients and PCI patients. Conclusions : Bleeding TEAEs, chiefly epistaxis and gingival bleeding, were the most common TEAEs in patients treated with caplacizumab. Results from laboratory tests confirmed the safety profile of caplacizumab. No new safety signals were identified in the other populations studied. This integrated analysis has shown that caplacizumab is well tolerated and has a favorable safety profile. Disclosures Knöbl: Ablynx: Consultancy, Other: Member of Advisory Board. Scully:Novartis: Honoraria, Other: Member of Advisory Board, Speakers Bureau. Cataland:Alexion: Research Funding; Shire: Consultancy; Ablynx: Consultancy, Other: Member of Advisory Board. Peyvandi:Shire: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Kedrion: Consultancy; Octapharma US: Honoraria; Roche: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Octapharma US: Honoraria; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Grifols: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Novo Nordisk: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau. Coppo:Ablynx: Consultancy. Kremer Hovinga:Ablynx: Other: Member of Advisory Board; Shire: Other: Member of Advisory Board, Research Funding. Metjian:Ablynx: Other: Member of Advisory Board. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Minkue:Ablynx: Employment. Callewaert:Ablynx: Employment. De Winter:Ablynx: Employment.

Introduction : Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening thrombotic microangiopathy. A severe deficiency in ADAMTS13 activity caused by inhibitory autoantibodies leads to accumulation of ultra large von Willebrand factor (ULvWF) multimers and formation of microthrombi in small blood vessels with associated thrombocytopenia, hemolytic anemia, tissue ischemia and organ dysfunction (e.g., brain, heart, and kidneys). Caplacizumab directly blocks the interaction of the vWF A1 domain with the GPIb platelet receptor and prevents formation of microthrombi. The key efficacy and safety results of the double-blind (DB), placebo-controlled, phase 3 HERCULES study of caplacizumab for the treatment of aTTP were reported previously (Scully et al., Blood 2017 130:LBA-1). Herein, we present the results of a post-hoc analysis of the safety results normalized to time of exposure during the DB treatment period. Methods : Patients with an acute episode of aTTP who had received one plasma exchange (PE) treatment were randomized 1:1 to placebo or 10 mg caplacizumab, in addition to daily PE and corticosteroids. A single IV dose of study drug was given before the first on-study PE and a SC dose was given daily during the PE period and 30 days thereafter. If at the end of this period there was evidence of ongoing disease, such as suppressed ADAMTS13 activity, investigators were encouraged to extend the blinded treatment for a maximum of 4 weeks together with optimization of immunosuppression. All patients entered a 28-day treatment-free follow up period after the last dose of study drug. In case of a recurrence during the DB treatment period, patients were switched to open-label (OL) caplacizumab, together with re-initiation of daily PE and immunosuppression, while maintaining the blind for the initial treatment allocation. Analysis of treatment-emergent adverse events (TEAEs) was performed on the study's safety population (i.e., all patients who received at least 1 administration of study drug). To control for differences in time of exposure, incidence rates (IR) per 100 patients months were calculated as 100 x number of events / (total number of months observed within analysis period, summed for all patients in the treatment group). Results : The safety population consisted of 71 caplacizumab-treated and 73 placebo-treated patients. 31 patients experienced an exacerbation during the DB period, 28 in the placebo group and 3 in the caplacizumab group; 28 of them were switched to OL treatment with caplacizumab (26 of the 28 placebo-treated patients and 2 of the 3 caplacizumab-treated patients). As a consequence, the median (min; max) duration of study drug treatment during the DB treatment period, was 35 (1; 65) days for the DB caplacizumab group and 23 (2; 66) days for the DB placebo group. During the overall study period, at least one TEAE was reported in 69 patients (97.2%) in the caplacizumab group and 71 patients (97.3%) in the placebo group; the most frequent (occurring in >10% of patients in at least one of the treatment groups) TEAEs are presented in Table 1. After normalization for the time of exposure, the IR of any TEAE was lower in the caplacizumab group (535.6) vs. placebo group (821.7). TEAEs with a higher IR (≥5/100 patients months difference) in the caplacizumab group vs. placebo were epistaxis (39.1 vs. 3.3) and gingival bleeding (14.9 vs 1.7); TEAEs with a higher IR in the placebo group vs. caplacizumab were TTP (48.3 vs. 3.4), hypokalemia (25.0 vs 5.7), contusion (40.0 vs 8.0), rash (16.7 vs 5.7), insomnia (13.3 vs 8.0) and hypertension (13.4 vs 4.6). The IR of any SAE was 26.4 in the caplacizumab group and 83.3 in the placebo group. There were no SAEs with a higher IR (≥5/100 patients months difference) in the caplacizumab group compared to placebo. SAEs with an IR higher in the placebo group vs. caplacizumab were TTP (48.3 vs. 3.4) and anaphylactic transfusion reaction (5.0 vs. 0). Conclusions : After normalization to time of exposure, TEAEs occuring more frequently in the caplacizumab group were epistaxis and gingival bleeding, while TTP, hypokalemia, contusion, rash, imsomnia and hypertension occurred more frequently in the placebo group. This post-hoc analysis confirms the overall good tolerability of caplacizumab for the treatment of aTTP with mucocutaneous bleeding being the most relevant risk, consistent with the mechanism of action of this drug. Disclosures Kremer Hovinga: Shire: Other: Member of Advisory Board, Research Funding; Ablynx: Other: Member of Advisory Board. Scully:Novartis: Honoraria, Other: Member of Advisory Board, Speakers Bureau. Cataland:Alexion: Research Funding; Shire: Consultancy; Ablynx: Consultancy, Other: Member of Advisory Board. Peyvandi:Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Grifols: Speakers Bureau; Octapharma US: Honoraria; Shire: Speakers Bureau; Shire: Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Shire: Speakers Bureau; Kedrion: Consultancy; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau. Coppo:Ablynx: Consultancy. Knöbl:Ablynx: Consultancy, Other: Member of Advisory Board. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Minkue:Ablynx: Employment. Sousa:Ablynx: Employment. Callewaert:Ablynx: Employment. De Winter:Ablynx: Employment. Metjian:Ablynx: Other: Member of Advisory Board.

Introduction : Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening thrombotic microangiopathy, in which accumulation of ultra large von Willebrand factor (ULvWF) multimers leads to an increased risk of thrombus formation in small blood vessels due to platelet adhesion. A combination of plasma exchange (PE) and immunosuppression is the current mainstay of treatment for aTTP. The efficacy of caplacizumab in aTTP patients, in conjunction with PE and immunosuppression, was demonstrated in both placebo-controlled Phase II TITAN study and Phase III HERCULES study. Herein, we present the results of the integrated efficacy analyses of both studies. Methods : All randomized patients in the TITAN and HERCULES studies were integrated and included in the analysis population. Patients had a single-blind (SB, TITAN) or a double-blind (DB, HERCULES) treatment period followed by a follow-up period of 30 days. Patients in the HERCULES study could enter an open-label treatment period (i.e., in case of exacerbation during the DB treatment period). The primary endpoint was time to platelet count response, analyzed according to the corresponding platelet count response definition for each individual study (Figure 1). Secondary endpoints included: (i) the proportion of patients with TTP-related death, a recurrence of TTP, or at least one treatment-emergent major thromboembolic event; (ii) the proportion of patients with a recurrence of TTP during the DB/SB treatment period and the overall study period; (iii) the proportion of patients with refractory TTP (defined as the absence of platelet count doubling after 4 days of standard treatment, and LDH above normal); (iv) mortality rate during the DB/SB treatment period and the overall study period; (v) the number of PE days during the DB/SB treatment period. Results : 220 patients were randomized in both studies, 108 to the caplacizumab group and 112 to the placebo group. The groups were balanced with respect to demographics and baseline disease characteristics except for an imbalance relating to a history of previous TTP episode (Table 1). There was a statistically significant difference in favor of caplacizumab in time to platelet count response (p Conclusions : This integrated efficacy analyses confirmed results from the individual Phase II and III studies showing that treatment with caplacizumab significantly reduces the time to platelet count response compared to treatment with placebo. In addition, treatment with caplacizumab was associated with clinically meaningful and statistically significant reductions in: (i) the proportion of patients with TTP-related death, a recurrence of TTP, or at least one treatment-emergent major thromboembolic event; (ii) the proportion of patients who died from TTP during the study drug treatment period; (iii) the proportion of patients with a recurrence of TTP during treatment and overall; (iv) the number of patients refractory to therapy; (v) the mean number of days of plasma exchange. Disclosures Peyvandi: Kedrion: Consultancy; Roche: Speakers Bureau; Octapharma US: Honoraria; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Roche: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Shire: Speakers Bureau; Shire: Speakers Bureau; Octapharma US: Honoraria; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Octapharma US: Honoraria; Kedrion: Consultancy. Cataland:Alexion: Research Funding; Shire: Consultancy; Ablynx: Consultancy, Other: Member of Advisory Board. Scully:Novartis: Honoraria, Other: Member of Advisory Board, Speakers Bureau. Coppo:Ablynx: Consultancy. Knöbl:Ablynx: Consultancy, Other: Member of Advisory Board. Kremer Hovinga:Shire: Other: Member of Advisory Board, Research Funding; Ablynx: Other: Member of Advisory Board. Metjian:Ablynx: Other: Member of Advisory Board. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Minkue:Ablynx: Employment. Callewaert:Ablynx: Employment. De Winter:Ablynx: Employment.

Introduction : Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening autoimmune blood clotting disorder, manifested by systemic microvascular thrombosis leading to profound thrombocytopenia, hemolytic anemia, and organ ischemia. Results of the Phase 3 HERCULES study demonstrated the efficacy of caplacizumab in aTTP patients (Scully et al., Blood 2017;130:LBA-1). Consistent with its mechanism of action, an increase in mainly mild mucocutaneous bleeding events was observed in patients treated with caplacizumab. Here we report on the risk factors and manageability of these bleeding events. Methods : Analyses were performed on the study's safety population (i.e., all patients who received at least 1 administration of study drug). Bleeding-related treatment-emergent adverse events (TEAEs) were identified using the Standardized MedDRA (Medical Dictionary for Regulatory Activities) Query (SMQ) for 'Hemorrhage', excluding laboratory terms and the Preferred Term TTP. Bleeding events were analyzed in relation to the use of concomitant antithrombotic therapy and direct oral anticoagulants (DOACs), the severity of the bleeding events, and the requirement and type of therapeutic intervention. Bleeding-related TEAEs were analyzed during the double-blind treatment period. Results : The safety population consisted of 71 caplacizumab- and 73 placebo-treated patients. During the treatment period, at least one bleeding event was reported in 44 patients (62.0%; in total 108 events) in the caplacizumab group and 34 patients (46.6%; in total 61 events) in the placebo group. Twelve patients (16.9%) had a bleeding event while on concomitant antithrombotic therapy in the caplacizumab group vs. 9 patients (12.3%) in the placebo group. In patients not receiving antithrombotics, or in patients in whom the bleeding event occurred prior to onset of antithrombotic therapy, bleeding event occurred in 32 patients (45.1%) in the caplacizumab group vs. 26 patients in the placebo group (35.6%). Table 1 summarizes the most frequent bleeding events in relation to the use of antithrombotic therapy. Of note, 3 patients (4.2%) in the caplacizumab group vs. none in the placebo group received a DOAC while on study drug treatment (all administered for the treatment of major thromboembolic events). All 3 patients were reported with at least 1 bleeding event. One of these events was a SAE of menorrhagia which was treated with transfusion of red blood cells and resolved. Other events were mild AEs of epistaxis, injection site hemorrhage and gingival bleeding (all resolved without therapy). The majority of bleeding TEAEs were of mild or moderate severity (Table 2). The most common mild or moderate bleeding events in the caplacizumab group were epistaxis (27 mild events in 17 patients [23.9%] and 6 moderate events in 5 patients [7.0%]), gingival bleeding (12 mild events in 11 patients [15.5%]) and contusion (6 mild events in 5 patients [7.0%], and 1 patient [1.4%] with a moderate event). In the placebo group, contusion was the most frequently reported bleeding event (22 mild events in 9 patients [12.3%] and 2 moderate events in 1 patient [1.4%]). Severe bleeding TEAEs were epistaxis (treated with Wilate), gingival bleeding (treated with tranexamic acid), and upper gastrointestinal hemorrhage (requiring transfusion of red blood cells) each in 1 patient (1.4%) in the caplacizumab group. In the placebo group there was 1 severe (fatal) bleeding of hemorrhagic transformation stroke. Overall, therapeutic intervention for bleeding events was reported in 14 patients (19.7%) in the caplacizumab group for a total of 15 events (15/108 [13.9%]), compared to 2 patients (2.7%) in the placebo group for a total of 2 events (2/61 [3.3%]). Conclusions : The safety profile of caplacizumab was favorable. In line with its pharmacology, treatment with caplacizumab was associated with an increased risk of mucocutaneous bleeding. These events were generally mild to moderate, and the majority did not require therapeutic intervention. While the number of patients receiving DOACs was low, no increased risk for bleeding with antithrombotic therapy was observed. Disclosures Cataland: Alexion: Research Funding; Shire: Consultancy; Ablynx: Consultancy, Other: Member of Advisory Board. Scully:Novartis: Honoraria, Other: Member of Advisory Board, Speakers Bureau. Peyvandi:Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Kedrion: Consultancy; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Grifols: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Sobi: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Sobi: Speakers Bureau; Octapharma US: Honoraria; Roche: Speakers Bureau; Roche: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Octapharma US: Honoraria; Octapharma US: Honoraria; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau. Coppo:Ablynx: Consultancy. Knöbl:Ablynx: Consultancy, Other: Member of Advisory Board. Kremer Hovinga:Shire: Other: Member of Advisory Board, Research Funding; Ablynx: Other: Member of Advisory Board. Metjian:Ablynx: Other: Member of Advisory Board. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Minkue:Ablynx: Employment. Sousa:Ablynx: Employment. Callewaert:Ablynx: Employment. De Winter:Ablynx: Employment.

A defect in RelB, a member of the Rel/nuclear factor (NF)-κB family of transcription factors, affects antigen presenting cells and the formation of lymphoid organs, but its role in T lymphocyte differentiation is not well characterized. Here, we show that RelB deficiency in mice leads to a selective decrease of NKT cells. RelB must be expressed in an irradiation-resistant host cell that can be CD1d negative, indicating that the RelB expressing cell does not contribute directly to the positive selection of CD1d-dependent NKT cells. Like RelB-deficient mice, aly/aly mice with a mutation for the NF-κB–inducing kinase (NIK), have reduced NKT cell numbers. An analysis of NK1.1 and CD44 expression on NKT cells in the thymus of aly/aly mice reveals a late block in development. In vitro, we show that NIK is necessary for RelB activation upon triggering of surface receptors. This link between NIK and RelB was further demonstrated in vivo by analyzing RelB+/− × aly/+ compound heterozygous mice. After stimulation with α-GalCer, an antigen recognized by NKT cells, these compound heterozygotes had reduced responses compared with either RelB+/− or aly/+ mice. These data illustrate the complex interplay between hemopoietic and nonhemopoietic cell types for the development of NKT cells, and they demonstrate the unique requirement of NKT cells for a signaling pathway mediated by NIK activation of RelB in a thymic stromal cell.

Background & Aims: Interleukin (IL)-10 is a cytokine with anti-inflammatory properties. The aim of this study was to explore the effect of a site-specific delivery of IL-10 on intestinal immune responses. Methods: Transgenic mice were created in which IL-10 is expressed by the intestinal epithelial cells. Results: Transgenic mice showed a marked increase in the number of intraepithelial lymphocytes in the small intestine. Mucosal lymphocytes of transgenic animals produced fewer T helper type 1 cytokines than wild-type lymphocytes. By contrast, the production of transforming growth factor β was increased. Moreover, the epithelial layer in transgenic mice was significantly enriched for CD4 + CD25 + T cells. Furthermore, transgenic mice had increased numbers of immunoglobulin A–producing B cells in the small intestine. These effects were local because splenic lymphocytes were not affected. Studies in models of inflammatory bowel disease showed that transgenic IL-10 was able to attenuate the acute colitis induced by dextran sodium sulfate administration or by adoptive transfer of CD4 + CD45RB high splenocytes, with a modest effect on the chronic intestinal inflammation arising spontaneously in IL-10 −/− mice. Conclusions: These observations provide evidence for an in vivo lymphoepithelial cross talk, by which cytokines locally produced by epithelial cells can regulate immune responses in the intestine without systemic modifications. GASTROENTEROLOGY 2002;122:1829-1841

Inflammatory bowel disease (IBD) is a multifactorial immune disorder of uncertain etiology. The advent of several mouse models of mucosal inflammation that resemble IBD has provided insight into the mechanisms governing both normal and pathological mucosal immune function. In a widely used adoptive transfer model, the injection into immunodeficient mice of a subset of CD4+T lymphocytes, the CD4+CD45RBhighcells, leads to inflammation of the intestine. Pathogenesis is due in part to the secretion of proinflammatory cytokines. The induction of colitis can be prevented by cotransfer of another CD4+subpopulation, the CD4+CD45RBlowT cells. This population behaves analogously to the CD4+CD45RBhighpopulation in terms of the acquisition of activation markers and homing to the host intestine. However, their lymphokine profile when activated is different, and anti-inflammatory cytokines secreted and/or induced by CD4+CD45RBlowT cells prevent colitis. In this themes article, a description of the adoptive transfer model is given, the factors that promote and prevent colitis pathogenesis are discussed, and some controversial aspects of the model are addressed.

OBJECTIVE Whether anticytokine therapies have a place in the treatment of severe sepsis and septic shock remains a question. Although a number of preclinical studies have shown efficacy in primate models of bacteremic shock when administered prophylactically, these same therapies have a significantly diminished effectiveness when administered therapeutically. This study investigated whether delayed administration of a novel anti-human interferon-gamma monoclonal antibody could improve outcome and reduce organ injury in a lethal model of Escherichia coli bacteremia, when administered after the onset of shock. DESIGN Randomized, prospective, double-blinded intervention study. SUBJECTS Cynomolgus monkeys. INTERVENTIONS Treatment with a humanized monoclonal antibody directed against human interferon-gamma (INNO 202), administered after the onset of shock, induced by the infusion of live E. coli. MEASUREMENTS AND MAIN RESULTS Five of the six vehicle-treated monkeys died or were killed within 24-72 hrs after E. coli administration, and all died within 5 days. In contrast, six of the eight animals treated with the anti-interferon-gamma survived for 7 days, and three of the eight animals survived 14 days (p = .013 vs. vehicle). Delayed treatment with the anti-interferon-gamma monoclonal antibody did not restore hemodynamics or reduce the amount of crystalloid-containing fluid required to resuscitate the animals but did attenuate renal failure (p < .05) and the magnitude of the inflammatory cytokine response (p < .05). CONCLUSIONS In a primate model of E. coli bacteremic shock, delayed neutralization of interferon-gamma after the onset of shock improved survival and attenuated the pathologic changes associated with the development of organ dysfunction. These findings suggest that interferon-gamma blockade represents a potentially effective mode of late intervention in lethal septic shock.

The development of lymphoid organs requires membrane-bound lymphotoxin (LT), a heterotrimer containing LTα and LTβ, but the effects of LT on T cell function have not been characterized extensively. Upon TCR cross-linking in vitro, splenocytes from both LTα−/− and LTβ−/− mice failed to produce IL-4 and IL-10 due to a reduction in NK T cells. Concordantly, LTα−/− and LTβ−/− mice did not respond to the lipoglycan α-galactosylceramide, which is presented by mouse CD1 to Vα14+ NK T cells. Interestingly, both populations of NK T cells, including those that are mouse CD1 dependent and α-galactosylceramide reactive and those that are not, were affected by disruption of the LTα and LTβ genes. NK T cells were not affected, however, in transgenic mice in which LT signaling is blocked, beginning on day 3 after birth, by expression of a soluble decoy LTβ receptor. This suggests that membrane-bound LT is critical for NK T cells early in ontogeny, but not for the homeostasis of mature cells.