Complement C5 inhibition is the standard of care (SoC) for patients with paroxysmal nocturnal hemoglobinuria (PNH) with significant clinical symptoms. Constant and complete suppression of the ...terminal complement pathway and the high serum concentration of C5 pose challenges to drug development that result in IV-only treatment options. Crovalimab, a sequential monoclonal antibody recycling technology antibody was engineered for extended self-administered subcutaneous dosing of small volumes in diseases amenable for C5 inhibition. A 3-part open-label adaptive phase 1/2 trial was conducted to assess safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy in healthy volunteers (part 1), as well as in complement blockade–naive (part 2) and C5 inhibitor–treated (part 3) PNH patients. Twenty-nine patients were included in part 2 (n = 10) and part 3 (n = 19). Crovalimab concentrations exceeded the prespecified 100-µg/mL level and resulted in complete and sustained terminal complement pathway inhibition in treatment-naive and C5 inhibitor–pretreated PNH patients. Hemolytic activity and free C5 levels were suppressed below clinically relevant thresholds (liposome assay <10 U/mL and <50 ng/mL, respectively). Safety was consistent with the known profile of C5 inhibition. As expected, formation of drug-target-drug complexes was observed in all 19 patients switching to crovalimab, manifesting as transient mild or moderate vasculitic skin reactions in 2 of 19 participants. Both events resolved under continued treatment with crovalimab. Subcutaneous crovalimab (680 mg; 4 mL), administered once every 4 weeks, provides complete and sustained terminal complement pathway inhibition in patients with PNH, warranting further clinical development (ClinicalTrials.gov identifier, NCT03157635).
•Multiple engineering steps led to efficient recycling, antigen disposal, and infrequent low-volume subcutaneous self-administration of crovalimab.•PNH patients, treatment naive or switching from SoC, were stably controlled on up to every 4-week subcutaneous self-administered injections of crovalimab.
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All Japanese patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with eculizumab were enrolled in post-marketing surveillance (PMS) between June 2010 and August 2019 to assess the ...long-term effectiveness and safety of eculizumab. The reduction in intravascular hemolysis, the change in hemoglobin (Hb) level, and the change in renal function were assessed to determine the effectiveness of eculizumab. The types and frequencies of adverse events (AEs) were assessed to determine its safety. A total of 632 patients were enrolled and the median treatment duration was 3.6 years. Treatment with eculizumab significantly reduced lactate dehydrogenase (LDH) levels and significantly increased Hb levels. These changes were maintained for up to 5 years of treatment. An estimated glomerular filtration rate ≥ 60 ml/min/1.73 m
2
and higher LDH level at baseline were associated with increases in Hb levels during eculizumab treatment. The overall incidence of any AE was 69.92/100 patient-years. Hemolysis was the most common AE (6.43/100 patient-years). The incidence of infection-related AEs was 20.57/100 patient-years, and included meningococcal infection in three patients (0.12/100 patient-years). This long-term follow-up of patients with PNH demonstrated the sustained effectiveness of eculizumab and supports its well-established safety profile.
All healthcare professionals must understand information on a patient's biophysical functions, and it is important to educate professionals on how to use this information in an interprofessional team ...for diagnosis. However, there is little interprofessional education for students of medical technology and radiological science involved in biophysical function diagnosis. In the present study, we developed a case-based interprofessional learning tool for using biophysical information for diagnosis. The study examined the effects of a collaborative exercise workshop for healthcare professional students using the tool. Participants were 234 students from three healthcare professions (medical technology, radiological science, and physical therapy). They completed the Japanese version of the Readiness for Interprofessional Learning Scale before and after the workshops. The workshops incorporated digital materials that allowed students to examine the test results of a virtual patient, answer questions, and discuss their diagnoses and prognoses. For analysis, a two-way analysis of variance was performed on the total score on the Readiness for Interprofessional Learning Scale of the three departments, and the effectiveness of the workshop for the three departments was compared. Statistical analyses showed no interaction between time and department (p = 0.283). After the workshop, students from all three departments showed significant improvements in total scores on the Readiness for Interprofessional Learning Scale (p < 0.01) with medium to large effect sizes (r = 0.33-0.52). In the comparison between departments, there was a significant difference in the awareness levels of only medical technology and radiological science students before the workshop (p = 0.015). This study conducted case-based learning workshops with students from three departments, in which a patient's biophysical information was conveyed between occupational practices. The workshops improved the awareness of interprofessional education in students from all departments and revealed that interprofessional education is important for healthcare professions involved in biophysical function diagnosis.
Small populations of glycosylphosphatidylinositol-anchored protein-deficient (GPI-) cells accounting for up to 0.01% of total granulocytes can be accurately detected by a high-sensitivity flow ...cytometry (FCM) assay established by the Clinical and Laboratory Standards Institute (CLSI method) and have a prognostic value in bone marrow failure (BMF); however, the significance of GPI(-) granulocytes accounting for 0.001–0.009% of granulocytes remains unclear. To clarify this issue, we examined the peripheral blood of 21 BMF patients in whom minor (around 0.01%) populations of GPI(-) granulocytes had been previously detected by a different high-resolution FCM method (OPTIMA method, which defines ≥ 0.003% GPI(-) granulocytes as an abnormal increase) using both the CLSI and OPTIMA methods simultaneously. These two methods detected an “abnormal increase” in GPI(-) granulocytes in 10 patients (48%) and 17 patients (81%), respectively. CLSI detected 0.002–0.005% (median, 0.004%) GPI(-) granulocytes in 7 patients who were deemed positive for PNH-type cells according to the OPTIMA method, which detected 0.003–0.012% (median 0.006%) GPI(-) granulocytes. The clone sizes of GPI(-) cells detected by each assay were positively correlated (
r
= 0.994,
p
< 0.001). Of the seven patients who were judged positive for PNH-type cells by OPTIMA alone, five received immunosuppressive therapy, and all of them achieved a partial or complete response. GPI(-) granulocytes detected in BMF patients by the CLSI method should thus be considered significant, even at percentages of < 0.01%.
Summary
Thrombosis in paroxysmal nocturnal haemoglobinuria (PNH) has been suggested to be due to several pathophysiological states: a suppressed fibrinolytic system, increased leucocyte‐derived ...tissue factor, complement (C′)‐mediated damage to platelets and endothelia, or increased platelet‐ and endothelium‐derived microparticles (MPs). Because haemolytic attack is often accompanied by thrombosis in PNH, we studied the role of C′‐induced release of MPs in the thrombogenesis of PNH. C′ activation induced procoagulant alteration in PNH red blood cells (RBC), when assessed by thrombin generation in the presence of C′‐activated PNH RBC, which was abolished by their subsequent treatment with annexin V. Significant amounts of procoagulant MPs, measured by phosphatidylserine‐binding prothrombinase activity, were released from PNH RBC in association with the formation of C5b‐9, but not significantly before C5b‐8. Generation of procoagulant, annexin V‐binding, MPs from C′‐activated RBC was studied also by flow cytometry. While phorbol 12‐myristate 13‐acetate, an activator of protein kinase C (PKC), induced the release of MPs from normal RBC as well as PNH RBC, C′‐induced release of MPs from PNH RBC was Ca2+‐independent and not associated with the activation of PKC, calpain or caspase. Procoagulant properties of MPs released from PNH RBC could contribute to the thrombogenesis of PNH.
Data characterizing the safety and effectiveness of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) are limited. We describe the safety and effectiveness of eculizumab in PNH ...patients enrolled in a post-marketing surveillance study. Types and frequencies of observed adverse events were similar to those reported in previous clinical trials and no meningococcal infection was reported. Effectiveness outcomes included the reduction of intravascular hemolysis, the change in hemoglobin (Hb) level, the withdrawal of transfusion and corticosteroids, the change of renal function, and overall survival. The effect of eculizumab on intravascular hemolysis was demonstrated by a reduction in lactate dehydrogenase levels at all measurements after baseline. Significant increases in Hb levels from baseline were also observed after 1 month’s treatment with eculizumab (
p
< 0.01). Of those who were transfusion-dependent at baseline, the median number of transfusions decreased significantly from 18 to 0 unit/year after 1 year of treatment with eculizumab (
p
< 0.001). An increase in Hb and a high rate of transfusion independence were observed, especially in patients with platelet count ≥150 × 10
9
/L. Approximately 97 % of patients showed maintenance or improvement of renal function. Overall survival rate was about 90 % (median follow-up 1.9 years). These results suggest an acceptable safety profile and favorable prognosis after eculizumab intervention.
Pregnancy with paroxysmal nocturnal hemoglobinuria (PNH) is associated with significant risk of complications, such as life-threatening thrombosis. Recently, eculizumab has come into clinical use and ...revolutionized the treatment of PNH. However, clinical information regarding eculizumab use for PNH during pregnancy is limited. The present report describes pregnancies with PNH treated with eculizumab that were registered with the Japan PNH study group and reviews the literature. In case 1, the patient received eculizumab throughout pregnancy and delivered a healthy neonate at term, although breakthrough hemolysis occurred at 20 weeks of gestation. In case 2, the patient discontinued eculizumab before pregnancy and developed preeclampsia at 27 weeks of gestation. She received eculizumab and delivered a preterm, but healthy, neonate by cesarean section. In case 3, the patient received eculizumab from 18 weeks of gestation and delivered a healthy neonate at term without any complications. Reports of 11 pregnant women treated with eculizumab were identified in the literature. Of 14 pregnancies, including our own cases, breakthrough hemolysis and preeclampsia occurred in five and two cases, respectively. There were no thrombotic complications, maternal or neonatal deaths, or fetal structural abnormalities. Thus, eculizumab appears to be safe and effective for managing PNH during pregnancy.
In paroxysmal nocturnal hemoglobinuria (PNH), various symptoms due to intravascular hemolysis exert a negative impact on patients’ quality of life (QOL). To determine clinical factors related with ...improvements in QOL in PNH patients treated, we analyzed changes in QOL scales in PNH patients treated with eculizumab based on data collected from post-marketing surveillance in Japan. Summary statistics were obtained using figures from QOL scoring systems and laboratory values, and evaluated by
t
test. One-year administration of eculizumab improved the most QOL items in comparison with the baseline. In particular, significant improvement of EORTC QLQ-C30 was observed in fatigue, dyspnea, physical function, and global health status. Canonical correlation analysis revealed a high correlation between QOL and laboratory values. Changes in serum lactate dehydrogenase (LDH) and hemoglobin showed strong correlations with QOL improvement. Quality of life improvement was independent of patients’ baseline characteristics of co-occurrence of bone marrow failure (BMF), or the degree of LDH. In this analysis, we found that the degree of QOL improvement was independent of the baseline LDH before eculizumab treatment and of co-occurrence of BMF. Paroxysmal nocturnal hemoglobinuria patients who have not received eculizumab treatment due to mild hemolysis may benefit from eculizumab treatment.
Paroxysmal nocturnal hemoglobinuria (PNH) is a progressive and life-threatening disease characterized by complement-mediated chronic hemolysis, resulting in serious life-threatening complications and ...early mortality. Eculizumab, a humanized anti-C5 monoclonal antibody that inhibits terminal complement activation, has been shown to reduce hemolysis in PNH patients. The pivotal open-label, 12-week phase II registration study (AEGIS) was designed to evaluate the efficacy and safety of eculizumab in Japanese patients with PNH. This trial achieved its primary endpoint of reducing intravascular hemolysis with high statistical significance. Twenty-seven of the 29 patients responded to eculizumab treatment, resulting in an 87% reduction in hemolysis (
P
< 0.0001) and subsequent improvement in anemia (
P
= 0.0003) despite reduction in transfusion requirements (
P
= 0.006). Fatigue and dyspnea significantly improved within 1–2 weeks of eculizumab treatment and the improvement was independent of changes in hemoglobin. Chronic kidney disease (CKD) was common (66%) and eculizumab treatment improved CKD in 41% of patients at 12 weeks (
P
< 0.001). Elevated thrombotic risk was evident in Japanese PNH patients and eculizumab treatment normalized
d
-dimer levels in 45% of patients with elevated
d
-dimers at baseline (
P
< 0.001). The AEGIS results demonstrate that eculizumab is effective, safe and well tolerated in Japanese patients with PNH.
ABSTRACT
BACKGROUND:
Appropriate hemostasis is essential for clear visualization of the neural structures and cleavage planes. It is also essential for avoiding heat-induced injury, minimizing blood ...loss, and reducing operative time.
OBJECTIVE:
To determine the role of cerebrospinal fluid (CSF) in platelet-dependent hemostasis during neurosurgery.
METHODS:
The amplification of aggregation, activation of integrin αIIbβ3, intrinsic and extrinsic coagulation pathways, and activation of signaling cascades in platelets were evaluated. For comparison, various concentrations of a commercially available artificial CSF solution (aCSF), an artificial CSF solution prepared by the authors, and normal saline (NS) were used. Differences between aCSF and NS in obtaining in vivo hemostasis were assessed by measuring the tail vein bleeding time in C57BL/6N mice.
RESULTS:
Platelet aggregation was directly amplified by the addition of aCSF through increased activation of integrin αIIbβ3, phosphatidylserine exposure, and P-selectin expression. However, the prothrombin time and activated partial thromboplastin time were not primarily related to coagulation activity with the addition of aCSF. Activation of Src kinase was related to platelet activation by aCSF. The elimination of sodium bicarbonate from aCSF and the addition of the selective inhibitor of the HCO3−/Cl− exchanger, 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid disodium salt, significantly inhibited platelet aggregation. The bleeding time in aCSF-treated mice was significantly shorter than that in NS-treated mice.
CONCLUSION:
Sodium bicarbonate facilitates hemostasis through the amplification of platelet aggregation function. The existence of CSF and irrigation with aCSF provide better conditions for physiological hemostasis and they have the potential of improving hemostasis by bipolar coagulation or with irrigation during neuroendoscopic procedures.
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